HK1243305B - Electromechanical pill device with localization capabilities - Google Patents

Description

Electromechanical pill machine with positioning capabilities

Background Art

The gastrointestinal (GI) tract often contains a wealth of information about an individual's body. For example, the contents of the GI tract can provide information about an individual's metabolism. Analysis of the contents of the GI tract can also provide information that can be used to identify relationships between the composition of the GI content (e.g., the relationship between bacterial and biochemical content) and certain diseases or disorders.

Current methods and devices for analyzing the GI tract are limited in certain respects, such as the accuracy of data retrieved from the GI tract. The data retrieved from the GI tract may include physical samples and/or measurements. The value of the retrieved data may depend, to some extent, on how accurately the location from which the data was retrieved can be identified. However, in vivo location detection within the GI tract can be difficult. Different segments within the GI tract may sometimes include certain substances (e.g., blood) that may affect in vivo location detection and may also vary in the GI tract between different individuals.

Summary of the Invention

In certain aspects, provided herein is an ingestible device for identifying a location within the gastrointestinal (GI) tract of the body. The ingestible device includes a housing defined by a first end, a second end, and a radial wall, the second end being substantially opposite the first end, the radial wall extending longitudinally from the first end to the second end; a sensing unit within the housing, the sensing unit comprising: an axial optical sensing subunit located proximal to at least one of the first and second ends, the axial optical sensing subunit configured to transmit axial illumination toward an environment external to the housing and detect axial reflectivity caused by the axial illumination from the environment; and a radial optical sensing subunit located proximal to the radial wall, the radial optical sensing subunit configured to transmit radial illumination toward the environment external to the housing and detect radial reflectivity caused by the radial illumination from the environment, the radial illumination being substantially perpendicular to the axial illumination; wherein a processing module is configured to identify the location of the ingestible device based on at least the detected radial and axial reflectivities.

In at least some embodiments, the processing module can be an external processing module, and the device can also include a communication module configured to transmit one or more radial reflectivity values corresponding to the detected radial reflectivity and one or more axial reflectivity values corresponding to the detected axial reflectivity to the external processing module.

In at least some embodiments, the apparatus may include a processing module.

In at least some embodiments, the axial optical sensing subunit may include at least one axial sensor having an axial illuminator and an axial detector, wherein the axial illuminator is configured to transmit axial illumination and the axial detector is configured to detect axial reflectivity.

In at least some embodiments, the radial optical sensing subunit may include at least one radial sensor having a radial illuminator configured to transmit radial illumination and a radial detector configured to detect radial reflectivity.

In at least some embodiments, the radial optical sensing subunit may include three radial sensors, with the radial illuminator and radial detector of a given radial sensor arranged at approximately 60 degrees from each other along the circumference of the radial wall.

In at least some embodiments, the radial optical sensing sub-unit further includes four radial sensors, each radial sensor being positioned substantially equidistant from one another along the circumference of the radial wall.

In at least some embodiments, the axial optical sensing subunit may include a first axial sensor located proximate a first end of the ingestible device, the first axial sensor configured to transmit a first axial illumination toward the environment and detect a first axial reflectivity caused by the first axial illumination from the environment; and a second axial sensor located proximate a second end of the ingestible device, the second axial sensor configured to transmit a second axial illumination toward the environment and detect a second axial reflectivity caused by the second axial illumination from the environment, the second axial illumination being in a direction substantially opposite to the first axial illumination.

In at least some embodiments, the radial optical sensing subunit may include a first radial sensor, which is located proximate to a first wall portion of the radial wall, the first radial sensor being configured to transmit a first radial illumination toward the environment and to detect a first radial reflectivity caused by the first radial illumination from the environment; and a second radial sensor, which is located proximate to a second wall portion of the radial wall, the second radial sensor being configured to transmit a second radial illumination toward the environment and to detect a second radial reflectivity caused by the second radial illumination from the environment, the second wall portion being spaced apart from the first wall portion by at least 60 degrees along the circumference of the radial wall, and the second radial illumination being along a radial direction different from the first radial illumination.

In at least some embodiments, the first wall portion can be spaced apart from the second wall portion by approximately 180 degrees along the circumference of the radial wall.

In at least some embodiments, the radial optical sensing subunit may further include a third radial sensor located proximal to a third wall portion of the radial wall, the third radial sensor configured to transmit a third radial illumination toward the environment and detect a third radial reflectivity caused by the third radial illumination from the environment, the third wall portion being spaced apart from each of the first wall portion and the second wall portion by approximately 60 degrees along the circumference of the radial wall, and the third radial illumination being along another radial direction different from the first radial illumination and the second radial illumination.

In at least some embodiments, the axial optical sensing subunit may include an infrared light emitting diode (LED).

In at least some embodiments, the radial optical sensing subunit may include an LED emitting light having a wavelength of approximately 571 nm.

In at least some embodiments, the radial optical sensing sub-unit may include an RGB LED package.

In at least some embodiments, the housing is capsule-shaped.

In certain aspects, a method for identifying a location within the GI tract of a body is provided herein. The method includes using an ingestible device comprising: a housing having a first end, a second end, and a radial wall, the second end being substantially opposite the first end, the radial wall extending longitudinally from the first end to the second end; and a sensing unit within the housing, the sensing unit comprising: an axial optical sensing subunit located proximal to at least one of the first and second ends, the axial optical sensing subunit configured to transmit axial illumination toward an environment external to the housing and detect axial reflectivity caused by the axial illumination from the environment; and a radial optical sensing subunit located proximal to the radial wall, the radial optical sensing subunit configured to transmit radial illumination toward the environment external to the housing and detect radial reflectivity caused by the radial illumination from the environment, the radial illumination being substantially perpendicular to the axial illumination; and operating a processing module to identify the location based on at least the detected radial illumination and the axial reflectivity.

An ingestible device may also be defined according to any of the teachings herein.

In certain aspects, a system for identifying a location within the GI tract of a body is provided herein. The system includes: an ingestible device comprising: a housing having a first end, a second end, and a radial wall, the second end being substantially opposite the first end, the radial wall extending longitudinally from the first end to the second end; a sensing unit within the housing, the sensing unit comprising: an axial optical sensing subunit located proximal to at least one of the first and second ends, the axial optical sensing subunit configured to transmit axial illumination toward an environment external to the housing and detect axial reflectivity caused by the axial illumination from the environment; and a radial optical sensing subunit located proximal to the radial wall, the radial optical sensing subunit configured to transmit radial illumination toward the environment external to the housing and detect radial reflectivity caused by the radial illumination from the environment, the radial illumination being substantially perpendicular to the axial illumination; and a processing module configured to identify the location of the ingestible device based on the radial and axial reflectivities detected at least during transport within the body.

An ingestible device may also be defined according to any of the teachings herein.

In certain aspects, another method for identifying a location within the GI tract of a body is provided herein. The method includes providing an ingestible device having a sensing unit to collect reflectance data, the sensing unit including: an axial optical sensing subunit operable to transmit axial illumination toward an environment external to the ingestible device and to detect axial reflectance from the environment caused by the axial illumination; and a radial optical sensing subunit operable to transmit radial illumination toward an environment external to the ingestible device and to detect radial reflectance from the environment caused by the radial illumination, the radial illumination being substantially perpendicular to the axial illumination; operating the sensing unit to collect at least a series of reflectance data as the ingestible device is transported through the body, the reflectance data including: The reflectivity data series includes an axial reflectivity data series and a radial reflectivity data series, each of the axial reflectivity data series and the radial reflectivity data series includes one or more reflectivity values, and the one or more reflectivity values correspond to the corresponding axial reflectivity and radial reflectivity detected by the sensing unit during at least a portion of the transport; and a processing module is operated to use the reflectivity data series to identify the position, the processing module is in electronic communication with the sensing unit, and the processing module is configured to: determine the quality of the environment outside the ingestible device based on the axial reflectivity data series and the radial reflectivity data series; and indicate the position based on the determined quality of the environment outside the ingestible device.

In at least some embodiments, determining the quality of the environment outside the ingestible device based on each of the axial reflectance data series and the radial reflectance data series can include: generating an axial standard deviation for the axial reflectance data series and a radial standard deviation for the radial reflectance data series; determining whether each of the axial standard deviation and the radial standard deviation satisfies a corresponding deviation threshold; and, in response to determining that the axial standard deviation and the radial standard deviation satisfy the deviation threshold, defining the quality of the environment as homogeneous.

In at least some embodiments, the deviation threshold may include an axial deviation threshold for the axial reflectivity data series and a radial deviation threshold for the radial reflectivity data series, the radial deviation threshold having a different value than the axial deviation threshold.

In at least some embodiments, in response to determining that the axial standard deviation and the radial standard deviation meet the deviation threshold and before defining the quality of the environment as homogeneous, the method may also include: generating an axial average from a portion of the axial reflectivity data series and generating a radial average from a portion of the radial reflectivity data series; determining whether the radial average is less than the axial average; and, in response to determining that the radial average is less than the axial average, defining the quality of the environment as homogeneous.

In at least some embodiments, determining whether the radial average value is less than the axial average value may include determining whether the radial average value is less than the axial average value by a minimum difference.

In at least some embodiments, generating an axial average from a portion of the axial reflectivity data series and generating a radial average from a portion of the radial reflectivity data series may include selecting a plurality of reflectivity values from each of the axial reflectivity data series and the radial reflectivity data series, wherein the plurality of reflectivity values are selected from the latest portion of the corresponding axial reflectivity data series and the radial reflectivity data series.

In at least some embodiments, the sensing unit may further include a temperature sensor for collecting a series of temperature data as the ingestible device is transported through the body; and before associating the quality of the environment as homogeneous, the method may further include: determining whether a portion of the temperature data series includes a temperature change that exceeds a temperature threshold; and, in response to determining that the portion of the temperature data series does not include a temperature change that exceeds the temperature threshold, associating the quality of the environment as homogeneous.

In at least some embodiments, the processing module may be operable to indicate that the location is the small intestine in response to determining that the quality of the environment external to the ingestible device is homogenous.

[0014] In certain aspects, provided herein is another ingestible device for identifying a location within the GI tract of the body. The ingestible device may include a sensing unit configured to collect reflectance data, the sensing unit comprising: an axial optical sensing subunit operable to transmit axial illumination toward an environment outside the ingestible device and detect axial reflectance caused by the axial illumination from the environment; and a radial optical sensing subunit operable to transmit radial illumination toward the environment outside the ingestible device and detect radial reflectance caused by the radial illumination from the environment, the radial illumination being substantially perpendicular to the axial illumination; wherein the processing module is configured to: operate the sensing unit to collect at least a reflectance data series as the ingestible device is transported through the body, the reflectance data series comprising an axial reflectance data series and a radial reflectance data series, each of the axial reflectance data series and the radial reflectance data series comprising one or more reflectance values corresponding to corresponding axial reflectance and radial reflectance detected by the sensing unit during at least a portion of the transport; determine a quality of the environment outside the ingestible device based on the axial reflectance data series and the radial reflectance data series; and indicate the position based on the determined quality of the environment outside the ingestible device.

The processing module may be configured to perform at least one of the methods according to the teachings herein.

In at least some embodiments, the processing module may be an external processing module, and the apparatus may further include a communication module in electronic communication with the external processing module.

In at least some embodiments, the processing module may be located within the device.

In certain aspects, a method for identifying a location within the GI tract of a body is provided herein. The method includes: operating an axial optical sensing subunit to transmit axial illumination toward an environment within the GI tract and detecting axial reflectivity from the environment caused by the axial illumination; operating a radial optical sensing subunit to transmit radial illumination toward the environment within the GI tract and detecting radial reflectivity from the environment caused by the radial illumination, the radial illumination being substantially perpendicular to the axial illumination; and operating a processing module to identify the location using the detected axial reflectivity and the detected radial reflectivity, the processing module being configured to: determine a quality of the environment within the GI tract based on the detected axial reflectivity and the detected radial reflectivity; and indicating the location based on the determined quality of the environment within the GI tract.

In at least one embodiment, the method may further include collecting at least a reflectivity data series over a time period, wherein the reflectivity data series includes an axial reflectivity data series and a radial reflectivity data series, each of the axial reflectivity data series and the radial reflectivity data series includes one or more reflectivity values, and the one or more reflectivity values correspond to the corresponding axial reflectivity and radial reflectivity detected by the corresponding axial optical sensing sub-unit and radial optical sensing sub-unit during the time period.

In at least one embodiment, determining the quality of the environment within the GI tract based on the detected axial reflectivity and the detected radial reflectivity can include generating an axial standard deviation for the axial reflectivity data series and a radial standard deviation for the radial reflectivity data series; determining whether each of the axial standard deviation and the radial standard deviation satisfies a corresponding deviation threshold; and, in response to determining that the axial standard deviation and the radial standard deviation satisfy the deviation threshold, defining the quality of the environment as homogeneous.

In at least one embodiment, the deviation threshold may include an axial deviation threshold for the axial reflectivity data series and a radial deviation threshold for the radial reflectivity data series, the radial deviation threshold having a different value than the axial deviation threshold.

In at least one embodiment, the method may further include, in response to determining that the axial standard deviation and the radial standard deviation meet the deviation threshold and before defining the quality of the environment as homogeneous: generating an axial average from a portion of the axial reflectivity data series and generating a radial average from a portion of the radial reflectivity data series; determining whether the radial average is less than the axial average; and, in response to determining that the radial average is less than the axial average, defining the quality of the environment as homogeneous.

In at least one embodiment, determining whether the radial average value is less than the axial average value may include determining whether the radial average value is less than the axial average value by a minimum difference.

In at least one embodiment, generating an axial average value from a portion of the axial reflectivity data series and generating a radial average value from a portion of the radial reflectivity data series may include selecting multiple reflectivity values from each of the axial reflectivity data series and the radial reflectivity data series, and the multiple reflectivity values are selected from the latest portion of the corresponding axial reflectivity data series and the radial reflectivity data series.

In at least one embodiment, the method may further include operating a temperature sensor to collect a temperature data series; and before associating the quality of the environment as homogeneous, the method also includes determining whether a portion of the temperature data series includes a temperature change that exceeds a temperature threshold; and, in response to determining that the portion of the temperature data series does not include a temperature change that exceeds the temperature threshold, associating the quality of the environment as homogeneous.

In at least one embodiment, the processing module may be operable to indicate that the GI location is the small intestine in response to determining that the quality of the environment external to the ingestible device is homogenous.

In certain aspects, provided herein is a computer-readable medium having a plurality of instructions executable on a processing module of a device for adapting the device to implement any of the methods described for identifying a location within the GI tract of a body.

In certain aspects, provided herein is another method for determining the position of an ingestible device within the gastrointestinal tract of a body. The method includes transmitting first illumination at a first wavelength toward an environment external to a housing of the ingestible device; detecting a first reflectivity caused by the first illumination from the environment and storing the first reflectivity value in a first data set, wherein the first reflectivity value indicates an amount of light in the first reflectivity; transmitting second illumination at a second wavelength toward the environment external to the housing of the ingestible device, wherein the second wavelength is different from the first wavelength; detecting a second reflectivity caused by the second illumination from the environment and storing the second reflectivity value in a second data set, wherein the second reflectivity value indicates an amount of light in the second reflectivity; identifying a state of the ingestible device, wherein the state is a known or estimated position of the ingestible device; and determining a change in the position of the ingestible device within the gastrointestinal tract of the body by detecting whether a state transition has occurred, wherein the state transition is detected by comparing the first data set to the second data set.

In some embodiments, comparing the first data set to the second data set includes taking a difference between a first reflectance value stored in the first data set and a second reflectance value stored in the second data set.

In some embodiments, comparing the first data set to the second data set includes integrating at least one of (i) a difference between a reflectance value stored in the first data set and a reflectance value stored in the second data set or (ii) a difference between a moving average of the first data set and a moving average of the second data set.

In some embodiments, comparing the first data set and the second data set includes obtaining a first average value from the reflectance values stored in the first data set, obtaining a second average value from the reflectance values stored in the second data set, and obtaining a difference between the first average value and the second average value.

In some embodiments, comparing the first data set and the second data set includes incrementing a count when a multiple of the mean of the first data set minus the standard deviation of the first data set is greater than a multiple of the mean of the second data set plus the standard deviation of the second data set.

In certain embodiments, the first wavelength is in at least one of a red spectrum and an infrared spectrum, and the second wavelength is in at least one of a blue spectrum and a green spectrum.

In certain embodiments, the identified state is stomach, and wherein a state transition has occurred when the comparison indicates that the first and second data sets have diverged in a statistically significant manner, wherein the state transition is a pyloric transition.

In certain embodiments, the identified state is duodenum, and wherein a state transition has occurred when the comparison indicates that the difference between the first and second data sets is constant in a statistically significant manner, wherein the state transition is a ligament of Treitz transition.

In certain embodiments, the first wavelength is in the infrared spectrum and the second wavelength is in at least one of the green spectrum and the blue spectrum.

In certain embodiments, the identified state is jejunum, and wherein a state transition has occurred when the comparison indicates that the first and second data sets have converged in a statistically significant manner, wherein the state transition is an ileocecal transition.

In certain embodiments, the first wavelength is in the red spectrum and the second wavelength is in at least one of the green spectrum and the blue spectrum.

In certain embodiments, the identified state is cecal, and wherein a state transition has occurred when the comparison indicates that the first and second data sets have converged in a statistically significant manner, wherein the state transition is a cecal transition.

In some embodiments, the method further includes measuring a temperature change in the environment external to the housing of the ingestible device.

In certain embodiments, the identified state is outside the body, and wherein the measured temperature change is above a threshold, a state transition has occurred, wherein the state transition is entering the stomach.

In certain embodiments, the identified state is the large intestine, and wherein the measured temperature change is above a threshold, a state transition has occurred, wherein the state transition is leaving the body.

In some embodiments, the method further includes: disabling functionality of the ingestible device for a predetermined period of time after detecting whether a state transition has occurred; re-enabling functionality of the ingestible device after the predetermined period of time; transmitting third illumination at a first wavelength toward an environment outside the housing of the ingestible device; detecting a third reflectivity caused by the third illumination from the environment and storing a third reflectivity value in a first data set, wherein the third reflectivity value indicates an amount of light detected by the ingestible device from the third reflectivity; transmitting fourth illumination at a second wavelength toward an environment outside the housing of the ingestible device; detecting a fourth reflectivity caused by the fourth illumination from the environment and storing a fourth reflectivity value in a second data set, wherein the fourth reflectivity value indicates an amount of light detected by the ingestible device from the fourth reflectivity; identifying a state of the ingestible device; and determining a change in position of the ingestible device within the gastrointestinal tract of the body by detecting whether a state transition has occurred, wherein the state transition is detected by comparing the first data set with the second data set.

In certain embodiments, the state of the ingestible device is selected from one of: outside the body; stomach; pylorus; small intestine; duodenum; jejunum; ileum; large intestine; cecum; and colon.

In certain embodiments, the state transition is selected from one of: entering the body; entering the stomach; pyloric transition; ligament of Treitz transition; ileocecal transition; cecal transition; and exiting the body.

In certain aspects, the present invention provides another ingestible device, which includes a housing defined by a first end, a second end, and a radial wall, the second end being opposite to the first end, and the radial wall extending longitudinally from the first end to the second end; a sensing unit within the housing, the sensing unit including: a first optical sensing subunit configured to transmit a first illumination at a first wavelength toward an environment outside the housing and detect a first reflectivity caused by the first illumination from the environment; a second optical sensing subunit configured to transmit a second illumination at a second wavelength toward the environment outside the housing, wherein the second wavelength is different from the first wavelength, and detect a first reflectivity caused by the second illumination from the environment. a second reflectivity caused by the ingestible device; and a processing module located within the ingestible device, the processing module configured to: store a first reflectivity value in a first data set, wherein the first reflectivity value indicates an amount of light detected by the device from the first reflectivity; store a second reflectivity value in a second data set, wherein the second reflectivity value indicates an amount of light detected by the device from the second reflectivity; identify a state of the device, wherein the state is a known or estimated position of the ingestible device; and determine a change in position of the ingestible device within the gastrointestinal tract of the body by detecting whether a state transition has occurred, the state transition being detected by comparing the first data set with the second data set.

In some embodiments, the ingestible device may also be defined according to any of the teachings herein.

In certain embodiments, another system for determining the position of an ingestible device within the gastrointestinal tract of a body is provided herein. The system includes means for transmitting first illumination at a first wavelength toward an environment external to a housing of the ingestible device; means for detecting a first reflectivity caused by the first illumination from the environment, and means for storing a first reflectivity value in a first data set, wherein the first reflectivity value indicates an amount of light in the first reflectivity; means for transmitting second illumination at a second wavelength toward the environment external to the housing of the ingestible device, wherein the second wavelength is different from the first wavelength; means for detecting a second reflectivity caused by the second illumination from the environment, and means for storing the second reflectivity value in a second data set, wherein the second reflectivity value indicates an amount of light in the second reflectivity; means for identifying a state of the ingestible device, wherein the state is a known or estimated position of the ingestible device; and means for determining a change in the position of the ingestible device within the gastrointestinal tract of the body by detecting whether a state transition has occurred, wherein the state transition is detected by comparing the first data set to the second data set.

In certain embodiments, the system may also be defined according to any of the teachings herein.

In certain aspects, provided herein is a method for sampling the gastrointestinal tract with an ingestible device. The method includes transmitting first illumination at a first wavelength toward an environment external to a housing of the ingestible device; detecting a first reflectivity caused by the first illumination from the environment; transmitting second illumination at a second wavelength toward the environment external to the housing of the ingestible device; detecting a second reflectivity caused by the second illumination from the environment; determining a position of the ingestible device within the gastrointestinal tract of a body based on the first reflectivity and the second reflectivity; and sampling the gastrointestinal tract when the determined position matches a predetermined position.

In certain embodiments, sampling the gastrointestinal tract includes moving a portion of the housing of the ingestible device from an orientation that does not allow the sample to enter the sample chamber from the gastrointestinal tract to an orientation that allows the sample to enter the sample chamber.

In certain embodiments, the method further includes determining an amount of time after sampling the gastrointestinal tract; and resampling the gastrointestinal tract when the determined amount of time is greater than a threshold.

In certain embodiments, the method further includes determining a second location of the ingestible device within the gastrointestinal tract based on the detected third reflectivity; and resampling the gastrointestinal tract when the determined location matches a second predetermined location.

In certain embodiments, resampling the gastrointestinal tract comprises moving a portion of the housing of the ingestible device from an orientation that does not allow the second sample to enter the second sample chamber from the gastrointestinal tract to an orientation that allows the second sample to enter the second sample chamber.

In certain aspects, provided herein is yet another ingestible device. The ingestible device includes a housing defined by a first end, a second end, and a radial wall, the second end being opposite the first end, the radial wall extending longitudinally from the first end to the second end; a sampling chamber located proximal to the housing; a sensing unit within the housing, the sensing unit comprising: a first optical sensing subunit configured to transmit a first illumination at a first wavelength toward an environment external to the housing and to detect a first reflectivity caused by the first illumination from the environment; a second optical sensing subunit configured to transmit a second illumination at a second wavelength toward the environment external to the housing and to detect a second reflectivity caused by the second illumination from the environment; a processing module within the ingestible device, the processing module configured to: determine a position of the ingestible device within a gastrointestinal tract of the body based on the first reflectivity and the second reflectivity; and, when the identified position matches a predetermined position by actuating at least one of a portion of the housing and the sampling chamber, sample the gastrointestinal tract.

In some embodiments, the ingestible device may also be defined according to any of the teachings herein.

In certain aspects, a system for sampling the gastrointestinal tract with an ingestible device is provided herein. The system includes means for transmitting a first illumination at a first wavelength toward an environment outside a housing of the ingestible device; means for detecting a first reflectivity caused by the first illumination from the environment; means for transmitting a second illumination at a second wavelength toward the environment outside the housing of the ingestible device; means for detecting a second reflectivity caused by the second illumination from the environment; means for determining a position of the ingestible device within the gastrointestinal tract of the body based on the first reflectivity and the second reflectivity; and means for sampling the gastrointestinal tract when the determined position matches a predetermined position.

In certain embodiments, the system may also be defined according to any of the teachings herein.

In certain aspects, provided herein is another method for releasing a substance into the gastrointestinal tract with an ingestible device. The method includes transmitting first illumination at a first wavelength toward an environment external to a housing of the ingestible device; detecting a first reflectivity caused by the first illumination from the environment; transmitting second illumination at a second wavelength toward the environment external to the housing of the ingestible device; detecting a second reflectivity caused by the second illumination from the environment; determining a position of the ingestible device within the gastrointestinal tract of the body based on the first reflectivity and the second reflectivity; and releasing the substance into the gastrointestinal tract when the determined position matches a predetermined position.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects and advantages will become apparent upon consideration of the following detailed description taken in conjunction with the accompanying drawings, in which like reference numerals designate like parts throughout, and in which:

Figure 1A is a view of an exemplary embodiment of an ingestible device.

1B is an exploded view of the ingestible device of FIG. 1A .

Figure 2A is an exemplary block diagram of electrical components that may be used with the ingestible device of Figure 1A.

2B and 2C are exemplary embodiments of circuit designs that may be used in the ingestible device of FIG. 1A .

2D is a top view of a circuit design for a flexible PCB that may be used in the ingestible device of FIG. 1A .

FIG. 2E is a bottom view of the circuit design of FIG. 2D .

3A and 3B are simplified diagrams of exemplary sensor configurations for an ingestible device.

4A and 4B are simplified diagrams of another exemplary sensor configuration for an ingestible device.

5A and 5B are simplified diagrams of yet another exemplary sensor configuration for an ingestible device.

6A and 6B are simplified diagrams of yet another exemplary sensor configuration for an ingestible device.

7A-7C illustrate simplified diagrams of the ingestible device of FIG. 3A in exemplary operation.

8A is a cross-sectional view of an exemplary embodiment of an ingestible device illustrating areas for light that may be transmitted and detected during operation.

8B and 8C are simplified diagrams of the ingestible device of FIG. 8A in exemplary operation.

Figure 9A is a flow chart of an exemplary embodiment of a method of operating an ingestible device as described herein.

9B is a flow chart of an exemplary embodiment of a method for determining the quality of an environment external to an ingestible device as described herein.

10A-10C are simplified illustrations of the ingestible device of FIG. 3A during exemplary transit through the gastrointestinal (GI) tract of an individual.

11A-11C are simplified diagrams of the ingestible device of FIG. 4A during exemplary transit through the GI tract of an individual.

12A-12C are simplified diagrams of the ingestible device of FIG. 5A during exemplary transit through the GI tract of an individual.

13A-13C are plots illustrating data collected during exemplary operation of the ingestible device of FIG. 3A .

Figure 14A is an exploded view of another exemplary embodiment of an ingestible device.

Figure 14B is a cross-sectional view of the ingestible device of Figure 14A.

15 is an exemplary block diagram of electrical components that may be used with the ingestible device of FIG. 14A .

16 is a flow chart of an exemplary embodiment of a method of operating the ingestible device of FIG. 14A .

Figures 17A-17C are different views of an exemplary embodiment of a base station that can be used with an ingestible device.

Figures 18A-18C are screenshots of exemplary embodiments of a user interface for interacting with the ingestible device described herein.

19 is a view of another exemplary embodiment of an ingestible device.

20 is a simplified top and side view of the apparatus of FIG. 19 .

FIG. 21 illustrates how optical wavelengths may be used in certain embodiments of a device that interacts with different environments.

Figure 22 shows the reflective properties of different regions of the gastrointestinal tract when associated with the device.

Figure 23 shows how different types of reflected light can be detected in different areas of the gastrointestinal tract.

FIG24 shows the reflectivity measured in different regions of the gastrointestinal tract and the process used to localize the device.

25 is an external view of another embodiment of an ingestible device that can be used to sample the gastrointestinal tract or deliver a pharmaceutical agent.

Figure 26 is an exploded view of the ingestible device of Figure 25.

Figure 27 shows the main electrical subunits corresponding to certain embodiments of the device.

FIG. 28 illustrates firmware corresponding to certain embodiments of a device.

29 is a flow chart illustrating "fast cycling" operation of the apparatus, which may allow for high speed processing at shorter intervals, according to certain embodiments of the apparatus.

30A and 30B show flow charts illustrating "slow cycle" operation of the device, according to certain embodiments of the device.

31 is a flow chart illustrating operational states of the device in an exemplary application, according to certain embodiments of the device.

32 is a flow chart illustrating a cecum detection algorithm used in certain embodiments of the apparatus.

33 is a flow chart illustrating a duodenum detection algorithm used in certain embodiments of the device.

FIG. 34 is data from an ingestible device administered to patients during a trial.

FIG. 35 is a color graph showing the degree of variation in reflected light detected by the device in thirteen different experiments.

DETAILED DESCRIPTION

Various systems, devices and methods are described herein to provide examples of at least one embodiment of the subject matter claimed. The embodiments do not limit any subject matter claimed, and any subject matter claimed can cover systems, devices and methods different from those described herein. It is possible that the subject matter claimed is not limited to the system, device and method with all the features of any one of the systems, devices and methods described herein or is not limited to the features common to multiple or all of the systems, devices and methods described herein. It is possible that the system, device or method described herein is not an embodiment of any subject matter claimed. Any subject matter disclosed in the system, device and method described herein and not claimed in this document can be the subject matter of another protection device, for example, a continuous patent application, inventor or owner is intended to be not abandoned, not waived or not dedicated to any such subject matter of publication by the disclosure in this document.

It will be understood that for brevity and clarity of description, reference numerals may be repeated among the drawings to indicate corresponding or similar elements where deemed appropriate. In addition, many specific details are set forth in order to provide a thorough understanding of the embodiments described herein. However, it will be understood by those skilled in the art that the embodiments described herein can be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the embodiments described herein. Furthermore, this description is not to be construed as limiting the scope of the embodiments described herein.

It should be noted that terms of degree such as "substantially," "about," and "approximately" when used herein mean a reasonable amount of deviation of the modified term so that the end result is not significantly changed. These terms of degree should be construed to include deviations of the modified term if such deviations would not negate the meaning of the term it modifies.

Additionally, as used herein, the term "and/or" is intended to represent an inclusive logical OR. That is, "X and/or Y" is intended to mean X or Y or both, for example. As another example, "X, Y, and/or Z" is intended to mean X or Y or Z or any combination thereof.

As used herein, the term “coupled” indicates that two elements may be coupled to each other directly or to each other through one or more intermediate elements.

As used herein, the term "body" refers to the body of a patient, subject, or individual that receives an ingestible device. The patient or subject is typically a human or other animal.

Various embodiments described herein generally relate to an ingestible device for identifying one or more locations within the gastrointestinal (GI) tract and, in certain embodiments, for collecting data and/or releasing substances, including pharmaceutical and therapeutic agents, at the identified locations. As used herein, the term "gastrointestinal tract" or "GI tract" refers to all parts of the organ system responsible for consuming and digesting food, absorbing nutrients, and excreting waste. This includes orifices and organs, such as the mouth, throat, esophagus, stomach, small intestine, large intestine, rectum, anus, and the like, as well as the various channels and sphincters connecting the aforementioned components.

As used herein, the term "reflectivity" refers to a value resulting from light emitted by a device, reflected back to the device, and received by a detector in or on the device. For example, in some embodiments, this relates to light emitted by a device, where a portion of the light is reflected by a surface external to the device, and the light is received by a detector located in or on the device.

As used herein, the term "illumination" refers to any electromagnetic emission. In some embodiments, the illumination can be within the range of infrared light (IR), visible light spectrum, and ultraviolet light (UV), and the illumination can have most of its power centered on a specific wavelength within the range of 100nm to 1000nm. In some embodiments, it is advantageous to use such illumination, that is, most of the power of the illumination is limited to one of the infrared spectrum (750nm to 1000nm), the red spectrum (620nm to 750nm), the green spectrum (495nm to 570nm), the blue spectrum (450nm to 495nm), or the ultraviolet spectrum (100nm to 400nm). In some embodiments, multiple illuminations with different wavelengths can be used.

Referring now to FIG. 1A , shown therein is a view of an exemplary embodiment of an ingestible device 10 with portions of the housing 12 of the ingestible device 10 removed. The ingestible device 10 can be used to autonomously identify a location within the body, such as a portion of the gastrointestinal tract. In certain embodiments, the ingestible device 10 can distinguish whether it is located in the stomach, in the small intestine, or in the large intestine. In certain embodiments, the ingestible device can also be able to distinguish in what portion of the small intestine, such as the duodenum, jejunum, or ileum. The ingestible device 10 can generally have the shape of a capsule, like a conventional pill. Thus, the shape of the ingestible device 10 is configured for easy ingestion and to be familiar to healthcare practitioners and patients.

Unlike conventional pills, the ingestible device 10 is designed to withstand the chemical and mechanical environment of the GI tract (e.g., the effects of muscle contraction forces and high concentrations of hydrochloric acid in the stomach). However, unlike other devices that are intended to remain within a patient's body (e.g., medical implants), the ingestible device 10 can be designed to temporarily travel within the body. Therefore, the regulatory rules governing the materials and manufacturing of the ingestible device 10 can be less stringent than those used for devices intended to remain within the body. However, because the ingestible device 10 enters the body, the materials used to manufacture the ingestible device 10 are typically selected to at least comply with standards for biocompatibility (e.g., ISO 10993). In addition, the components within the ingestible device 10 are free of any restricted and/or toxic metals and are lead-free in accordance with Directive 2002/95/EC of the European Parliament, which is also known as the Restriction of Hazardous Substances (RoHS) Directive.

A wide range of materials can be used to make the ingestible device 10. A different material can be used for each of the different components of the ingestible device 10. Examples of these materials include, but are not limited to, thermoplastics, fluoropolymers, elastomers, stainless steel, and glass that comply with ISO 10993 and USP Class VI specifications for biocompatibility; and any other suitable materials and combinations thereof. In some embodiments, these materials can also include: liquid silicone materials having a hardness rating of 10 to 90 as determined using a durometer (e.g., MED-4942 ^™ manufactured by NuSil ^™ ); soft biocompatible polymeric materials, such as, but not limited to, polyvinyl chloride (PVC), polyethersulfone (PES), polyethylene (PE), polyurethane (PU), or polytetrafluoroethylene (PTFE); and rigid polymeric materials coated with a biocompatible material that is soft or flexible, (e.g., poly(methyl methacrylate) (PMMA) material coated with a silicone polymer). Using different materials for different components can functionalize some surfaces for interaction with proteins, antibodies, and other biomarkers. For example, a material can be used in the ingestible device 10 for movable parts in order to reduce friction between these parts. Other exemplary materials can include other materials commonly used in microfabrication, such as polydimethylsiloxane (PDMS), borosilicate glass, and/or silicon. Although we may refer to specific materials being used to construct the device for illustrative purposes, the materials listed are not intended to be limiting, and one skilled in the art can readily adapt the device for use with any number of different materials without affecting the overall operation or functionality of the device.

In certain embodiments, the housing 12 of the ingestible device 10 can be made of a type of plastic, such as a photosensitive acrylic polymer material or an inert polycarbonate material. The housing 12 can also be formed using a material that can be sterilized by chemicals.

Housing 12 can be formed by coupling two shell parts together. For example, the two shell parts can be mated and fused together with an adhesive material, such as a cyanoacrylate variant. In effect, housing 12 protects the interior of ingestible device 10 from its external environment, and also protects the external environment (e.g., the gastrointestinal tract) from the components within ingestible device 10.

Additionally, the ingestible device 10 can include one or more additional layers of protection. The additional protection can protect the patient or individual from adverse effects caused by any structural issues associated with the housing 12 (e.g., collapse of two enclosure portions or development of cracks in the housing 12). For example, the power supply within the ingestible device 10 can be coated with an inert and flexible material (e.g., a thin layer of silicone polymer) so that only the electrical contacts on the power supply are exposed. This additional protection of the power supply can prevent chemicals within the ingestible device 10 from seeping into the patient's body.

In certain embodiments, the surfaces of the ingestible device 10 and the surfaces of different components within the ingestible device 10 can receive different treatments that vary depending on the intended use of the ingestible device 10. For example, the surfaces of the ingestible device 10 can receive plasma activation for increasingly hydrophilic rendering. In another example, to minimize cross-contamination among collected samples and/or substances for release, some storage components that may come into contact with such samples and/or substances can receive a hydrophilic treatment while some other components can receive a hydrophobic treatment.

The components of the ingestible device 10 may be too small and too complex to be manufactured using conventional tools (e.g., machine tools, manual milling machines, press drills, and the like), but too large to be efficiently constructed using microfabrication techniques. Manufacturing techniques that fall between conventional and microfabrication techniques may be used, including, but not limited to, 3D printing (e.g., 3D multi-nozzle modeling (MJM)), mechanical computer-aided design (CAD). Software packages such as SolidWorks ^™ and/or Alibr ^™ are examples of CAD software that may be used to design some components of the ingestible device 10, but any suitable CAD software may be used.

In certain embodiments, the components of the ingestible device 10 can be manufactured using various conventional manufacturing techniques, such as injection molding, computer numerical control (CNC) machining, and by using a multi-axis lathe. For example, the housing 12 of the ingestible device 10 can be manufactured from a CNC-machined polycarbonate material, and the storage component can be manufactured by applying a biocompatible material, such as a silicone polymer, to a 3D-printed mold or casting.

Silicone polymers can offer certain advantages to the manufacturing process of the ingestible device 10. For example, components formed using silicone polymer materials in the ingestible device 10 can be manufactured using conventional methods, such as molding techniques. Silicone polymer materials are also flexible materials. Therefore, components of the ingestible device 10 formed from silicone polymer materials can accommodate a range of design deviations during the manufacturing stage and can also be adapted for compression fit.

Still referring to FIG1A , an ingestible device 10 is shown according to an exemplary embodiment. The ingestible device 10 includes a housing 12 for providing an enclosure for various electronic and mechanical components. The housing 12 includes a first end portion 16 a, a second end portion 16 b, and a radial wall 14 extending from the first end portion 16 a to the second end portion 16 b.

The radial wall 14 can be formed from one or more components. In the example of FIG1A , the radial wall includes a first wall portion 14a, a second wall portion 14b, and a connecting wall portion 14c for connecting the first wall portion 14a to the second wall portion 14b. Other configurations of the radial wall 14 can be used depending on the application of the ingestible device 10.

Referring now to FIG. 1B , shown is an exploded view of the components of the ingestible device 10 in one exemplary embodiment. As shown in FIG. 1A and FIG. 1B , enclosed within the first wall portion 14a is a printed circuit board (PCB) 30, a battery 18, sensing subunits 32, 42, and a communication subunit 120. The various components within the ingestible device 10 are described with reference to FIG. 2A through FIG. 2E .

2A is a block diagram 100 of an exemplary embodiment of electrical components that may be used with the ingestible device 10. As shown in block diagram 100, the ingestible device 10 may include a microcontroller 110, a communication sub-unit 120, a sensing sub-unit 130, a power supply 160, and a memory sub-unit 140. At least some of the electronic components may be embedded on the PCB 30.

In certain embodiments, the microcontroller 110 includes programming, control, and memory circuitry for maintaining and executing firmware or software and coordinating all functions of the ingestible device 10, as well as other peripherals embedded on the PCB 30. For example, the microcontroller 110 may be implemented using a 32-bit microcontroller, such as the STM32 series from STMicroelectronics ^™ , although any suitable microcontroller may be used.

2A may include a general purpose input/output (I/O) interface 112, an SPI or universal asynchronous receiver/transmitter (UART) interface 114, and an analog-to-digital converter (A/D converter) 116. The microcontroller 110 may consider the A/D converter 116 to be a peripheral device.

The general purpose I/O interface 112 includes a fixed number of general purpose input/output pins (GPIOs). These GPIOs can be grouped into groups of two or three pins to implement various communication protocols, such as a single-wire interface (SWI), a two-wire interface (e.g., Inter-Integrated Circuit or I ² C), and/or a serial peripheral interface (SPI). The GPIO groups assigned to these communication protocols can be used as a bus to connect the microcontroller 110 to one or more peripheral devices.

Using any of the communication protocols listed above, or using any other suitable communication protocol, the microcontroller 110 can send a series of requests to the address associated with a particular GPIO group to detect which peripheral devices, if any, are present on the bus. If any of the peripheral devices are present on the bus, the present peripheral device returns an acknowledgment signal to the microcontroller 110 within a specified time frame. If no response is received within the specified time frame, the peripheral device is considered absent.

The A/D converter 116 can be coupled to any of the sensors in the sensing sub-unit 130. In some embodiments, the ingestible device 10 can communicate by receiving and/or transmitting infrared light, in which case an infrared (IR) sensitive phototransistor and resistor coupled to the A/D converter 116 are included in the communication sub-unit 120. Additionally, in some embodiments, the ingestible device 10 can include an infrared (IR) light emitting diode (LED) coupled to the microcontroller 110 to communicate signals to the outside of the device.

In some embodiments, the communication sub-unit 120 can receive operating instructions from an external device, such as a base station (e.g., an infrared transmitter and/or receiver on a dock). The base station can be used to initially program and/or communicate with the ingestible device 10 with operating instructions in real time during operation or after retrieving the ingestible device 10 from the body. In some embodiments, the communication sub-unit 120 does not receive any operating instructions from an external device, and instead the ingestible device 10 operates independently and autonomously within the body.

In some embodiments, the communication sub-unit 120 may include an optical encoder 20, for example, an infrared transmitter and receiver. The IR transmitter and receiver may be configured to operate using modulated infrared light, that is, light in the wavelength range of 850 nm to 930 nm. In addition, an IR receiver may be included in the ingestible device 10 for receiving programming instructions from an IR transmitter at a base station, and an IR transmitter may be included in the ingestible device 10 for transmitting data to an IR receiver at a base station. Thus, two-way IR communication may be set up between the ingestible device 10 and the base station. It will be understood that other types of optical encoders or communication sub-units may be used in some embodiments; for example, some communication sub-units may utilize Bluetooth, radio frequency (RF) communication, near field communication, and the like, instead of (or in addition to) optical signals.

The sensing subunit 130 may include various sensors to obtain in vivo information while the ingestible device 10 is transported within the body. Various sensors may be provided at different locations on the ingestible device 10, for example, radial sensors 32 and axial sensors 42, to help identify where the ingestible device 10 may be located within the body. In some embodiments, the data provided by the sensors 32, 42 may be used to trigger the operation of the ingestible device 10. For example, in some embodiments, the ingestible device 10 may be adapted to include a sampling chamber capable of obtaining a sample from the gastrointestinal tract from an area surrounding the device, and the data provided by the sensors 32, 42 may trigger the device to obtain the sample. Each sensor 32, 42 may include an illuminator 32i and 42i and a detector 32d and 42d. The sensors 32, 42 are further illustrated with reference to Figures 3A to 8C. As another example, in some embodiments, the ingestible device 10 may be adapted to deliver substances including pharmaceuticals and therapeutic agents, and the data provided by the sensors 32, 34 may trigger the device to deliver the substance.

The memory sub-unit 140 may include a memory storage component 142, such as a flash memory, an EEPROM, and the like. The memory sub-unit 140 may be used to store instructions received from the base station and various other operational data, such as transport data and sensor data collected by the sensing sub-unit 130. In some embodiments, the microcontroller 110 may be operable to execute instructions stored in the memory sub-unit 140, which may be related to operating other components of the ingestible device 10, such as the sensing sub-unit 130, the communication sub-unit 120, and the power supply 160.

In some embodiments, the power source 160 may include one or more batteries 18 formed of different chemistries, such as lithium polymer, lithium carbon, silver oxide, alkaline, and the like. This can help accommodate the different power requirements of the various components in the ingestible device 10. In some embodiments, the power source 160 may include silver oxide battery cells for supplying power to the various components in the ingestible device 10. The battery cells that power the power source 160 may operate at 1.55V. For example, a silver oxide button cell type battery, such as that manufactured by Renata ^™ , may be used because the button cell type battery has discharge characteristics suitable for the operation of the ingestible device 10. In some embodiments, other types of battery cells may be used.

In some embodiments, the power source 160 can include one or more battery cells. For example, multiple button cells can be used to provide a higher voltage for the operation of the ingestible device. The power source 160 can also include one or more different types of battery cells.

Furthermore, the power supply 160 can be divided into one or more cell groups to prevent temporary interruptions or variations in the power supply 160 from affecting the overall operation of the ingestible device 10. For example, an exemplary power supply 160 may include three cells, each operable to provide 1.55 volts. In one exemplary embodiment, the three cells can be arranged into a cell group operable to provide 4.65 volts as the full voltage. A voltage regulator can control the voltage provided by the cell group. The voltage regulator can be operable to provide a regulated voltage, for example, 3.3 volts, to the microcontroller 110 while simultaneously operating to provide full voltage to the sensing sub-unit 130. In another exemplary embodiment, the three cells can be arranged into two different cell groups, with the first cell group comprising two cells and the second cell group comprising one cell. Thus, the first cell group can provide 3.1 volts, while the second cell group can provide 1.55 volts. The first cell group can be operable to provide 3.1 volts to the microcontroller 110 to prevent voltage variations. The first cell group and the second cell group can then be combined to provide 4.65 volts to the sensing sub-unit 130.

In certain embodiments, the power supply 160 may include a magnetic switch 162 that is configured to operate as an 'ON'/'OFF' mechanism for the ingestible device 10. When exposed to a stronger magnetic field, the magnetic switch 162 may be maintained in an 'OFF' position in which the ingestible device 10 is not activated. The stronger magnetic field may effectively stop the flow of current in the ingestible device 10, causing an open circuit to occur. For example, this may prevent the ingestible device 10 from consuming energy and discharging the battery 18 prior to administration to a patient. However, when the magnetic switch 162 is no longer exposed to the stronger magnetic field, the magnetic switch 162 may be switched to the 'ON' position to activate the ingestible device 10. Current may then flow through electrical pathways in the ingestible device 10 (e.g., pathways on the PCB 30).

In some embodiments, the MK24 magnetic ring inductor from MEDER ^™ Electronics can be used as the magnetic switch 162, but any suitable magnetic switch can be used. For example, in some embodiments, the magnetic switch 162 can be a magnetically actuated, normally closed, single-pole, single-throw (SPST to NC) switch. In some embodiments, a microelectromechanical system (MEMS) magnetic switch manufactured by MEMSCAP ^™ can be used as the magnetic switch 162. In some embodiments, the magnetic switch 162 can be a Hall effect sensor.

In some embodiments, the power source 160 can be removed from the ingestible device 10 to be recharged via charging circuitry external to the ingestible device 10. In some embodiments, when charging circuitry is included on the PCB 30, the power source 160 can be recharged while in the ingestible device 10; for example, by providing circuitry that allows the ingestible device 10 to be inductively coupled to a base station and wirelessly charged.

2B is an exemplary circuit design 102 of certain electrical components of the ingestible device 10. It will be understood that the circuit design 102 is merely an example and that other configurations and designs may similarly be used. FIG2C is an exemplary circuit design 104 of the sensing sub-unit 130.

As described above, some of the electronic components may be embedded on the PCB 30. Figures 2D and 2E illustrate a top view 106t and a bottom view 106b of the circuit design of the flexible PCB 30, respectively.

The PCB 30 may be constructed from a flexible printed circuit. A flexible printed circuit can maximize space utilization within the ingestible device 10 by being able to more easily conform to the dimensional constraints of the ingestible device 10. Increased flexibility allows the PCB, or certain components of the PCB, to be twisted, bent, and shaped more easily, ultimately resulting in a smaller pill that is more robust to vibrational or torsional forces.

PCB 30 in this example includes a communication subunit 120, a microcontroller 110, a sensing subunit 130, and other peripheral components described below. Electronic components on PCB 30 are electrically coupled to other components via one or more electronic signal paths, traces, or tracks.

The flexible PCB 30 can be manufactured using a combination of flexible plastic material and rigid material, for example, a woven fiberglass cloth material, or any other suitable material. Thus, the resulting flexible PCB 30 can exhibit both flexible and rigid qualities. The flexible quality of the flexible PCB 30 enables the electronic components located on the flexible PCB 30 to conform to the dimensional constraints of the ingestible device 10. In particular, as generally shown in Figure 1A, the flexible PCB 30 can be inserted into the first wall portion 14a. At the same time, the rigid quality of the flexible PCB 30 can reinforce areas that may be susceptible to higher levels of physical stress. For example, in some embodiments, the contact terminals (e.g., 218b, 218b) used to connect the flexible PCB 30 to the power source 160 will have added reinforcement.

As shown in Figures 2D and 2E, the flexible PCB 30 includes one or more separate but connected segments. For example, the flexible PCB 30 may include a main PCB segment 202 and one or more smaller PCB segments 204, such as smaller PCB segments 204a and 204b. The smaller PCB segments 204 may be directly or indirectly connected to the main PCB segment 202. The main PCB segment 202 may be rolled into a generally cylindrical shape to conform to the structural dimensions of the ingestible device 10.

1B , the smaller PCB segments 204a and 204b may be folded into one or more overlapping layers and fitted into the ingestible device 10. In certain embodiments, the smaller PCB segments 204a and 204b may be layered around the battery 18. It will be appreciated that the flexible PCB 30 may have different configurations, e.g., different shapes and sizes and/or different numbers of segments.

The electronic components can be located on either the main PCB segment 202 or the smaller PCB segments 204a and 204b. For example, as shown in Figures 2D and 2E, the main PCB segment 202 can include the microcontroller 110, the magnetic switch 162, and the radial sensor 32. The smaller PCB segment 204a can include the optical encoder 20 and the axial sensor 42. The smaller PCB segments 204a and 204b can also include corresponding power contact terminals 218a and 218b for engaging the battery 18. In some embodiments, other arrangements of these components are possible on the flexible PCB 30.

1A , the first end portion 16a generally encapsulates components at the first wall portion 14a of the ingestible device 10. The first end portion 16a and the first wall portion 14a may be fabricated from optically and radio-translucent or transparent materials. This type of material allows for transmission and reception of light, such as by sensors 32, 42. In some embodiments, the first end portion 16a and the first wall portion 14a may be fabricated from plastic.

In some embodiments, sensing sub-unit 130 can be oriented or positioned relative to housing 12 to reduce internal reflections caused by the output of sensing sub-unit 130. For example, sensing sub-unit 130 can be oriented at an angle relative to the circumference of housing 12 so that the output of sensing sub-unit 130 causes minimal internal reflections from housing 12 when it reaches housing 12. In some embodiments, a transition medium, such as an oily substance, can be positioned between sensing sub-unit 130 and housing 12 so that the refractive index of the transition medium and sensing sub-unit 130 matches that of housing 12, reducing reflections and scattering. In some embodiments, the illuminator and detector of each sensor (e.g., illuminator 32i and detector 32d of sensor 32) can be physically separated around the circumference of the device. For example, in the embodiments discussed in Figures 8A-8C, 19, and 20, separating illuminator 32i and detector 32d can also reduce internal reflections.

In certain embodiments, the sensing subunit 130 includes axial sensing subunits 42 and radial sensing subunits 32 at various locations on the ingestible device 10 to help infer the location of the ingestible device 10 within the body. The ingestible device 10, 300 moves within the body at variable speeds. Within the gastrointestinal tract, for example, the varying sizes, shapes, and environments of different gastrointestinal segments can make location identification difficult.

3A and 3B , shown therein are simplified diagrams of an exemplary ingestible device 300. FIG3A and 3B generally illustrate an exemplary configuration of sensors 332, 342 relative to certain components of housing 12. FIG3A is a cross-sectional view 300A of ingestible device 300, and FIG3B is a three-dimensional side view 300B of ingestible device 300.

The axial sensing subunit 42 is located proximal to at least one of the first end portion 16a and the second end portion 16b. As shown in FIG3A , the axial sensor 342 is located proximal to the first end portion 16a. It will be appreciated that, depending on the configuration of the ingestible device 300, the axial sensor 342 may instead be located proximal to the second end portion 16b. The radial sensing subunit 32 is typically located proximal to the radial wall 14. For example, as shown in FIG3A and FIG3B , the radial sensor 332 is located proximal to a portion of the radial wall 14.

An exemplary transport of the ingestible device 300 is shown in Figures 10A to 10C. Transport of the ingestible device 300 through the stomach 452, the small intestine 454, and then the large intestine 456 is generally shown at 450A, 450B, and 450C, respectively. The movement of the ingestible device 300 varies substantially depending on its location. As shown in Figure 10A, the stomach 452 is a large, open, and cavernous organ, and therefore the ingestible device 300 can have a larger range of motion. On the other hand, as shown in Figure 10B, the small intestine 454 has a tubular structure, and the ingestible device 300 is generally limited to longitudinal movement. Similar to the stomach 452, the large intestine 456 is a larger, open structure, and the ingestible device 300 can have a larger range of motion as compared to transport through the small intestine 454. By providing the axial sensing subunit 42 and the radial sensing subunit 32, different levels and types of reflectivity data can be obtained depending on the shape and/or size of the transport location. The varying reflectivity data is further illustrated in Figures 13A, 13B, and 13C.

In some embodiments, each axial sensor 342 and each radial sensor 332 may include an illuminator for directing illumination toward the environment outside the housing 12 and a detector for detecting reflectivity from the environment caused by the illumination. The illumination may include any electromagnetic emission within the infrared (IR), visible spectrum, and ultraviolet (UV) range. Exemplary operation of the sensors 342 and 332 is described below with reference to FIG7A through FIG7C .

7A-7C illustrate the operation of the axial sensor 342 and the radial sensor 332 in different environments. In each of FIG7A-7C , the illuminators and detectors of the sensors 332 and 342 are shown for use with the ingestible device 300. The axial sensor 342 includes an axial illuminator 342i for transmitting axial illumination to the external environment and an axial detector 342d for detecting axial reflectivity from the external environment (i.e., outside the ingestible device 300). The axial reflectivity can be caused by different illumination depending on the external environment.

Similarly, radial sensor 332 includes a radial illuminator 332i and a radial detector 332d. The radial illuminator 332i is used to transmit radial illumination to the external environment, and the radial detector 332d is used to detect radial reflectivity from the external environment. Similar to axial reflectivity, radial reflectivity can be caused by different illuminations depending on the external environment. For example, in certain embodiments, there can be multiple radial illuminations, and the detected radial reflectivity can be caused by multiple radial illuminations reflected from the external environment and scattered in multiple directions. As shown in Figures 7A to 7C, the position of radial illuminator 332i is such that the resulting radial illumination is along a direction different from the axial illumination produced by axial illuminator 332i. In certain embodiments, the radial illumination is substantially perpendicular to the axial illumination.

7A illustrates the transit of the ingestible device 300 through the opaque liquid 410. The opaque liquid 410 comes into contact with the radial walls 14 of the ingestible device 300 as it transits through the gastrointestinal tract under certain conditions, similar to the manner in which opaque fluid within the large intestine (e.g., large intestine 456 of FIG. 10C ) may come into contact with the ingestible device 300. Thus, the radial illumination transmitted by the radial illuminator 332i is almost entirely internally reflected and detected by the radial detector 332d, causing a greater reflectivity to be detected. In this example, the axial detector 342d does not detect any reflectivity because no matter or tissue is disposed in front of the axial illuminator 342i.

FIG7B illustrates the transport of the ingestible device 300 near tissue 412. Radial illumination transmitted by the radial illuminator 332i is partially reflected (and partially absorbed by the tissue 412) and detected by the radial detector 332d, similar to how radial illumination may interact with tissue of the small intestine (e.g., the small intestine 454 of FIG10B) or other organs under certain conditions. Similar to FIG7A, in this example, the axial detector 342d also does not detect any reflectivity because no matter or tissue is disposed within the range of the axial detector 342d. The amount of illumination reflected and absorbed by the tissue 412 can depend on the wavelength of the illumination. For example, red tissue can reflect illumination having a wavelength in the red spectrum (i.e., 620nm to 750nm) well, causing the ingestible device 300 to detect a higher reflectivity. In contrast, illumination having a wavelength in the green spectrum (495nm to 570nm) or the blue spectrum (450nm to 495nm) can be absorbed by the tissue, causing the ingestible device 300 to detect a lower reflectivity. In certain embodiments, given that different organs and portions of the gastrointestinal tract have different reflective properties, multiple radial or axial illuminations having different corresponding wavelengths may be used to help identify the location of the ingestible device 300 within the gastrointestinal tract.

FIG7C illustrates the transport of the ingestible device 300 through a transparent liquid having particles 414. This type of environment can, under certain conditions, be similar to the environment found in a stomach (e.g., stomach 452 of FIG10A ). As shown, axial illumination and radial illumination are reflected by particles 414a to 414d within the range of respective axial illuminators 342i and radial illuminators 332i. Some of the illumination can also be reflected from one particle to another, such as from particle 414c to particle 414b. The reflectivity detected by each of the axial detector 342d and radial detector 332d may not be limited to the illumination generated by the respective axial illuminator 342i and radial illuminator 332i. The axial detector 342d can detect the reflectivity caused by the radial illumination. Similarly, the radial detector 332d can detect the reflectivity caused by the axial illumination. In some embodiments, this effect can be reduced by having the axial sensor 342 and radial sensor 332 use illumination having two different wavelengths. For example, if radial sensor 332 has an illuminator 332i and detector 332d that transmit and detect wavelengths in the red spectrum and axial sensor 342 has an illuminator 342i and detector 342d that transmit and detect wavelengths in the infrared spectrum, the effect of axial illuminator 342i on radial detector 332d is reduced.

Various embodiments of the sensors 32 , 42 are described below with reference to FIG. 4A to FIG. 8C .

Referring now to Figures 4A and 4B, shown therein are simplified diagrams of another exemplary ingestible device 302. Figure 4A is a cross-sectional view 302A of the ingestible device 302, and Figure 4B is a three-dimensional side view 302B of the ingestible device 302. The ingestible device 302 includes an axial sensing sub-unit 42 having two axial sensors 342 and 344, and a radial sensing sub-unit 32 having two radial sensors 332 and 334.

As described with reference to Figures 3A and 3B , axial sensor 342, or the first axial sensor, is located proximal to first end portion 16a. Axial sensor 344, or the second axial sensor, is located proximal to second end portion 16b. As shown in Figures 4A and 4B , first axial sensor 342 and second axial sensor 344 are substantially opposed to each other relative to housing 12. Therefore, the first axial illumination generated by first axial sensor 342 will be in a substantially opposite axial direction to the second axial illumination generated by second axial sensor 344.

The radial sensor 332 or first radial sensor of the ingestible device 302 is located proximal to the first wall portion 14 of the radial wall, while the radial sensor 334 or second radial sensor is located proximal to the second wall portion. As shown in Figures 4A and 4B, the first wall portion is spaced approximately 180 degrees apart from the second wall portion along the circumference of the radial wall 14. The first radial illumination and the second radial illumination generated by the respective first radial sensor 332 and second radial sensor 334 are along different radial directions. As a result, the first radial illumination and the second radial illumination are transmitted in substantially opposite directions.

Typically, in embodiments where the radial sensing sub-unit 32 is comprised of two or more radial sensors 332, 334, the radial sensors 332 and 334 can be spaced at least 60 degrees apart along the circumference of the radial wall 14 so that the resulting first and second radial illuminations are in substantially different radial directions. Furthermore, the separation between the radial sensors 332 and 334 can help minimize internal reflections.

More reflectivity data becomes available as more sensors are provided in the ingestible device 10, 300, 302. As described with reference to Figures 10A-12C, the reflectivity data can increase the accuracy with which the location of the ingestible device 10, 300, 302 within the body can be identified.

5A and 5B , shown therein are simplified diagrams of yet another exemplary ingestible device 304. FIG5A is a cross-sectional view 304A of ingestible device 304, and FIG5B is a three-dimensional side view 304B of ingestible device 304. Similar to ingestible device 300, ingestible device 304 includes an axial sensing sub-unit 42 having one axial sensor 342. However, unlike ingestible devices 300 and 302, the radial sensing sub-unit 32 of ingestible device 304 includes four radial sensors 332, 334, 336, and 338.

As described above, the radial sensors 332, 334, 336, and 338 are typically positioned so that they are spaced at least 60 degrees apart along the circumference of the radial wall 14. In the ingestible device 304, the radial sensors 332, 334, 336, and 338 can be positioned substantially equidistant from one another along the circumference of the radial wall 14. Note that, similar to the ingestible device 300, but unlike the ingestible device 302, the ingestible device 304 has a single axial sensor 342 near the first end portion 16a. In certain embodiments, the ingestible device (e.g., ingestible devices 300, 304) can have a sampling chamber located proximal to the second end portion 16b, the sampling chamber being substantially opposite to the location of the axial sensor 342. This embodiment is shown in Figures 14A, 14B, and 25. In certain embodiments, the ingestible device (e.g., ingestible devices 700, 2500) can have a chamber for storing a substance that is delivered to the gastrointestinal tract. These embodiments are shown in Figures 14A-14B and 25.

6A and 6B , shown therein are simplified diagrams of yet another exemplary ingestible device 306. FIG6A is a cross-sectional view 306A of the ingestible device 306, and FIG6B is a three-dimensional side view 306B of the ingestible device 306. The ingestible device 306 includes an axial sensing sub-unit 42 having two axial sensors 342 and 344, similar to the ingestible device 302 of FIG4A and FIG4B , and a radial sensing sub-unit 32 having four radial sensors 332, 334, 336, and 338, similar to the ingestible device 304 of FIG5A and FIG5B .

Referring now to FIG8A , shown therein is a cross-sectional view of yet another exemplary embodiment of an ingestible device 308. For ease of illustration, the axial sensing subunit 42 of the ingestible device 308 is not shown in FIG8A . The radial sensing subunit 32 includes three radial sensors 352, 354, and 356. In the ingestible device 308, the illuminators and detectors of each of the respective radial sensors 352, 354, and 356 are separated from each other by approximately 60 degrees. In this configuration, each of the radial illuminators 352i, 354i, and 356i has a respective illumination area 362i, 364i, and 366i that is approximately 120 degrees relative to the circumference of the radial wall 14. Similarly, each of the radial detectors 352d, 354d, and 356d has a respective detection area 362d, 364d, and 366d that is approximately 120 degrees relative to the circumference of the radial wall 14.

The separation between radial sensors 352, 354, and 356 can help minimize internal reflections. For example, when radial sensors 352, 354, and 356 in an ingestible device 308 are approximately 60 degrees apart from one another, radial sensors 352, 354, and 356 are approximately equidistant from one another along the circumference of the ingestible device 308 and are also separated from one another by a maximum distance. As a result, internal reflections at the interface of the housing 12 can be minimized.

8B and 8C illustrate exemplary operations of radial sensors 352, 354, and 356 in different environments. FIG8B illustrates, at 402A, ingestible device 308 being transported through the small intestine 454. Due to the tubular structure of the small intestine 454, the walls of the small intestine 454 tightly surround the ingestible device 308. FIG8C illustrates, at 402B, ingestible device 308 being transported through a larger space, such as the stomach 452. By physically separating radial illuminators 352i, 354i, and 356i and radial detectors 352d, 354d, and 356d in the manner shown in FIG8A, more variable reflectivity can be detected as shown in FIG8B and FIG8C.

For the ingestible devices 10, 300, 302, 304, 306, and 308 described herein, the axial sensing sub-unit 42 may include one or more axial sensors. At least one of the axial sensors may have an infrared light emitting diode (IR-LED) as an illuminator and a detector sensitive to illumination in the infrared spectrum. The radial sensing sub-unit 32 may also include one or more radial sensors. In some embodiments, the radial sensor may include a yellow-green LED emitting light having a wavelength of approximately 571 nm as an illuminator. In some embodiments, the radial sensor may include a green LED emitting light having a wavelength of approximately 517 nm and a red LED emitting light having a wavelength of approximately 632 nm. In some embodiments, the radial sensor may include an RGB LED package capable of emitting illumination at multiple different wavelengths.

When the radial sensor includes an RGB LED package, the ingestible device 10 can emit different wavelengths sequentially. Some tissues and fluids may have different absorption rates for different wavelengths of illumination. When using RGB LEDs, a wider range of reflectance data can be collected and analyzed.

For example, an RGB LED package may transmit red illumination having a wavelength at approximately 632 nm and detect the reflectivity caused by the red illumination. The RGB LED package may then transmit green illumination having a wavelength at approximately 518 nm and detect the reflectivity caused by the green illumination. The RGB LED package may then transmit blue illumination having a wavelength at approximately 465 nm and detect the reflectivity caused by the blue illumination. In order to determine the corresponding position of the ingestible device 10 based on the reflectivity data collected by the RGB LED package at various frequencies, the microcontroller 110 and/or the external processing module may compare each reflectivity data series with each other. It may be possible to disregard one or more portions of the reflectivity data series at a particular wavelength. Such an embodiment is shown in Figures 19 to 24, where the embodiment determines the position of the device by comparing reflectivity data from different wavelengths.

The detected reflectivity from each of the different types of illumination may be stored in the memory subunit 140 for subsequent processing by the microcontroller 110. Additionally, in certain embodiments, the processing may be performed by an external processing module.

In some embodiments, the axial and radial sensors may include collimated light sources. The collimated light sources may orient the reflected light to maximize reflectivity from certain external environments, such as circular anatomical structures. For example, illumination may be provided by a collimated light source, which may be provided using LED binning or supplemental lenses, or by a combination of collimated and non-collimated light sources.

In some embodiments, after the sensing sub-unit 130 of the various ingestible devices 10, 300, 302, 304, and 306 described herein collects reflectivity data, the communication sub-unit 120 can transmit the detected radial and axial reflectivity data to an external processing module. In some embodiments, a device processing module (not shown) is provided in the ingestible device 10, 300, 302, 304, and 306, and the reflectivity data can be provided to the device processing module for processing. The processing module, regardless of which type it is, can then identify the location of the corresponding ingestible device 10, 300, 302, 304, and 306 according to the methods described herein. In some embodiments, the microcontroller 110 can function as the processing module.

As described above, the processing module can be the microcontroller 110 disposed on the PCB 30 or an external processing module. When the detected data is provided to the external processing module for analysis, the communication sub-unit 120 can store the detected data in the memory sub-unit 140 and subsequently provide the detected data to the external processing module (e.g., after the ingestible device 10, 300, 302, 304, and 306 is removed from the body), or the communication sub-unit 120 can provide the detected data in real time using a wireless communication component, such as a radio frequency (RF) transmitter. However, it should be noted that some or all of the processing for determining the location of the device can be performed by the microcontroller 110 within the device.

As described above, the reflectivity data collected by the sensing sub-unit 130 can be used to infer the in vivo location of the ingestible device 10. As described with reference to Figures 9 to 12C, the axial reflectivity data and the radial reflectivity data can be used to identify different organs and/or delivery points. For example, the levels of axial reflectivity and radial reflectivity can indicate the type of external environment.

Furthermore, different materials can have different refractive indices, and thus the resulting absorption characteristics can vary. For example, fluids tend to have lower refractive indices than tissues. Depending on the type of organ, different materials may be present. For example, in the stomach, some liquid and food particles may be present. On the other hand, in the small intestine, limited liquid is present, but bubbles or gas may be present. Based on the reflectivity data, the processing module can determine certain characteristics of the environment in which the reflectivity data was detected.

9A , which is a flow chart of an exemplary method 500 or another embodiment described herein for operation of ingestible devices 10 , 300 , 302 , 304 , 306 , and 308 . To illustrate the operation of ingestible devices 10 , 300 , 302 , 304 , 306 , and 308 , reference is also made to FIGs. 10A through 12C .

At step 510, any of the ingestible devices described herein may be provided, such as 10, 300, 302, 304, 306, and 308. As described above, the sensing sub-unit 130 may transmit illumination and collect reflectance data resulting from the interaction of the illumination with the external environment.

Ingestible devices 10, 300, 302, 304, 306, and 308 can be ingested by an individual and can then be transported through the individual's body. Exemplary transport of each of ingestible devices 300, 302, 304, and 306 within a portion of the GI tract is shown in Figures 10A-12C.

At step 520, the sensing sub-unit 130 is operated to collect a series of reflectance data as the ingestible devices 10, 300, 302, 304, 306 and 308 are transported through the body.

The reflectivity data series may include an axial reflectivity data series and a radial reflectivity data series. Each of the axial reflectivity data series and the radial reflectivity data series may include one or more reflectivity values that indicate the respective axial reflectivity and radial reflectivity detected by the sensing sub-unit 130 during at least a portion of the transport. In some embodiments, the processing module may receive the reflectivity data series in real time and operate to identify the in vivo location in real time, and thus the processing module will only have access to a portion of the reflectivity data series. In some embodiments, the processing module may receive the reflectivity data after the ingestible device 10, 300, 302, 304, 306, and 308 has exited the body, and thus the complete reflectivity data series is available to the processing module.

10A-10C generally illustrate the transit of the ingestible device 300 through the stomach 452 , through the small intestine 454 , and then through the large intestine 456 .

As shown in diagram 450A, the stomach 452 is a relatively large space. Therefore, the ingestible device 300 can be moved along all axes. The movement of the ingestible device 300 can cause a higher deviation in the reflectance data series. Furthermore, the contents of the stomach 452 can include not only relatively clear liquids but also particulates if the individual has not fasted or has not fasted sufficiently before ingesting the ingestible device 300. Therefore, some reflectance data can be distorted by the presence of particulates.

In the example of FIG10A , the ingestible device 300 rotates several times as it transits through the stomach 452. It will be understood that the path and orientation of the ingestible device 300 are merely examples, and other paths and orientations are possible. At position "I," both the axial sensor 342 and the radial sensor 332 face the wall of the stomach 452, but at different distances. The resulting reflectivity detected by the axial sensor 342 and the radial sensor 332 may vary due to the different amounts of absorption caused by the different distances. The axial and radial reflectivity may be caused by the interaction of the wall of the stomach 452 with the particles 414 within the stomach 452. The axial sensor 342 may also detect reflectivity caused by the illumination generated by the radial sensor 332, and vice versa. The axial and radial reflectivity values may vary depending on the contents that may be present in the stomach 452. If the individual has been sufficiently fasting, there may be fewer particles 414 in the stomach 452, and therefore, the resulting reflectivity values may be lower.

At position "II," the axial sensor 342 is in closer proximity to the wall of the stomach 452 than at position "I." The axial sensor 342 will detect higher reflectivity values from the wall of the stomach due to its close proximity to the wall of the stomach 452. The radial sensor 332 does not directly face the wall of the stomach 452. However, because the radial sensor 332 is exposed to the contents of the stomach 452, the radial sensor 332 will detect reflectivity caused by any particles 414 present within the stomach 452.

The axial and radial reflectivities detected by the axial sensor 342 and the radial sensor 332 at position "III" are similar to the reflectivities detected at position "I." The values may vary due to different absorption amounts of the contents of the stomach 452.

However, at position "IV," the ingestible device 300 begins transiting through the pylorus, which is a significantly narrower structure compared to the stomach 452. As shown in FIG10A , the axial sensor 342 faces the small intestine 454 and, therefore, will continue to detect reflectivity caused by contents that will be present in the small intestine 454. However, the radial sensor 332 is in close contact with the pyloric wall and will detect higher reflectivity values caused by illumination of the pyloric wall. Due to the close contact between the pyloric wall and the radial sensor 332, the axial sensor 342 will detect very little, if any, reflectivity caused by the illumination transmitted by the radial sensor 332.

10B illustrates the delivery of the ingestible device 300 through the small intestine 454. As described above, the small intestine 454 has a tubular structure, and therefore, the ingestible device 300 is limited to longitudinal and rotational movement along its longitudinal axis. Furthermore, the small intestine 454 typically contains limited liquid, but may contain a moist mucus layer and bubbles or gas.

The axial and radial reflectivities detected by the ingestible device 300 at positions "V" and "VI" are similar to the reflectivities detected at position "IV". The axial sensor 342 faces one end of the small intestine 454 and will detect reflectivities caused by particles 414 (if present) or bends in the small intestine 454. However, the radial sensor 332 is in close contact with the wall of the small intestine 454 and will detect higher reflectivity values caused by illumination of the wall of the small intestine 454. Due to the close contact between the wall of the small intestine 454 and the radial sensor 332, the axial sensor 342 will detect very little, if any, reflectivity caused by the illumination transmitted by the radial sensor 332.

After the ingestible device 300 is transported through the small intestine 454, the ingestible device 300 enters the large intestine 456. Typically, the large intestine 456 is characterized by having opaque brown contents due to the presence of fecal matter. The opaque contents may include liquids and/or solids. Depending on the type of illumination being generated, the reflectivity detected at positions "VII", "VIII", and "IX" will change. For example, it is possible that when the illumination is within the visible spectrum (as shown in Figure 7A with respect to radial sensor 332), the reflectivity detected at positions "VII", "VIII", and "IX" may be primarily internal reflectivity. When the illumination is IR illumination or green illumination, the reflectivity detected at positions "VII", "VIII", and "IX" may be associated with fairly high values due to the brown contents.

11A-11C illustrate the transit of ingestible device 302 through stomach 452, through small intestine 454, and then through large intestine 456. As shown in Figures 4A and 4B, ingestible device 302 includes two radial sensors 332 and 334 and two axial sensors 342 and 344. Thus, additional reflectivity values can be detected.

11A , the reflectance values detected by sensors 332, 334, 342, and 344 in ingestible device 302 at position “I” are similar to the reflectance values detected by sensors 332 and 342 in ingestible device 300. Axial sensors 342, 344 and radial sensors 332, 334 are generally exposed to the contents, if any, within stomach 452.

At position "II," first axial sensor 342 detects a first axial reflectivity that is different from a second axial reflectivity detected by second axial sensor 344. First axial sensor 342 is in close proximity to the wall of stomach 452, while second axial sensor 344 is farther from the wall of stomach 452. Thus, first axial sensor 342 will detect a higher reflectivity value due to its proximity to the stomach wall, but second axial sensor 344 will detect a reflectivity value that depends solely on the type of contents present in stomach 452. Based on a comparison of the greatly varying first and second axial reflectivities, the processing module can determine that ingestible device 302 has not yet reached small intestine 454.

At position "III," second radial sensor 334 will detect a higher reflectance value due to its proximity to the wall of stomach 452. However, first radial sensor 332 detects a reflectance value that varies with the amount of microparticles 414, as described with reference to FIG10A. Again, the processing module can determine that ingestible device 304 has not yet reached small intestine 454.

As the ingestible device 302 moves into the pylorus, the first radial sensor 332 and the second radial sensor 334 begin to detect higher reflectivity values due to close contact with the pyloric wall. The processing module can determine from the radial reflectivity values that a transition is occurring. The reflectivity values detected by the first axial sensor 342 and the second axial sensor 344 will continue to depend on the contents of the small intestine 454 and the stomach 452, respectively, due to their orientation.

11B illustrates the transit of ingestible device 302 through small intestine 454. The radial reflectivity values detected by ingestible device 302 will generally be similar to the radial reflectivity values detected by ingestible device 300 in FIG 10B due to the close proximity of radial sensors 332 and 334 to the wall of small intestine 454. The axial reflectivity values detected by axial sensors 342 and 344 will again vary depending on the contents that may be present in small intestine 454.

As described above, the large intestine 456 is characterized by having opaque brown contents. Thus, the reflectance detected at positions "VII," "VIII," and "IX" (an example of which is shown in FIG11C ) as the ingestible device 302 travels through the large intestine 456 can be primarily internal reflectance when the illumination is within the visible spectrum, and can include higher reflectance values due to the brown color when the illumination is IR or green.

12A-12C for ingestible device 304. Ingestible device 304 includes four radial sensors 332, 334, 336, and 338 (as shown in FIG5A and FIG5B) and an axial sensor 342.

The axial reflectivity values detected in the examples shown in Figures 12A to 12C are generally similar to the axial reflectivity values detected in the examples shown in Figures 10A to 10C. Therefore, the axial reflectivity values will not be described again with reference to Figures 12A to 12C. It is possible that in certain locations within the GI tract, the axial sensor 342 can detect a greater amount of reflectivity caused by the illumination generated by one of the radial sensors 332, 334, 336, and 338.

In FIG12A , the radial reflectivity values detected by radial sensors 332, 334, 336, and 338 at positions “I” and “II” will generally be similar to the radial reflectivity values detected by ingestible devices 300 and 302 in FIG10A and FIG11A , respectively. The radial reflectivity values detected by radial sensors 336 and 338 will vary depending on the width of stomach 452. At position “III,” the radial reflectivity values detected by radial sensors 336 and 338 will be similar to the radial reflectivity detected by radial sensor 332. Therefore, from the radial reflectivity values collected at positions “I,” “II,” and “III,” the processing module can determine that ingestible device 304 has not yet entered the small intestine 454 because the radial reflectivity data from the various radial sensors 332, 334, 336, and 338 may be inconsistent values due to their dependence on the contents of stomach 452 and its changing direction.

Similar to the transit of the ingestible devices 300 and 302 shown in Figures 10A and 11A, the radial reflectance values collected at position "IV" will also indicate that pyloric transit is occurring. In the example shown in Figure 12, because four different radial sensors 332, 334, 336, and 338 are in the ingestible device 304, a larger number of reflectance values are provided, and therefore, the processing module can more easily determine that transit to the small intestine 454 is occurring. Similarly, transit of the ingestible device 304 in Figure 12B through the small intestine 454 produces radial reflectance values similar to the configuration of the sensing subunit 130 of Figures 10B and 11B. However, as described above, the ingestible device 304 provides a larger number of reflectance values and, therefore, provides more reliable position detection.

Finally, as described above, transit of the ingestible device 304 through the large intestine 456 can result in primarily internal reflectivity when the illumination is within the visible spectrum due to the presence of primarily opaque contents in the large intestine 456, and can result in higher reflectivity values due to the brown color when the illumination is IR illumination or green illumination.

In some embodiments, the sensing subunit 130 may include a temperature sensor. The temperature sensor may be operable to collect a series of temperature data as the ingestible device 10 is transported through the body. The temperature sensor may operate while the sensors 32, 42 are in operation or may operate in response to a trigger provided by the microcontroller 110 or by an external device (e.g., a base station) via the communication subunit 120. In some embodiments, temperature may be used to determine when the ingestible device has entered or exited the gastrointestinal tract. For example, as the ingestible device enters the stomach from an environment external to the body, the temperature measured by the ingestible device 10 may reflect a value close to body temperature. Similarly, as the ingestible device naturally exits the body, the temperature measured by the ingestible device 10 may change to ambient room temperature.

In certain embodiments, the temperature value can be used to determine the in vivo location of the ingestible device 10. The temperature value in the stomach 452 can change due to the liquid and/or food that may have been ingested. For example, a large decrease in the temperature value can generally indicate that the ingestible device 10 is still within the stomach 452.

9A , at step 530, the processing module can determine the quality of the environment outside the ingestible device 10 using the reflectance data series collected by the sensing sub-unit 130. The reflectance data series will include an axial reflectance data series including axial reflectance values and a radial reflectance data series including radial reflectance values. Exemplary reflectance data series are described with reference to FIG13A through FIG13C .

Different segments of the GI tract are generally associated with different characteristics. The quality of the environment within the stomach 452 is generally inconsistent because the environment varies depending on the presence or absence of particles 414. The larger space in the stomach 452 also allows for constant speed movement of particles 414 and the ingestible device 10, which further increases the variability of the environment of the stomach 452. On the other hand, the small intestine 454 is a narrower space and typically includes a consistent type of contents. Therefore, the small intestine 454 can be associated with a more homogeneous quality. Similar to the stomach 452, the large intestine 456 is a larger space than the small intestine 454 and therefore allows for more variable speed movement of its contents and the ingestible device 10.

FIG13A is a plot 600A illustrating a reflectance data series collected by the ingestible device 300 of FIG3A during transit through a subject's GI tract. The y-axis of the plot 600A is configured as raw ADC values representing reflectance values, and the x-axis of the plot 600A is configured as time (hours). The plot 600A illustrates a radial reflectance data series 602A collected by the radial sensor 332 and an axial reflectance data series 604A collected by the axial sensor 342.

The radial reflectivity data series 602A is particularly aggressive between hours 0 and 3, or during the transit period 610A. As described with reference to FIG10A, the ingestible device 300 may be transported through the stomach 452 during the transit period 610A, as the stomach 452 provides a large space for movement of the ingestible device 300, and thus the resulting reflectivity data series may vary significantly.

At approximately 3 hours, or at transport point 620A, the values of the reflectivity data series decrease. Between 3 hours and about 7 hours, or during transport period 612A, the reflectivity data series appears to be relatively stable. The reflectivity values at transport point 620A decrease and are relatively consistent thereafter until transport point 622A, which generally indicates transit within the small intestine 454.

The transit time through the small intestine 454 of a healthy adult is approximately four hours. Furthermore, as described with reference to FIG10B , the reflectance data series collected by the ingestible device 300 increases in stability as the ingestible device 300 transits through the pylorus and into the small intestine 454. In particular, due to the close proximity of the ingestible device 300 to the wall of the small intestine 454, the radial reflectance data series 602A may include consistently higher reflectance values as the ingestible device 300 transits through the small intestine 454.

Transport point 622A is approximately 7 hours after ingestible device 300 enters the GI tract. As shown in plot 600A, a substantial peak occurs at transport point 622A, and the reflectance data series thereafter continues at approximately increasing values during transport period 614A. During transport of ingestible device 300 through large intestine 456, as described with reference to FIG. 10C , since the contents of large intestine 456 are primarily opaque brown, axial sensor 342 and radial sensor 332 may detect primarily internal reflectance when illumination is within the visible range. Therefore, transport point 622A may indicate transport into large intestine 456.

13B is another plot 600B illustrating a reflectance data series collected by the ingestible device 300 of FIG 3A during another transit through the subject's GI tract. Plot 600B illustrates a radial reflectance data series 602B collected by the radial sensor 332 and an axial reflectance data series 604B collected by the axial sensor 342.

Similar to the reflectivity data series shown in plot 600A, plot 600B shows a transit point 620B between the stomach 452 and the small intestine 454, and a transit point 622B between the small intestine 454 and the large intestine 456. The transit period 612B through the small intestine 454 is approximately four hours, which is typical for a healthy adult. However, the transit period 610B through the stomach 452 is substantially longer than the transit period 610A. The variation between transit periods 610A and 610B may depend on various factors, such as, but not limited to, whether the individual has adequately fasted prior to ingestion of the device 300 and other possible events.

13C shows yet another plot 600C illustrating a reflectance data series collected by the ingestible device 300 of FIG 3A during yet another transit through the subject's GI tract. Plot 600C shows a radial reflectance data series 602C collected by the radial sensor 332 and an axial reflectance data series 604C collected by the axial sensor 342. Unlike plots 600A and 600B, plot 600C also includes a temperature data series 606.

As shown, the temperature in temperature data series 606 increases slightly at approximately 2.5 hours (at transport point 620C) and is maintained at the elevated temperature for most of transport periods 612C and 614C. The temperature increase at transport point 620C may indicate transport from stomach 452 to small intestine 454.

The reflectivity data series shown in exemplary plots 600A to 600C are provided as raw ADC values. As shown in FIG6A to FIG6C , it is possible for the processing module to generally identify delivery points 620, 622 within the GI tract based on the raw ADC values. In certain embodiments, when determining the quality of the environment external to the ingestible device 10, the processing module may analyze the raw ADC values to infer the in vivo location of the ingestible device 10. An exemplary method 550 for determining the quality of the environment external to the ingestible device 10 is described with reference to FIG9B .

It will be understood that the steps and descriptions of the flowchart of the present disclosure, including FIG. 9B , are illustrative only. Any of the steps and descriptions of the flowchart, including FIG. 9B , may be modified, omitted, rearranged, performed in turn or in parallel, two or more of the steps may be combined, or any additional steps may be added without departing from the scope of the present disclosure. For example, in some embodiments, the ingestible device may calculate the standard deviation and the mean simultaneously to speed up the overall calculation time. Furthermore, it should be noted that the steps and descriptions of FIG. 9B may be combined with any other systems, devices, or methods described herein, and any of the ingestible devices or systems discussed herein may be used to perform one or more of the steps in FIG. 9B .

To infer the in vivo location of the ingestible device 10 , at step 560 , the processing module may determine a standard deviation for each of the axial reflectance data series 604 and the radial reflectance data series 602 .

Typically, the axial standard deviation value and the radial standard deviation value are higher due to the varying environment of the stomach 452. The axial standard deviation value and the radial standard deviation value decrease as the ingestible device 10 transits through the pylorus and into the small intestine 454 due to the more homogeneous environment of the small intestine 454. To identify the transit point 620 between the stomach 452 and the small intestine 454, the processing module may determine whether each of the axial standard deviation value and the radial standard deviation value satisfies a deviation threshold. When each of the axial standard deviation value and the radial standard deviation value is equal to or less than the deviation threshold, each of the axial standard deviation value and the radial standard deviation value may satisfy the deviation threshold.

The deviation threshold can include different values for the axial reflectance data series and the radial reflectance data series or the same value for the axial reflectance data series and the radial reflectance data series. The deviation threshold is a value that can be used to indicate that the standard deviation of the corresponding portion of the data series has reached a level that is representative of the environment of the small intestine 454. When the ingestible device 10 is first activated, the deviation threshold can be varied based on various factors, for example, to account for individual characteristics or requirements. The deviation threshold can be predetermined and/or can be varied during use based on reflectance data collected by the sensing sub-unit 130 over a predetermined period of time.

In some embodiments, the deviation threshold can be adjusted during use based on certain aspects of the reflectivity data. For example, an average can be determined for reflectivity data collected during a predetermined time period. When the determined average indicates that the reflectivity data values are generally lower than a desired value, the processing module can correspondingly decrease the deviation threshold to accommodate the lower reflectivity data values. Similarly, when the determined average indicates that the reflectivity data values are generally higher than a desired value, the processing module can correspondingly increase the deviation threshold to accommodate the higher reflectivity data values.

When the processing module determines at step 562 that both the axial standard deviation value and the radial standard deviation value satisfy the deviation threshold, the processing module may indicate that the quality of the external environment of the ingestible device 10 is homogenous (at step 582), and thus the ingestible device 10 may have reached the small intestine 454. Otherwise, the processing module may indicate that it is unlikely that the ingestible device 10 is in a homogenous environment (at 580). In certain embodiments, at step 564, the processing module may further verify the determination at step 562 and generate an average value for the portion of the reflectance data series at step 566 before determining the quality of the external environment to further verify the determination at step 562.

In some embodiments, a comparison between the axial standard deviation value and the radial standard deviation value may be performed. To facilitate the comparison, the processing module may adjust the axial standard deviation value and the radial standard deviation value using an average of the corresponding reflectivity data values.

While determining that the axial standard deviation value and the radial standard deviation value meet the deviation threshold may indicate delivery into the small intestine 454 (at step 582), there may be applications in which the accuracy of the position of the ingestible device 10 may be significant. For example, when the ingestible device 10 is operated specifically to collect samples from the small intestine 454, the ingestible device 10 should be within the small intestine 454 prior to any sample collection, particularly because there is limited space within the ingestible device 10 for receiving the sample.

To verify the in vivo location, the processing module may compare a portion of the axial reflectance data series with a portion of the radial reflectance data series. For example, at step 566, an average may be generated for the portion of the axial reflectance data series to obtain an axial average, and another average may be generated for the radial reflectance data series to obtain a radial average. As described with reference to at least Figures 10B and 13A, radial reflectance values typically decrease significantly as the ingestible device is transported through the small intestine 454 due to greater light absorption compared to axial reflectance values. Therefore, when the ingestible device 10 is within the small intestine 454, the radial average should be less than the axial average. In some embodiments, when the radial average is determined to be less than the axial average by a minimum difference at step 568, the processing module may indicate that the quality of the external environment is homogenous (at step 582). Otherwise, the processing module may indicate that the ingestible device 10 is unlikely to be in a homogenous environment (at 580).

Similar to the deviation threshold, the minimum difference value can vary based on various factors, such as certain characteristics or requirements of the presenting individual, when the ingestible device 10 is first activated. The minimum difference value can be predetermined and/or can be changed during use based on data collected during transportation.

In some embodiments, the processing module may vary the minimum difference based on the sum of the collected reflectivity data and/or based on the absolute value of the sum of the axial reflectivity data series and/or the radial reflectivity data series.

The portion used to compare the selected reflectivity values may also vary. In some embodiments, after initially detecting the transport point 620 based on the standard deviation value, the processing module may select multiple reflectivity values after the transport point 620. In some embodiments, the multiple reflectivity values may be adjusted during use based on data collected during transport.

In some embodiments, the plurality of reflectivity values can be adjusted based on a total axial standard deviation (which is the sum of the axial standard deviation values) and a total radial standard deviation (which is the sum of the radial standard deviation values). For example, when both the total axial standard deviation and the radial standard deviation are less than a detectable deviation threshold, the plurality of reflectivity values can be reduced, as the total axial standard deviation and the radial standard deviation can be considered negligible when below the detectable deviation threshold. The detectable deviation threshold generally indicates a minimum level of deviation in the reflectivity values that can alter the determination of the in vivo location for the ingestible device 10.

13C , the sensing sub-unit 130 may further include a temperature sensor for collecting temperature values. In some embodiments, the temperature sensor may be provided at the microcontroller 110 of the ingestible device 10 .

The collected temperature values may be used by the processing module to further verify the in vivo location at steps 570 and 572. Because the temperature within the stomach 452 is more variable than the temperature within the small intestine 454, any significant change in temperature may indicate that the ingestible device 10 has not entered the small intestine 454. For example, the processing module may indicate a temperature change that exceeds a temperature threshold, as determined at step 572, which may be a maximum allowable change in value, as indicating that the environment is inhomogeneous (at step 580) and that the ingestible device 10 is not in the small intestine 454. The temperature values may also indicate entry into the body (e.g., the temperature may increase upon entry into the body) and/or exit from the body (e.g., the temperature may decrease upon exit from the body).

In some embodiments, the temperature value may be used in temperature correction for the circadian clock to improve time accuracy. The temperature value may be used using a lookup table or formula to determine whether the time recorded at each wake cycle of the microcontroller 110 should be corrected due to varying temperatures during use of the ingestible device 10.

In some embodiments, when not in use (e.g., outside the body), the temperature sensor can detect a temperature value from the surrounding environment to indicate the storage condition of the ingestible device 10.

Referring again to FIG. 9A , at step 540 , the processing module may identify the location of the ingestible device 10 based on the quality of the external environment determined at step 530 .

Different segments of the GI tract are associated with different characteristics. Thus, the processing module can use data collected from the external environment of the ingestible device 10 described herein to identify an in vivo location. For example, the small intestine 454 is typically associated with a more homogeneous environment due to its restricted structure and consistent contents. Therefore, when the quality of the external environment is determined to be homogeneous, the processing module can indicate that the in vivo location of the ingestible device 10 is likely the small intestine 454.

With the position detection methods described herein, such as method 500, for example, the in vivo location of the ingestible device 10 can be identified with a higher degree of accuracy. As a result, the ingestible device 10 can have greater control over when certain tasks are performed.

It will be understood that the steps and descriptions of the flowchart of the present disclosure, including FIG. 9A , are illustrative only. Any of the steps and descriptions of the flowchart, including FIG. 9A , may be modified, omitted, rearranged, performed in turn or in parallel, two or more of the steps may be combined, or any additional steps may be added without departing from the scope of the present disclosure. For example, in some embodiments, the ingestible device may begin to determine the quality of the environment using existing data while simultaneously operating the axial sensing subunit and the radial sensing subunit to collect new data. Furthermore, it should be noted that the steps and descriptions of FIG. 9A may be combined with any other systems, devices, or methods described herein, and any of the ingestible devices or systems discussed herein may be used to perform one or more of the steps in FIG. 9A .

As described above, any of the ingestible devices described herein, such as ingestible devices 10, 300, 302, 304, 306, and 308, can be used for different tasks. In some cases, ingestible device 10 can be used to collect a usable sample (e.g., a 100 μL sized sample) from the contents of the GI tract and maintain each sample isolated from each other until the sample is extracted. In some embodiments, ingestible device 10 can be used to release a substance into the body in a controlled manner. In this case, at least one chamber in ingestible device 10 can be loaded with a substance in liquid form or dry powder form prior to introduction of ingestible device 10 into the body.

In certain embodiments, an ingestible device for identifying a location within the GI tract of the body (e.g., ingestible device 700) contains a medicament, including a therapeutic agent, and a device for controllably administering the medicament for treating a disease. In certain aspects, the device for controllably administering can include a control device for distributing the medicament to a specific area of the GI tract based on the location of the device in the GI tract as determined by the methods provided herein. For example, in the case of ileocolitis, distributing the medicament at the site of inflammation, such as the ileum, the most common form of Crohn's disease, will facilitate administration to the inflamed diseased tissue while minimizing concentrations in the systemic circulation. As a result, the ingestible device for delivering the medicament can reduce potential side effects. Similar methods can be used to treat other GI diseases where local delivery provides a benefit. For example, treatment of gastrointestinal tumors or treatment of celiac disease can be effectively targeted.

In certain embodiments, an ingestible device (e.g., ingestible devices 10, 300, 302, 304, 306, and 700) for identifying locations within the body's GI tract collects data (e.g., transit times) about transit from one location to another in the GI tract. For example, the device can measure transit times through different regions of the GI tract, such as the stomach, small intestine, and large intestine. Such transit times can be used to detect pathological states of motility, such as gastroparesis and slow-transit constipation. By recognizing specific anatomical locations and by determining transit times as described herein, the device provides an accurate method for measuring whole intestinal transit time (WGTT), gastric emptying time (GET), small bowel transit time (SBTT), and colonic transit time (CTT). In certain embodiments, this results in a significant amount of additional knowledge, as compared to ingestible devices that rely on pH or imaging data to determine location.

In certain embodiments, the ingestible device 10 may be configured to collect a sample after releasing one or more substances into the body (in a predetermined order in the case of multiple agents), and the ingestible device 10 may then collect the resulting physical sample from the body. For example, substances that can inhibit enzymes and chemical processes may be released into the body prior to collecting the sample (e.g., to prevent potential degradation of the collected sample in order to obtain a "snap-shot" of the environment in which the sample was collected).

An exemplary ingestible device 700 is described with reference to Figures 14A, 14B, and 15, which is configured to independently implement the position detection method described herein and to carry a substance. As can be seen from Figures 14A, 14B, and 15, some components of the ingestible device 700 correspond to components of the ingestible device 10 (e.g., see Figures 1A, 1B, and 2A). Therefore, similar components in the ingestible devices 10 and 700 will not be described again.

Figures 14A and 14B show an exploded view 700A and a cross-sectional view 700B, respectively, of the ingestible device 700. The ingestible device 700 is configured in a similar manner to the ingestible device 10, but the ingestible device 700 is configured to store a substance (e.g., a sample, a reagent, a medicament, or a therapeutic agent). Similar to the ingestible device 10, the ingestible device 700 includes a battery 18 and a PCB 30. The PCB 30 has at least an axial sensing subunit 42 and a radial sensing subunit 32 embedded therein. The battery 18 and the PCB 30 are encapsulated by the first wall portion 14a and the first end portion 16a. However, unlike the ingestible device 10, the ingestible device 700 includes a motor 704 and a storage subunit 702, which are encapsulated by a second wall portion 714b and a second end portion 716b, which is configured to receive the end of the motor 704. The second wall portion 714b can also serve as a chamber enclosure.

The storage subunit 702 includes a chamber, such as 706, for storing a substance. The substance can be collected from the body as a sample during transport and/or released into the body during transport. In some cases, the substance can be loaded into the ingestible medical device 700 prior to use so that the substance can be released into the body during transport. An access port 718 is provided on the second wall portion 714b to accommodate the entry and exit of the substance into and out of the chamber 706. The second wall portion 714b can be referred to as a chamber enclosure.

The chambers 706 are generally long rectangular recesses along the length of the cylindrical storage subunit 702. However, it will be understood that the chambers 706 can take any shape, and the shape can vary depending on the intended application of the ingestible device 700. Each of the chambers 706 can be isolated from each other so that one or more discrete substances can be stored for sampling during operation or stored prior to use for release during operation. Typically, each of the chambers 706 is sized to store a usable sample size, such as a capacity of approximately 100 μL, for example.

Each chamber 706 has a corresponding chamber opening 708. The chamber openings 708 can span an arc of approximately 60°. Thus, an unrecessed area can be provided between each of the chamber openings 708 on the storage subunit 702 (e.g., each having a span of approximately 60°). In some embodiments, the chamber openings 708 and corresponding chambers 706 are unevenly distributed around the circumference of the storage subunit 702. For example, when it is not desired for the ingestible device 700 to pause between each collection or release of a substance, the chamber openings 708 and corresponding chambers 706 can be arranged closer together. In some embodiments, the chamber openings 708 can span arcs having different circumferential extents.

As described above, chamber 706 in storage subunit 702 can be used to store samples collected from the GI tract and/or to store substances for release into the GI tract. Accordingly, both chamber opening 708 and access port 718 are large enough to accommodate the movement of substances into or out of chamber 706 by peristaltic motion.

The operation of the storage subunit 702 is further explained with reference to FIG. 15 .

Similar to the ingestible device 10, a connecting wall portion 14c can connect the first wall portion 14a to the second wall portion 714b. The housing 712 is formed by the first end portion 16a, the second end portion 716b, and the radial wall 14, which is formed by the first wall portion 14a, the connecting wall portion 14c, and the second wall portion 714b. As shown in Figure 14B, the radial wall 714 extends from the first end portion 16a to the second end portion 716b.

Due to the storage sub-unit 702 and the motor 704, the axial sensing sub-unit 42 is limited to an axial sensor located proximal to the first end portion 16a. However, the radial sensing sub-unit 32 may include any number of radial sensors as described herein. For example, the ingestible device 700 may include the radial sensing sub-unit 32 configured in a manner similar to that shown in Figures 5A, 4A, and 8A.

Furthermore, the storage subunit 702 and the chamber enclosure 714b can be configured differently. For example, the storage subunit 702 can be rotated, and the chamber enclosure 714b can be fixed. Other embodiments of the storage subunit 702 and the chamber enclosure 714b can be used.

Figure 15 is a block diagram 750 of an exemplary embodiment of electrical components that may be used with the ingestible device 700 of Figure 14A.

The memory sub-unit 140, power supply 160, and sensing sub-unit 130 can operate in a manner similar to that used for both ingestible devices 10 and 700.

The communication subunit 720 in the ingestible device 700 includes the optical encoder 20 similar to the ingestible device 10, and the communication subunit 720 also includes an RF transceiver 722. The ingestible device 10 can also include an RF transceiver 722 for implementing wireless communication with an external processing module.

The RF transceiver 722 can be considered a peripheral device of the microcontroller 710. Thus, the microcontroller 710 can initiate RF communication by sending RF transceiver 722 data specifying the channel on which the RF transceiver 722 will transmit, as well as power, frequency, and other parameters for RF communication, along with data for the operation of the ingestible device 700.

In certain embodiments, the RF transceiver 722 in the ingestible device 700 can facilitate real-time telemetry during the collection and/or release of a substance. For example, the RF transceiver 722 can transmit data associated with the operation of the ingestible device 700 and/or the collected sample to a base station in real time.

The microcontroller 710 may be configured using similar processing as the microcontroller 110. However, the microcontroller 710 in the ingestible device 700 will be configured to handle additional functions, such as those provided by the motor control subunit 740 and the positioning subunit 730.

For most of the time that the ingestible device 700 is operating, the microcontroller 710 may be the only component drawing power from the power supply 160. When the microcontroller 710 is not in use, most of the other components can be powered down.

The positioning subunit 730 and the microcontroller 710 may operate together to determine the position of the access port 718 relative to each of the chamber openings 708. The positioning subunit 730 may include a magnetic sensor or sensors.

When a magnetic sensor is used to determine the location of the access port 718, an encoded magnet arrangement 734 is also included in the ingestible device 700. As a magnet in the encoded magnet arrangement 734 rotates past the magnetic sensor, the magnetic sensor senses the magnet and generates a corresponding positioning signal, which may be a quasi-sine wave or a square wave, depending on the particular embodiment.

The motor control subunit 740 includes a motor driver 742 and the motor 704. The motor driver 742 may be a dual full-bridge driver including a DPDT switch and a protection circuit including a resistor-diode combination in a single integrated form.

When motor 704 receives power, it rotates chamber enclosure 714b a distance corresponding to the power received. Because encoded magnet assembly 734 is embedded in chamber enclosure 714b, encoded magnet assembly 734 rotates along with chamber enclosure 714b. As the magnet rotates past the magnetic sensor, the magnetic sensor senses the changing magnetic induction intensity from the magnet and encodes this information in a positioning signal, which is then sent to microcontroller 710 via A/D converter 116.

Unlike the microcontroller 710, in certain aspects, the motor 704 can have a higher discharge capacity. For example, at a 3V operating voltage, a 6mm pager gear motor can draw 120mA of current when unloaded and 230mA of current when stalled. It will be understood that a 6mm motor is merely an example of a motor that can be used in the ingestible device 700, and other types of motors with similar operating characteristics and different sizes can be used.

The power source 160 may need to supply a higher energy density and discharge a higher current on demand (e.g., to discharge a higher level of current over a brief period of time). An example of such a power source may be a plurality of silver oxide batteries (e.g., two 30 mAh batteries, each of which operates at 1.55 V, for a total combined current of 3.1 V). Silver oxide chemistry provides a higher energy density and can discharge sufficient current on demand (e.g., 150 mColombs/second, with a maximum of 250 mColombs/second). The higher energy density of silver oxide chemistry also indicates that silver oxide batteries have a longer battery life, with a lower self-discharge rate of approximately 5%/yr. Batteries formed using silver oxide chemistry can also have a compact form factor and exist as standard button cell batteries. Other exemplary battery chemistries with higher energy density, longer life, and higher required discharge rates may include lithium polymer.

The motor 704 is coupled to the microcontroller 710 for receiving power from the power supply 160. The motor 704 can be coupled to the microcontroller 710 via a control circuit. The motor 704 can, in turn, rotate the chamber enclosure 714b around the storage subunit 702. Typically, the motor 704 is implemented so that it provides high torque without an external gear transmission. In some embodiments, the motor 704 can be a micro DC motor. In some embodiments, the DC motor can be brushless. For example, a micro DC motor with a 700:1 reduction planetary gear transmission (e.g., as manufactured by Precision Microdrive) can be used. The 700:1 reduction planetary gear transmission generally provides a proportional increase in torque and a decrease in revolutions per minute (RPM).

14B , two concentric layers are formed around the motor 704. To maximize space within the ingestible device 700, the storage subunit 702 and the chamber enclosure 714b are constructed to fit concentrically around the motor 704. The first layer around the motor 704 is the storage subunit 702, and the second layer around the motor 704 is the chamber enclosure 714b.

Referring now to FIG. 16 , shown therein is a flow chart of an exemplary method 800 of operating an ingestible device 700 .

At step 810, the ingestible device 700 is activated. The ingestible device 700 can be activated by activating the magnetic switch 162. For example, the ingestible device 700 can be removed from the magnetic field to switch the magnetic switch 162 to the 'ON' position. Current can then flow through an electrical pathway in the ingestible device 700 (e.g., a pathway on the PCB 30).

In response to the ingestible device 700 being activated, the microcontroller 710 can begin detecting and initializing peripheral components and/or devices. The microcontroller 710 can detect, for example, whether one or more peripheral devices are present on the bus via the general purpose I/O 112 by sending a series of requests to a specific address associated with the general purpose I/O 112. In response, any peripheral devices present then send an acknowledgment signal to the microcontroller 710. If the microcontroller 710 does not receive a response within a specified time frame, the microcontroller 710 operates as if the peripheral device is not present. The specified time frame can vary. An exemplary time frame can be 20 seconds. The microcontroller 710 then initializes the peripheral devices present. The initialization process can vary for different peripheral devices.

After the microcontroller 710 initializes the peripherals, the microcontroller 710 typically places the peripherals in a low-power state, or may even completely power down peripherals with non-volatile memory, in order to avoid unnecessary power consumption.

At step 820 , the microcontroller 710 receives operating instructions for the ingestible device 700 .

After initializing the peripheral device, the microcontroller 710 may poll the communication subunit 720, e.g., the RF transceiver 722, for an initiation signal from the base station. The initiation signal may typically be followed by operational instructions from the base station. The initiation signal and operational instructions may be provided wirelessly via IR or RF transmission, depending on the specific embodiment of the ingestible device 700.

The base station can include a cradle that acts as a peripheral device for an external computer and can communicate with the external computer through the external computer's COM port using the SPI protocol. In some embodiments, the base station includes a microcontroller and a transceiver, the microcontroller being, for example, a processing module for identifying the in vivo location of an ingestible device as described herein. The transceiver is selected to facilitate communication between the ingestible device 700 and the base station.

Referring now to Figures 17A-17C, different views of an exemplary embodiment of a base station 950 are shown.

The base station 950 includes a programming and charging base 952, a magnetized area 960 at a top surface 950t, and a universal serial bus (USB) connection port 962 at a front surface 950f. The magnetized area 960 can be used to trigger a magnetic switch 162. When the magnetic switch 162 is activated, the magnetic switch 162 can reset the microcontroller 110 so that the microcontroller 110 continues to activate the ingestible device 700. After being activated by the microcontroller 110, the ingestible device 700 can engage with the programming and charging base 952 to receive operating instructions. The operating instructions can be received via the USB connection port 962 or wirelessly.

In some embodiments, the base station 950 may also include a chamber engagement base for retrieving a sample from the ingestible device 700 or inserting a substance into the ingestible device 700.

In some embodiments, the base station 950 may include an LED to indicate the status of the programming and charging base 952 and certain commands received from the external computer. For example, when extracting a substance or inserting a substance into the ingestible device 700, the LED may be used to indicate an emergency stop and an override command from the computer.

The programming and charging base 952 may include one or more electrical contacts for connecting to the programming and charging connector on the PCB 30. The power supply 160 may also be charged through the electrical contacts on the programming and charging base 952. It will be appreciated that the number of electrical contacts may vary for different applications.

While a programming and charging base 952 is shown in FIG17A , it should be understood that in some embodiments, there may be a charging base for charging the ingestible device 700 and a separate programming component for programming the ingestible device. The programming component may be a radio transceiver or an infrared (IR) transceiver. For example, an IR transceiver may operate using modulated infrared light (e.g., in the wavelength range of 850 nm to 930 nm). The wireless transceiver may operate using the Zigbee ^™ protocol or the ANT ^™ protocol, depending on the specific type of transceiver at the base station 950.

The USB connection port 962 can be connected to an external computing device via a USB data cable. The external computing device can be a desktop computer, a laptop computer, a tablet computer, and the like. A graphical user interface can be provided via the external computing device to enable interaction with the ingestible device 700 by an administrator. Interaction can include various operations, such as data transfer, control communication, and other similar functions.

Operational instructions may include data identifying an operating mode (e.g., a task type, such as collecting a sample and/or releasing a substance), operating parameters (e.g., sampling time, sampling interval, error log, and sampling location), parameters for managing peripheral devices in the ingestible device 700, and operating parameters associated with performing a specific test or treatment procedure with respect to an individual ingesting the ingestible device 700.

18A-18C , shown therein are screenshots of exemplary embodiments of user interfaces 900, 932, and 942, respectively, for interacting with the ingestible device 700. It will be appreciated that similar interfaces 900, 932, and 942 may be used to interact with the ingestible devices 10, 300, 302, 304, 306, and 308, but may provide different functionality due to the ingestible devices 10, 300, 302, 304, 306, and 308 not including the storage sub-unit 702. For example, the user interface for interacting with the ingestible devices 10, 300, 302, 304, 306, and 308 may include additional controls for the sensing sub-unit 130 and may not necessarily include controls for the operation of the storage sub-unit 702.

18A illustrates a primary user interface 900 for configuring the ingestible device 700. As shown, the primary user interface 900 includes a status component 910, a communications component 920, a data retrieval component 922, a programming definition component 930, and a motor control component 940.

The status component 910 may display information corresponding to the operational status of the ingestible device 700. For example, the operational status may include the status of peripheral components on the ingestible device 700, the battery status 916 of the power source 160, and/or measurements 914 detected by the sensing sub-unit 130. The real-time in-vivo location 912 may also be displayed.

Using the communication component 920, the administrator can select a communication port and start connecting to the selected communication port. The administrator can also start retrieving data from the ingestible device 700 (e.g., from the memory storage component 142) via the data retrieval component 922.

The programming definition component 930 may provide a program interface 932 shown in FIG18B. The program interface 932 may provide a sample acquisition control 934 for defining a sample acquisition algorithm and a data acquisition control 936 for defining a data acquisition algorithm. In the example shown in FIG18B, the sample acquisition control 934 includes three sample acquisition definitions 934(a), 934(b), and 934(c).

In the first sample collection definition 934(a), the ingestible device 700 collects a first sample sixty minutes after detecting entry into the stomach, and the ingestible device 700 exposes the chamber opening 708 for ten minutes. In the second sample collection definition 934(b), the ingestible device 700 collects a second sample sixty minutes after detecting entry into the small intestine 454 (duodenum), and the ingestible device 700 exposes the chamber opening 708 for ten minutes. In the third sample collection definition 934(c), it is shown that sampling has been prohibited.

In this example, the data collection control 936 indicates that reflectivity data is collected immediately after the ingestible device 700 is ingested. Reflectivity data can be recorded every 15 seconds instead of continuously. This helps reduce the amount of data collected and subsequently processed, which can also reduce the energy required from the battery 18 during operation.

Referring again to FIG18A , the motor control component 940 may provide a motor control interface 942 shown in FIG18C . The configuration of the chambers 706 may be shown in the motor control interface 942. In the example shown, the ingestible device 700 has three chambers, 706 ( a ) through 706 ( c ). Controls such as a motion type control 946 and a corresponding pulse duration control 944 may also be provided.

The microcontroller 710 may determine whether the operating instructions were successfully received. If so, the microcontroller 710 continues to program and initialize the ingestible device 700 according to the operating instructions at step 830. If not, the microcontroller 710 may request that the operating instructions be resent.

Referring again to FIG. 16 , at step 840 , the ingestible device 700 is ingested by an individual.

After being ingested, the microcontroller 710 can place the ingestible device 700 in a low-energy state (e.g., a sleep state) for a predetermined wait period. During this time, the RF transceiver 722 can be intermittently turned on to poll for new instructions from the base station 950 (e.g., new instructions overwriting previously received instructions) and/or transmit data to the base station 950. In some embodiments, the placement in the low-energy state can include disabling or deactivating the functionality of the device for a predetermined period of time. For example, turning off individual sensors, encoders, analog to digital converters, entire subunits (e.g., the communication subunit 120 (Figure 2A) or the sensing subunit 130 (Figure 2A)), and the like can conserve energy and avoid draining the battery 18. In some embodiments, the predetermined wait period can be a predetermined time period programmed into memory (e.g., the memory storage component 142). For example, this can be set as part of the manufacturing process or set as part of programming by the base station.

A predetermined waiting period can be provided as part of the operating instructions. For example, as indicated in data acquisition control 936 of FIG18C , the microcontroller 710 can initialize operation of the ingestible device 700 immediately after ingesting the ingestible device 700 or after a certain amount of time has passed since ingesting the ingestible device 700 (e.g., to allow the ingestible device 700 time to travel to a target location within the individual's body).

For example, once a predetermined waiting period has passed, or if no predetermined waiting period has occurred, the microcontroller 710 can activate the sensing sub-unit 130 to detect reflectivity from the external environment at step 850 to identify the in vivo location of the ingestible device 700 according to various methods described herein, such as method 500.

At step 860, the microcontroller 710 determines whether the ingestible device 700 has reached the target location, as identified, for example, in an operating instruction from the sample acquisition control 934. If the microcontroller 710 determines that the ingestible device 700 has not reached the target location, the microcontroller 710 returns to step 850.

In response to detecting that the ingestible device 700 has reached the target position, at step 870, the microcontroller 710 can initialize the operation of the ingestible device 700 according to the operating instructions.

For example, according to sample collection definition 934(a), the ingestible device 700 collects a sample after detecting entry into the stomach. Thus, in response to the processing module indicating entry into the stomach based on reflectivity data collected by the sensing sub-unit 130 according to the methods described herein, the microcontroller 710 begins collecting a first sample.

After the ingestible device 700 completes the tasks associated with the sample collection definition 934(a), the microcontroller 710 determines at step 880 whether all operational instructions have been completed.

If the operational instructions have not yet been completed, the microcontroller 710 returns to step 850. For example, after the ingestible device 700 collects the first sample, the microcontroller 710 may continue to collect the remaining samples according to the operational instructions. Regarding the second sample, in response to the processing module indicating that the small intestine 454 has been reached according to the sample collection definition 934(b) (at step 860), the microcontroller 710 will begin collecting the second sample. After the ingestible device 700 collects the second sample, the microcontroller 710 will return to step 850.

If the operating instructions have been completed or the ingestible device cannot continue its operation, the ingestible device 700 can be retrieved (at step 890). The microcontroller 710 can place all peripheral devices in a low-power state to save power.

After retrieval, the ingestible device 700 can be subjected to further analysis according to its programmed task. For example, if the ingestible device 700 is programmed to collect a sample from an individual, the ingestible device 700 can be retrieved so that the sample it collects can be further analyzed. Generally, the sample in the ingestible device 700 can be extracted by manual pipetting or another suitable technique, which can be automated, as known by those skilled in the art. The extracted sample can be analyzed using various techniques, such as, but not limited to, biochemical analysis, for example.

It will be understood that the steps and descriptions of the flowchart of the present disclosure, including FIG. 16 , are illustrative only. Any of the steps and descriptions of the flowchart, including FIG. 16 , may be modified, omitted, rearranged, performed in turn or in parallel, two or more of the steps may be combined, or any additional steps may be added without departing from the scope of the present disclosure. For example, the ingestible device may be provided with default programming during the manufacturing process, or operating instructions may be encoded onto the device prior to activation. Furthermore, it should be noted that the steps and descriptions of FIG. 16 may be combined with any other systems, devices, or methods described herein, and any of the ingestible devices or systems discussed herein may be used to perform one or more of the steps in FIG. 16 .

19 , shown therein is a view of another exemplary embodiment of an ingestible device 1900. Similar to other ingestible devices (e.g., ingestible devices 10, 300, 302, 304, 306, 700, and 2500), ingestible device 1900 can be used to identify a location within the gastrointestinal tract. Embodiments of ingestible device 1900 are configured to independently and autonomously determine whether a person is located in the stomach, in the small intestine, or in the large intestine by utilizing sensors that operate with light of different wavelengths. Additionally, ingestible device 1900 can distinguish whether a person is located within certain portions of the small or large intestine, such as the duodenum, jejunum, or cecum.

Ingestible device 1900 can have the same overall shape and construction as other ingestible devices discussed in this application (e.g., ingestible devices 10, 300, 302, 304, 306, 700, and 2500), and it will be apparent that the disclosure relating to ingestible device 1900 can be combined with the disclosure relating to any other ingestible device discussed in this application. For example, the individual types of sensor configurations, materials, device housings, electronics, functionality, and detection algorithms described with respect to ingestible devices 10, 300, 302, 304, 306, 700, and 2500 can be used in certain embodiments of ingestible device 1900.

For example, the ingestible device 1900 can have a housing that includes a first end portion 14a, a second end portion 14b, and a connecting wall portion 14c that is substantially similar to the ingestible device 10. The ingestible device 1900 can also utilize similar electrical systems or components as those discussed with respect to the ingestible device 10. The ingestible device 1900 employs a sensing array constructed from sensing subunits that include illuminators 1906a and 1906b and a detector 1904. Although not shown in their entirety in the accompanying drawings, the ingestible device 1900 has three sets of radial illuminators and detectors arranged around the circumference of the PCB 1902. In some embodiments, other numbers or configurations of sensing units may be used. The ingestible device 1900 can also have a top axial sensing subunit 42 at the axial end of the PCB 1902. In general, PCB 1902 can be made and constructed similarly to other circuits discussed in this application and utilize similar types of PCB segments as other devices (e.g., PCB segments 202 and 204), with slight variations in illuminator and detector locations. Although not visible, ingestible device 1900 can also include a bottom axial sensing sub-unit located on PCB segment 204 of PCB 1902, substantially opposite to the top axial sensing sub-unit.

Figure 20 is a simplified top and side view of an ingestible device showing exemplary illuminator or detector positions. Figure 20 can correspond to any number of ingestible devices, but for illustrative purposes, we will refer to ingestible device 1900. The ingestible device 1900 as shown features a sensor array, which is shown as including three radial detectors 2002a, 2002b, and 2002c, along with three radial illuminators 2004a, 2004b, and 2004c that produce illumination. A similar configuration of detectors and illuminators is shown in Figure 8A. Each radial illuminator and radial sensor is evenly spaced approximately 60 degrees apart along the circumference of the ingestible device 1900. This positioning has been found to reduce internal reflections from the illuminators due to the housing of the ingestible device 1900. However, in some embodiments, other arrangements of illuminators and detectors can be used to similar effect, for example, the arrangements described by ingestible devices 10, 300, 302, 304, and 306.

The radial illuminators 2004a, 2004b, and 2004c are capable of generating illumination at a plurality of different wavelengths, and in certain embodiments of the ingestible device 1900, they may be implemented using red-green-blue light emitting diode packages (RGB-LEDs). These types of RGB-LED packages are capable of transmitting red, blue, or green illumination. The radial illuminators 2004a, 2004b, and 2004c of the ingestible device 1900 are each configured to transmit a specific wavelength simultaneously, sending illumination from the device along a plurality of different radial directions. For example, when the ingestible device 1900 is configured to transmit red light, all three radial illuminators may transmit red light simultaneously. Based on the environment surrounding the ingestible device 1900, portions of the light may be reflected from the environment, and the resulting reflectivity may be detected by the radial sensors 2002a, 2002b, and 2002c.

Similar to the sensors discussed with respect to the ingestible device 10, the radial sensors 2002a, 2002b, and 2002c may include light detectors that convert received light into electrical signals. This signal may then be transmitted to an analog-to-digital converter (ADC), and the resulting digital signal may be manipulated by a processor or microcontroller (e.g., microcontroller 110 located on PCB 30).

In some embodiments, the radial illuminators may each transmit light of a different wavelength, or they may be operated to transmit light at different times. For example, operating each of the radial illuminators independently may allow the device to detect features about the environment located at a particular side of the device.

Figure 20 also shows a pair of axial detectors 2006a and 2006b and a pair of axial illuminators 2008a and 2008b that can be included on certain variations of the ingestible device at substantially opposite ends of the ingestible device. These axial detectors and axial illuminators can be arranged in a manner similar to the axial illuminator 42i and axial detector 42d described with reference to the axial sensing subunit 42 of the ingestible device 10. The axial illuminators 2008a and 2008b are operated to transmit illumination in substantially opposite directions. In some embodiments, the axial illuminators 2008a and 2008b are configured to transmit illumination in the infrared spectrum, but in some embodiments, other wavelengths of light may be used, for example, white light having a wavelength range covering the entire visible spectrum.

Similar to radial illuminators 2004a, 2004b, and 2004c, axial illuminators 2008a and 2008b can be configured to transmit light simultaneously, but in some embodiments, they can be adapted to transmit light of different wavelengths or at different times or in an alternating manner. Depending on the environment surrounding the ingestible device 1900, portions of the illumination transmitted by axial illuminators 2008a and 2008b can be detected by various detectors located on the device, such as axial detectors 2006a and 2006b.

During transit of the ingestible device 1900 through the gastrointestinal tract, the ingestible device 1900 is configured to periodically obtain sensor data sets. This is achieved by flashing different types of illumination in a predetermined sequence and by acquiring reflectance data for each flash. Each time sensor data is obtained, the ingestible device 1900 may first transmit a signal to transmit red illumination from illuminators 2004a, 2004b, and 2004c and detect the resulting reflectance from detectors 2002a, 2002b, 2002c. The amount of light detected in the reflectance is then quantified (e.g., by using an analog-to-digital converter 116) and stored in a memory within the ingestible device. The ingestible device 1900 may then repeat this process for blue illumination and green illumination. In some embodiments, the ingestible device can complete the data set by transmitting white illumination or infrared illumination from an axial illuminator (e.g., axial illuminators 2008a and 2008b), detecting the resulting reflectance using an axial or radial detector (e.g., axial detectors 2006a and 2006b), quantifying the data and storing it in the device memory. In some embodiments, other types of temperature, pH, voltage, or other sensors can be provided to the ingestible device, and measurements of the outputs of these sensors can also be included in the sensor data set.

Figure 21 illustrates the wavelengths of light used in certain embodiments of the device and how different wavelengths of light can interact with the environment surrounding the ingestible device according to certain embodiments. As an ingestible device (e.g., ingestible device 1900) is transported through the gastrointestinal tract, each portion of the gastrointestinal tract will have a different environment with different absorption and reflection characteristics for different wavelengths of light. For example, the stomach is typically characterized by a mixture of water, occasional particulates, loose tissue contact, and naturally occurring mucus. In contrast, the small intestine is characterized by a more restricted environment where the ingestible device comes into close contact with smooth muscle, and the colon can be characterized by opaque brown fecal matter. These different environments can cause the absolute value of the illumination detected by the various sensors on the ingestible device to vary, and can also result in diverging signals from light of different wavelengths.

By providing at least two wavelengths of light, the ingestible device 1900 can also reduce variations in detected reflectance due to patient-to-patient variations. In certain aspects, by comparing response levels from multiple wavelengths of light together rather than interrogating variations in absolute levels, the ingestible device 1900 can also account for the effects of manufacturing variability (e.g., cannula opacity, photoreceptor response, mounting distance) and fluctuations in battery voltage levels.

It is known in the art that for tissues containing high amounts of fat and/or water, the absorbance values diverge from those of normal tissue at wavelengths above approximately 600 nm and above (see "Optical properties of biological tissues: A review," Journal of Physics and Medicine, Vol. 27, 2, pp. 149-52, November 2013). Additionally, a sharp drop in absorbance from approximately 575 nm to approximately 700 nm (i.e., near the red spectrum) has also been observed (see id.). By using two different wavelengths of illumination with substantially different absorption characteristics, as disclosed herein, it is possible to discern when the environment surrounding the device is composed of biological tissue. For example, graph 2100 illustrates the different absorption characteristics of blue illumination 2106, green illumination 2108, red illumination 2110, and infrared illumination 2112, similar to the illumination used by certain embodiments of the device.

When the environment surrounding the ingestible device 1900 causes illumination to be primarily reflected from biological tissue, as in the enclosed space of the small intestine, the lower absorbance values for red illumination 2110 cause a greater amount of red illumination 2110 to be reflected by the biological tissue. As a result, higher levels of red light reflectance are detected in the small intestine by the radial sensors 2002a, 2002b, and 2002c of the ingestible device 1900, as compared to blue or green light reflectance.

Those skilled in the art will also recognize that soft tissue generally affects the scattering of light of different wavelengths. As shown on graph 2104, soft tissue generally has lower levels of scattering for increasing wavelengths. In turn, the scattering of light also affects the number of photons returning to the light detector. Additionally, the scattering characteristics of soft tissue are different from alternative reflective media (e.g., gastric fluid in the stomach versus fecal matter in the large intestine). As described herein, an ingestible device 1900 using different wavelengths of light (e.g., blue illumination 2106, green illumination 2108, and red illumination 2110) is able to take advantage of these different scattering characteristics as it determines its location within the gastrointestinal tract.

Due to the above factors, among other factors, such as slightly different colors in gastric juice, bile in the small intestine, and humic decomposition materials near the ileocecal region leading to the large intestine, the ingestible device 1900 is able to collect data at multiple different wavelengths as it passes through the gastrointestinal tract and reliably distinguish different locations within the gastrointestinal tract.

In some embodiments, the ingestible device 1900 can be implemented using an appropriate RGB LED package for a radial illuminator. In some embodiments, the radially mounted illuminator in the ingestible device 1900 can include an SML-LX0404SIUPGUSB RGB LED. In some embodiments, additional LEDs can be mounted alongside the RDB LED package to allow for additional wavelengths, and in some embodiments, IR LEDs or multi-colored white light LEDs can be mounted in an axial position of the ingestible device 1900 (e.g., to implement axial illuminators 2008a or 2008b).

Figure 22 illustrates the reflective characteristics of different regions of the gastrointestinal tract as they relate to the device. As an ingestible device (e.g., ingestible device 1900) is transported through the gastrointestinal tract, different environments affect the total amount of reflectance measured by the various radial sensors under different circumstances. These changes in the absolute level of light detected do not take into account additional variations between light of different wavelengths. Although Figure 22 is illustrated using the embodiment of ingestible device 1900 equipped with radial and axial illuminators, the discussion applies to any ingestible device described in this application (e.g., ingestible devices 10, 300, 302, 304, 306, and 700), which may have different numbers or different orientations of illuminators and detectors. Additionally, in some embodiments, an ingestible device having only radial sensors may be used to implement some of the positioning techniques described herein.

For example, image 2200 shows a longitudinal view of an ingestible device (e.g., ingestible device 1900) in the stomach and shows how the amount of light detected by various radial sensors on ingestible device 1900 from various radial illuminators varies under different conditions. Illumination 2202 being transmitted from a slightly smaller distance from the stomach wall is reflected by the wall into the acceptance angle of the adjacent radial detector. This causes a very large amount of total reflectance to be detected. By comparison, illumination 2204 directed away from any tissue or particle causes minimal light to be reflected back into the detector. Illumination 2206 shows that when ingestible device 1900 is too close to the surrounding wall or tissue, very little light is reflected in a way that will be detected by the radial detector. Finally, illumination 2208 shows that the presence of particles allows light to be reflected and scattered, resulting in a larger signal being received by the radial detector. These different types of performance cause different absolute levels of light to be detected by ingestible device 1900 while it is in the stomach. As described with reference to Figures 8 to 13, this also causes a large variation in the amount of light to be detected by ingestible device 1900.

As another example, image 2210 shows a side view of an ingestible device (e.g., ingestible device 1900) in the stomach and shows the amount of light detected by various radial sensors on ingestible device 1900 from axial illumination. The axial illumination reflects off the nearby stomach wall, and the resulting reflections are scattered in multiple directions. Reflections 2212 directed into the gastric fluid can be easily detected by the radial sensors. By comparison, reflections 2214 directed into tissue on the side of the stomach are not easily detected by the radial sensors.

As another example, image 2216 shows a longitudinal view of an ingestible device (e.g., ingestible device 1900) in the small intestine and illustrates how the amount of light is detected by various radial sensors on ingestible device 1900 from various radial illuminators under different conditions. The closed, confined space of the small intestine prevents a significant amount of radial illumination from being reflected back into the detectors. Similar to illumination 2206, because ingestible device 1900 is so close to the wall of the small intestine, very little illumination is able to be reflected directly back into the radial detectors, resulting in a lower overall level of illumination being detected. However, this effect can be mitigated when red light is used due to the wavelength absorption characteristics of the small intestinal mucosa.

As yet another example, image 2218 shows a side view of an ingestible device (e.g., ingestible device 1900) in the small intestine and illustrates how the environment changes the amount of light detected by the various radial sensors on ingestible device 1900 from the axial illuminator. Typically, the small, confined space of the small intestine will cause ingestible device 1900 to be oriented along the longitudinal axis of the capsule-shaped ingestible device. The axial illumination transmitted from the end of the device causes minimal tissue or particulates to reflect from the confined space and in combination with the confined space, very little axial illumination is detectable by the radial sensors. As a result, minimal light from the axial illuminator is detectable by the radial sensors of ingestible device 1900 in the small intestine. In contrast, in the environment of the stomach or large intestine, the axial illumination will cause a greater reflectivity to be detected. In some embodiments, the axial illuminator of ingestible device 1900 can be configured to transmit light of a wavelength that can be detected by the radial detector, such as white light. In some embodiments, the radial detector and axial illuminator can be designed such that light transmitted by the axial illuminator cannot be easily detected by the radial illuminator. For example, the axial illuminator may be configured to transmit light in infrared wavelengths, and the radial detector may be configured to receive light in the visible spectrum.

Figure 23 shows detection light reflected from different areas of the gastrointestinal tract as associated with an ingestible device (e.g., ingestible device 1900). In particular, Figure 23 shows how radial illumination can be reflected by the environment and received by various radial detectors. This description can be combined with or supplemented by the description with reference to Figures 8A to 8C and Figure 22, which illustrate similar subject matter. In some aspects, radial illuminators on an ingestible device (e.g., radial illuminators 2002a, 2002b, and 2002c (Figure 20) of ingestible device 1900 (Figure 19)) transmit illumination 2308 away from the housing of the device in an arc of approximately 120 degrees. In some embodiments, this arc can be larger or smaller depending on the materials and components used to construct the ingestible device. Similarly, a radial detector (e.g., radial detectors 2002a, 2002b, and 2002c (FIG. 20)) will have a detector acceptance range 2310, and light traveling toward a radial detector (e.g., radial detectors 2002a, 2002b, and 2002c (FIG. 20)) of the ingestible device within the detector acceptance range 2310 will be detectable by the radial detector. In some aspects, the acceptance range is approximately 120 degrees of arc, but those skilled in the art will understand that this depends on a number of factors, including the configuration of the internal components of the ingestible device and optical considerations, such as the refractive index of the device housing, the refractive index of the immediate surrounding environment, and the resulting acceptance angle of the interface between the device housing and the surrounding environment.

The open environment 2300, lacking any type of reflective surfaces or particles, has no way to deflect the light transmitted as part of the illumination 2308. As a result, the light travels in a relatively straight path away from the device, and substantially none of the illumination 2308 will be detected by the radial detector.

The environment containing particles 2302 can cause illumination to be received by the radial detector after reflecting from smaller particles. The presence of smaller, irregular particles surrounding the device can cause illumination to be reflected in multiple directions, causing portions of the illumination to be redirected into the radial detector's acceptance angle. Depending on the distance between the radial illuminator and the particles, varying amounts of illumination can be detected by the radial detector. For example, particle 2316 is within the arc of illumination 2308 and closer to the source of illumination 2308. As a result, a portion of the light contained in illumination 2308 will be reflected from particle 2316 and redirected into radial detector acceptance range 2310. By comparison, particle 2318 is still within the arc of illumination 2308, but is further from the source of illumination 2308. As such, a smaller amount of light will be reflected from particle 2318, diverted into detector acceptance range 2310, and detected by the radial detector. For example, this may be due to both decreasing light intensity as the light travels farther from the illumination source and possible shadows caused by other particles (e.g., particle 2316 in the path between the illumination source and particle 2318) or shadows in the fluid or other substance surrounding the device.

The environment near the stomach wall 2304 illustrates how illumination can be received by the radial detector after reflecting from stomach tissue at a slightly smaller distance from the device. Although this is illustrated with reference to stomach tissue, this can be applied to any type of organ tissue at a sufficient distance from the device. At a sufficient distance from the stomach, a large amount of illumination 2308 will be reflected from the gastric mucosa 2312 and diverted into the detector acceptable range 2310. As a result, a larger portion of the illumination 2308 can be detected by the radial detector. It will be apparent that the position of the ingestible device in the actual stomach will move and change, causing large variations in the amount of light detected, and a larger amount of light being received on average. In certain embodiments (e.g., ingestible devices 10, 300, 302, 304, 306, 700, 1900), both the large variations in the absolute amount of light detected and the average amount of light detected can be used to determine that the ingestible device is located in the stomach.

The small intestinal environment 2306 can cause a relatively small amount of illumination to be received by the radial detector. Typically, the enclosed space of the small intestinal mucosa 2320 would prevent illumination 2308 from reaching the radial detector. Illumination 2308 is reflected by the small intestinal mucosa 2320, but due to its positioning, very little of the illumination 2308 is able to be directly reflected into the radial detector's acceptable range 2310. This small amount of light will continue to reflect back and forth between the small intestinal mucosa 2320 and the housing of the ingestible device and will eventually reach the appropriate acceptable range 2310 where it can be detected, but this typically results in a very small amount of overall light being detected. However, due to the reddish color of the small intestine, red illumination, as compared to green or blue light, is more likely to be reflected multiple times and reach the radial detector.

FIG24 illustrates typical reflectance measurements in different regions of the gastrointestinal tract. The ingestible device 1900 functions primarily to track the current region of the gastrointestinal tract around the device and monitor the environment around the device to determine changes from one region to another. In some embodiments, the ingestible device 1900 can autonomously identify the location of the device within the gastrointestinal tract of the body by monitoring changes from one region to another. In some embodiments, the ingestible device 1900 functions as a state machine, wherein the state tracks the current portion of the gastrointestinal tract in which the ingestible device 1900 is disposed. The ingestible device 1900 can distinguish various locations, including a starting point 2402 outside the body, a stomach 2404, a duodenum 2406, a jejunum 2408, a cecum 2410, a large intestine 2412, and an exit point 2414 outside the body. In some embodiments, the ingestible device 1900 may distinguish only the stomach 2404, the small intestine (e.g., which may include the duodenum 2406 and the jejunum 2408), and the large intestine (e.g., which may include the cecum 241 and the large intestine 2412). In some embodiments, the ingestible device 1900 may distinguish a subset of the above locations and/or a combination of the above locations and other locations, such as the mouth, ileum, or rectum.

In some embodiments, the ingestible device 1900 can transmit illumination at a first wavelength toward an environment outside of a housing of the ingestible device, detect the resulting reflectance, and store reflectance values in a dataset based on the first reflectance. For example, the ingestible device can transmit illumination at a red wavelength, detect the red reflectance, and store reflectance values in a red dataset that indicates how much light was measured in the red reflectance. The ingestible device 1900 can repeat this process for multiple other types of illumination at other wavelengths, such as blue wavelengths, green wavelengths, or infrared wavelengths. The ingestible device 1900 can track reflectance data collected from reflectance sensors (i.e., radial detectors) in each of the red, green, blue, and IR spectrums.

This data can then be used by the onboard microprocessor to execute a positioning algorithm that identifies the pyloric transition 2416 from the stomach 2404 to the duodenal portion of the small intestine 2406; the ligament of Treitz transition 2418 from the duodenum 2406 to the jejunum 2408; the ileocecal transition 2420 from the ileum (i.e., the area at the end of the jejunum 2408) to the cecum 2410; and the cecal transition 2422 from the cecum 2410 to the remainder of the large intestine 2412. This can be achieved by using multiple different wavelengths of light, measuring the different amounts of light reflected by the environment surrounding the device, and determining the location of the device given the different light absorption characteristics of different regions of the gastrointestinal tract. The ingestible device 1900 can collect this data at regular intervals, and in some embodiments these intervals can be spaced from one second to ten minutes apart. For example, the ingestible device 1900 can take new data samples several times a minute until it detects its location in the small intestine, and then can take new data samples every few minutes. While not acquiring samples, the ingestible device 1900 may enter a dormant sleep or standby state to conserve energy reserves.

In certain embodiments, the ingestible device 1900 can detect the various positions and transitions identified in FIG. 24 by using an appropriate sensor array (e.g., as shown in FIG. 20 ) comprised of a plurality of radial and axial light emitting diode (LED)/phototransistor pairs that function as reflectivity sensors. In certain embodiments, the ingestible device 1900 can also include a temperature sensor and an internal real-time clock (RTC) oscillator for timekeeping. Those skilled in the electrical arts will appreciate that temperature sensors and oscillators are readily available components that can be integrated into the circuitry of a PCBA (e.g., PCBA 202) using known techniques.

The ingestible device 1900 described with reference to FIG. 24 has a set of radial illuminators (e.g., illuminators 2004a, 2004b, and 2004c (FIG. 20)) capable of transmitting light in the red spectrum, the green spectrum, and the blue spectrum, and an axial illuminator (e.g., axial illuminator 2008a (FIG. 20)) capable of transmitting light in the infrared spectrum. The ingestible device 1900 may then have a set of detectors (e.g., radial detectors 2002a, 2002b, and 2002c (FIG. 20)) capable of measuring the reflectivity of these different types of light. However, in some embodiments, particular transitions may be detected using only two different wavelengths of light, and the hardware used to implement the illuminators and detectors may be appropriately modified. For example, the identification of the pyloric transition, the ligament of Treitz transition, and the cecal transition may be achieved by comparing the red light reflectivity with the green light reflectivity or the blue light reflectivity.

As the ingestible device 1900 is transported through different regions of the gastrointestinal tract shown in FIG24 , the ingestible device 1900 can collect sensor data over time. Device software stored in memory (e.g., stored on memory subunit 140 ( FIG2A )) and executed by a processor or microcontroller (e.g., microcontroller 110 ( FIG2A )) tracks all measurements and events. An onboard algorithm, described further below, is then applied to determine the position of the ingestible device 1900 by monitoring various locations and transitions. The algorithm has been designed to traverse states representing anatomical locations of the ingestible device 1900 (e.g., origin 2402, stomach 2404, duodenum 2406, jejunum 2408, cecum 2410, large intestine 2412, and exit 2414) by using sub-algorithms to identify anatomical transitions (e.g., entrance to the stomach, pyloric transition 2416, ligament of Treitz transition 2418, ileocecal transition 2420, cecal transition 2422, and exit 2414 from the body). In some embodiments, the ingestible device 1900 will have a state corresponding to a known or estimated location of the device, and based on the current state, the ingestible device 1900 may run an algorithm to search for the next state transition. For example, when the ingestible device 1900 knows that it is in the stomach (e.g., stomach 2404), it will identify the current state as the "STOMACH" state. The ingestible device 1900 will then execute an algorithm to identify a pyloric transition (e.g., pyloric transition 2416). Once the pyloric transition is identified, the ingestible device 1900 may determine that it is now in the duodenal portion of the small intestine (e.g., duodenum 2406) and the state will switch to "DUODENUM". In some embodiments, the ingestible device may determine the state by inferring or reasoning about the current location of the device. For example, in some embodiments, the ingestible device 1900 may assume that in the absence of a detected state transition, the location of the device has remained unchanged and maintained the same state. As another example, when the device is first activated, it may assume an initial on state outside the body (eg, starting point 2402).

24 also shows a plot of the detected reflectance due to illumination at different wavelengths and the temperature measured by the device over time. The temperature 2424 changes to a temperature close to body temperature shortly after the ingestible device 1900 enters the body and returns to a different ambient temperature once the ingestible device 1900 leaves the body. The detected green reflectance 2426 and blue reflectance 2428 behave similarly, with lower responses throughout the duodenum 2406, jejunum 2408, cecum 2410, and large intestine 2412. For purposes of the algorithm described with reference to the ingestible device 1900, the detected green reflectance 2426 and the detected blue reflectance 2428 are largely interchangeable, but for simplicity we can refer only to the detected green reflectance 2426.

Detected red reflectance 2430 has a more variable response over time than detected green reflectance 2426 and blue reflectance 2428. Detected red reflectance 2430 is low in the stomach 2404 and rises during the pyloric transition 2416 as the ingestible device 1900 enters the duodenal portion of the small intestine 2406. Detected red reflectance 2430 rises as it advances through the duodenum, reaching its peak near the ligament of Treitz transition 2418 as the ingestible device 1900 approaches the jejunum 2408. Detected red reflectance 2430 decreases as the ingestible device 1900 passes through the jejunum 2408 and cecum 2410, reaching a local minimum near the cecal transition 2422.

24 is the result of an axial illuminator and an axial detector, in contrast to the other detected reflectivities 2426, 2428, and 2430 typically measured by a radial detector. During transit through the stomach, duodenum, and jejunum, the detected infrared reflectivity 2432 behaves similarly to the detected red reflectivity 2430. However, the detected infrared reflectivity 2432 reaches a lower point near the ileocecal transition 2420 and increases during transit through the large intestine 2412 before reaching a larger value in the cecum 2410.

In some embodiments, the ingestible device 1900 can determine when a state transition has occurred by comparing a reflectivity (e.g., red reflectivity 2430) to another reflectivity (e.g., green reflectivity 2426 and blue reflectivity 2428). For example, a pyloric transition (e.g., pyloric transition 2416) can be detected when the red reflectivity 2430 or the infrared reflectivity 2432 has diverged from the green reflectivity 2426 or the blue reflectivity 2428 in a statistically significant manner. In some embodiments, determining whether the two reflectivities (e.g., red reflectivity 2430 and green reflectivity 2426) have diverged in a statistically significant manner can include determining whether a sample mean of the red reflectivity data and a sample mean of the green reflectivity data are statistically different using an appropriate statistical technique. For example, this can be achieved by performing a t-test and determining whether the two sample means are statistically different at a significance level of p < .05. In some embodiments, the test can be performed on the most recent value recorded in the reflectivity dataset. In certain embodiments, the data set may be cleaned (e.g., by detecting and removing outliers) before being used for statistical comparisons. Those skilled in the art will appreciate that a variety of test statistics and statistical techniques may be used to determine statistical significance. These techniques may include, but are not limited to, comparisons of means, standard deviations, and variances, t-tests, f-tests, data cleaning methods, machine learning techniques, feature extraction, and the like, or any combination thereof.

Those skilled in the art will also appreciate that various known statistical techniques or specialized techniques can be used to identify a relationship between one or more reflectances, for example, to determine when two reflectances converge or diverge or when each reflectance reaches a local maximum or minimum. For example, one specific method can determine statistically significant divergence by estimating when the simple moving average of the red reflectance 2430 is twice the simple moving average of the green reflectance 2426. As another example, in some embodiments, the ingestible device 1900 can integrate the difference between the weighted or simple moving averages and determine when the integral is greater than a threshold to determine that the two reflectances have diverged in a statistically significant manner. The threshold itself can be a multiple of one of the simple moving averages, for example, ten times the simple moving average of the last 50 data points in the green reflectance data set 2426. In some embodiments, the ingestible device 1900 can determine statistical significance when the measured red reflectance 2430 is, for example, 10 times greater than or equal to the measured green reflectance 2426. In some embodiments, the ingestible device may increment a counter by one when the measured first reflectance (e.g., red reflectance 2430) is greater than the measured second reflectance (e.g., green reflectance 2426). In some embodiments, the counter may increment when a multiple of the mean of a first data set (e.g., red reflectance 2430) minus the standard deviation of the first data set is greater than a multiple of the mean of a second data set (e.g., green reflectance 2430) plus the standard deviation of the second data set. For example, in some embodiments, the duodenum detection algorithm may increment a counter by one when the mean of the red reflectance 2430 minus the standard deviation of the red reflectance 2430 is greater than the mean of the green reflectance 2430 minus the standard deviation of the green reflectance 2430, and when the counter is greater than 7000, the pyloric transition 2416 is detected. In some embodiments, when the mean of the infrared reflectance 2432 minus the standard deviation of the infrared reflectance 2432 is greater than the mean of the green reflectance 2430 minus the standard deviation of the green reflectance 2430, the cecal detection algorithm may increment a counter by one and detect an ileocecal transition 2420 when the counter is greater than 1000. In some embodiments, the ingestible device 1900 may periodically reset the counter. In some embodiments, because the counter is unitless and the count may depend on the frequency with which samples are acquired by the device, the ingestible device 1900 may detect a transition when the count reaches different thresholds. For example, in some embodiments, the ingestible device 1900 may acquire new data at a faster rate and the duodenum detection algorithm may detect a state transition when the counter is greater than 700.

As the ingestible device 1900 is transported through portions of the gastrointestinal tract, the ingestible device 1900 utilizes a positioning algorithm to determine its position. In certain aspects, this is accomplished by selecting from various states of the device corresponding to the gross anatomy of the gastrointestinal tract stored in the device. The states tracked by the ingestible device 1900 and the sub-algorithms implemented to track state transitions are described according to certain embodiments below.

[00126] GI State: START_EXTERNAL. This state is entered when the device is programmed and begins recording operations. For example, at starting point 2402, the ingestible device 1900 may be set to the START_EXTERNAL state prior to administering the device to a patient. In some embodiments, the ingestible device 1900 may include a communication subunit (e.g., the communication subunit 120 (FIG. 2A) described with reference to the embodiment of the ingestible device 10 (FIG. 1)) and may communicate with a base station (e.g., base station 950 (FIGS. 17A-17C)). When the ingestible device 1900 is connected to the base station, the ingestible device 1900 may be set to the START_EXTERNAL state by default. In some embodiments, the START_EXTERNAL state may also be the default state each time the ingestible device 1900 is activated for the first time.

GI State: STOMACH. This state is entered once the ingestible device 1900 determines that it has entered the stomach 2404. In some embodiments, the ingestible device 1900 may include a temperature sensor for measuring the temperature of the environment surrounding the device. Once the measured temperature is close to the patient's internal body temperature, the ingestible device 1900 may determine that it has transitioned into the stomach. For example, for a typical human patient, the internal body temperature is close to 37 degrees Celsius, and the ingestible device 1900 may then determine that it has entered the stomach when the temperature sensor measures a temperature in the range of 30 to 40 degrees. In some embodiments, the temperature range may be manually set by programming the ingestible device 1900 using a base station. In some embodiments, the ingestible device 1900 may also be adapted to use radial and axial detectors (e.g., detectors 2002a, 2002b, 2002c, 2006a, and 2006b) to determine changes in ambient light levels in the environment. Upon measuring a decrease in ambient light that would typically engulf the ingestible device, the ingestible device 1900 can determine that it has entered the body and automatically determine that it has transitioned from the START_EXTERNAL state to the STOMACH state. This can be particularly useful when the ingestible device 1900 does not include a temperature sensor or when the ambient temperature is similar to internal body temperature.

[00156] GI State: DUODENUM. This state is entered once the ingestible device 1900 detects the pyloric transition 2416 from the stomach 2404 to the duodenum 2406. This may be accomplished using a duodenum detection sub-algorithm that operates automatically whenever the ingestible device 1900 is in the STOMACH state. In certain aspects, the duodenum detection sub-algorithm may determine when the red reflectance 2430 or infrared reflectance 2432 diverges from the green reflectance 2426 or blue reflectance 2428 in a statistically significant manner. One skilled in the art will appreciate that various statistical, filtering, or specialized techniques may be used to identify this point. For example, this may be calculated using various known statistical techniques or specialized techniques, such as performing a t-test using, for example, the last 30 data points, or by determining when the red reflectance 2430 or infrared reflectance 2432 is, for example, twice the value of the green reflectance 2426 or blue reflectance 2428. In some aspects, the duodenum detection sub-algorithm compares the difference between the detected red spectrum 2430 versus the detected green or blue spectrum and marks a transition when the difference is greater than a threshold. In some aspects, the algorithm uses an average of multiple data points in the detected red reflectance data and the detected green reflectance data, takes the difference between the two averages, and compares the difference to a threshold. For example, the ingestible device 1900 can be configured to take a new data sample every 15 seconds and take a simple moving average of the most recent 40 samples to determine the average red reflectance and the average green reflectance. In some embodiments, the duodenum detection algorithm can include taking an integral of the difference between the average red reflectance and the average green reflectance. For example, in some aspects, taking an average of the difference between the two simple moving averages can help the ingestible device 1900 avoid false transitions or help detect transitions earlier. Other aspects of the duodenum detection algorithm are shown in Figure 33. Although the above discussion uses detected red light reflectance 2430 and detected green light reflectance 2426, in some embodiments, a similar algorithm may be performed using detected infrared reflectance 2432 instead of detected red light reflectance 2430 or by using detected blue light reflectance 2428 instead of detected green light reflectance 2426.

[0116] GI State: JEJUNUM. This state is entered upon detection of the ligament of Treitz transition 2418 between the duodenum 2406 and the jejunum 2408. In some aspects, this can be detected using a jejunum detection sub-algorithm that can be automatically executed once the ingestible device 1900 is in the DUODENUM state. In some aspects, the jejunum detection sub-algorithm can determine when the red reflectance 2430 or infrared reflectance 2432 reaches a local maximum or when the difference between the red reflectance 2430 or infrared reflectance 2432 and the green reflectance 2426 or blue reflectance 2428 is constant in a statistically significant manner (e.g., due to the red reflectance 2430 reaching a local maximum). One skilled in the art will appreciate that various statistical, filtering, or specific techniques can be used to identify this point. For example, this can be calculated by finding when the derivative or finite difference of the red reflectance 2430 or infrared reflectance 2432 reaches zero or changes sign. In some aspects, the jejunum detection sub-algorithm identifies the point of maximum reflected light in the red spectrum versus the green and blue spectra. In some aspects, the jejunum detection sub-algorithm can compare the detected red reflectance value to a threshold value, and in some aspects, the algorithm estimates the difference between a simple moving average of the detected red reflectance 2430 and a simple moving average of the detected green reflectance 2426 or the detected blue reflectance 2428. In some embodiments, the detected infrared reflectance 2432 can be used in place of the detected red reflectance 2430.

[00116] GI State: CAECUM. This state is entered once the ingestible device 1900 detects the ileocecal transition 2420 from the ileum (i.e., the portion of the gastrointestinal tract at the end of the jejunum 2408) to the cecum 2410. In some aspects, this can be detected using a cecal detection sub-algorithm. In some aspects, the cecal detection sub-algorithm can determine when the infrared reflectivity 2430 reaches a local minimum or when the infrared reflectivity 2430, 2432 converges with the green reflectivity 2426 or the blue reflectivity 2428 in a statistically significant manner (e.g., due to the red reflectivity 2430 reaching a local maximum). One skilled in the art will appreciate that various statistical, filtering, or specific techniques can be used to identify this point. For example, in some embodiments, this can be calculated by finding when the derivative or finite difference of the infrared reflectivity 2432 reaches zero or finding when a simple moving average of the difference between the infrared reflectivity 2430 and the green reflectivity 2426 is statistically equal to zero. 32 . This sub-algorithm may be automatically executed when the ingestible device 1900 is in the JEJUNUM state. In some aspects, the cecum detection sub-algorithm may compare the detected red reflectance 2430 or the detected infrared reflectance 2432 to the detected green reflectance 2326 or the detected blue reflectance 2328 to find a point where the difference is less than a first threshold. Similar to our discussion of other sub-algorithms, in some aspects, the algorithm may use a simple moving average, such as compared to the raw data points. In some aspects, the cecum detection sub-algorithm may integrate the difference between the average reflected light in the infrared spectrum versus the average reflected light in the green spectrum and test for the difference being less than a detection threshold. In some embodiments, other techniques may be incorporated into the cecum detection sub-algorithm, such as those shown in FIG. 32 .

[0116] GI State: LARGE INTESTINE. This state is entered once the ingestible device 1900 detects the cecal transition 2422 from the cecum 2410 to the remainder of the large intestine 2412. In some aspects, this can be detected using a large intestine detection sub-algorithm. This sub-algorithm can be automatically executed when the ingestible device 1900 is in the CAECUM state. In some aspects, the large intestine detection sub-algorithm can determine when the red reflectance 2430 reaches a minimum and converges with the green reflectance 2426 or the blue reflectance 2428 in a statistically significant manner or when the infrared reflectance 2432 rises in a statistically significant manner and levels off at a sufficiently large value. Those skilled in the art will appreciate that various statistical, filtering, or specific techniques can be used to identify this point. For example, in some embodiments, this can be calculated by finding when the sample mean of the red reflectance 2430 is statistically the same as the blue or green reflectance 2426, 2428. In some embodiments, this can be achieved by calculating when the infrared reflectivity 2432 is, for example, an order of magnitude greater than the other reflectivities or when a finite difference or derivative of the infrared reflectivity 2432 has decreased to, for example, 20% of its maximum value. In some aspects, the large intestine detection sub-algorithm can compare the detected red reflectivity 2430 with the detected green reflectivity 2426 to determine when the difference is below a threshold. Similar to our discussion of other sub-algorithms, in some aspects, the algorithm uses a simple moving average, such as compared to the raw data points. In some embodiments, an advanced version of the algorithm integrates the difference between the simple moving averages of the detected red reflectivity 2430 and the detected green reflectivity 2426 and tests for a difference less than a threshold. For example, as each new data set is acquired, the ingestible device 1900 can calculate an updated simple moving average. A cautious integral can then be calculated by summing the differences between a predetermined number of the most recent simple moving averages. It will be apparent to those skilled in the art that the integral can be calculated in a number of different ways, some of which may be more or less computationally efficient than others. For example, taking the difference between appropriately weighted moving averages or adding and subtracting the most recent and oldest simple moving averages from the previously calculated integral can produce equivalent results. In some embodiments, a detected infrared reflectivity 2432 above a threshold value can be incorporated into the large intestine detection sub-algorithm.

[0116] GI State: END EXTERNAL. This state is entered after the ingestible device 1900 detects the transition from the large intestine 2412 to the exit 2414. In some aspects, the ingestible device 1900 may detect this transition via an exit detection sub-algorithm, which may run automatically when the ingestible device is in the LARGE INTESTINE state. In some embodiments, the ingestible device 1900 may be equipped with a temperature detector, and the exit detection sub-algorithm may simply check for changes in the measured temperature away from the patient's internal body temperature. For example, if the ingestible device 1900 detects a temperature below 30 degrees Celsius or outside the range of 30 degrees Celsius to 40 degrees Celsius, the ingestible device 1900 may determine that it has naturally exited the patient's body.

In some embodiments, the ingestible device 1900 can measure the total amount of time that has passed since the ingestible device 1900 was first activated in the START state. In some aspects, this measured amount of time can be incorporated into the exit detection sub-algorithm. For example, by determining that a significantly long period of time has passed (e.g., fifteen hours), the ingestible device can determine that the changing temperature reading is the result of a natural exit from the body rather than a transient disturbance (e.g., being stuck in the stomach, such as a patient drinking cold water). In some embodiments, the ingestible device 1900 can also use radial or axial detectors (e.g., detectors 2002a, 2002b, 2002c, 2006a, or 2006b) to measure ambient light to help determine exit from the body. In some embodiments, the ingestible device 1900 can also enter the END EXTERNAL state and go into a dormant state after an extremely long period of time has passed. In some aspects, this can serve as both a means for conserving energy and as a failsafe. For example, regardless of other indicators, the ingestible device 1900 can enter the END EXTERNAL state and be dormant after seven days have passed.

It will be understood that the positions and transitions discussed with reference to Figure 24 are for illustrative purposes and should not be considered limiting. In addition, the systems, devices, and methods described herein can be used to identify a plurality of other positions or transitions (e.g., identifying the ileum and the transition between the duodenum and ileum by comparing different wavelengths of light to a threshold). Additionally, certain embodiments of the device can reduce the number of states by merging the DUODENUM, JEJUNUM, and CAECUM into a single SMALL INTESTINE state. In this case, the DUODENUM detection sub-algorithm determines when the ingestible device transitions into the SMALL INTESTINE state, and the CECA detection sub-algorithm determines when the ingestible device transitions away from the SMALL INTESTINE state into the LARGE INTESTINE state. In certain embodiments, other states such as the MOUTH, ILIEUM, or COLON states may also be used by the device.

While we specifically describe ingestible device 1900 with reference to Figure 24, it will be understood that any of the ingestible devices may be used in the present application. This includes, for example, ingestible devices 10, 300, 302, 304, 306, 700, as well as ingestible device 2500 discussed with reference to Figures 26-28, and other ingestible devices having various combinations of features found on the aforementioned devices.

Figure 25 shows an external view of another embodiment of an ingestible device that can be used to independently identify a location within the gastrointestinal tract and independently sample from the gastrointestinal tract or release a drug into the gastrointestinal tract. Similar to the exemplary ingestible device 700, the exemplary ingestible device 2500 shown in Figure 25 is configured to perform the position detection method described herein and obtain samples and/or carry substances including drugs and therapeutic agents. During transportation through the gastrointestinal tract, the ingestible device 2500 can obtain multiple samples based on the determined location of the device or at a predetermined time after the location of the device has been established. The systems, devices and methods used by the ingestible device 2500 are described with reference to Figures 25 to 35, but the features of the ingestible device 2500 can be combined with any other part of this application. The various components of the ingestible device 2500 are interchangeable with the components used in the ingestible devices 10, 300, 302, 304, 306, 700 and 1900. Therefore, components similar to the ingestible devices already described will not be discussed in greater detail and instead attention will be focused on the distinguishing features of this embodiment. It will also be understood that any of the ingestible devices described herein (e.g., ingestible devices 10, 300, 302, 304, 306, 700, and 1900) can be modified to include the systems, devices, and methods described with reference to ingestible device 2500.

25 , an external view of an ingestible device 2500 is shown. The ingestible device 2500 is shown as having a housing including a first wall portion 2502 connected to a first end portion 2504 and a second wall portion 2512 connected to a second end portion 2514. The first wall portion 2502 and the second wall portion 2512 are connected via a connection step 510.

The first wall portion 2502 is shown as having an optically transparent or translucent window 2506. The window 2506 can have different optical properties than the rest of the first wall portion 2502 and can be more transparent or translucent to visible light and infrared light than other portions of the first wall portion 2502. However, in some embodiments, the ingestible device 2500 can be adapted to use the first wall portion 14a and first end portion 16a from the ingestible device 10 of Figure 1 in place of the first wall portion 2502 and first end portion 2504. The first end portion 2504 is substantially similar to the first end portion 16a shown in Figure 1; however, the first end portion 2504 can have a window located at the end of the device. In some aspects, the window can have different optical properties than the rest of the first end portion 2504 and be configured to allow illumination to enter and exit the end where the axial sensor subunit can be disposed.

The second wall portion 2512 has an opening 2518 and is configured to rotate about the longitudinal axis of the device. The opening 2518 serves as a passage for a sample to enter the housing of the ingestible device 2500 from the gastrointestinal tract or as a passage for a pharmaceutical agent stored in the ingestible device 2500 to be released into the gastrointestinal tract. In certain embodiments, the sample obtained by the ingestible device 2500 can be analyzed. The gear motor 704 within the ingestible device 2500 is capable of rotating and causing the second wall portion 2512 to move. In certain embodiments, this is achieved by using a motor pinion connected to the interior of the second wall portion 2512. The motor pinion can be connected using cyanoacrylate, or any other suitable adhesive material or bonding agent. The second end portion 2514 is connected to the second wall portion 2512 and includes a small opening 2516. The small opening 2516 can be used to anchor the end of the gear motor 704. The end of the gear motor 704 can be positioned within the small opening 2516, allowing it to be locked into place. In some embodiments, the second end portion 2514 will rotate with the second wall portion 2512, but in some embodiments the second end portion 2514 will remain stationary as the second wall portion 2512 moves. As the second wall portion 2512 moves, the opening 2518 will move with it. In some configurations, there will be one or more chambers (e.g., chamber 706 (Figure 14A)) below the second wall portion 2512. As the opening 2518 moves, the chamber can become alternately exposed to the environment surrounding the ingestible device 2500 or closed from the environment surrounding the ingestible device 2500.

The PCB 2508 used in the ingestible device 2500 has similar features and functionality as the PCB 30 discussed with reference to Figures 2A through 2E. However, the PCB 2508 may have slightly different electrical and mechanical systems as described later in Figure 27 and slightly different firmware as discussed in Figure 28. The PCB 2508 may also be programmed to execute the positioning algorithms described with reference to other embodiments of the device or additionally or alternatively execute other algorithms discussed with reference to Figures 29 through 33. The PCB 2508 may also have an axial sensing subunit (e.g., axial sensing subunit 42 of FIG. 1A ) and may feature a radial sensor array that utilizes radial illuminators and radial detectors (e.g., illuminators 1906a and 1906b and detector 1904 of FIG. 19 ) to determine the position of the device similar to other ingestible devices (e.g., ingestible devices 10, 300, 302, 304, 306, and 1900 of FIG. 1A-1B , FIG. 3A-6B , and FIG. 19 ). To accommodate other sampling components in the ingestible device 2500, in some embodiments, the PCB 2508 may extend in only one direction and fit into the first wall portion 14a.

Figure 26 shows an exploded view of the ingestible device 2500. The magnetic ring 2600 is connected to the second wall portion 5212 and rotates with the second wall portion 5212. In some embodiments, the magnetic ring 2600 can be adhered to the second wall portion 2512 using cyanoacrylate, or any other suitable adhesive material or bonding agent. In some embodiments, the interior of the magnetic ring 2600 can interlock with the gear motor 704, causing the magnetic ring 2600, the second wall portion 2512, and the second end portion 2514 to rotate as the gear motor 704 rotates. In some embodiments, the second wall portion 2512 or the second end portion 2514 will be directly connected to the gear motor. For example, the gear motor can interlock with the second end portion 2514 at a small opening 2516. To assist in the operation of the device, the PCB 2508 can feature an additional magnetic sensor 2602, which can determine the orientation of the magnetic ring 2600. For example, the magnetic ring 2600 can include a series of magnets positioned so that the magnets are closest to the magnetic sensor 2602 when the opening 2518 is aligned with the chamber 706. The PCB 2508 can then use the signal detected by the magnetic sensor 2602 as part of the feedback to adjust the position of the opening 2518 by controlling the gear motor 704. Typically, the PCB 2508 can include a gear motor controller, and the PCB 2508 can transmit an electrical DC or AC signal to move the gear motor 704. The locking end 2606 of the second wall portion 2512 is configured to work with the connecting portion 2 step 510. The locking end 2606 is designed to allow the second wall portion 2512 to rotate freely relative to the first wall portion 2502 while also remaining connected to the first wall portion 2502.

The storage subunit 2604 is similar to the storage subunit 702 ( FIG. 14A ) and is enclosed by the second wall portion 2512 . The storage subunit 2604 includes chambers, such as chamber 706 . Each chamber 706 on the storage subunit 2604 is accessible when the corresponding chamber opening 708 is aligned with the opening 2518 in the second wall portion 2512 . As the second wall portion 2512 moves, the chambers can become accessible to the environment surrounding the ingestible device 2500 , or they can become inaccessible to the environment surrounding the ingestible device 2500 . Each chamber 706 can also contain a hydrophilic foam or sponge to assist in obtaining a sample. Additionally, the hydrophilic foam or sponge can be provided with or without a biological agent for immobilizing or detecting a target analyte, modifying the chamber 706 into a sampling and diagnostic chamber. This can be combined with other diagnostic and assay techniques to diagnose or detect different conditions that affect specific portions of the gastrointestinal tract.

As described with reference to ingestible device 2500, storage subunit 2604 includes two chambers (e.g., replicas of chamber 706) distributed around approximately two-thirds of the circumference of storage subunit 2604. The final portion of storage subunit 2604 is a dead chamber 2608, which forms a protrusion that blocks opening 2518. In some aspects, dead chamber 2608 can be fabricated from silicone, and in other aspects, dead chamber 2608 can be fabricated from silicone having a Shore A durometer of approximately 45. In some embodiments, the final portion of storage subunit 2604 can include a third chamber that is unused or allowed to be in constant contact with the environment surrounding ingestible device 2500. In some embodiments, the first chamber can be used to sample the gastrointestinal tract, and the second chamber can be used to resample the gastrointestinal tract as a result of obtaining a second sample. For example, in some embodiments, ingestible device 2500 can resample the gastrointestinal tract a fixed period of time after the first sample as a result of obtaining a second sample. In some embodiments, the ingestible device 2500 can resample the gastrointestinal tract at a second location that is different from the first location. For example, the ingestible device 2500 can be programmed with two different predetermined locations to be sampled (the duodenum and the jejunum). In this case, the ingestible device 2500 can take a first sample when the ingestible device 2500 determines that it is located in the duodenum, and can take a second sample when the ingestible device 2500 determines that it is located in the jejunum. In some embodiments, after each of the samples is taken, the ingestible device prevents the sample from leaving the chamber (e.g., a replica of chamber 706) by moving the second wall portion 2512 to a position that aligns the opening 2518 with the null chamber 2608.

In certain embodiments, as the second wall portion 2512 rotates, the storage subunit 2604 remains stationary, but in certain embodiments, as the second wall portion 2512 remains stationary, the storage subunit 2604 can rotate. In certain embodiments, the opening 2518 can be covered by a sliding door that can move to the side that uncovers the opening 2518. When used in conjunction with the rotating storage subunit 2604, this can be particularly effective in maximizing the available space in the storage subunit. In certain embodiments, the storage subunit can also be adapted to include sample diagnostics, such as assays. The storage subunit can alternately isolate new samples, perform diagnostics on samples, and release the sample back into the gastrointestinal tract. In certain embodiments, the rear wall of chamber 706 can include an electromechanical actuator to push the sample out of the chamber. In certain embodiments, a similar electromechanical actuator can be used to pull a sample or fluid into the chamber by suction. In some embodiments, once the ingestible device 2500 reaches a particular position by reconfiguring the second wall portion 2512 relative to the storage subunit 2604, the ingestible device 2500 can also isolate the sample in chamber 706, test the sample using a diagnostic, such as an assay, and based on the results of the diagnostic, reconfigure the second wall portion 2512 relative to the storage subunit 2604 to release the agent stored in a different one of chambers 706.

FIG27 illustrates various electrical subunits corresponding to certain embodiments of the device. In particular, FIG27 illustrates an electrical subunit that may be implemented in a PCB 2508 associated with the ingestible device 2500, although any of the systems, devices, and methods discussed with reference to FIG27 may be combined with any other system, device, or method herein. For example, the systems, devices, and methods illustrated in FIG2A through 2E and FIG15 may be implemented in addition to or alternatively to the systems, devices, and methods of FIG27, and vice versa. In certain embodiments, PCB 2508 is a flexible PCB with rigid reinforcements that is powered by three silver oxide 370 batteries. The electrical system of PCB 2508 is controlled by a microcontroller 2700, which in certain embodiments may be similar to microcontroller 110 (FIG. 2A). In certain embodiments of the ingestible device 2500, microcontroller 2700 is an STM32L051k8, which has a low-power ARM Coretex core. The microcontroller 2700 features a memory subunit 2702, which may include both flash memory 2704 and EEPROM memory 2706 for storing both instructions and data obtained from various sensors.

The electrical system includes a top axial sensing subunit 2708, a radial sensing subunit 2710, and in some embodiments, an additional bottom axial sensing subunit 2712, all of which can be similar to the sensing subunits discussed with reference to FIG. 2A and FIG. 15, and in some embodiments, each subunit can include an LED/light sensor pair. The microcontroller 2700 can communicate with these sensing subunits using a general-purpose input/output interface (e.g., general-purpose I/O 112) in combination with an analog-to-digital converter (e.g., analog-to-digital converter 116) for converting and quantizing the signals detected by the light sensors contained in the sensing subunits 2708, 2710, and 2712. The electrical system can also include an IR light receiver/transmitter 2714, which can be used to assist in positioning or can be used to transmit and receive signals. For example, this can be used in conjunction with the communication subunit 120 and the optical encoder 20 (FIG. 2A) to communicate with the base station and allow the ingestible device 2500 to be programmed. In some embodiments, PCB 2508 may also include an RF transceiver for use in communications (e.g., RF transceiver 722). IR optical receiver transmitter 2714 may communicate with microcontroller 2700 using general purpose I/O 112 or a UART (e.g., universal asynchronous receiver/transmitter (UART) interface 114 (FIG. 2A)).

In certain embodiments, PCB 2508 includes a real-time clock (RTC) oscillator 2716 operating at 32.768 kHz. This clock communicates directly with microcontroller 2700 and can be used to quantify capsule delivery time with real-time accuracy, or to track time as the ingestible device enters a temporary sleep state and wakes itself up at regular intervals. The power supply for microcontroller 2700 features a power regulator 2718, which controls and filters the voltage delivered by battery 18, and a power failure protection circuit 2720, which prevents or substantially prevents minor voltage variations from interfering with device function. For example, in certain aspects, the power failure protection circuit can mitigate potential voltage drops as battery 18 is used to power motor 2722. Motor 2722 can be substantially similar to gear motor 704, but the circuitry can be readily adapted to power other types of motors or actuators. In some embodiments, the power-off protection circuit 2720 may include a Schottky diode connected between the battery 18 and the microcontroller 2700, and the power-off protection circuit 2720 may additionally include bulk capacitance on the side of the Schottky diode with the microcontroller 2700. In some embodiments, the voltage drop in the battery 18 caused by moving the motor 2722 may cause the Schottky diode to electrically isolate the microcontroller 2700 from the battery 18, while allowing the microcontroller 2700 to maintain operation by drawing stored energy from the bulk capacitance. In some embodiments, the microcontroller 2700 may also suspend the functions of some devices while the motor 2722 is moving. For example, when the motor 2722 is moving, the microcontroller 2700 may suspend the use of the sensing sub-units 2708, 2710, and 2712 and draw less energy from the bulk capacitance. In certain aspects, the power-off protection circuitry can allow the ingestible device 2500 to use the same battery 18 to operate both the motor 2722 and the microcontroller 2700. In certain embodiments, the power-off protection circuitry can also include a voltage sensor for sensing the voltage level and/or bulk capacitance of the battery 18, and the ingestible device 2500 can prevent movement of the motor 2722 unless one or both of the sensed voltage levels are above a threshold. For example, the ingestible device 2500 will prevent movement of the motor 2722 unless the voltage on the bulk capacitor is sufficient to maintain operation of the microcontroller 2700 for the duration of the motor's movement.

In certain embodiments, the PCB 2508 also includes a motor position sensor 2724 and a motor direction control 2726, which communicate with the microcontroller 2700 via GPIO. The motor position sensor 2724 and motor direction control 2726 are used in combination to operate the motor 2722 (e.g., the gear motor 704). The motor direction control 2726 is a motor direction H-bridge circuit that can alternate between clockwise and counterclockwise rotation of the DC motor (e.g., motors 2722, 704). This can be used in combination with a motor driver (e.g., motor driver 742 ( FIG. 15 )) or a motor control subunit (e.g., motor control subunit 740 ( FIG. 15 )). This ensures that the opening 2518 can be aligned with a specific chamber opening 708 without interfering with other chambers.

In some embodiments, the motor position sensor 2724 is a magnetic sensor, such as a Hall effect sensor, which can detect the orientation of the magnetic ring 2600 connected to the second wall portion 2512 containing the opening 2518. The combination of the motor position sensor 2724, the microcontroller 2700, and the motor direction control 2726 can act as a simple feedback circuit to ensure that the motor 2722 is correctly oriented. In some embodiments, the PCB 2508 can also include other sensors, such as a temperature sensor, and can be adapted to include optical, electrical, or chemical diagnostics for studying samples taken in the chamber 706. In some embodiments, the microcontroller 2700 can also be adapted to sense the position of the chamber (e.g., chamber 706). For example, by using the magnetic sensing subunit 2602 in combination with a magnet embedded in the wall of the chamber.

The microcontroller 2700 activates and monitors various sensors and sensing subunits 2708, 2710, and 2712 to locate itself within the gastrointestinal tract. For example, the microcontroller 2700 can operate the axial and radial sensing subunits 2708 and 2701 to flash different colors of light and use the light sensors in the sensing subunits to detect the resulting reflectivity. Similarly, in some embodiments, the microcontroller 2700 can also obtain temperature data from a temperature sensor. These detected data values are stored as a log (e.g., in the EEPROM memory 2706 of the memory subunit 2702), which can be later retrieved for subsequent analysis or execution of one of the positioning algorithms described herein.

FIG28 illustrates firmware corresponding to certain embodiments of the device. Specifically, FIG28 illustrates firmware 2800 and a software system that may be used in certain embodiments to control the operation of the PCB 2508 and the ingestible device 2500. The firmware 2800 is installed into the internal non-volatile flash memory 2704 of the microcontroller 2700 at the time of manufacture or during authorized service time, and generally does not change or is not reprogrammed after being installed on the ingestible device 2500. In certain aspects, this may be achieved by having the programming leads (i.e., the physical connections to write to or rewrite to the flash memory 2704) housed within the housing of the ingestible device 2500, or by having the programming leads printed onto a portion of a flexible circuit board used to construct the PCB 2508, which is physically severed after the firmware 2800 has been installed.

Firmware 2800 controls various functions of the device, as shown in Figure 28. As will be apparent, firmware 2800 is encoded with instructions that can control the functions of the microcontroller 2700 and, by proxy, can control the system described in Figure 27. Real-time clock (RTC) and power cycle control 2802 determine how the microcontroller 2700 communicates and interacts with the RTC oscillator 2716. In some embodiments, the ingestible device 2500 is set to sleep most of the time, disabling various device functions to conserve energy. The ingestible device 2500 is set to wake up at predetermined times, collect sensor data, periodically analyze the collected data, perform actions (sampling, identifying GI features) as needed, and return to sleep. Maintaining a large percentage of the time in sleep mode can conserve onboard power reserves. Power cycle control 2802 allows the ingestible device 2500 to wake up at appropriate intervals. Two exemplary methods for controlling the operation of the device based on these sleep and wake intervals are subsequently shown with reference to Figures 29 and 30. The motor position and magnetic sensing control 2804 contains instructions for allowing the microcontroller 2700 to interact with the motor position sensor 2724. In some embodiments, the motor position sensor 2724 is replaced by other types of magnetic sensing units (e.g., magnetic sensing unit 2602) that can be used to determine the position and orientation of various parts of the ingestible device. The motor control 2806 contains instructions for allowing the microcontroller 2700 to operate the motor direction control 2726 via the GPIO and control the movement of the motor 2722. In some embodiments, the motor 2722 can be the same motor as the gear motor 704, although other types of motors can be used in some embodiments.

Internal EEPROM storage control 2808 includes drivers for allowing microcontroller 2700 to interact with EEPROM memory 2706. Internal flash memory control 2810 includes similar drivers for allowing microcontroller 2700 to interact with flash memory 2704. Reflectivity sensor control 2812 includes instructions for microcontroller 2700 to acquire and quantify the light detected by the light sensor (e.g., the light sensing halves of sensing sub-units 2708, 2710, and 2712, or detector 1904). In certain embodiments, any reflectivity (i.e., light reflected onto the detector) will cause the detector to generate a voltage or current directly proportional to the amount of light detected. This is fed into an ADC, and the resulting digital signal can be used by microcontroller 2700 to quantify the amount of light received in the reflection. Reflectivity sensor LED control 2814 contains instructions for causing the microcontroller 2700 to operate the various illuminators of the ingestible device 2500 (e.g., the LED halves of sensing sub-units 2708, 2710, 2712 or illuminators 1902a and 1902b). Using GPIO, the microcontroller 1700 can control when the LEDs illuminate or, in the case of an RGB-LED package, the color of the light being produced (i.e., selecting different wavelengths for illumination). Serial communication control 2816 contains instructions for operating the IR light receiver/transmitter 2714 to transmit signals to and from the device using a universal asynchronous receiver/transmitter (UART). For example, the microcontroller 2700 can encode digital pulse sequences onto the IR transmitter (e.g., using optical encoder 20) to communicate with a base station (e.g., base station 950). Similarly, the IR receiver can be used to receive signals from the base station, allowing a physician to set device parameters or reprogram selected features of the ingestible device 2500.

While the firmware 2800 is discussed primarily with reference to the electrical subsystem described by FIG. 27 , similar firmware may be used to control other electrical systems in the ingestible device (e.g., the systems described by FIG. 2A through FIG. 2E and FIG. 15 ). As described above with reference to the RTC and power cycle control 2802, the firmware may include instructions that conserve device power by setting the ingestible device 2500 to spend a significant portion of its time in sleep mode and to take samples and perform a full range of device functions at regular intervals. In these embodiments, the firmware 2800 has two main execution paths, a main program slow loop and a timer-based fast loop. The main program slow loop is shown in FIG. 30A through FIG. 30B and may run a list of predetermined tasks. Each task in the main program slow loop may be executed at a fixed rate and in response to uncertain external events, such as new data obtained from a light sensor (e.g., from sensing sub-units 2708 , 2710 , 2712 ). In contrast, a fast timer-based loop will periodically interrupt the main program slow loop and is concerned with processes that require high-speed processing at frequent intervals.

29 is a flow chart illustrating certain embodiments and processes for waking an ingestible device from a sleep or standby state and operating the ingestible device. In some aspects, a wake-up process 2975 controls the operation of the device and sets intervals to interrupt the sleep or standby state of the ingestible device 2500, causing it to wake up and perform the slow loop processing shown in FIG30A to FIG30B, as well as the fast loop processing 2950. The fast loop processing 2950 can periodically interrupt the slow loop processing and take care of processes that need to be processed at high speeds at frequent intervals. For example, after the ingestible device 2500 wakes up, the slow loop processing can track which task needs to be completed next (e.g., collecting data or running a positioning algorithm), while the fast loop processing 2950 can monitor external communications (e.g., communications from the base station 950 (FIGS. 17A to 17C)) and operate sensors.

At step 2900 of the fast loop process 2950, the ingestible device 2500 interrupts the slow loop process via the fast loop process 2950. To perform high speed processing, the fast loop process 2950 may interrupt and take control of the ingestible device 2500 at a frequency higher than 6 kHz.

At step 2902, the ingestible device 2500 checks for external communications. For example, the ingestible device 2500 may check whether a signal is received by the IR light receiver 2714 from the base station 950. In some embodiments, the ingestible device 2500 may also be equipped with other types of wireless communication means, such as Bluetooth, near field communication, RF transceivers, and the like. In these cases, the ingestible device 2500 may monitor for any type of communication at step 2902. In some embodiments, if communication is detected, the ingestible device 2500 may continue to monitor for communication until the communication is complete.

At step 2904, the ingestible device 2500 checks whether one millisecond has passed since the last time the time counter was incremented at step 2906. In some aspects, this can allow the ingestible device 2500 to check for communications at a higher frequency at step 2902 and perform other operations (e.g., servicing sensors at steps 2910, 2912, 2914, and 2916) at a lower frequency. In some embodiments, the ingestible device 2500 can count out one millisecond intervals by decrementing the counter at step 2904 and resetting the counter at step 2906. For example, if the process 2950 is repeated at a frequency of 6 kHz, the counter will initially be set to "6" and the fast loop process 2950 will repeat six times before the ingestible device enters step 2906, causing the ingestible device 2500 to enter step 2906 at one millisecond intervals. If one millisecond has passed since the last time the time counter was incremented at step 2906, the ingestible device 2500 proceeds to step 2906, otherwise the ingestible device 2500 proceeds to step 2918.

At step 2906, the ingestible device 2500 will increment a time counter that tracks the number of milliseconds since the device woke up. In some aspects, the time counter can be used by the ingestible device to determine how long it has been into a particular step of the slow cycle process. For example, in some embodiments, the slow cycle process can indicate when the ingestible device 2500 moves a motor (e.g., motor 2720 or 704) to open the chamber 706 and take a sample, and the time counter can be used by the slow cycle process to determine how long the chamber 706 has been open.

At step 2908, the ingestible device 2500 selects a sensor to sample. In some embodiments, the ingestible device 2500 will sample the sensors sequentially, selecting a sensor to sample every millisecond. For example, the ingestible device 2500 may proceed to step 2910 during a first iteration, to step 2912 during a second iteration, to step 2914 during a third iteration, and to step 2916 during a fourth iteration, and then repeat the sequence after all sensors have been sampled. In some embodiments, some sensors may be sampled more or less often than others. For example, a temperature sensor may be ignored while the ingestible device is in the small intestine, and the ingestible device 2500 may not proceed to step 2912 at all. In some embodiments, the ingestible device 2500 communicates data to the sensors while they are being sampled, but the sensors will continue to operate while not being sampled. For example, each time the ingestible device 2500 samples a radial sensing sub-unit, it can determine whether a particular radial LED should be turned on, turned off, or left in its current state, and the radial LED will remain in its current state while being sensed. In certain embodiments of the ingestible device 2500, selecting the sensor to sample can additionally include using a multiplexer.

At step 2910, the ingestible device 2500 uses a voltage sensor to diagnose a possible fault within the electrical system (e.g., the electrical system described by FIG27 ). For example, the ingestible device 2500 may use GPIO to test communications to various subunits (e.g., motor 2722), and the ingestible device may determine the current voltage supplied by the battery 18. In some embodiments, the ingestible device 2500 may only operate a motor (e.g., motor 704 or 2722) when the sensed voltage of the battery 18 is above a threshold.

At step 2912, the ingestible device 2500 uses a temperature sensor to collect temperature measurements. For example, the ingestible device 2500 can collect temperature measurements to determine entry into or exit from the body. In certain embodiments, temperature measurements can also be used to infer other locations within the gastrointestinal tract. For example, in certain embodiments, the ingestible device 2500 can determine that a sudden change in temperature (e.g., due to the patient ingesting a hot meal or a cold drink) indicates that the ingestible device may be located in the stomach.

At step 2914, the ingestible device 2500 uses radial sensors (e.g., radial sensing subunits 32 and 2710) to collect radial reflectance data. For example, the ingestible device 2500 can use the microcontroller 2700 to direct the radial sensing subunit 2710 to flash light of a particular wavelength and measure the resulting reflectance. Doing so can collect radial reflectance data (e.g., for radial reflectance data series 602 (Figures 13A-13B), or the detected red reflectance 2426, green reflectance 2428, or blue reflectance 2430 (Figure 24)). Additionally, in some embodiments, the ingestible device 2500 can test the radial sensing subunits to detect device malfunctions. For example, if a first radial illuminator does not produce a induced signal in any of the radial detectors, but the other radial illuminators do, the ingestible device 2500 can determine that the first radial illuminator is not functioning properly.

At step 2916, in some embodiments, the ingestible device 2500 uses axial sensors (e.g., axial sensing sub-units 42, 2708, and 2712) to collect axial reflectivity data. Doing so can collect axial reflectivity data (e.g., for axial reflectivity data series 604 (Figures 13A-13B) or detected infrared reflectivity 2432 (Figure 24)). Additionally, in some embodiments, the ingestible device 2500 can use this data to detect anomalies within the gastrointestinal device or possible device failure. For example, if the ingestible device 2500 measures multiple anomaly data points due to a medical anomaly, the ingestible device 2500 can use fast loop processing 2950 to collect more data points in the vicinity of the anomaly.

At step 2918, the ingestible device 2500 terminates the fast loop process 2950 and returns to the sleep state. However, in some embodiments, the fast loop process 2950 can restart almost immediately thereafter.

The RTC wakeup process 2975 is distinct from the fast cycle method step 2900 and in some aspects can control the operation of the device based on a power saver (e.g., as part of the RTC and power cycle control 2802 ( FIG. 28 )). When the ingestible device 2500 temporarily enters a sleep state, the RTC oscillator 2716 continues to run and track the passage of time. The microcontroller 2700 is configured to wake up the ingestible device 2500 at regular intervals based on the output of the RTC oscillator 2716 and perform the device's primary sampling and data collection functions.

At step 2920, the ingestible device 2500 receives a signal from the RTC oscillator 2716 and wakes up. In some aspects, this can occur at intervals between one second and 10 minutes, and in other aspects, the interval can depend on the current location of the ingestible device as well as the ingestible device settings and energy reserves. For example, while in the stomach (e.g., in the starting point 2402 or the stomach 2404 (Figure 24)), the ingestible device 2500 can be woken up and data samples can be taken every second. In the small intestine (e.g., in the duodenum 2406 and the jejunum 2408 (Figure 24)), there is less variability in the environment surrounding the ingestible device 2500, and the device can be woken up and data samples can be taken every 30 seconds instead.

At step 2922, the ingestible device 2500 wakes up and begins executing the fast/slow cycle operation of the device, which is described with reference to Figures 30A to 30B and process 2950.

At step 2924, the ingestible device 2500 has completed collecting the new data set and executing the positioning algorithm, and the ingestible device 2500 returns to the sleep or standby state. Depending on the device settings, the ingestible device 2500 can configure the RTC oscillator to wake the device again after a predetermined period of time.

It is contemplated that the steps or instructions of FIG. 29 may be used with any other embodiment of the present application. Additionally, the steps and instructions described with reference to FIG. 29 may be implemented in an alternative order or in parallel further consistent with the objectives of the present application. For example, performing the steps described by steps 2910, 2912, 2914, and 2916 in parallel may reduce latency or allow collected data points to be synchronized to a specific time. Furthermore, it should be noted that any of the ingestible devices or systems discussed in this application may be used to perform one or more of the steps in FIG. 29 .

30A-30B are flow charts illustrating various aspects of the slow-loop operation of an ingestible device, according to certain embodiments of the device. An ingestible device (e.g., ingestible device 2500) may spend a significant portion of its time in a sleep or standby state to conserve energy reserves. In certain aspects, each time the ingestible device 2500 wakes up, the fast-loop process 2950 and the slow-loop process 3050 will run to collect data, run a positioning algorithm to determine the device's location, and take samples as needed.

The slow loop process 3050 begins at step 3000. At step 3000, the ingestible device 2500 is awakened by the real time clock (e.g., at step 2922 of the wakeup process 2975), by a magnet (e.g., from activating the magnetic switch 162 ( FIG. 2A )), or by a watchdog algorithm. In some aspects, the watchdog algorithm will guard against errors that would otherwise halt program execution. In some embodiments, the watchdog algorithm will include independent hardware timers that will periodically check various device functions, sensors, and/or hardware/software systems and will only allow the ingestible device 2500 to operate if all of the checked functions and/or systems are operating correctly. For example, if the ingestible device 2500 cannot establish a connection with a sensor, the ingestible device 2500 may reset itself by setting an RTC alarm and entering a sleep or standby state.

At step 3002, the system state is read from memory. For example, the current state of the ingestible device 2500 may be stored in the flash memory 2704. The state may indicate the current position of the ingestible device 2500 within the gastrointestinal tract. The state may also indicate whether the ingestible device 2500 has been programmed and properly initialized. For example, the state may indicate whether a physician or technician has properly assembled the ingestible device 2500 before administering it to a patient.

At step 3004, the ingestible device 2500 determines whether it has been properly programmed. If the ingestible device 2500 has been programmed, the process may proceed to step 3006. If the ingestible device 2500 has not been programmed, the process may proceed to step 3030 instead.

At step 3006, the ingestible device 2500 determines whether it has been awakened by the real-time clock (e.g., at step 2922 of the wake-up process 2975). If the ingestible device 2500 has been awakened by the real-time clock, the process may proceed to step 3008, and otherwise proceed to step 3024.

At step 3008, the ingestible device 2500 collects data from various sensors on the device, such as from the axial and radial sensing sub-units 2708, 2710, and 2712 (FIG. 27). The sensing mode and data collection mode may vary based on the intended usage of the ingestible device 2500, but in some embodiments, the ingestible device will collect red, green, blue, and infrared reflectance data samples, as well as temperature measurements.

At step 3010, the ingestible device 2500 logs the sensor data collected at step 3008 to internal memory (e.g., to memory subunit 2702 ( FIG. 27 )). In the ingestible device 2500, the data log is logged to 50 kB of internal flash memory (e.g., flash memory 2704 ( FIG. 27 )) and can be retrieved when requested by an external system, although different amounts of memory may be available in some embodiments. In some aspects, the data log will include the capsule transit time, derived algorithmically or obtained from the RTC oscillator 2716, and a complete set of sensor data corresponding to red, green, blue, and infrared reflectivity, along with temperature measurements.

At step 3012, the ingestible device 2500 runs a positioning algorithm (e.g., as described with reference to Figures 9-13 or Figure 24) to determine the location of the device. In some aspects, the ingestible device 2500 does so by analyzing the sensor data acquired at step 3008 or using a dataset of previous and current sensor data stored in a flash memory (e.g., flash memory 2704). For example, the ingestible device can use a duodenum detection algorithm to determine the pyloric transition (e.g., pyloric transition 2416 (Figure 24)) from the stomach (e.g., stomach 2404 (Figure 24)) to the duodenum (e.g., duodenum 2406 (Figure 24)).

At step 3014, the ingestible device 2500 determines whether a physical sample will be collected. For example, the ingestible device 2500 can be programmed to collect a sample as soon as a specific region of the gastrointestinal tract is identified at step 3012. The ingestible device 2500 can also be programmed to collect a sample a certain amount of time after the specific region of the gastrointestinal tract is identified at step 3012. For example, the ingestible device 2500 can be programmed to collect a sample as soon as the jejunum is detected or to collect a sample 10 minutes after the duodenum is detected. If the ingestible device 2500 is to collect a sample, the ingestible device 2500 can proceed to step 3016, and otherwise proceed to step 3018.

At step 3016, the ingestible device 2500 collects the solid sample using a motor motion algorithm. This can be accomplished by causing the device to change from one configuration that does not allow material to enter the sample chamber to a second configuration that does allow material to enter the sample chamber. For example, the ingestible device 2500 can use the microcontroller 2700 to transmit a signal to the motor 2722 to move the second wall portion 2512 and align the opening 2518 with the chamber opening 708. After a predetermined period of time, such as 10 minutes, the ingestible device 2500 can also cause the motor 2722 to rotate the opening 2518 away from the chamber opening 708, thereby sealing the chamber 706 with the sample inside.

At step 3018, the ingestible device 2500 may determine whether the maximum number of sensor logs has been reached. In some embodiments, the ingestible device 2500 will have 50kB of flash memory available for storing sensor data. In some embodiments, this is sufficient to record approximately 5,000 to 10,000 samples, depending on the number of sensors, the data format, and the accuracy used. In some embodiments, the ingestible device 2500 may also remove data samples or store them in a compressed format. For example, the ingestible device 2500 may remove all other data samples after they are no longer needed for positioning, leaving sufficient resolution for a physician or doctor to later interpret the data. For data that is relatively redundant or linear (e.g., temperature data taken within the body), the ingestible device 2500 may approximate portions of the data set as linear functions, storing the start and end points, and reducing the total amount of memory required. If the maximum number of logs has been reached, the ingestible device 2500 may proceed to step 3022; otherwise, the ingestible device 2500 may proceed to step 3020.

At step 3020, the ingestible device 2500 sets a real-time clock wake-up alarm. In some embodiments, the ingestible device 2500 can be configured to set an alarm to wake the device and collect a new data set at a later time. In some aspects, the interval between sleep and wake-up is between one second and ten minutes. When the alarm sounds (e.g., at step 2920 of process 2975), the ingestible device 2500 is interrupted from the sleep or standby state, and process 3050 is repeated.

At step 3022, the ingestible device 2500 will enter a deep sleep or standby state. In some embodiments, if no RTC wake-up alarm is set, the ingestible device 2500 will enter a deep sleep state by default and suspend certain device functions. In some embodiments, the ingestible device 2500 will shut down certain device functions in the standby state, but will continue to monitor the real-time clock (e.g., RTC oscillator 2716 ( FIG. 27 )) to determine when the ingestible device 2500 will resume operation.

At step 3024, the ingestible device 2500 will be able to communicate. In some embodiments, the ingestible device 2500 may disable communication to conserve energy reserves and avoid draining the battery 18. However, in some embodiments, in the event that the ingestible device 2500 is awakened by something other than an RTC alarm, the ingestible device 2500 will check for external communication (e.g., from the base station 950 via the IR light receiver 2714). This may be accomplished by powering and operating the IR light receiver 2714 or the communication sub-unit 120. In some embodiments, the ingestible device 2500 may use other types of communication, such as radio frequency (RF), Bluetooth, or other near field communication (NFC) that can be turned on and off as required.

At step 3026, the ingestible device 2500 checks for external communications. For example, in some embodiments, after the ingestible device 2500 activates communications (e.g., the communications sub-unit 120), the ingestible device 2500 can monitor the IR light receiver 2714 for communications from the base station 950.

At step 3028, the ingestible device 2500 will wait for incoming communication for 20 seconds. If no communication is detected within 20 seconds, the ingestible device 2500 will turn off communication to conserve energy. In some embodiments, the ingestible device 2500 can wait for a different period of time, or can reset the 20-second timer whenever an incoming communication is received.

At step 3030, if the ingestible device 2500 has not been programmed, the ingestible device 2500 will be enabled to communicate by default. In some embodiments, the ingestible device 2500 needs to be programmed or initialized by a physician or technician before the device is administered to a patient. If no programming is found on the ingestible device 2500, the default mode will be to enable communication and await programming instructions.

At step 3032, the ingestible device 2500 will await programmed instructions from the user. In some embodiments, the user may be provided with a computer, cell phone, tablet, or monitoring application, a radio transceiver, a base station, or the like, for communicating with the ingestible device 2500. For example, the user may be provided with a base station 950 that is capable of transmitting an infrared signal to the ingestible device 2500, which will be detected and interpreted (e.g., a signal detected by the IR light receiver 2714 and interpreted by the communication sub-unit 120).

At step 3034, the ingestible device 2500 will wait for the sensor acquisition to complete. After the ingestible device 2500 begins receiving incoming communication signals, the ingestible device 2500 will wait until the complete communication has been received. For example, it may take several minutes for the user to program the ingestible device 2500, and the ingestible device 2500 will keep the communication channel open while receiving instructions.

At step 3036, the ingestible device 2500 will check whether it has received any communication within the last 20 seconds. Similar to step 3028, if no communication is detected within 20 seconds, the ingestible device 2500 will shut down to conserve energy. In some embodiments, the ingestible device 2500 can wait for a different period of time.

It will be understood that the steps and descriptions of the flowcharts of the present disclosure, including Figures 30A to 30B, are illustrative only. Without departing from the scope of the present disclosure, any of the steps and descriptions of the flowcharts, including Figures 30A to 30B, may be modified, omitted, rearranged, performed in turn or in parallel, two or more of the steps may be combined, or any additional steps may be added. For example, the ingestible device 2500 may continue to collect new data samples and run the positioning algorithm simultaneously with the samples being collected. In addition, it should be noted that the steps and descriptions of Figures 30A to 30B may be combined with any other systems, devices, or methods described in this application, and any of the ingestible devices or systems discussed in this application may be used to perform one or more of the steps in Figures 30A to 30B.

Figure 31 is a flow chart illustrating the overall operation of the device, according to certain embodiments of the device. In some aspects, sample operation processing 3150 describes the generation of a sample from the gastrointestinal tract of a patient using an ingestible device. Although Figure 31 may be described with reference to ingestible device 2500 for illustrative purposes, this is not intended to be limiting, and any portion or all of the processing described in Figure 31 may be applied to any device discussed in this application (e.g., ingestible devices 10, 300, 302, 304, 306, 700, and 1900), and any of the ingestible devices may be used to perform one or more portions of the processing described in Figure 31. In addition, the features of Figure 31 may be combined with any other system, method, or process described in this application. For example, the processing described by Figure 31 may utilize the hardware and electrical systems of Figures 2, 15, 27, and 28 or the positioning methods of Figures 8 to 13, 21 to 24, or 32 to 33.

At step 3100, the ingestible device 2500 will detect whether it has been activated by being separated from the magnet. As described in Figure 2A, an ingestible device (e.g., ingestible device 2500) can have a magnetic switch 162 for turning the device on or off. After manufacturing, the ingestible device can be placed in a dedicated container near a magnet and the resulting magnetic field holds the magnetic switch 162 in the "Off" position. When the ingestible device 2500 is ready to be programmed by the user and to be administered to a patient, the ingestible device 2500 is moved away from the magnet and the magnetic switch 162 will change to the "On" position. Once the ingestible device 2500 is turned on for the first time, it will attempt to establish communication.

At step 3102, the ingestible device 2500 will wait for user input via UART. The ingestible device is provided with a communication subunit (e.g., communication subunit 120) that can be used to communicate with the ingestible device 2500 via UART (e.g., universal asynchronous receiver/transmitter (UART) interface 114). The ingestible device 2500 will then provide the user with an opportunity to program the device. In some embodiments, the ingestible device 2500 can be provided with a base station or dock that can be connected to a computer, tablet, handheld device, smartphone, or smartwatch; for example, for the user to program the ingestible device 2500. In some embodiments, the ingestible device 2500 can also communicate using other means, such as radio frequency, Bluetooth, near field communication, and the like, all of which can be used to program the ingestible device 2500 or retrieve information from the ingestible device 2500. In some aspects, the ingestible device 2500 is administered to the patient after being programmed and initialized by the user.

At step 3104, the ingestible device 2500 will perform sensing, record data, and execute a positioning algorithm to determine the location of the device. After being administered to the patient, the ingestible device 2500 will continue to collect data from the sensors, record data, and execute a positioning algorithm to identify the location of the device based on the collected data. For example, the ingestible device 2500 can collect a set of axial and radial data as it passes through the gastrointestinal tract and execute a positioning algorithm as described with reference to Figures 8 to 13. As another example, the ingestible device 2500 can collect a reflectance data set at different wavelengths from illumination and execute a positioning algorithm as described with reference to Figure 24. In certain aspects, the ingestible device 2500 will attempt to identify the pyloric transition (e.g., pyloric transition 2416 (Figure 24)) as it enters the duodenal portion of the small intestine (e.g., duodenum 2406). Once the ingestible device 2500 is determined to be located in the duodenum, the ingestible device can obtain a sample or wait a predetermined period of time (e.g., 10 minutes) before obtaining a sample.

At step 3106, the ingestible device 2500 will collect the sample and continue to collect and record sensor data. After locating the duodenum, the ingestible device can obtain a sample from the gastrointestinal tract in the environment surrounding the device by providing access to a sampling chamber (e.g., chamber 706). For example, the ingestible device 2500 can use a motor (e.g., motor 704, 2722) to change the device from a configuration that does not allow a sample to enter the sampling chamber from the gastrointestinal tract to another configuration that allows a sample to enter the sampling chamber from the gastrointestinal tract. This can be achieved by transmitting a signal from the microcontroller 2700 to the motor 2722 to move the second wall portion 2512 so that the opening 2518 is aligned with the chamber opening 708 for the sampling chamber. Similarly, after waiting for a certain period of time, the ingestible device 2500 can move the second wall portion 2512 back to seal the sampling chamber after the sample has been obtained. As the sample is being collected, and later, the ingestible device 2500 will continue to measure and record sensor data.

In some embodiments, the ingestible device 2500 will be configured to release a medicament rather than collect a sample. For example, before the ingestible device 2500 is administered to a patient, the chamber 706 may be provided with a drug, powder, liquid, or other medicament. In some embodiments, the user may have the ability to load the medicament into the chamber 706. For example, during the time that the ingestible device 2500 is being programmed (e.g., by the user using the base station 950), the user may have the ability to transmit instructions to the ingestible device 2500 to expose the chamber 706 by rotating the second wall portion 2512.

In certain embodiments, the ingestible device 2500 is configured to analyze the captured sample using diagnostics. For example, each chamber 706 may also contain a hydrophilic foam or sponge to aid in sample collection. Additionally, the hydrophilic foam or sponge may be provided with or without a biological agent for immobilizing or detecting target analytes, effectively converting the chamber 706 into a sampling and diagnostic chamber. This can be combined with other diagnostic and assay techniques to diagnose or detect different conditions that affect specific portions of the gastrointestinal tract.

At step 3108, the ingestible device 2500 will continue to collect and record sensor data even after one or more samples have been obtained. In some aspects, the ingestible device 2500 will continue to record sensor data until a maximum number of data logs have been collected.

At step 3110, the ingestible device 2500 will enter a deep sleep state after reaching a maximum operating time, detecting separation from the body, or recording a maximum number of data samples. In some aspects, the ingestible device 2500 shuts down some device functions in the deep sleep state until the ingestible device wakes up. In some embodiments, the ingestible device 2500 can be awakened using a magnet or base station provided to the user. In some embodiments, the patient can retrieve the ingestible device 2500 after it has left the body, and the collected samples and data logs can be collected from the retrieved device. In some embodiments, the ingestible device can use wireless communication technology in the body, such as RF, Bluetooth, or near field communication to transmit the collected data to a computer, base station, tablet, phone, smart watch, or other similar device.

At step 3112, the ingestible device 2500 can be awakened via the UART after being retrieved by the user. In those embodiments where the device has been retrieved by the user, the retrieved device can be brought back to a base station (e.g., base station 950) or a similarly equipped computer for data and sample retrieval. In some embodiments, the ingestible device 2500 will also be awakened from its deep sleep by exposure to a magnet; for example, a magnet that can be provided as part of the base station 950.

At step 3114, the ingestible device 2500 will have completed its operation and will provide the user with the ability to retrieve the physical sample. After retrieval and reactivation from the deep sleep state, the ingestible device 2500 can automatically communicate the collected data back to the user and the ingestible device can provide access to chamber 706. In certain embodiments, the user or a certified technician can be provided with a means for collecting physical storage and samples directly from the ingestible device 2500. For example, by providing authorized individuals with specialized tools for disassembling the ingestible device 2500, any potentially sensitive data or samples can be protected from access by unauthorized users.

It will be understood that the steps and descriptions of the flowchart of the present disclosure, including FIG. 31 , are illustrative only. Any of the steps and descriptions of the flowchart, including FIG. 31 , may be modified, omitted, rearranged, performed in turn or in parallel, two or more of the steps may be combined, or any additional steps may be added without departing from the scope of the present disclosure. For example, the ingestible device 2500 may enter a deep sleep state immediately after collecting a sample in order to conserve energy. Furthermore, it should be noted that the steps and descriptions of FIG. 31 may be combined with any other systems, devices, or methods described herein, and any of the ingestible devices or systems discussed herein may be used to perform one or more of the steps in FIG. 31 .

FIG32 is a flow chart illustrating certain aspects of a cecum detection algorithm used by the device. While FIG32 may be described with reference to the ingestible device 2500 for illustrative purposes, this is not intended to be limiting, and any portion or all of the cecum detection process 3250 described in FIG31 may be applied to any of the devices discussed herein (e.g., ingestible devices 10, 300, 302, 304, 306, 700, and 1900), and any of the ingestible devices may be used to perform one or more portions of the process described in FIG32. Furthermore, features of FIG32 may be combined with any other system, method, or process described herein. For example, portions of the algorithm described in FIG32 may be integrated into any of the algorithms described in FIG24.

At step 3200, the ingestible device 2500 wakes up. This is accomplished due to a previously set RTC alarm set by the ingestible device 2500.

At step 3202, the ingestible device 2500 collects and stores new sensor data points. The ingestible device 2500 begins by flashing different colored LEDs (e.g., illuminators 1902a and 1902b) to produce illumination at red and green wavelengths and by detecting (e.g., by detector 1904) the resulting reflectivity from the environment surrounding the ingestible device 2500. These data points are then stored in flash memory.

At step 3204, the ingestible device 2500 determines whether the duodenum has been detected. For example, if the current state of the ingestible device 2500 is the DUODENUM or JEJUNUM state, or if the duodenum detection algorithm has determined that a pyloric transition has occurred (e.g., pyloric transition 2416).

At step 3206, the ingestible device 2500 will load the last "n" stored light sensor values from the flash memory (e.g., flash memory 2704). The number of points "n" should be large enough to calculate a statistically significant mean and standard deviation, but a value of 30 is chosen in many aspects.

At step 3208, the ingestion device 2500 may calculate the intra-set standard deviation.

At step 3210, the ingestible device 2500 may calculate the average within the group.

At step 3212, the ingestible device 2500 compares the red data to the green data. In some embodiments, this may involve subtracting a multiple of the red standard deviation from the mean of the red data and subtracting a multiple of the green standard deviation from the mean of the green data. In some embodiments, the multiple "k" is selected to be approximately 1.5. In some embodiments, the multiple may be programmed by the user prior to administering the device to the patient, or the multiple may be changed based on the measured sensor data. If the condition in step 3212 is not met, the ingestible device 2500 deems the data point unreliable and the data point is not considered.

At step 3214, the ingestible device 2500 increases the value of the integrator. In some embodiments, the ingestible device 2500 adds the difference between the average of the green data and the average of the red data to the integrator. In some embodiments, the ingestible device 2500 may normalize the difference by the average of the green data before adding the difference to the integrator. In some embodiments, the ingestible device 2500 will increment by one rather than adding the difference between the green data and the red data. In some embodiments, the integrator may also be periodically reset to zero or decreased by a certain proportion each time the algorithm is executed. The ingestible device 2500 stores the value of the integrator and uses the value to determine when the transition to the cecum has occurred.

At step 3216, the ingestible device 2500 compares the integrator to a detection threshold to determine if a transition has occurred. In some embodiments, the threshold will be a multiple of the average green or blue measurement, for example, ten times the average green measurement. In some embodiments, the threshold can be a predetermined number when the integrator is incremented by one at step 3214 or when the value added to the integrator at step 3214 has been normalized. In some embodiments, the predetermined number can be based on how frequently sensor data is collected, or the predetermined number can be programmed into the device before the device is administered to the patient.

At step 3218, the ingestible device 2500 determines that the ileocecal transition has occurred and the device is now in the cecum. This is achieved after the algorithm determines that the combined difference between the average red reflectance data and the average green reflectance data is above a threshold.

At step 3220, the ingestible device 2500 enters a deep sleep state. However, in some aspects, the ingestible device 2500 can set an RTC oscillator alarm that wakes the ingestible device 2500 from its sleep to obtain additional data samples and execute additional positioning algorithms as needed.

It will be understood that the steps and descriptions of the flowchart of the present disclosure, including FIG. 32 , are illustrative only. Any of the steps and descriptions of the flowchart, including FIG. 32 , may be modified, omitted, rearranged, performed in turn or in parallel, two or more of the steps may be combined, or any additional steps may be added without departing from the scope of the present disclosure. For example, the ingestible device 2500 may calculate the mean and standard deviation of multiple data sets in parallel in order to speed up the overall calculation time. Furthermore, it should be noted that the steps and descriptions of FIG. 32 may be combined with any other systems, devices, or methods described herein, and any of the ingestible devices or systems discussed herein may be used to perform one or more of the steps in FIG. 32 .

Figure 33 is a flow chart illustrating certain aspects of the duodenum detection algorithm used by the device. Although Figure 33 may be described with reference to the ingestible device 2500 for illustrative purposes, this is not intended to be limiting, and any portion or all of the duodenum detection process 3350 described in Figure 33 may be applied to any of the devices discussed in this application (e.g., ingestible devices 10, 300, 302, 304, 306, 700, and 1900), and any of the ingestible devices may be used to perform one or more portions of the process described in Figure 33. Furthermore, the features of Figure 33 may be combined with any other system, method, or process described in this application. For example, portions of the algorithm described in Figure 33 may be integrated into any of the algorithms described in Figure 24.

At step 3300, the ingestible device 2500 wakes up. The ingestible device 2500 will normally wake up at regular intervals based on the RTC oscillator. Once the ingestible device 2500 wakes up, it will continue with the rest of the processing.

At step 3302, the ingestible device 2500 collects and stores new sensor data points. The ingestible device 2500 begins by flashing different colored LEDs (e.g., illuminators 1902a and 1902b) to produce illumination at red and green wavelengths. The ingestible device 2500 then detects (e.g., via detector 1904) the resulting reflectance and stores the data in memory.

At step 3304, the ingestible device 2500 will load the last "n" stored light sensor values from the flash memory (e.g., flash memory 2704). The number of points "n" should be large enough to calculate a statistically significant mean and standard deviation, but in many aspects a value above 30 is chosen.

At step 3306, the ingestion device 2500 may calculate the standard deviation within the group.

At step 3308, the ingestion device 2500 may calculate the average within the group.

At step 3310, the ingestible device 2500 compares the red data to the green data. Similar to step 3212 ( FIG. 32 ), in some embodiments, this may involve subtracting multiples of the red standard deviation from the mean of the red data and subtracting multiples of the green standard deviation from the mean of the green data. If the conditions in step 3310 are not met, the ingestible device 2500 may not consider the data point further.

At step 3312, the ingestible device 2500 increments the value of the integrator. Similar to step 3214 ( FIG. 32 ), in some embodiments, the ingestible device 2500 adds the difference between the average of the green data and the average of the red data to the integrator, and in some embodiments, the integrator is incremented by one rather than adding the difference between the green data and the red data. The ingestible device 2500 can then use the stored value in the integrator to determine when the transition to the duodenum has occurred.

At step 3314, the ingestible device 2500 compares the integrator to a detection threshold to determine whether a transition has occurred. The threshold may depend on a number of factors, such as those described with reference to step 3216 ( FIG. 32 ). Additionally, the threshold may depend on the components used in the ingestible device 2500 and may vary based on the magnitude of the detected signal.

At step 3316, the ingestible device 2500 determines that a pyloric transition has occurred and is currently located in the duodenum. This is achieved after the algorithm determines that the combined difference between the average red reflectance data and the average green reflectance data is above a threshold.

At step 3318, the ingestible device 2500 enters a deep sleep state. However, in some aspects, the ingestible device 2500 can set an RTC oscillator alarm that wakes the ingestible device 2500 from its sleep to take additional data samples and execute additional positioning algorithms as needed.

At step 3320, the ingestible device 2500 resets the integrator to 0. In some aspects, this is done when the ingestible device 2500 determines that the most recently acquired data is unreliable.

It will be understood that the steps and descriptions of the flowchart of the present disclosure, including FIG. 33 , are illustrative only. Any of the steps and descriptions of the flowchart, including FIG. 33 , may be modified, omitted, rearranged, performed in turn or in parallel, two or more of the steps may be combined, or any additional steps may be added without departing from the scope of the present disclosure. For example, the ingestible device 2500 may calculate the mean and standard deviation of multiple data sets in parallel in order to speed up the overall calculation time. Furthermore, it should be noted that the steps and descriptions of FIG. 33 may be combined with any other system, device, or method described herein, and any of the ingestible devices or systems discussed herein may be used to perform one or more of the steps in FIG. 33 .

FIG34 is data from an example of a rapid transit through an individual's GI tract, according to certain embodiments of a device. Graph 3400 shows a sample data set collected by an ingestible device flashing light of different wavelengths as the ingestible device transits through the gastrointestinal tract. This raw data shows an actual transit performed by an ingestible device configured similarly to ingestible device 1900 and collecting data similarly to the methods described with reference to FIG21-24. FIG34 also shows that consuming a cold beverage and/or food for more than 30 minutes after ingestion of the device does not change the device's temperature reading, indicating that the device exited the stomach more than 30 minutes ago.

24 , it can be seen that the radial green and radial blue data sets closely follow each other and follow a similar pattern with relatively flat detection values. Also, similar to the red reflectance data 2430 of FIG. 24 , it can be seen that the red data set begins to diverge rapidly from the blue and green data sets near the first hour mark as the ingestible device 1900 undergoes a pyloric transition (e.g., pyloric transition 2416 ( FIG. 24 )). Between the second and third hours, the response to red wavelength illumination and axial infrared illumination increases substantially, reaching a peak near the third hour mark. This corresponds to transit through the duodenum (e.g., duodenum 2406 ( FIG. 24 )) to the Treitz ligament transition in the jejunum (e.g., to the Treitz ligament transition 2418 in the jejunum 2408 ( FIG. 24 )). From the third to the fifth hour, a decrease in the detected red reflectance and axial infrared reflectance is consistent with transit through the jejunum, with an ileocecal transition occurring near the fifth hour mark (e.g., ileocecal transition 2420 ( FIG. 24 )). From the fifth to the seventh hour mark, an increase in the detected infrared reflectance response relative to the red reflectance is similarly consistent with the cecum transitioning into the large intestine (e.g., cecal transition 2422 into the large intestine 2412 ( FIG. 24 )).

Figure 35 is a color graph showing the varying levels of reflected light detected by the device over 13 different attempts. This corresponds to a set of tests conducted using an ingestible device similar to ingestible device 1900. In Figure 35, after the ingestible device has been retrieved and the data has been extracted from the device, the data collected from the red, green, and blue sensors are normalized and subsequently combined into a single color. Each data set collected from the detector is mapped into a single hexadecimal color code that represents the relative magnitude of the measured red, green, and blue data in each data set. After each data set is mapped into a single representative color, chart 3400 is generated to show the differences in the measured data as the device is transported through the gastrointestinal tract. Graph 3400 shows data collected by an ingestible device during multiple human attempts, where p1t3, p1t4, p2t1, p2t2, p2t5, p3t1, p3t3, p3t4 illustrate rapid transit, and p1t1, p1t2, p2t3, p2t4, p3t2 illustrate feeding transit (i.e., the subject has recently consumed food). Note that the device itself does not function as a color imaging device, and graph 3400 is present for illustrative purposes only.

In FIG35 , higher samples are shown at the top of the graph and later samples are shown towards the top. In general, a red shift is observed in almost all cases of the pyloric transition. Certain cases of impaired gastric emptying indicate a yellow-green color, and the unidentified food of p2t3 shows a varying purple/blue color between samples 100 to 700. The color shift due to exiting the body is shown from sample steps 5400 to 5500 of p3t2, resulting in a generally light blue color being detected. The location of the determined pyloric transition from the stomach to the small intestine (e.g., pyloric transition 2416 ( FIG24 )) is shown with a small circle, and it has generally been found that the ingestible device is able to reliably identify the portion of the gastrointestinal tract.

For illustrative purposes, the examples given herein focus primarily on a number of different exemplary embodiments of ingestible devices. However, the possible ingestible devices that may be constructed are not limited to these embodiments, and the overall shape and design may be varied without significantly altering the functionality and operation of the device. For example, certain embodiments of the ingestible device may feature a sampling chamber generally oriented toward the middle of the device, along with two sets of axial sensing subunits, each set of axial sensing subunits being located at generally opposite ends of the device. Moreover, the applications of ingestible devices are not limited to simply collecting data, sampling and testing portions of the gastrointestinal tract, or delivering pharmaceutical agents. For example, in certain embodiments, the ingestible device may be adapted to include multiple chemical, electrical, or optical diagnostics for diagnosing a variety of diseases. Similarly, multiple different sensors for measuring bodily phenomena or other physiological qualities may be included on the ingestible device. For example, the ingestible device may be adapted to measure elevated levels of certain chemical constituents or impurities in the gastrointestinal tract, or a combination of positioning, sampling, and appropriate diagnostic and assay techniques incorporated into the sampling chamber may be particularly well suited for determining the presence of small intestinal bacterial overgrowth (SIBO).

At least some of the elements of the various embodiments of the ingestible device described herein that are implemented via software can be written in a high-level programming language, such as object-oriented programming, a scripting language, or both. Thus, the program code can be written in C, C ⁺⁺ , or any other suitable programming language and can include modules or classes, as known to those skilled in the art of object-oriented programming. Alternatively or in addition, at least some of the elements of the various embodiments of the ingestible device described herein that are implemented via software can be written in assembly language, machine language, or firmware, as desired. In either case, the language can be a compiled or interpreted language.

At least some of the program code for implementing the ingestible device may be stored on a storage medium or computer-readable medium that is read by a general-purpose or special-purpose programmable computing device having a processor, operating system, and associated hardware and software necessary for the functionality of at least one of the embodiments described herein. The program code, when read by the computing device, configures the computing device to operate in a novel, specific, and predefined manner to perform at least one of the methods described herein.

In addition, at least some of the programs associated with the systems, devices, and methods of the exemplary embodiments described herein can be distributed in a computer program product comprising a computer-readable medium carrying computer-usable instructions for one or more processors. The medium can be provided in various forms, including non-transitory forms, such as, but not limited to, one or more disks, optical disks, tapes, chips, and magnetic and electronic memories. In some embodiments, the medium can be transient in nature, such as, but not limited to, wire transmission, satellite transmission, network transmission (e.g., download), media, digital and analog signals, and the like. The computer-usable instructions can also be in various formats, including compiled and uncompiled code.

Various embodiments of the systems, processes, and devices have been described herein by way of example only. It is contemplated that the features and limitations described in any one embodiment may be applied to any other embodiment herein, and that the processes or examples associated with one embodiment may be combined with any other embodiment in an appropriate manner, in a different order, or in parallel. It should be noted that the above-described systems and/or methods may be applied to or used in accordance with other systems and/or methods. Various modifications and variations may be made to these exemplary embodiments without departing from the spirit and scope of the embodiments, the spirit and scope of which are limited only by the appended claims. The appended claims should be given the broadest interpretation consistent with this specification as a whole.

Claims (13)

1. An ingestible device comprising: shell; A first optical sensing unit within the housing is configured to transmit first illumination at a first wavelength toward an environment outside the housing located within the gastrointestinal tract of the body, and to detect a first reflectivity caused by the first illumination from the environment. A second optical sensing unit within the housing is configured to transmit second illumination toward the environment outside the housing at a second wavelength, the second wavelength being different from the first wavelength, and to detect a second reflectivity caused by the second illumination from the environment; and The processing module located within the housing is configured to: A first reflectance value is stored in a first dataset, wherein the first reflectance value indicates the amount of light detected by the ingestible device from the first reflectance; and a second reflectance value is stored in a second dataset, wherein the second reflectance value indicates the amount of light detected by the ingestible device from the second reflectance. Identify the state of the ingestible device, wherein the state is a known or estimated location of the ingestible device; and The positional change of the ingestible device within the body's gastrointestinal tract is determined by detecting whether a state transition has occurred, the state transition being detected by comparing the first dataset with the second dataset. 2. The ingestible device of claim 1, wherein the processing module is configured such that comparing the first dataset with the second dataset includes integrating at least one of (i) the difference between reflectance values stored in the first dataset and reflectance values stored in the second dataset and (ii) the difference between the moving average of the first dataset and the moving average of the second dataset. 3. The ingestible device according to claim 1, wherein the processing module is configured such that: Comparing the first dataset and the second dataset includes obtaining a first average value from the reflectance values stored in the first dataset; A second average value is obtained from the reflectance values stored in the second dataset; and Obtain the difference between the first average value and the second average value. 4. The ingestible device of claim 1, wherein the processing module is configured such that comparing the first dataset and the second dataset includes incrementing the count once when the average of the first dataset minus a multiple of the standard deviation of the first dataset is greater than the average of the second dataset plus a multiple of the standard deviation of the second dataset. 5. The ingestible device according to claim 1, wherein: The first wavelength is located in at least one of the red spectrum and the infrared spectrum; The second wavelength falls within at least one of the blue and green spectra; The identified state is the stomach; and A state transition has occurred when comparing the first dataset and the second dataset indicates that the first dataset and the second dataset have diverged in a statistically significant manner, and the state transition is a pyloric transition. 6. The ingestible device according to claim 1, wherein: The first wavelength is located in at least one of the red spectrum and the infrared spectrum; The second wavelength falls within at least one of the blue and green spectra; The identified state is the duodenum; and A state transition has occurred when comparing the first dataset with the second dataset indicates that the difference between the first dataset and the second dataset is constant in a statistically significant manner, and the state transition is a Treitz ligament transition. 7. The ingestible device according to claim 1, wherein: The first wavelength is in the infrared spectrum; The second wavelength falls within at least one of the green and blue spectra; The identified state is jejunum; and A state transition has occurred when comparing the first dataset and the second dataset indicates that the first dataset and the second dataset have converged in a statistically significant manner, and the state transition is an ileocecal transition. 8. The ingestible device according to claim 1, wherein: The first wavelength is in the red spectrum; The second wavelength falls within at least one of the green and blue spectra; The identified condition is the appendix; and A state transition has occurred when the comparison indicates that the first dataset and the second dataset have converged in a statistically significant manner, and the state transition is a cecum transition. 9. The ingestible device of claim 1 further includes a temperature sensor configured to measure temperature changes in the environment, wherein: the identified state is outside the body; a state transition has occurred when the measured temperature change is above a threshold, and the state transition is entering the stomach. 10. The ingestible device according to claim 1, wherein the identified state is the ileum; and A state transition has occurred when comparing the first dataset and the second dataset indicates that the first dataset and the second dataset have converged in a statistically significant manner, and the state transition is an ileocecal transition. 11. The ingestible device of claim 10, wherein the first wavelength is in the red spectrum and the second wavelength is in the green spectrum. 12. An ingestible device comprising: shell; A first optical sensing unit is configured to transmit first illumination at a first wavelength toward an environment outside the housing and to detect a first reflectivity caused by the first illumination from the environment. A second optical sensing unit is configured to transmit second illumination toward the environment outside the housing at a second wavelength, the second wavelength being different from the first wavelength, and to detect a second reflectivity caused by the second illumination from the environment; The processing module located within the housing is configured to: The positional change of the ingestible device within the body's gastrointestinal tract is determined by comparing the first reflectance and the second reflectance; and The gastrointestinal tract is sampled when the identified location matches a predetermined location by actuating at least one of the outer casing and the sampling chamber. 13. The ingestible device of claim 12, wherein sampling the gastrointestinal tract by actuating at least one of the portion of the housing and the sampling chamber comprises moving at least one of the portion of the housing and the sampling chamber from an orientation that does not allow the sample to enter the sample chamber from the gastrointestinal tract to an orientation that allows the sample to enter the sample chamber.