INGESTIBLE APPARATUS AND METHOD FOR COLLECTING SAMPLES IN THE GASTROINTESTINAL TRACT AND/OR DELIVERING HEALTH-RELATED SUBSTANCE THERETO

Abstract

An ingestible apparatus for collecting samples from a target area of a gastrointestinal (GI) tract of a subject and/or for delivering a health-related substance thereto. An example ingestible apparatus includes a housing defining a sample compartment, a stopper configured to seal an access port, and an actuation assembly connected to the stopper. The actuation assembly is movable between a first working position where the access port is open and a second working position where the access port is sealed with the stopper. The apparatus also includes a dissolvable block configured to prevent the actuation assembly from moving between the first and second working positions until the apparatus is within a target area of the GI tract. The actuation assembly is configured, in the second working position, to apply a linear force at an interface between the stopper and a sealing surface to seal the access port with the stopper.

Claims

1. An ingestible apparatus for collecting a sample from a target area of a gastrointestinal (GI) tract of a subject, the ingestible apparatus comprising: a housing defining a sample compartment, the housing comprising a sealing surface having an access port formed therein, and the sample compartment being communicable with the access port; a stopper configured to seal the access port; an actuation assembly connected to the stopper, the actuation assembly being movable between a first working position where the access port is open and a second working position where the access port is sealed with the stopper; and a dissolvable block configured to prevent the actuation assembly from moving between the first and second working positions until the ingestible apparatus is within a target area of the GI tract of the subject, wherein the actuation assembly is configured, in the second working position, to apply a linear force at an interface between the stopper and the sealing surface to seal the access port with the stopper.

2. The ingestible apparatus of claim 1, wherein a direction of the linear force applied by the actuation assembly, in the second working position, is approximately perpendicular to the interface between the stopper and the sealing surface.

3. The ingestible apparatus of claim 1 or 2, wherein the dissolvable block is not arranged between the stopper and the sealing surface.

4. The ingestible apparatus of any one of claims 1-3, wherein the actuation assembly comprises a compression spring, wherein the compression spring is in a first compressed state in the first working position and a second compressed state in the second working position, a potential energy associated with the second compressed state is greater than zero and less than a potential energy associated with the first compressed state.

5. The ingestible apparatus of any one of claims 1-3, wherein the actuation assembly comprises an extension spring, wherein the extension spring is in a first extension state in the first working position and a second extension state in the second working position, a potential energy associated with the second extension state is greater than zero and less than a potential energy associated with the first extension state.

6. The ingestible apparatus of claim 4 or 5, wherein the actuation assembly comprises a plurality of springs, each of the springs being a compression or expansion spring.

7. The ingestible apparatus of claim 5, wherein the extension spring is made of an elastic material.

8. The ingestible apparatus of any one of claims 4-7, wherein the actuation assembly further comprises a rigid or flexible piston.

9. The ingestible apparatus of any one of claims 1-8, wherein a surface area of the stopper at the interface between the stopper and the sealing surface is larger than an area of the access port.

10. The ingestible apparatus of claim 9, wherein at least a portion of the surface area of the stopper overlaps with and contacts at least a portion of the sealing surface at the second working position of the actuation assembly.

11. The ingestible apparatus of claim 9 or 10, further comprising a recess arranged at least partially around a perimeter of the sealing surface.

12. The ingestible apparatus of claim 11, wherein the recess is configured to enhance a seal between the stopper and the sealing surface at the second working position of the actuation assembly.

13. The ingestible apparatus of any one of claims 1-12, further comprising a gasket arranged between the stopper and the sealing surface.

14. The ingestible apparatus of any one of claims 1-13, further comprising a mucosal-layer brush.

15. The ingestible apparatus of claim 14, wherein the mucosal-layer brush is configured for collecting the sample.

16. The ingestible apparatus of claim 14 or 15, wherein the stopper is connected to an end of the mucosal-layer brush.

17. The ingestible apparatus of any one of claims 14-16, wherein at least a portion of the mucosal-layer brush extends outside of the housing at the first working position of the actuation assembly.

18. The ingestible apparatus of claim 17, wherein the portion of the mucosal-layer brush extends outside of the sample compartment at the first working position of the actuation assembly.

19. The ingestible apparatus of any one of claims 14-18, wherein the mucosal-layer brush is retracted inside the housing at the second working position of the actuation assembly.

20. The ingestible apparatus of claim 19, wherein the mucosal-layer brush is retracted inside the sample compartment at the second working position of the actuation assembly.

21. The ingestible apparatus of any one of claims 14-20, wherein the mucosal-layer brush is distributed radially around at least a portion of the housing.

22. The ingestible apparatus of any one of claims 14-21, wherein the mucosal-layer brush extends beyond a perimeter of the stopper at the first working position of the actuation assembly.

23. The ingestible apparatus of claim 22, wherein the mucosal-layer brush extends beyond a perimeter of the housing at the first working position of the actuation assembly.

24. The ingestible apparatus of any one of claims 14-23, wherein the mucosal-layer brush comprises one or more bristles.

25. The ingestible apparatus of claim 24, wherein the mucosal-layer brush further comprises a stem, wherein the one or more bristles are connected to the stem.

26. The ingestible apparatus of claim 24 or 25, wherein the one or more bristles are elongate members.

27. The ingestible apparatus of claim 24 or 25, wherein the one or more bristles are made of a porous material.

28. The ingestible apparatus of any one of claims 24-27, further comprising an isolating structure configured to dissolve in a gastrointestinal content of the GI tract of the subject, wherein the housing and the one or more bristles are enclosed within the isolating structure.

29. The ingestible apparatus of claim 28, wherein the one or more bristles are compressed or spring loaded by the isolating structure.

30. The ingestible apparatus of claim 28 or 29, wherein the isolating structure is a shell.

31. The ingestible apparatus of any one of claims 14-30, wherein the mucosal-layer brush is connected to the actuation assembly.

32. The ingestible apparatus of any one of claims 14-31, wherein the mucosal-layer brush comprises a fluid-absorbent material.

33. The ingestible apparatus of any one of claims 1-32, wherein the housing comprises a first portion that houses the stopper and a second portion that defines the sample compartment, the first portion being configured to removably couple with the second portion.

34. The ingestible apparatus of claim 33, wherein the first portion comprises a first wall section and the second portion comprises a second wall section, the first and second wall sections being in an overlapping condition when the first portion is coupled with the second portion.

35. The ingestible apparatus of claim 34, wherein the overlapping condition of the first and second wall sections extends for about 20-25% of a total length of the housing.

36. The ingestible apparatus of claim 34 or 35, wherein the first and second wall sections are coupled by interference fit.

37. The ingestible apparatus of claim 34 or 35, wherein the first and second wall portions are coupled by threading.

38. The ingestible apparatus of any of claim 36 or 37, wherein the coupling extends only a portion of the overlapping portion.

39. The ingestible apparatus of any one of claims 33-38, wherein the second compartment has a volume of at least about 20 microliters (μL) to 100 μL.

40. The ingestible apparatus of any one of claims 1-39, wherein the dissolvable block is arranged between a portion of the actuation assembly and a portion of the housing.

41. The ingestible apparatus of claim 40, wherein the dissolvable block is a latch that maintains the actuation assembly in the first working position, the latch being dissolvable when contacting a gastrointestinal content of the GI tract of the subject.

42. The ingestible apparatus of any one of claims 1-41, wherein the housing further comprises at least one inlet port communicable with an exterior environment, the at least one inlet port being communicable with the access port.

43. The ingestible apparatus of any one of claims 1-26 and 29-42, further comprising an isolating structure configured to dissolve in a gastrointestinal content of the GI tract of the subject, wherein the housing is enclosed within the isolating structure.

44. The ingestible apparatus of claim 43, wherein the isolating structure is a shell.

45. The ingestible apparatus of any one of claims 1-44, further comprising a circuit structure configured to: trigger a first signal-event when the ingestible apparatus arrives within the target area, and trigger a second signal-event when the sample collection is complete.

46. An ingestible apparatus for collecting a sample from a target area of a gastrointestinal (GI) tract of a subject, the ingestible apparatus comprising: a housing defining a sample compartment, the housing comprising a sealing surface having an access port formed therein, and the sample compartment being communicable with the access port; a stopper configured to seal the access port; an actuation assembly connected to the stopper, the actuation assembly being movable between a first working position where the access port is open and a second working position where the access port is sealed with the stopper; and a mucosal-layer brush, wherein the mucosal-layer brush extends beyond a perimeter of the stopper at the first working position of the actuation assembly.

47. The ingestible apparatus of claim 46, wherein the mucosal-layer brush extends beyond a perimeter of the housing at the first working position of the actuation assembly.

48. The ingestible apparatus of any one of claim 46 or 47, wherein the actuation assembly comprises a compression spring, wherein the compression spring is in a first compressed state in the first working position and a second compressed state in the second working position, a potential energy associated with the second compressed state is greater than zero and less than a potential energy associated with the first compressed state.

49. The ingestible apparatus of claim 46 or 47, wherein the actuation assembly comprises an extension spring, wherein the extension spring is in a first extension state in the first working position and a second extension state in the second working position, a potential energy associated with the second extension state is greater than zero and less than a potential energy associated with the first extension state.

50. The ingestible apparatus of claim 48 or 49, wherein the actuation assembly comprises a plurality of springs, each of the springs being a compression or expansion spring.

51. The ingestible apparatus of claim 49, wherein the extension spring is made of an elastic material.

52. The ingestible apparatus of any one of claims 46-51, wherein the actuation assembly further comprises a rigid or flexible piston.

53. The ingestible apparatus of any one of claims 46-52, wherein the mucosal-layer brush is configured for collecting the sample.

54. The ingestible apparatus of any one of claims 46-53, wherein the stopper is connected to an end of the mucosal-layer brush.

55. The ingestible apparatus of any one of claims 46-54, wherein at least a portion of the mucosal-layer brush extends outside of the housing at the first working position of the actuation assembly.

56. The ingestible apparatus of any one of claims 46-55, wherein the mucosal-layer brush is retracted inside the housing at the second working position of the actuation assembly.

57. The ingestible apparatus of any one of claims 46-56, wherein the mucosal-layer brush is distributed radially around at least a portion of the housing.

58. The ingestible apparatus of any one of claims 46-57, wherein the mucosal-layer brush comprises one or more bristles.

59. The ingestible apparatus of claim 58, wherein the mucosal-layer brush further comprises a stem, wherein the one or more bristles are connected to the stem.

60. The ingestible apparatus of claim 58 or 59, wherein the one or more bristles are elongate members.

61. The ingestible apparatus of claim 58 or 59, wherein the one or more bristles are made of a porous material.

62. The ingestible apparatus of any one of claims 46-61, further comprising an isolating structure configured to dissolve in a gastrointestinal content of the GI tract of the subject, wherein the housing and the one or more bristles are enclosed within the isolating structure.

63. The ingestible apparatus of claim 62, wherein the one or more bristles are compressed or spring loaded by the isolating structure.

64. The ingestible apparatus of any one of claims 46-63, wherein the mucosal-layer brush is connected to the actuation assembly.

65. The ingestible apparatus of any one of claims 46-64, wherein the mucosal-layer brush comprises a fluid-absorbent material.

66. The ingestible apparatus of any one of claims 46-65, wherein the housing further comprises at least one inlet port communicable with an exterior environment, the at least one inlet port being communicable with the access port.

67. An ingestible apparatus for collecting a sample from a target area of a gastrointestinal (GI) tract of a subject, the ingestible apparatus comprising: a housing defining a sample compartment, the housing comprising a sealing surface having an access port formed therein, and the sample compartment being communicable with the access port; a stopper configured to seal the access port; an actuation assembly connected to the stopper, the actuation assembly being movable between a first working position where the access port is open and a second working position where the access port is sealed with the stopper; and a mucosal-layer brush, wherein the stopper is connected to an end of the mucosal-layer brush.

68. The ingestible apparatus of any one of claim 67, wherein the actuation assembly comprises a compression spring, wherein the compression spring is in a first compressed state in the first working position and a second compressed state in the second working position, a potential energy associated with the second compressed state is greater than zero and less than a potential energy associated with the first compressed state.

69. The ingestible apparatus of claim 67, wherein the actuation assembly comprises an extension spring, wherein the extension spring is in a first extension state in the first working position and a second extension state in the second working position, a potential energy associated with the second extension state is greater than zero and less than a potential energy associated with the first extension state.

70. The ingestible apparatus of claim 68 or 69, wherein the actuation assembly comprises a plurality of springs, each of the springs being a compression or expansion spring.

71. The ingestible apparatus of claim 69, wherein the extension spring is made of an elastic material.

72. The ingestible apparatus of any one of claims 67-71, wherein the actuation assembly further comprises a rigid or flexible piston.

73. The ingestible apparatus of any one of claims 67-72, wherein the mucosal-layer brush is configured for collecting the sample.

74. The ingestible apparatus of any one of claims 67-73, wherein at least a portion of the mucosal-layer brush extends outside of the housing at the first working position of the actuation assembly.

75. The ingestible apparatus of any one of claims 67-74, wherein the mucosal-layer brush is retracted inside the housing at the second working position of the actuation assembly.

76. The ingestible apparatus of any one of claims 67-75, wherein the mucosal-layer brush is distributed radially around at least a portion of the housing.

77. The ingestible apparatus of any one of claims 67-76, wherein the mucosal-layer brush comprises one or more bristles.

78. The ingestible apparatus of claim 77, wherein the mucosal-layer brush further comprises a stem, wherein the one or more bristles are connected to the stem.

79. The ingestible apparatus of claim 77 or 78, wherein the one or more bristles are elongate members.

80. The ingestible apparatus of claim 77 or 78, wherein the one or more bristles are made of a porous material.

81. The ingestible apparatus of any one of claims 67-80, further comprising an isolating structure configured to dissolve in a gastrointestinal content of the GI tract of the subject, wherein the housing and the one or more bristles are enclosed within the isolating structure.

82. The ingestible apparatus of claim 81, wherein the one or more bristles are compressed or spring loaded by the isolating structure.

83. The ingestible apparatus of any one of claims 67-82, wherein the mucosal-layer brush is connected to the actuation assembly.

84. The ingestible apparatus of any one of claims 67-83, wherein the mucosal-layer brush comprises a fluid-absorbent material.

85. The ingestible apparatus of any one of claims 67-84, wherein the housing further comprises at least one inlet port communicable with an exterior environment, the at least one inlet port being communicable with the access port.

86. An ingestible apparatus for collecting a sample from a target area of a gastrointestinal (GI) tract of a subject, the ingestible apparatus comprising: a housing defining a sample compartment, the housing comprising a sealing surface having an access port formed therein, and the sample compartment being communicable with the access port; a stopper configured to seal the access port; and an actuation assembly connected to the stopper, the actuation assembly being movable between a first working position where the access port is open and a second working position where the access port is sealed with the stopper, wherein the housing comprises a first portion that houses the stopper and a second portion that defines the sample compartment, the first portion being configured to removably couple with the second portion.

87. The ingestible apparatus of claim 86, wherein the first portion comprises a first wall section and the second portion comprises a second wall section, the first and second wall sections being in an overlapping condition when the first portion is coupled with the second portion.

88. The ingestible apparatus of claim 87, wherein the overlapping condition of the first and second wall sections extends for about 20-25% of a total length of the housing.

89. The ingestible apparatus of claim 87 or 88, wherein the first and second wall sections are coupled by interference fit.

90. The ingestible apparatus of claim 87 or 88, wherein the first and second wall portions are coupled by threading.

91. The ingestible apparatus of any of claim 89 or 90, wherein the coupling extends only a portion of the overlapping portion.

92. The ingestible apparatus of any one of claims 86-91, wherein the second compartment has a volume of at least about 20 microliters (μL) to 100 μL.

93. The ingestible apparatus of any one of claims 86-92, wherein the housing further comprises at least one inlet port communicable with an exterior environment, the at least one inlet port being communicable with the access port.

94. The ingestible apparatus of any one of claims 86-93, further comprising an isolating structure configured to dissolve in a gastrointestinal content of the GI tract of the subject, wherein the housing is enclosed within the isolating structure.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0133] The components in the drawings are not necessarily to scale relative to each other. Like reference numerals designate corresponding parts throughout the several views.

[0134] FIG. 1A is a cross-sectional view of an ingestible apparatus for delivering a health-related substance through the gastrointestinal (GI) tract of a human or mammal (collectively denoted as a “user”) to a target area therein, according to some embodiments of this disclosure.

[0135] FIG. 1B is a circuit diagram of the ingestible apparatus shown in FIG. 1A.

[0136] FIG. 2 is a cross-sectional view of the ingestible apparatus shown in FIG. 1A in the GI tract, wherein an enteric-targeted coating thereof is substantively deformed.

[0137] FIG. 3A is a cross-sectional view of the ingestible apparatus shown in FIG. 1A, wherein a shell of the ingestible apparatus is substantively deformed.

[0138] FIG. 3B is a circuit diagram of the ingestible apparatus shown in FIG. 3A.

[0139] FIG. 4A is a cross-sectional view of the ingestible apparatus shown in FIG. 1A, wherein the ingestible apparatus discharges the health-related substance to the target area.

[0140] FIG. 4B is a circuit diagram of the ingestible apparatus shown in FIG. 4A.

[0141] FIG. 5 shows the output of a tracking device monitoring the ingestible apparatus shown in FIG. 1A during a health-related-substance-delivery process.

[0142] FIG. 6 shows the output of a tracking device monitoring the ingestible apparatus shown in FIG. 1A during a health-related-substance-delivery process, according to some embodiments of this disclosure.

[0143] FIG. 7 is a cross-sectional view of an ingestible apparatus for collecting gastrointestinal-content samples from the mucosal layer in a target area of the GI tract of a user, according to some embodiments of this disclosure.

[0144] FIG. 8 is a cross-sectional view of the ingestible apparatus shown in FIG. 7, wherein a coating of the ingestible apparatus is substantively deformed.

[0145] FIG. 9 is a cross-sectional view of the ingestible apparatus shown in FIG. 7, wherein a shell of the ingestible apparatus is substantively deformed thereby allowing the ingestible apparatus to collect samples from the mucosal layer of the GI tract.

[0146] FIG. 10 is a cross-sectional view of the ingestible apparatus shown in FIG. 7, wherein a compartment of the ingestible apparatus is sealed with the collected samples from the mucosal layer received therein.

[0147] FIG. 11 is a cross-sectional view of an ingestible apparatus for collecting samples in a target area of the GI tract of a user, according to some embodiments of this disclosure.

[0148] FIG. 12 is a cross-sectional view of the ingestible apparatus shown in FIG. 11, wherein a coating of the ingestible apparatus is substantively deformed.

[0149] FIG. 13 is a cross-sectional view of the ingestible apparatus shown in FIG. 11, wherein a shell of the ingestible apparatus is substantively deformed thereby allowing the ingestible apparatus to collect samples.

[0150] FIG. 14 is a cross-sectional view of the ingestible apparatus shown in FIG. 11, wherein a compartment of the ingestible apparatus is sealed with the collected mucosal-layer samples received therein.

[0151] FIG. 15 is a cross-sectional view of an ingestible apparatus for collecting samples from a target area of the GI tract of a user and then delivering a health-related substance thereto, according to some embodiments of this disclosure.

[0152] FIG. 16 is a cross-sectional view of the ingestible apparatus shown in FIG. 15, wherein a coating and a shell of the ingestible apparatus are substantively deformed thereby allowing the ingestible apparatus to collect samples to a second compartment thereof and then discharge the health-related substance from a first compartment thereof.

[0153] FIG. 17 is a cross-sectional view of the ingestible apparatus shown in FIG. 15, wherein the collected samples are sealed in the second compartment and the health-related substance has been discharged from the first compartment.

[0154] FIG. 18 is a cross-sectional view of an ingestible apparatus for delivering a health-related substance through the GI tract of a user to a target area therein and then collecting samples therefrom, according to some embodiments of this disclosure, wherein the ingestible apparatus comprises a sampling actuation-structure having two biased springs.

[0155] FIG. 19 is a cross-sectional view of the ingestible apparatus shown in FIG. 18, wherein a shell of the ingestible apparatus is substantively deformed thereby allowing the ingestible apparatus to discharge the health-related substance from a compartment and then collect samples into the compartment.

[0156] FIG. 20 is a cross-sectional view of the ingestible apparatus shown in FIG. 18, wherein the health-related substance has been discharged from the compartment.

[0157] FIG. 21A is a cross-sectional view of the ingestible apparatus shown in FIG. 18, wherein the samples are collected into the compartment.

[0158] FIG. 21B is a circuit diagram of the ingestible apparatus shown in FIG. 21A.

[0159] FIG. 22 is a cross-sectional view of the ingestible apparatus shown in FIG. 18, wherein the collected samples are sealed in the compartment.

[0160] FIG. 23 is a cross-sectional view of an ingestible apparatus for delivering a health-related substance through the GI tract of a user to a target area therein and then collecting samples therefrom, according to some embodiments of this disclosure, wherein the ingestible apparatus comprises a sampling actuation-structure having one biased spring.

[0161] FIG. 24 is a cross-sectional view of the ingestible apparatus shown in FIG. 23, wherein a shell of the ingestible apparatus is substantively deformed thereby allowing the ingestible apparatus to discharge the health-related substance from a compartment and then collect samples into the compartment.

[0162] FIG. 25 is a cross-sectional view of the ingestible apparatus shown in FIG. 23, wherein the health-related substance has been discharged from the compartment.

[0163] FIG. 26 is a cross-sectional view of the ingestible apparatus shown in FIG. 23, wherein the samples are collected into the compartment.

[0164] FIG. 27 is a cross-sectional view of the ingestible apparatus shown in FIG. 23, wherein the collected samples are sealed in the compartment.

[0165] FIG. 28 is a cross-sectional view of an ingestible apparatus for delivering a health-related substance through the GI tract of a user to a target area therein and then collecting mucosal-layer samples therefrom, according to some embodiments of this disclosure.

[0166] FIG. 29 is a cross-sectional view of the ingestible apparatus shown in FIG. 28, wherein a shell of the ingestible apparatus is substantively deformed thereby allowing the ingestible apparatus to discharge the health-related substance from a compartment and then collect mucosal-layer samples into the compartment.

[0167] FIG. 30 is a cross-sectional view of the ingestible apparatus shown in FIG. 28, wherein the health-related substance has been discharged from the compartment.

[0168] FIG. 31 is a cross-sectional view of the ingestible apparatus shown in FIG. 28, wherein the mucosal-layer samples are collected by a mucosal-layer brush.

[0169] FIG. 32 is a cross-sectional view of the ingestible apparatus shown in FIG. 28, wherein the collected mucosal-layer samples are sealed in the compartment.

[0170] FIGS. 33A and 33B are cross-sectional views of a first switch of an ingestible apparatus configured in an off and an on configurations, respectively, according to some embodiments of this disclosure.

[0171] FIGS. 34A and 34B are cross-sectional views of a first switch of an ingestible apparatus configured in an off and an on configurations, respectively, according to some alternative embodiments of this disclosure.

[0172] FIGS. 35A and 35B are cross-sectional views of a first switch of an ingestible apparatus configured in an off and an on configurations, respectively, according to yet some alternative embodiments of this disclosure.

[0173] FIGS. 36A and 36B are cross-sectional views of a second switch of an ingestible apparatus configured in an off and an on configurations, respectively, according to some embodiments of this disclosure.

[0174] FIGS. 37A and 37B are cross-sectional views of a second switch of an ingestible apparatus configured in an off and an on configurations, respectively, according to some alternative embodiments of this disclosure.

[0175] FIG. 38 is a block diagram of a wearable tracking device for tracking an ingestible apparatus in a sampling and/or health-related-substance-delivery process, according to some embodiments of this disclosure.

[0176] FIG. 39 is a schematic diagram showing a user ingesting a plurality of ingestible apparatuses and wearing the wearable tracking device shown in FIG. 38 for tracking the plurality of ingestible apparatuses in a sampling and/or health-related-substance-delivery process.

[0177] FIG. 40 shows the output of the tracking device shown in FIG. 38 during the sampling and/or health-related-substance-delivery process shown in FIG. 39.

[0178] FIG. 41 is a flowchart showing the steps of a monitoring process for monitoring the sampling and/or health-related-substance-delivery process shown in FIG. 39 with X-Ray confirmation.

[0179] FIG. 42 is a schematic diagram showing an ingestible apparatus, according to in some embodiments of this disclosure, wherein the ingestible apparatus comprises a string coupled to a shell thereof for monitoring the travelling of the ingestible apparatus in a GI tract.

[0180] FIG. 43 is a cross-sectional view of an ingestible apparatus for delivering a health-related substance through the GI tract of a user to a target area therein and then collecting mucosal-layer samples therefrom, according to some embodiments of this disclosure, wherein the ingestible apparatus comprises a mucosal-layer brush rotatable with a piston mandrel.

[0181] FIG. 44 is a cross-sectional view of an ingestible apparatus for delivering a health-related substance through the GI tract of a user to a target area therein and then collecting mucosal-layer samples therefrom, according to some embodiments of this disclosure, wherein the ingestible apparatus comprises a mucosal-layer brush rotatable with a rotatable sleeve on a piston mandrel.

[0182] FIG. 45 is a cross-sectional view of an ingestible apparatus for delivering a health-related substance through the GI tract of a user to a target area therein and then collecting mucosal-layer samples therefrom, according to some embodiments of this disclosure, wherein the ingestible apparatus does not comprises a dissolvable shell.

[0183] FIG. 46 is a cross-sectional view of an ingestible apparatus for collecting samples from a target area of the GI tract of a user and then delivering a health-related substance thereto, according to some embodiments of this disclosure.

[0184] FIG. 47 is a cross-sectional view of the ingestible apparatus shown in FIG. 46, wherein a coating and a shell of the ingestible apparatus are substantively deformed.

[0185] FIG. 48 is a cross-sectional view of the ingestible apparatus shown in FIG. 46, wherein bristles of a brush of the ingestible apparatus are extended out of a housing thereof for collecting samples.

[0186] FIG. 49 is a cross-sectional view of the ingestible apparatus shown in FIG. 46, wherein the bristles of the brush and the collected samples are retrieved into the housing and sealed in a compartment thereof.

[0187] FIGS. 50A, 50B and 50C are a series of cross sectional views of the ingestible apparatus for collecting samples according to some embodiments of this disclosure where the stopper is designed to form and effective seal with the sample compartment.

[0188] FIG. 51 is a cross section of an alternative embodiment where the actuation assembly is an elastic material in extension at a first working position.

[0189] FIGS. 52A, 52B and 52C are a series of cross sectional views of the ingestible apparatus that include a mucosal layer brush with rod like bristles extended through the inlet port and out past the perimeter of the housing (FIG. 52A) and the isolation structure upon its dissolution (FIG. 52B). The bristles are retracted with the full recovery of the actuation assembly from a first working position to a final working position (FIG. 52C).

[0190] FIGS. 53A and 53B are a series of cross sectional views of the ingestible apparatus with a mucosal layer brush where the bristles are a sponge positioned between the sampling compartment and a stopper with the an actuation assembly at a first extension position (FIG. 53A). Upon the dissolution of the isolation structure surrounding the ingestible apparatus the bristles extend past the perimeter of the housing and past the original perimeter set by the isolation structure (FIG. 53B). FIGS. 53C and 53D are a top view of the same embodiment shown in FIGS. 53A and 53B, respectively, depicting the radial distribution of the bristles around the full perimeter of the device where the bristles extend past the periphery of the housing (FIG. 53C) and the isolation structure upon its dissolution (FIG. 53D). FIG. 53E is a cross sectional view of the ingestible apparatus where the mucosal-layer brush has been retracted within the sampling compartment and the stopper is held against the sealing surface with the actuation assembly at a second extension position.

[0191] FIGS. 54A and 54B are a series of cross sectional views of the ingestible apparatus with a mucosal layer brush where the bristles are rod-like and positioned between the sampling compartment and a stopper with the an actuation assembly at a first extension position (FIG. 54A). The first extension position is held by a dissolvable block that is positioned between the stopper and the sealing surface. Upon the dissolution of the isolation structure surrounding the ingestible apparatus the bristles extend past the perimeter of the housing and past the original perimeter set by the isolation structure (FIG. 54B).

[0192] FIG. 55A is a cross sectional view of the ingestible apparatus where the mucosal-layer brush is positioned outside of the sampling compartment between the stopper and the sealing surface with the plurality of actuation assemblies held in a first extension position. FIGS. 55B and 55C are cross sectional and top view respectably of the ingestible apparatus where the brush extends radially past the perimeter of the housing and stopper around a portion of the periphery of the device. FIG. 55D is a cut section of a cross sectional view depicting an alternative positioning for the dissolvable block away from the sealing surface of the sampling compartment.

[0193] FIG. 56A is a cross sectional view of the ingestible apparatus depicting a mucosal-layer brush with a spring-like stem constrained within an isolation structure with the actuation assembly at a first compression position. FIG. 56B is a cross sectional view of the ingestible apparatus depicting a mucosal-layer brush with a spring-like stem released beyond the perimeter of the ingestible apparatus following the dissolution of the isolation structure with the actuation assembly at a first compression position.

[0194] FIG. 57 is a cross sectional view of the ingestible apparatus for collecting samples with a mucosal-layer brush with a curved housing and a spring in held in a first extension position of the actuation assembly.

[0195] FIG. 58 is a cross sectional view of the ingestible apparatus for collecting samples with a mucosal-layer brush with a curved housing and a spring in held in a first extension position of the actuation assembly with an alternate mucosal-layer brush and stopper embodiment.

[0196] FIG. 59 is a cross sectional view of the ingestible apparatus for collecting samples with a mucosal-layer brush where multiple compartments are used.

[0197] FIG. 60A is a cross sectional view of the of the ingestible apparatus where the housing is formed of two separate portions that are removably connected. FIGS. 60B and 60C are cross sectional views of the lower portion of the housing removed from the remainder of the apparatus and used to collect the sample. The two embodiments depict different portions of coupling along the overlapping portions.

[0198] FIGS. 61A and 61B are cross sectional views of a portion of the apparatus which demonstrates the use of the spring as a structural electrical component in the RFID circuit in the state with the spring in a compressed state (FIG. 61A) and extended state (FIG. 61B).

[0199] FIGS. 62A and 62B are circuit diagrams with the use of the spring as a structural electrical component in the RFID circuit in the state with the spring in a compressed state (FIG. 62A) and extended state (FIG. 62B).

[0200] FIG. 63 is a chart depicting the absence of contamination as measured by qPCR cycle count in 15 sealed ingestible apparatus after transit through the gastrointestinal tract as compared to the controls.

DETAILED DESCRIPTION

[0201] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure. As used in the specification, and in the appended claims, the singular forms “a,” “an,” “the” include plural referents unless the context clearly dictates otherwise. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. The terms “optional” or “optionally” used herein mean that the subsequently described feature, event or circumstance may or may not occur, and that the description includes instances where said feature, event or circumstance occurs and instances where it does not. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, an aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0202] As used herein, the terms “about” or “approximately”, when used in reference to a measurable quantity (e.g., such as a length, width, height, thickness, distance, radius, volume, etc., mean within plus or minus 10 percentage of the referenced measured quantity.

[0203] Embodiments disclosed herein relate to an ingestible apparatus for delivering health-related substance comprising one or more active compounds to a target area of a gastrointestinal (GI) tract of a human or mammal (collectively denoted as a “user” or a “subject”) and/or collecting gastrointestinal-content samples therefrom.

[0204] In one embodiment, an ingestible sampling apparatus comprises a housing defining a sample compartment, a stopper configured to seal an access port of the housing, an actuation assembly connected to the stopper, and a dissolvable block. The actuation assembly is movable between a first working position (referred to herein in some embodiments as a “first position”) where the access port is open and a second working position (referred to herein in some embodiments as a “second position”) where the access port is sealed with the stopper. The dissolvable block is configured to prevent the actuation assembly from moving between the first and second working positions until the ingestible apparatus is within a target area of the GI tract of the subject. Additionally, the actuation assembly is configured, in the second working position, to apply a linear force at an interface between the stopper and a sealing surface to seal the access port with the stopper.

[0205] In an alternative embodiment, the ingestible sampling apparatus comprises a housing defining a sample compartment, a stopper configured to seal an access port of the housing, an actuation assembly connected to the stopper, and a mucosal-layer brush. The actuation assembly is movable between a first working position where the access port is open and a second working position where the access port is sealed with the stopper. The mucosal-layer brush extends beyond a perimeter of the stopper at the first working position of the actuation assembly. Optionally, the mucosal-layer brush extends beyond a perimeter of the housing at the first working position of the actuation assembly.

[0206] In an alternative embodiment, the ingestible sampling apparatus comprises a housing defining a sample compartment, a stopper configured to seal an access port of the housing, an actuation assembly connected to the stopper, and a mucosal-layer brush. The actuation assembly is movable between a first working position where the access port is open and a second working position where the access port is sealed with the stopper. The stopper is connected to an end of the mucosal-layer brush.

[0207] In an alternative embodiment, the ingestible sampling apparatus comprises a housing defining a sample compartment, a stopper configured to seal an access port of the housing, an actuation assembly connected to the stopper, and a mucosal-layer brush. The actuation assembly is movable between a first working position where the access port is open and a second working position where the access port is sealed with the stopper. The housing includes a first portion that houses the stopper and a second portion that defines the sample compartment, where the first portion is configured to removably couple with the second portion.

[0208] In an alternative embodiment, the ingestible apparatus comprises at least one first compartment communicable with one or more first ports, and an actuation assembly for adjusting the conditions of the first compartment for above-described purposes. For example, in various embodiments, the actuation assembly may move from a first position (referred to herein in some embodiments as a “first working position”) to a second position (referred to herein in some embodiments as a “second working position”) thereby to (a) increase the volume of the first compartment to receive samples collected from the target area; or (b) reduce volume of the first compartment to discharge a health-related substance therein into the target area; or (c) reduce volume of the first compartment to discharge the health-related substance therein into the target area and then increase the volume of the first compartment to receive samples collected from the target area. Optionally, in some embodiments described herein, a port providing access to a sample compartment is open in the first position, while the port providing access to the sample compartment is closed in the second position. Alternatively, in some embodiments described herein, a port providing access to a sample compartment is closed in the first position, while the port providing access to the sample compartment is open in the second position.

[0209] In an alternate embodiment, the actuation assembly may move from a first position to a second position thereby adjusting the conditions of the first compartment by mechanisms other than changing the volume of the compartment. For example, the movement may close or seal the fluidly communicable port of the compartment to collect a gastrointestinal sample, or may expose a previously closed or sealed port to discharge the health-related substance.

[0210] In some embodiments, the ingestible apparatus may further comprise a second compartment in communication with one or more second ports. The first compartment may contain therein the health-related substance. The ingestible apparatus may receive samples collected from the target area into the second compartment and then reduce volume of the first compartment to discharge the health-related substance therein into the target area.

[0211] In some embodiments, the actuation assembly may comprise an actuation structure for actuating a piston to change the volume of the first compartment. The piston may be movable between the first position and a second position; and wherein one of the first and second positions is away from the at least one first port and the other one of the first and second positions is adjacent the at least one first port.

[0212] In some embodiments, the actuation structure may be one or more loaded, biased, or otherwise energy-stored springs. For example, the springs may be compressed extendible springs (sometimes referred to herein as “compression springs,” e.g., a spring configured to “push” an object) or extended compressed springs (sometimes referred to herein as “expansion springs,” e.g., a spring configured to “pull” an object). Alternatively or additionally, in some embodiments, the actuation structure may be an elastic band, or an elastic sleeve.

[0213] In some embodiments, the ingestible apparatus may comprise a sealing mechanism for sealing the first and/or the second compartments at the end of the action of the actuation assembly. The sealing mechanism may be a sealing component for closing the first and/or second ports, or may be an action of the actuation assembly that isolates the first and/or second compartment from the corresponding first and/or second port, or may be the first and/or second ports having a sufficiently small cross-sectional dimension to form a liquid interface therein with a surface tension sufficient for retaining the health-related substance in the corresponding compartment.

[0214] In some embodiments, the ingestible apparatus may comprise a mucosal-layer brush for collecting mucosal-layer samples.

[0215] In some embodiments, the mucosal-layer brush may alternatively or additionally be used to deliver a health-related-substance to the mucosal layer.

[0216] In some embodiments, the mucosal-layer brush may be retractable into the first compartment and may be rotatable for providing an improved sampling performance.

[0217] In some embodiments, the ingestible apparatus may comprise a fluid-absorbent material such as hydrophilic fibers for facilitating the sampling of gastrointestinal content.

[0218] In some embodiments, the mucosal-layer brush may comprise bristles to either collect gastrointestinal content or to deliver health-related substances.

[0219] In some embodiments, the bristles may comprise a fluid-absorbent material (i.e., a material suitable for absorbing gastrointestinal fluid) such as hydrophilic fibers, e.g., polyvinyl alcohol (PVA), to improve the collection of a mucosal sample from the mucosal layer of the GI tract in combination with the more fluid luminal sample from the intraluminal space.

[0220] The ingestible apparatus may also comprise a delay structure for delaying the action of the actuation assembly until the ingestible apparatus arrives or is about to arrive the target area. Such a delay structure may provide a regional delay (i.e., providing a delay until the ingestible apparatus has arrived a predefined area) or a time delay (i.e., providing a delay until a predefined period of time has passed).

[0221] In some embodiments, the delay structure may comprise a dissolvable component (referred to herein in some embodiments as a “dissolvable block”) retaining the actuation assembly at an initial state which may gradually dissolve and/or substantive deform after a regional delay and/or a time delay. In some embodiments, the delay structure may comprise a dissolvable shell enclosing other components therein. In some embodiments, the delay structure may comprise both a dissolvable component retaining the actuation assembly and a dissolvable shell enclosing other components therein. In some embodiments, the delay structure may further comprise a dissolvable coating for providing a regional delay. In some embodiments, the delay structure may comprise all of a dissolvable component retaining the actuation assembly, a dissolvable shell enclosing other components therein, and a dissolvable coating providing a regional delay. In some embodiments, the dissolving of the delay structure occurs over a period of time. The period of time relates to the sampling time or health-related substance delivery time. For example, in some implementations, the period of time may be relatively lengthy such as between about 15 and 150 minutes. It should be understood that the above range is provided only as an example and that the period of time may include values less or more than those in the example and dependent on the sampling or substance delivery time. This disclosure contemplates that the delay structure can be designed accordingly.

[0222] In some embodiments, the ingestible apparatus may further comprise a circuit structure for monitoring a sampling and/or health-related-substance-delivery process of the ingestible apparatus by detecting the arrival of the ingestible apparatus at the target area and by detecting an end of the process.

[0223] In some embodiments, the circuit structure is configured for detecting a start and an end of the condition-changing of the first compartment (which may correspond to a start and an end of the action of the actuation assembly, for example from a first position to a second position) as the arrival of the ingestible apparatus at the target area and the end of the sample collecting and/or the health-related-substance discharging, respectively.

[0224] In some embodiments, the circuit structure may use a timer to record the time instant of the occurrence of each state of the ingestible apparatus and stores the recorded time instants in a memory.

[0225] In some embodiments, the circuit structure may comprise a power-source component and a radio-frequency (RF) signal transmitter for transmitting a RF signal at least between the start and the end of the volume-changing of the first compartment. The circuit structure may transmit different RF signals for indicating various states of the ingestible apparatus during the sampling and/or health-related-substance-delivery process. A monitoring device may be used outside the user's body for monitoring the sampling and/or health-related-substance-delivery process by monitoring the RF signals. Herein, a RF signal has a set of unique property settings such as amplitude, frequency, modulation, coding, and/or the like. Two RF signals are different in at least one property setting. Moreover, no RF signal transmission may be considered a special RF signal which has a zero (0) amplitude.

[0226] In some embodiments, the circuit structure comprises a first detection circuit for detecting gastrointestinal content as an indication of the start of the action of the actuation assembly. In these embodiments, the first detection circuit may be disabled until the ingestible apparatus arrives or is about to arrive the target area. In these embodiments, the first detection circuit may be isolated from the gastrointestinal content until the ingestible apparatus arrives or is about to arrive the target area. In some embodiments, the first detection circuit may comprise a first set of spaced electrodes engageable with the gastrointestinal content (which is generally electrically conductive) forming a first switch. Alternatively the first detection circuit may be isolated from the gastrointestinal content until the ingestible apparatus arrives or is about to arrive the target area with the switch in the on condition. The circuit configuration set that upon contact with the gastrointestinal fluid the a short circuit is created to move the first detection to the off condition.

[0227] In some embodiments, the circuit structure comprises a second detection circuit for detecting the changing conditions of the first and/or second compartment as an indication of the end of the action of the actuation assembly. In the embodiments wherein the actuation assembly comprises a piston, the second detection circuit may detect the position-change or movement of the piston as an indication of the volume-change and or closing of the access port of the first and/or second compartment. In some embodiments, the second detection circuit may comprise a second set of spaced electrodes engageable with an electrically conductive surface forming a second switch, the second set of electrodes and the electrically conductive surface are movable relative to each other in accordance with the action of the actuation assembly.

[0228] In some embodiments, the first switch is electrically coupled to the power-source component and the RF-signal transmitter in series; wherein the second switch electrically coupled to the power-source component and in parallel with the second switch and the RF-signal transmitter.

[0229] In some embodiments, the RF signal transmission may be used to verify the quality of the ingestible capsule. A monitoring device may be used to scan the capsule as part of the delivery procedure and/or manufacturing procedure to ensure the ingestible apparatus components are in the correct position prior to ingestion. For example, the status of the abovementioned first switch and/or second switch can be changed as a result of the undesired actions of the actuation assembly prior to ingestion. An example of the undesired actions of the actuation assembly include but are not limited to the release of the spring as a result of the broken dissolvable latch due to the mishandling during the transportation and or storage, or as a result of a manufacturing defect.

[0230] The status change of the switches can change the status of the RF-signal transmission, which can be detected remotely using the monitoring device by the user. If such an event is detected, an alarm or other notification associated with the scanner may be used to trigger an alarm to inform the users and the ingestion could be avoided. Alternatively or in addition to, the scanner can be used as part of the manufacturing process to avoid in line failures.

[0231] In some embodiments, the RF signal transmission may be used to verify the presence of the ingestible capsule within the user remotely using a monitoring device.

[0232] In some embodiments, the RF-signal transmitter may be a radio-frequency identification (RFID) chip with an antenna.

[0233] In some embodiments, the ingestible apparatus may further comprise a string with marks for determining the position of the ingestible apparatus during a sampling and/or health-related-substance-delivery process. The string may be made of a dissolvable material.

[0234] Turning now to FIG. 1A, an ingestible apparatus according to some embodiments of this disclosure is shown and is generally identified using reference numeral 100. In these embodiments, the ingestible apparatus 100 is an ingestible health-related-substance-delivery apparatus in the form of a capsule and may be used for delivering a health-related substance through the GI tract of a user to a target area therein.

[0235] In various embodiments, the target area may not need to be highly precise. As those skilled in the art understand, the GI tract is a series of joined, hollow organs substantively in the form of a long and twisting tube from the mouth to the anus. In some embodiments, the target area may be anywhere within a particular organ along the GI tract. In some embodiments, the target area may be a specific range within a particular organ along the GI tract. Generally, the target area may be defined by a doctor or a specialist with a certain precision as needed. Examples of the target area include but not limited to esophagus, stomach, small intestine, and large intestine of the gastrointestinal tract.

[0236] Accordingly, some characteristics of the ingestible apparatus 100 (described in more detail below) may be customized such as by selecting a suitable one from a plurality of pre-manufactured ingestible apparatuses 100 with various characteristics thereof.

[0237] In some embodiments, a plurality of pre-manufactured ingestible apparatuses 100 with various characteristics are provided as a kit. The ingestible apparatuses 100 of the kit may have different settings such as different target areas, different functionalities (e.g., sampling and/or health-related-substance-delivery), and/or different health-related substances for delivery.

[0238] Depending on the characteristics of the patient or user, including the presence of medical conditions or medication use affecting motility rate, or depending on the intended target area, one or more ingestible apparatuses may be selected from the kit and provided to the user. Alternatively, the user may ingest multiple, including all ingestible apparatuses provided within the kit, to increase the likelihood that at least one device samples gastrointestinal content or delivers health-related-substance to the intended target area. In another embodiment, the user ingest multiple ingestible apparatus of various characteristics as provided in a kit to sample gastrointestinal contents and/or deliver a health-related substance at multiple points along the GI tract.

[0239] In another embodiment, a user may ingest one of the plurality of ingestible apparatuses 100 of the kit for collecting gastrointestinal samples. Based on the processing and analysis results of the collected samples, the user may further ingest one or more ingestible apparatuses 100 for sampling and/or for delivering necessary health-related substances to specific target area(s).

[0240] In the example shown in FIG. 1A, the ingestible apparatus 100 is for delivering a health-related substance to a target enteric area and comprises a dissolvable shell 102 coated with an enteric-targeted coating 104 and a delivery structure 110 enclosed in the dissolvable shell 102. Herein, the health-related substance may comprise one or more active compounds such as one or more pharmaceutical compounds, one or more probiotics, one or more prebiotics, one or more microbiomes, and/or the like.

[0241] In various embodiments, the one or more active compounds may be manufactured compounds, or compounds obtained directly or indirectly from human or animal. For example, the health-related substance may comprise active compounds obtained from the user or from another person (referred to as a donor), or a group of persons wherein the obtained active compounds may be processed, modified, and/or combined, and then directly delivered back to the user.

[0242] The health-related substance may be in the form of a fluid, a powder, a solid substance, or a mixture thereof. The health-related substance may be a sample of stool, or other GI contents from small intestine or large intestine, previously collected from the same user, or from a donor, which may be used to improve or treat the microbiome of the user or to reestablish a previous microbiome prior to treatment.

[0243] While the health-related substance may be in various forms, the following description uses a liquid-form health-related substance as an example for ease of description.

[0244] The enteric-targeted coating 104 is made of a suitable ingestible material which substantively maintains its integrity until arriving a predefined area (before the target enteric area) in which the coating 104 starts to dissolve at a significant rate and is sufficiently deformed after approximately a predefined period of time for exposing the shell 102 to the digestive system.

[0245] For example, the coating 104 may be formed by an ingestible material dissolvable at a fast rate in an environment (such as the stomach) in which the gastrointestinal content (generally comprising gastrointestinal fluid) has a pH value greater than a predefined pH-level threshold and dissolvable at a slow rate or even undissolvable in an environment (such as the GI tract before and in the stomach) in which the gastrointestinal content has a pH value less than the predefined threshold, thereby giving rise to a regional dissolution or regional delay.

[0246] In some embodiments, the pH-sensitive material is a pH-sensitive polymeric material.

[0247] In some embodiments, the coating is time-controllable which may have a predefined thickness and may dissolve gradually over a predefined (and sometimes prolonged) period of time.

[0248] With such a regional delay, the shell 102 is protected from being dissolved until the ingestible apparatus 100 reaches the stomach when the coating 104 is sufficiently deformed, thereby preventing the failure that the ingestible apparatus 100 releases the health-related substance before reaching the target enteric area.

[0249] In some embodiments, the coating 104 may be formed by an ingestible material that may dissolve after a predetermined time period. The predetermined time period may be longer than a typical gastric transit time (i.e. the time required for a capsule device to pass stomach and reach small intestine) thereby preventing the failure that the ingestible apparatus 100 may otherwise release the health-related substance before reaching the target enteric area such as small intestine.

[0250] In some embodiments, the coating 104 may be formed by an ingestible material that may be degraded by specific enzymes predominantly existing in the colon, in which the intestinal content has unique enzymatic ability produced by the colonic micro flora, thereby giving rise to a regional specific delay. With such a regional delay, the shell 102 is protected from being dissolved until the ingestible apparatus 100 reaches the stomach when the coating 104 is sufficiently deformed, thereby preventing the failure that the ingestible apparatus 100 may otherwise release the health-related substance before reaching the target enteric area.

[0251] In some embodiments, the ingestible apparatus 100 may not comprise the coating 104, thereby leaving the shell 102 directly exposed to the gastrointestinal content after oral administration and dissolves quickly in the stomach and the ingestible apparatus 100 starts to release the health-related substance in the stomach, or to obtain luminal or mucosal samples in the stomach (described in more detail later).

[0252] The shell 102 is made of a suitable ingestible and dissolvable material such as gelatin or other suitable animal proteins, carrageenans, modified starch, cellulose, and/or other plant polysaccharides or derivatives that are often used in making conventional ingestible capsules. Preferably, the shell is a hard-shelled capsule made of two pieces including a shell cap 106 and a shell body 108 coupled together and sealed at their interface by using suitable capsule manufacturing technologies such as the conventional capsule manufacturing technologies known in the art.

[0253] The shell 102 isolates the components therein from the digestive system and is dissolvable at a predetermined rate (determined by the characteristics of the material thereof) when in contact with the digestive system. By selecting a thickness thereof, the shell 102 provides a predetermined time delay such that its integrity is substantively maintained until the ingestible apparatus 100 arrives the target area (within approximately a predetermined period of time) when the shell 102 is sufficiently deformed for allowing the health-related substance therein to release.

[0254] In some embodiments, the shell 102 may be similar to that of the ingestible PILLCAM Patency Capsule (PillCam is a trademark of GIVEN IMAGING LTD. of ISRAEL).

[0255] Enclosed in the shell 102, the delivery structure 110 in these embodiments comprises a housing 112 having a front end 114 and a rear end 116 with a circuit structure 118 coupled to the rear end 116 thereof.

[0256] The housing 112 may comprise two portions coupled together via suitable coupling means such as threading, glue, screws, an/or the like to form a chamber 122 and receive therein a piston 124. The piston 124 is movable in the chamber 122 between a front position adjacent the front end 114 and a rear position adjacent the rear end 116 thereof. The piston 124 defines a compartment 126 between the piston 124 and the front end 114 for receiving therein the health-related-substances. The compartment 126 comprises one or more substance-release ports 128 on the housing 112 (e.g., one substance-release port 128 at the front end 114 of the housing 112 in the example shown in FIG. 1A) for releasing the health-related substance.

[0257] In these embodiments, each of the one or more substance-release ports 128 has a small cross-sectional dimension allowing the health-related substance in the compartment 126 to form a liquid surface or interface 130 with a surface-tension force (and optionally the friction of the sidewall of the substance-release port 128) that is sufficient for retaining the health-related substance in the compartment 126.

[0258] The piston 124 comprises a piston plate 142 and a piston mandrel 144 extending rearwardly from the piston plate 142 out of the housing 112 to an end piece 148 via the aligned access holes 146 respectively on the rear end 116 of housing 112 and on the circuit structure 118. As described in more detail below, the piston 124, a portion or component of the piston 124 (e.g., piston plate 142), or a component connected to the piston 124 can optionally serve as a plug configured to seal one or more ports of the device in some implementations. The component that plugs a port is referred to herein as a “stopper.” The end piece 148 has an extended diameter thereby forming a circumferential retaining-shoulder 150 facing the housing 112. The end piece 148 is made of an electrically conductive material such a copper or alternatively the circumferential retaining-shoulder 150 is coated, printed, deposited, or otherwise coupled with a layer of the electrically conductive material for forming an electrical switch (described in more detail later).

[0259] When the ingestible apparatus 100 is in an initial state T.sub.A, the piston 124 is located at the rear position adjacent the rear end 116 of the chamber 122 and is retained thereto by a dissolvable latch 164 engaging the circumferential retaining-shoulder 150 of the end piece 148 and the circuit structure 118, thereby configuring the compartment 126 to its maximum volume. An actuation structure comprising a biased spring 162 engages the piston 124 for moving the piston 124 to the front position when the dissolvable latch 164 is dissolved. The actuation structure and the piston thus form an actuation assembly for changing the volume of the compartment 126.

[0260] In the example shown in FIG. 1A, the biased spring 162 is a compressed extendable-spring located in the chamber 122 between the rear end 116 and the piston 124. The spring 162 is extendable to “push” the piston 124 towards the front end 114 to reduce the volume of the compartment 126 and discharge the health-related substance therein. In some alternative embodiments, the biased spring 162 may be an extended compressible-spring located in the chamber 122 between the front end 114 and the piston 124 (i.e., in the compartment 126). The spring 162 is retractable to “pull” the piston 124 towards the front end 114 to reduce the volume of the compartment 126 and discharge the health-related substance therein.

[0261] The circuit structure 118 comprises a sensing circuitry (not shown) electrically connected to a first set of electrodes 166 and a second set of electrodes 168 via necessary wiring (not shown). The first set of electrodes 166 form a first switch S.sub.1. The second set of electrodes 168 are enclosed by the dissolvable latch 164 (protecting the second set of electrodes 168 from contacting the gastrointestinal content, specifically the gastrointestinal fluid, in the digestive system) and are engageable with the circumferential retaining-shoulder 150 of the end piece 148 thereby forming a second switch S.sub.2. Both switches S.sub.1 and S.sub.2 are in an open or off configuration when the piston 124 is retained at the rear position.

[0262] FIG. 1B is a circuit diagram of the circuit structure 118 showing the sensing circuitry 200 when the piston 124 is retained at the rear position (i.e., when the ingestible apparatus 100 is in the initial state T.sub.A). As shown, the sensing circuitry 200 comprises a RFID chip 202 such as the TROVANUNIQUE ID-100A Microtransponder (TROVANUNIQUE is a trademark of TROVAN, LTD. of United Kingdom). The RFID chip 202 also comprises an antenna (not shown) for transmitting a RFID signal and is connected to a power source 204 via a resistor 206 and the first switch S.sub.1. The sensing circuitry 200 also comprises the second switch S.sub.2 for short-circuiting the power source 204 and the resistor 206 thereby effectively disabling the RFID chip 202.

[0263] In these embodiments, the sensing circuitry 200 is a passive RFID circuitry and the power source 204 is the antenna harnessing RF energy from an electromagnetic field generated by a RFID reader at a nearby location (outside the body of the user) and the resistor 206 represents the internal resistance of the RFID chip 202. Those skilled in the art will appreciate that in some alternative embodiments, the sensing circuitry 200 may be an active RFID circuitry and the power source 204 is a separate power-source such as a battery and/or the resistor 206 may be a separate resistor.

[0264] As described above, when the ingestible apparatus 100 is in the initial state T.sub.A, the piston 124 is configured at the rear position thereby giving rise to the maximum volume of the compartment 126 for accommodating therein a health-related substance. The surface-tension force of the liquid surface 130 at the one or more substance-release ports 128 retains the substance in the compartment 126.

[0265] The first set of electrodes 166 are separated by air thereby configuring the first switch S.sub.1 to the open of off configuration. The dissolvable latch 164 separates the electrically conductive retaining-shoulder 150 from the second set of electrodes 168 thereby configuring the second switch S.sub.2 to the open or off configuration.

[0266] In a health-related-substance-delivery process, the ingestible apparatus 100 in the initial state T.sub.A is ingested by a user into the GI tract and a RFID reader is positioned in proximity with the body of the user and paired with the RFID chip 202 for monitoring the health-related-substance-delivery process.

[0267] The enteric-targeted coating 104 protects the shell 102 until the ingestible apparatus 100 enters a predefined area such as the stomach. The enteric-targeted coating 104 is then substantively deformed thereby configuring the ingestible apparatus 100 to a second state T.sub.B as shown in FIG. 2 in which the shell 102 is exposed to the gastrointestinal content (generally containing gastrointestinal fluid) of the digestive system and starts to dissolve.

[0268] As shown in FIG. 3A, after approximately a predefined period of time, the shell 102 is substantively deformed thereby configuring the ingestible apparatus 100 to a third state T.sub.C, in which the delivery structure 110 is exposed to the gastrointestinal content 222 and the dissolvable latch 164 starts to dissolve.

[0269] As those skilled in the art will appreciate, the gastrointestinal content 222 generally comprises gastrointestinal fluid and is conductive. Therefore, the first set of electrodes 166, when in contact with the gastrointestinal content 222, are electrically connected by the gastrointestinal content 222 (schematically represented in FIG. 3A by a thick line 224) thereby configuring the switch S.sub.1 to a closed or on configuration. As shown in FIG. 3B, a closed circuit loop is formed from the power source 204 to the RFID chip 202 via the resistor 206 thereby triggering a signal event and enabling the RFID chip 202 to transmit a RFID signal. In the embodiments wherein the passive RFID circuitry is used, the RFID chip 202 transmits the RFID signal when a RFID reader is positioned in proximity therewith and the power source 204 is charged by the electromagnetic field of the RFID reader. In the embodiments wherein the active RFID circuitry is used, the RFID chip 202 transmits the RFID signal when the switch S.sub.1 is configured to the closed or on configuration.

[0270] As shown in FIG. 4A, after the dissolvable latch 164 is substantively deformed, the biased spring 162 is unbiased and actuates the piston 124 to the front position thereby configuring the ingestible apparatus 100 to a fourth state T.sub.D, in which the compartment 126 is configured to its minimum volume and the health-related substance therein is discharged to the target area in the GI tract through the one or more substance-release ports 128.

[0271] When the piston 124 is moved to the front position, the electrically conductive retaining-shoulder 150 engages the second set of electrodes 168 thereby configuring the second switch S.sub.2 to the closed or on configuration. As shown in FIG. 4B, the power source 204 and the resistor 206 are short-circuited thereby triggering another signal event and disabling the RFID chip 202 to stop transmitting the RFID signal.

[0272] The time for the ingestible apparatus 100 to transit from the state T.sub.C to the state T.sub.D may be controlled by selecting the characteristics of the dissolvable latch 164 such as the dissolving rate, materials, geometry, thickness, porosity, coatings, the unbiasing force of the spring 162, and/or the like, to achieve a predefined type of drug release profile such as rapid release, extended release, and the like.

[0273] With above design, the ingestible apparatus 100 uses one or more RF signals for indicating its state. In particular, the ingestible apparatus 100 uses the absence of a RFID signal (which may be considered a first RF signal having a zero amplitude) for indicating the ingestible apparatus 100 at state T.sub.A, T.sub.B, or T.sub.D, and uses the transmission of the RFID signal (which may be considered a second RF signal having a non-zero amplitude) for indicating the ingestible apparatus 100 at state T.sub.C for releasing the health-related-substance.

[0274] FIG. 5 shows the output of a tracking device such as a RFID reader monitoring the ingestible apparatus 100 during a health-related-substance-delivery process wherein the dots represent the outputs of the RFID reader which form an output curve represented by the solid lines. As can be seen, the RFID reader provides a first-type output (no RFID signal detected) until time t.sub.1, and then provides a second-type output (the RFID signal detected) until time t.sub.2 when the RFID reader turns back to the first-type output. Such an output pattern indicates that the ingestible apparatus 100 passed through the GI tract and arrived the target area approximately at time t.sub.1 when the shell 102 and the coating 104 had been substantively deformed and a substance-release sub-process was started. At time t.sub.2, the health-related substance had been discharged into the digestive system and the substance-release sub-process was completed.

[0275] Those skilled in the art will appreciate that the states T.sub.A and T.sub.B of the ingestible apparatus 100 may not be differentiable by the RFID reader and thus the states T.sub.A and T.sub.B may be considered a same (detectable) state.

[0276] In above embodiments, the one or more substance-release ports 128 are on the front wall of the housing 112. In some alternative embodiments, at least one of the one or more substance-release ports 128 may be on a sidewall of the housing 112.

[0277] In above embodiments, the enteric-targeted coating 104 provides a regional delay for protecting the shell 102 and the content therein before the ingestible apparatus 100 arrives a specific region, and the shell 102 provides a time delay before the releasing of the health-related-substance starts.

[0278] In some alternative embodiments, the ingestible apparatus 100 may not comprise an enteric-targeted coating 104. Rather, the ingestible apparatus 100 relies on the time delay provided by the shell 102 to ensure the ingestible apparatus 100 arrive the target area before the releasing of the health-related-substance starts. However, compared to the embodiments shown in FIG. 1A, the shell 102 may need to be thicker so as to provide a longer time delay. Moreover, the time delay provided by the shell 102 in these embodiments is generally selected as an average time for the ingestible apparatus 100 to travel from the mouth to the target area. However, as the actual travel time depends on the specific user's body condition and thus may be significantly different to the average travel time, the ingestible apparatus 100 in these embodiments may have a higher risk that the health-related substance therein is released outside the target area.

[0279] In above embodiments, the circuit structure 118 is coupled to the rear end of the housing 112. In some alternative embodiments, the circuit structure 118 may be coupled to the housing 112 at other suitable locations such as in the chamber 122 of the housing 112 and is electrically connected to the first and second sets of electrodes 166 and 168 via necessary wiring.

[0280] In some alternative embodiments, the RFID chip 202 of the ingestible apparatus 100 may continuously transmit RF signals during the entire health-related-substance-delivery process. In the initial state T.sub.A, the switches S.sub.1 and S.sub.2 are configured to their open or off configuration and the RFID chip 202 transmits a first RF signal with a first set of property settings (such as amplitude, frequency, modulation, coding, and/or the like). When the shell 102 and the coating 104 are sufficiently deformed and the ingestible apparatus 100 is in the state T.sub.C, the first switch S.sub.1 is configured to its closed or on configuration by the gastrointestinal content which triggers the RFID chip 202 to transmit a second RF signal with a second set of property settings. When the health-related substance is released and the second switch S.sub.2 is configured to its closed or on configuration by the electrically conductive retaining-shoulder 150, the RFID chip 202 is configured to transmit a third RF signal with a third set of property settings. In above embodiments, the third RF signal is the same as the first RF signal.

[0281] In some related embodiments, When the health-related substance is released and the second switch S.sub.2 is configured to its closed or on configuration by the electrically conductive retaining-shoulder 150, the RFID chip 202 is configured to transmit a third RF signal different from the first RF signal (e.g., with a different amplitude), as shown in FIG. 6.

[0282] FIG. 7 shows an ingestible apparatus 100 at an initial state T.sub.A, according to some embodiments of this disclosure. The ingestible apparatus 100 in these embodiments is an ingestible sampling apparatus for sampling mucosal-layer samples such as mucosal cells in the digestive system of a user.

[0283] The ingestible apparatus 100 comprises a dissolvable shell 102 coated with an enteric-targeted coating 104 and a sampling structure 300 enclosed in the dissolvable shell 102. The dissolvable shell 102 and the enteric-targeted coating 104 are similar to those described in above embodiments.

[0284] Enclosed in the shell 102, the sampling structure 300 comprises a housing 112 having an access port 302 at the front end 114 and a sample-communication port 304 at the rear end 116. The housing 112 may comprise two portions coupled together via suitable coupling means such as threading, glue, screws, an/or the like and form a chamber 122.

[0285] A piston 124 is received in the chamber 122 movable between a front position adjacent the front end 114 and a rear position adjacent the rear end 116 thereof and defines a compartment 126 between the piston 124 and the access port 302 at the front end 114 for receiving mucosal-layer samples to be collected from the digestive system.

[0286] The piston 124 comprises a piston plate 142 with a piston mandrel 144 extending forwardly from the piston plate 142 out of the housing 112 through the access port 302 to a stopper 306 having a diameter greater than that of the access port 302. In this embodiment, the stopper 306 is configured to plug the access port 302. As described herein, in other embodiments described herein, the piston 124, a portion or component of the piston 124 (e.g., piston plate 142), and/or a component connected to the piston 124 (e.g., stopper 306 or other stopper shown in the figures) can optionally serve as a plug configured to seal one or more ports of the device. The piston mandrel 144 comprises a mucosal-layer brush 308 having a plurality of bristles and at a suitable position such that the mucosal-layer brush 308 is outside the housing 112 when the ingestible sampling apparatus 100 is at the initial state T.sub.A, and may be at least partially retracted into the housing after sampling.

[0287] In some embodiments, the bristles may comprise a fluid-absorbent material (i.e., a material suitable for absorbing gastrointestinal fluid) such as hydrophilic fibers, e.g., polyvinyl alcohol (PVA), to improve the collection of a mucosal sample from the mucosal layer of the GI tract in combination with the more fluid luminal sample from the intraluminal space.

[0288] In particular, fluid-absorbent material may be suitable for absorbing gastrointestinal content. When absorbing fluid upon contact with the gastrointestinal contents, the material may change the properties of the bristles such that their contact with the mucosal layer is further improved. For example, the bristles of increased stiffness may be more adept at scratching off a mucosal sample from the mucosal layer, or contact with the mucosal layer may be improved.

[0289] When the ingestible sampling apparatus 100 is in an initial state T.sub.A, the piston 124 is configured at the front position adjacent the front end 114 of the chamber 122 (e.g., a first position or first working position of the actuation assembly) and is retained at the front position by a dissolvable latch 164 engaging the piston plate 142 and the rear wall of the housing 112, thereby configuring the compartment 126 to its minimum volume and extending the mucosal-layer brush 308 out of the housing 112. The dissolvable latch 164 also closes the sample-communication port 304 at the rear end 116.

[0290] An actuation structure comprising a biased spring 162 engages the piston 124 for moving the piston 124 to the rear position (e.g., a second position or second working position of the actuation assembly) when the dissolvable latch 164 is dissolved. In the example shown in FIG. 7, the biased spring 162 is a compressed spring (sometimes referred to herein as “compression spring”) located in the chamber 122 between the front end 114 and the piston 124 (i.e., in the compartment 126). The spring 162 is extendable to “push” the piston 124 towards the rear end 116 to increase the volume of the compartment 126 and retract the mucosal-layer brush 308 thereinto. In some alternative embodiments, the biased spring 162 may be an extended spring (sometimes referred to herein as “extension spring”) located in the chamber 122 between the rear end 116 and the piston 124. The spring 162 is retractable to “pull” the piston 124 towards the rear end 116 to increase the volume of the compartment 126 and retract the mucosal-layer brush 308 thereinto.

[0291] A circuit structure 118 is coupled to a rear surface of the piston plate 142. The circuit structure 118 comprises a sensing circuitry (not shown) electrically connected to a first set of electrodes 166 on the front surface of the piston plate 142 and a second set of electrodes 168 on the rear side of the circuit structure 118. The first set of electrodes 166 form a first switch S.sub.1. The second set of electrodes 168 are engageable with an electrically conductive surface such as a corresponding portion 312 of the inner surface of the rear wall of the housing 112 thereby forming a second switch S.sub.2.

[0292] When the piston 124 is retained at the front position (i.e., the ingestible sampling apparatus 100 is in the initial state T.sub.A), the circuit diagram of the circuit structure 118 is similar to that shown in FIG. 1B. Both switches S.sub.1 and S.sub.2 are in an open or off configuration.

[0293] In a sampling process, the ingestible sampling apparatus 100 in the initial state T.sub.A is ingested by a user into the GI tract and a RFID reader is positioned in proximity with the body of the user and paired with the RFID chip 202 for monitoring the sampling process.

[0294] Similar to the health-related-substance-delivery process described above, the enteric-targeted coating 104 protects the shell 102 until the ingestible sampling apparatus 100 enters the stomach. The enteric-targeted coating 104 is then substantively deformed thereby configuring the ingestible sampling apparatus 100 to a second state T.sub.B as shown in FIG. 8 in which the shell 102 is exposed to the gastrointestinal content of the digestive system and starts to dissolve.

[0295] As shown in FIG. 9, after approximately a predefined period of time, the shell 102 is substantively deformed thereby configuring the ingestible sampling apparatus 100 to a third state T.sub.C, in which the sampling structure 300 is exposed to the gastrointestinal content 222 of the digestive system. While the gastrointestinal content 222 causes the dissolvable latch 164 to start dissolving, the mucosal-layer brush 308 is exposed to the digestive system and interacts with the mucosal layer thereof to collect gastrointestinal samples 314.

[0296] Herein, the gastrointestinal samples may comprise all substances contained in or being part of the GI tract of the user. This may include but not limit to, tissue, cells, including those from the mucosal layer, gastrointestinal fluid, microbiome, viruses, biological markers as well as foreign substances introduced to the GI tract of the user. For example, pharmaceutical agents or markers, probiotics or other treatments administered to the user, chemicals ingested by or having been exposed to the user. The gastrointestinal samples may be collected from the intra-luminal space, which substantively include flowing gastrointestinal fluid and may also include some cells (e.g., debris from elsewhere in the user's body or free-floating cells that have detached from the mucosal layer). Samples collected from the intra-luminal space are referenced as luminal samples. The gastrointestinal samples can also be collected from the mucosal layer where there may be an increased density of mucosal cells adhering to the lining of the GI tract. These are more difficult to obtain, and are herein referred to as mucosal-layer samples. Herein, the terms “gastrointestinal samples” and “gastrointestinal-content samples” may be used interchangeably, which may comprise at least one of the luminal samples and mucosal-layer samples.

[0297] The gastrointestinal content 222 enters the chamber 122 from the access port 302. The electrically conductive gastrointestinal content 222 connects the first set of electrodes 166 (schematically represented in FIG. 9 by a thick line 224) thereby configuring the switch S.sub.1 to a closed or on configuration. A closed circuit loop is formed thereby enabling the RFID chip 202 to transmit a RFID signal. The circuit diagram of the circuit structure 118 is similar to that shown in FIG. 3B.

[0298] As shown in FIG. 10, after the dissolvable latch 164 is substantively deformed, the biased spring 162 is unbiased and actuates the piston 124 to the rear position thereby configuring the ingestible sampling apparatus 100 to a fourth state T.sub.D, in which the compartment 126 is configured to its maximum volume. The mucosal-layer brush 308 and the collected mucosal-layer samples 314 are retracted into the compartment 126. The stopper 306 engages the housing 112 to close the access port 302 thereby preventing content-exchange between the compartment 126 and the digestive system. The captured mucosal-layer samples 314 are thus isolated from the digestive system and are prevented from being contaminated when the ingestible sampling apparatus 100 continues its travel in the GI tract and eventually discharged therefrom. The process of substantially deforming the latch 164 and actuating the piston 124 occurs over a period of time. The period of time relating to the sample collection duration as the capsule travels along the small intestine.

[0299] When the piston 124 is moved to the rear position, the second set of electrodes 168 engage the electrically conductive portion 312 of the rear wall of the housing 112 thereby configuring the second switch S.sub.2 to the closed or on configuration. The power source 204 and the resistor 206 are short-circuited thereby disabling the RFID chip 202 to stop transmitting the RFID signal. The circuit diagram of the circuit structure 118 is similar to that shown in FIG. 4B. The RFID signal transmission is similar to that described above, and the output of the RFID reader is similar to that shown in FIG. 5.

[0300] In some embodiments, the ingestible sampling apparatus 100 shown in FIG. 7 may be used for collecting the luminal samples from the intraluminal space. In these embodiments, the ingestible sampling apparatus 100 may not comprise a mucosal-layer brush 308.

[0301] FIG. 11 shows an ingestible apparatus 100 at an initial state T.sub.A, according to some embodiments of this disclosure. The ingestible apparatus 100 in these embodiments is an ingestible sampling apparatus for fluid sampling in the digestive system of a user. The ingestible sampling apparatus 100 in these embodiments is similar to the ingestible apparatus shown in FIG. 1A with differences in the housing 112 and the piston 124. Therefore, the description of some common structural features is omitted.

[0302] In these embodiments, the housing 112 forms a chamber 122 and comprises one or more sample-communication ports 322 on a sidewall thereof at a distance to the front wall. Thus, the portion of the chamber 122 between the front wall of the housing 112 and the one or more sample-communication ports 322 forms a compartment 126 which receives therein a suitable fluid-absorbent material 324 such as a bundle of hydrophilic fibers for retaining the luminal samples therein.

[0303] The piston 124 is similar to that shown in FIG. 1A. However, in these embodiments, the piston 124 is retained at a position rearward to the one or more sample-communication ports 322 such that, during gastrointestinal-content sampling, luminal samples entering the one or more sample-communication ports 322 may flow into the compartment 126 and accumulate therein.

[0304] The luminal-sampling process is shown in FIGS. 11 to 14 which is similar to the health-related-substance-delivery process shown in FIGS. 1A, 2A, 3A, and 4A except the following differences:

[0305] (i) At state T.sub.C (see FIG. 13), the dissolvable shell 102 is sufficiently deformed and the luminal sample (not shown) flows into the compartment 126 via the one or more sample-communication ports 322 as indicated by the arrows 328 due to gravity and the peristaltic force of the digestive system. The fluid-absorbent material 324 facilitates the accumulation of the luminal samples in the compartment 126.

[0306] (ii) At state T.sub.D (see FIG. 14), the dissolvable latch 164 is substantively deformed and the biased spring 162 actuates the piston 124 to the front position forward to the one or more sample-communication ports 322 which effectively isolates the compartment 126 from the one or more sample-communication ports 322 thereby closing the compartment 126 and sealing the collected luminal samples therein.

[0307] The circuit diagrams in the states T.sub.A, T.sub.B, T.sub.C, and T.sub.D are similar to those shown in FIGS. 1B, 2B, 3B, and 4B, and the tracking process similar to that described above with the RFID reader outputting two types of outputs as shown in FIG. 5.

[0308] FIG. 15 shows an ingestible apparatus 100 at an initial state T.sub.A, according to some embodiments of this disclosure. The ingestible apparatus 100 in these embodiments is an ingestible health-related-substance-delivery and gastrointestinal-content-sampling apparatus for delivering a health-related substance and for sampling gastrointestinal/luminal content in the digestive system of a user.

[0309] The ingestible apparatus 100 in these embodiments comprises a dissolvable shell 102 coated with an enteric-targeted coating 104 similar to those shown in FIG. 1A.

[0310] Enclosed in the dissolvable shell 102, the ingestible apparatus 100 comprises a delivery-and-sampling structure 110 which comprises a housing 112 having a front end 114 and a rear end 116 and a circuit structure 118 coupled to the rear end 116 of the housing 112. The circuit structure 118 and the first and second sets of electrodes 166 and 168 are similar to those shown in FIG. 1A.

[0311] The housing 112 may comprise two portions coupled together via suitable coupling means such as threading, glue, screws, an/or the like to form a chamber 122. The housing 112 comprises a set of one or more substance-release ports 128 adjacent the front end 114 thereof and a set of one or more sample-communication ports 304 at a rear side of the substance-release ports 128 and spaced therefrom.

[0312] A piston 124 is movably received in the chamber 122 and is secured at a rear position adjacent the rear end 116 thereof by a dissolvable latch 164 in a same manner as shown in FIG. 1A. The piston 124 engages an actuation structure comprising a biased spring 162. When the dissolvable latch 164 is substantively deformed, the biased spring 162 may be unbiased and actuate the piston 124 to move from the rear position to a front position adjacent the front end 114.

[0313] The piston 124 comprises a front piston plate 142 and a rear piston plate 342 respectively located on the front and rear sides of the sample-communication ports 304 thereby defining a first compartment 126 between the front piston plate 142 and the front end 114 for accommodating therein one or more active compounds in a liquid form and a second compartment 344 between the front and rear piston plates 142 and 342 for receiving therein the gastrointestinal-content samples to be collected. A piston mandrel 144 couples the front and rear piston plates 142 and 342 to an end piece 148 outside the rear end of the housing 112. Similar to that described above, the end piece 148 forms an electrically conductive, circumferential retaining-shoulder 150 engageable with the second set of electrodes 168.

[0314] At state T.sub.A, the first compartment 126 is in communication with the set of substance-release ports 128. Each substance-release port 128 has a small dimension allowing the fluid in the compartment 126 to form a liquid surface 130 at the substance-release port 128 with a surface-tension force and/or the friction of the sidewall of the substance-release port 128 that are sufficient for retaining the fluid in the compartment 126. The second compartment 344 is in communication with the set of sample-communication ports 304.

[0315] The ingestible apparatus 100 may be used for collecting gastrointestinal samples in a target area in the GI tract of a user and then releasing a health-related substance thereto.

[0316] In a health-related-substance-delivery and gastrointestinal-sampling process, the ingestible apparatus 100 configured in the state T.sub.A is ingested into the GI tract. While travelling in the GI tract, the ingestible apparatus 100 transits to states T.sub.B and T.sub.C as described above.

[0317] FIG. 16 shows the ingestible apparatus 100 in the state T.sub.C. As shown, the shell 102 and coating 104 (not shown) are substantively deformed and the gastrointestinal sample 222 flows into the second compartment 344 through the set of sample-communication ports 304 as indicated by the arrows 328. In this state, the health-related substance is substantively retained in the first compartment 126.

[0318] When the dissolvable latch 164 is dissolved, the ingestible apparatus 100 transits to the state T.sub.D. As shown in FIG. 17, the biased spring 162 is unbiased and actuates the piston 124 to move to the front position at which the front piston plate 142 discharges the health-related substance from the first compartment 126 out of the housing 112 into the target area of the GI tract, as indicated by the arrow 212. The rear piston plate 342 is moved to the front side of the set of sample-communication ports 304 thereby isolating the second compartment 344 from the set of sample-communication ports 304 and sealing the collected gastrointestinal samples in the second compartment 344.

[0319] The circuit diagrams in the states T.sub.A, T.sub.B, T.sub.C, and T.sub.D are similar to those shown in FIGS. 1B, 2B, 3B, and 4B, and the tracking process is similar to that described above with the RFID reader outputting two types of outputs as shown in FIG. 5.

[0320] FIG. 18 shows an ingestible apparatus 100 at an initial state T.sub.A, according to some embodiments of this disclosure. The ingestible apparatus 100 in these embodiments is an ingestible health-related-substance-delivery and gastrointestinal-content-sampling apparatus for delivering a health-related substance having one or more active compounds and for sampling gastrointestinal content in the digestive system of a user.

[0321] The ingestible apparatus 100 in these embodiments comprises a dissolvable shell 102 coated with an enteric-targeted coating 104 similar to those shown in FIG. 1A.

[0322] Enclosed in the dissolvable shell 102, the ingestible apparatus 100 comprises a delivery-and-sampling structure 110 which comprises a housing 112 having a front end 114 and a rear end 116 and a circuit structure 118 coupled to the rear end 116 of the housing 112. The circuit structure 118 and the first and second sets of electrodes 166 and 168 are similar to those shown in FIG. 1A.

[0323] The housing 112 comprises a chamber 122 and a set of one or more substance-release and gastrointestinal-content-sampling ports 128 adjacent the front end 114 thereof. A piston 124 is movably received in the chamber 122 and is secured at a rear position adjacent the rear end 116 thereof by a dissolvable latch 164 in a same manner as shown in FIG. 1A. The piston 124 engages a substance-delivery actuation structure comprising a biased (e.g., compressed) substance-delivery spring 162. When the dissolvable latch 164 is substantively deformed, the biased substance-delivery spring 162 may be unbiased and actuate the piston 124 to move from the rear position to a front position adjacent the front end 114.

[0324] The piston 124 comprises a sealable-component 362 about a front end thereof and engaging an exterior surface of the housing 112 about the set of substance-release and gastrointestinal-content-sampling ports 128 and a piston plate 142 at a distance to the front end 144 of the housing 112 to form a compartment 126 for accommodating therein one or more health-related-substances in a liquid or a semi-liquid form and also for receiving therein the gastrointestinal samples to be collected. A piston mandrel 144 couples the sealable-component 362 and the piston plate 142 to an end cap 148 outside the rear end of the housing 112.

[0325] In these embodiments, the end cap 148 is in the form of a cylindrical sleeve having a rear wall 148A and a sidewall 148B and slidably receiving therein a rear portion of the housing 112. Similar to that described above, the rear wall 148A of the end cap 148 comprises an electrically conductive, circumferential retaining-shoulder 150 engageable with the second set of electrodes 168. One or more windows 364 are distributed on the sidewall 148B and/or the rear wall 148A for establishing communication between the interior of the end cap 148 and the digestive system when the shell 102 and coating 104 are substantively deformed.

[0326] The delivery-and-sampling structure 110 further comprises a sampling actuation-structure comprising a biased (e.g., compressed) outer sampling-spring 366 and a biased (e.g., compressed) inner sampling-spring 368 coupled to the rear end of the housing 112 and received in the end cap 148. Both sampling-springs 366 and 368 are retained in their biased configurations by a dissolvable circular block 370. A rupture disk 372 such as an undissolvable film is coupled to a rear end of the dissolvable block 370 for protecting the dissolvable block 370 and the sampling-springs 366 and 368 retained therein from contacting gastrointestinal content.

[0327] The ingestible apparatus 100 may be used for delivering a health-related substance to a target area in the GI tract of a user and then collecting gastrointestinal samples therein after a time delay from the health-related-substance-delivery.

[0328] In a substance-delivery and gastrointestinal-sampling process, the ingestible apparatus 100 configured in the state T.sub.A is ingested into the GI tract. While travelling in the GI tract, the ingestible apparatus 100 transits to states T.sub.B and T.sub.C as described above.

[0329] FIG. 19 shows the ingestible apparatus 100 in the state T.sub.C. As shown, the shell 102 and coating 104 (not shown) are substantively deformed and the gastrointestinal samples 222 flow into the interior of the end cap 148 via the windows 364 as indicated by the arrows 328. The dissolvable latch 164 then starts to dissolve.

[0330] When the dissolvable latch 164 is substantively deformed, the ingestible apparatus 100 transits to the state T.sub.D. As shown in FIG. 20, the biased substance-delivery spring 162 is unbiased and actuates the piston 124 to move to the front position at which the piston plate 142 discharges the health-related substance from the compartment 126 out of the housing 112 into the target area of the GI tract, as indicated by the arrow 212. The windows 364 of the end cap 148 are aligned with the dissolvable circular block 370 and introduce gastrointestinal content thereto. The dissolvable circular block 370 then starts to dissolve.

[0331] The circuit diagrams in the states T.sub.A, T.sub.B, T.sub.C, and T.sub.D are similar to those shown in FIGS. 1B, 2B, 3B, and 4B, and the tracking process is similar to that described above with the RFID reader outputting two types of outputs as shown in FIG. 5.

[0332] When the portion of the dissolvable circular block 370 retaining the outer sampling-spring 366 is substantively deformed, the ingestible apparatus 100 transits to a state T.sub.E. As shown in FIG. 21A, the biased outer sampling-spring 366 is unbiased, breaks the rupture disk 372, and overcomes the resistance of the substance-delivery spring 162 to rearwardly actuate the end cap 148. Consequently, the piston 124 is moved rearwardly to an intermediate position increasing the volume of the compartment 126. Gastrointestinal samples 222 then flow through the gap between the sealable-component 362 and the front end of the housing 112 and through the substance-release and gastrointestinal-content-sampling ports 128 into the compartment 126.

[0333] The circuit diagram of the ingestible apparatus 100 in the state T.sub.E is shown in FIG. 21B. As the electrically conductive retaining-shoulder 150 is not in contact with the second set of electrodes 168 and as the second set of electrodes 168 are spaced at a relatively large distance, switch S.sub.2 may be considered a resistor 382 with a relatively large resistance. The RFID chip 202 may be configured to transmit another RFID signal with a different set of property settings.

[0334] In the state T.sub.E, the remaining portion 370′ of the dissolvable circular block 370 continues to dissolve.

[0335] When the dissolvable circular block portion 370′ retaining the inner sampling-spring 368 is substantively deformed, the ingestible apparatus 100 transits to a state T.sub.F. As shown in FIG. 22, the biased inner sampling-spring 368 is unbiased, breaks the remaining rupture disk portion 372′, and overcomes the resistance of the substance-delivery spring 162 to further rearwardly actuate the end cap 148. Consequently, the piston 124 is moved rearwardly to the rear position giving rise to the maximum volume of the compartment 126. The sealable-component 362 engages the exterior surface of the housing 112 about the substance-release and gastrointestinal-content-sampling ports 128 thereby closing the substance-release and gastrointestinal-content-sampling ports 128 and sealing the collected gastrointestinal samples in the compartment 126.

[0336] The circuit diagram of the ingestible apparatus 100 in the state T.sub.F is similar to that shown in FIG. 21B.

[0337] In the embodiments shown in FIGS. 18 to 22, the ingestible apparatus 100 comprises two sampling-springs 366 and 368. In some embodiments as shown in FIG. 23, the ingestible apparatus 100 may only comprise one sampling-spring 368.

[0338] In these embodiments, the dissolvable circular block 370 comprises a suitable dissolvable material that may gradually dissolve without abrupt deformation. Moreover, the ingestible apparatus 100 does not comprise any rupture disk for isolating the dissolvable block 370 from the gastrointestinal content.

[0339] As shown in FIGS. 23 to 27, when the ingestible apparatus 100 is ingested into the GI tract, and after the shell 102 and coating 104 are substantively deformed, the dissolvable latch 164 is in contact with gastrointestinal content and starts to dissolve (FIG. 24). When the dissolvable latch 164 is substantively deformed, the substance-delivery spring 162 actuates the piston 144 to the front position thereby discharging the health-related substance from the compartment 126 into the target area of the GI tract (FIG. 25). Meanwhile, the dissolvable block 370 is in contact with the gastrointestinal content and starts to dissolve.

[0340] With the gradual dissolution of the dissolvable block 370, the sampling-spring 368 gradually actuates the piston 144 to move towards the rear position thereby increasing the volume of the compartment 126 and allowing the gastrointestinal content to flow thereinto (FIG. 26). When the dissolvable block 370 is substantively dissolved, the sampling-spring 368 actuates the piston 144 to the rear position thereby closing the port 128 to seal the collected gastrointestinal samples in the compartment 126 (FIG. 27).

[0341] The states and circuit diagrams of the ingestible apparatus 100 in these embodiments are similar to those described in the embodiments shown in FIGS. 18 to 22.

[0342] FIG. 28 shows an ingestible apparatus 100, according to some embodiments of this disclosure. The ingestible apparatus 100 in these embodiments is similar to that shown in FIGS. 23 to 27. However, in these embodiments, the ingestible apparatus 100 comprises a mucosal-layer brush 308 attached to the piston mandrel 144 about a distal end thereof. At the initial state T.sub.A as shown in FIG. 28, the mucosal-layer brush 308 is received in the compartment 126 with the health-related substance to be delivered.

[0343] The substance-delivery and luminal-sampling process is shown in FIGS. 28 to 32. When the ingestible apparatus 100 is ingested into the GI tract, and after the shell 102 and coating 104 are substantively deformed, the gastrointestinal content 222 flows into the interior of the end cap 148 via the windows 364 as indicated by the arrows 328. The dissolvable latch 164 is then in contact with gastrointestinal content and starts to dissolve (FIG. 29). When the dissolvable latch 164 is substantively deformed, the substance-delivery spring 162 actuates the piston 144 to the front position thereby discharging the health-related substance from the compartment 126 into the target area of the GI tract (FIG. 30). The mucosal-layer brush 308 is extended out of the compartment 126 for collecting mucosal-layer samples. The dissolvable block 370 is in contact with the gastrointestinal content and starts to dissolve (FIG. 31).

[0344] When the dissolvable block 370 is substantively deformed, the sampling-spring 368 actuates the piston 144 to the rear position thereby retracting the mucosal-layer brush 308 and the collected mucosal-layer samples into the compartment 126 and closing the port 128 to seal the compartment 126 (FIG. 32).

[0345] In these embodiments, the dissolvable block 370 may not need to be gradually dissolved. Rather, it may be abruptly deformed after a predefined period of time to retract the mucosal-layer brush 308 and the collected mucosal-layer samples into the compartment 126 and close the port 128 to seal the compartment 126.

[0346] The states and circuit diagrams of the ingestible apparatus 100 in these embodiments are similar to those described in the embodiments shown in FIGS. 18 to 22.

[0347] In above embodiments, the second switch S.sub.2 is implemented by using a second set of electrodes 168 engageable with an electrically conductive surface such as the electrically conductive retaining-shoulder 150. The second switch S.sub.2 may be turned from off (also see FIG. 33A, the second switch S.sub.2 off) to on (also see FIG. 33B, the second switch S.sub.2 on) by a spring force.

[0348] The second switch S.sub.2 may also be implemented by using a second set of electrodes 168 engageable with an electrically conductive portion of the rear wall of the housing 112. The second switch S.sub.2 may be turned from off (also see FIG. 34A, the second switch S.sub.2 off) to on (also see FIG. 34B, the second switch S.sub.2 on) by a spring force.

[0349] In various embodiments, the second switch S.sub.2 may be implemented in any suitable manner. For example, as shown in FIG. 35A the second switch S.sub.2 may comprise a set of electrodes 168A and 168B. The electrode 168A comprises an electrically conductive tab 422 extending therefrom to a location in proximity with the electrode 168B thereby configuring the second switch S.sub.2 to an open or off configuration.

[0350] A spring force may be used to actuate the second set of electrodes 168A and 168B (in this example the circuit structure 118 and the second set of electrodes 168A and 168B thereon) towards a stopper 424 which may be a wall of the housing 112 or the end piece 148 of the piston 124, to push the electrically conductive tab 422 in contact with the electrode 168B thereby configuring the second switch S.sub.2 to a closed or on configuration as shown in FIG. 35B.

[0351] Alternatively, a spring force may actuate the stopper 424 towards the second set of electrodes 168A and 168B to push the electrically conductive tab 422 in contact with the electrode 168B thereby configuring the second switch S.sub.2 to a closed or on configuration.

[0352] In above embodiments, the first switch S.sub.1 is implemented by using a first set of electrodes 166 initially electrically isolated by air and configured to an open or off configuration (also see FIG. 36A, the first switch S.sub.1 off).

[0353] The first switch S.sub.1 may be configured to a closed or on configuration when the first set of electrodes 166 are in contact with electrically conductive gastrointestinal-content 222. As shown in FIG. 36B, in some embodiments wherein the first set of electrodes 166 are at a short distance from each other, the resistance of the gastrointestinal content 224 therebetween is small and may be ignored. Therefore, the first switch S.sub.1 in the closed or on configuration may be modelled as a connection wiring with zero resistance.

[0354] In some embodiments wherein the first set of electrodes 166 may be at a relatively large distance from each other (see FIG. 37A). The first switch S.sub.1 may be configured to a closed or on configuration when the first set of electrodes 166 are in contact with electrically conductive gastrointestinal-content 222. As shown in FIG. 37B, the resistance of the gastrointestinal content 224 therebetween in these embodiments may not be ignored. Therefore, the first switch S.sub.1 in the closed or on configuration may be modelled a resistor R.sub.S1.

[0355] In above embodiments, the switches S.sub.1 and S.sub.2 are used for determining the RF signal to be transmitted for indicating the state of the ingestible apparatus 100. The first switch S.sub.1 acts as a detection circuit for detecting gastrointestinal content. The second switch S.sub.2 acts as a detection-circuit for detecting a volume-change of the first compartment 126 by detecting the position or movement of the piston 124. By detecting the gastrointestinal content and the volume-change of the first compartment 126, the state of the ingestible apparatus 100 may be determined which may be sent to a tracking device via one or more RF signals.

[0356] In some alternative embodiments, other gastrointestinal-content detection-circuit may be used.

[0357] In some alternative embodiments, other volume-change or piston-position detection-circuit may be used. For example, in one embodiment, the piston 124 may comprise a magnetic component such as a permanent magnet and the housing 112 may comprise a Hall-effect sensor in proximity with the magnetic component for detecting the piston position (and subsequently the volume-change of the first compartment 126). The output of the Hall-effect sensor may be used for determining the RF signal (or more specifically the property settings thereof) for indicating the state of the ingestible apparatus 100.

[0358] In another embodiment, the piston 124 may be coupled to the slider of a sliding rheostat for adjusting the resistance of the sliding rheostat for detecting the piston position which may be used for determining the RF signal (or more specifically the property settings thereof) for indicating the state of the ingestible apparatus 100.

[0359] In these embodiments, by using the sliding rheostat, the spring movement may be continuously monitored and the RF signal may be used for continuously reporting the monitored spring movement.

[0360] In above embodiments, a RFID reader is used as a tracking device for tracking the ingestible apparatus 100 during its travel in the GI tract. FIG. 38 is a block diagram of a wearable RFID reader 500. As shown. The wearable RFID reader 500 comprises an antenna 502, a RF-signal transceiver 504, a microcontroller 506 (which is a controlling circuitry), and a data logger 508. The microcontroller 506 is configured to command the RF-signal transceiver 504 to periodically (e.g., every five (5) minutes) interrogate the RFID chips 202 of one or more ingestible apparatus 100 using an RF signal.

[0361] As those skilled in the art will appreciate, each RFID chip 202 may transmit a RFID signal having a unique identity (ID). Therefore, a user may ingest one or more ingestible apparatuses 100 for health-related-substance-delivery, and/or gastrointestinal-content sampling as needed from either the intra-luminal space or the mucosal lining.

[0362] As shown in FIG. 39, a user 522 may digest N above-described ingestible apparatuses 100-1 to 100-N which may have different settings such as different regional dissolution characteristics, different time delays, and/or the like. Each ingestible apparatus 100 has a unique ID encoded in the RFID signal transmittable from the RFID chip 202 thereof. A wearable RFID reader 500 is attached to the user for tracking the ingestible apparatuses 100-1 to 100-N as described above. The signals detected by the wearable RFID reader 500 is shown in FIG. 40.

[0363] The microcontroller 506 of the wearable RFID reader 500 records the results of the interrogating-and-reading events of the ingestible apparatuses 100-1 to 100-N in the data logger 508.

[0364] Alternatively, a bench top RFID reader can be used to prescan the ingestible apparatus prior to delivery to the user. The prescan can be used to determine the correct positioning of the various components to ensure a correct use of the device. For example, the RFID scan can be used to determine in the device is in the initial state.

[0365] FIG. 41 is a flowchart showing the steps of a monitoring process 540 for monitoring a sampling and/or health-related-substance-delivery process using above-described ingestible apparatus 100 with X-Ray confirmation.

[0366] When the monitoring process 540 starts (step 542), a user ingests an ingestible apparatus 100 and a wearable RFID reader 500 is attached to the user for tracking the ingestible apparatus 100 (step 544). The wearable RFID reader 500 monitors the RFID signal (step 546). If no RFID signal is detected (step 548), the process loops back to step 546 and continues the monitoring of the RFID signal.

[0367] If the RFID signal is detected at step 548, a X-Ray scan is performed to confirm the detection of the ingestible apparatus 100 and to confirm that the ingestible apparatus 100 has arrived the target area (step 550). Then, the wearable RFID reader 500 continues the monitoring of the RFID signal (step 552). If the RFID signal continues to be detected (step 554), the ingestible apparatus 100 is still in the process of discharging the health-related substance and/or collecting samples of gastrointestinal content from either the intra-luminal space or the mucosal lining. The process then loops back to step 552 and continues the monitoring of the RFID signal.

[0368] If no RFID signal is detected at step 554, another X-Ray scan is performed to confirm that the ingestible apparatus 100 has completed sampling and/or health-related-substance-delivery (step 556). The process 540 then ends (step 558).

[0369] Those skilled in the art will appreciate that the X-Ray-scan steps 550 and 556 may be optional. Thus, in some alternative embodiments, the process 540 may omits at least one of steps 550 and 556.

[0370] Although in above embodiments, a RFID chip 202 and a RFID reader are used for tracking the ingestible apparatus 100, in various embodiments, the ingestible apparatus 100 may comprise any suitable RF-signal transmitter and a corresponding RF-signal receiver may be used for tracking the ingestible apparatus 100.

[0371] In some alternative embodiments, the ingestible apparatus 100 described above may not comprise any circuit structure 118. In these embodiments, no RFID reader is used for monitoring the ingestible apparatus 100 travelling in the GI tract.

[0372] In above embodiments, the ingestible apparatus 100 comprises one or more springs 162, 366, and 368 as one or more actuation structures for actuating the piston 124 to the front and/or rear positions. In some alternative embodiments, at least one of the one or more springs 162, 366, and 368 may be substituted with other suitable actuation structures such as a suitable shape-memory alloy or other memory materials, a material expandable when in contact with the gastrointestinal content, and/or the like. Depending on the actuation structure, the dissolvable block 370 may not be required.

[0373] FIG. 42 shows an ingestible assembly 100 according to some alternative embodiments of this disclosure. The ingestible assembly 100 in these embodiments may be the ingestible apparatus (identified using reference numeral 100′ in FIG. 42) described in above embodiments and further comprises a string 570 coupled to the shell 102. The string 570 is made of a suitable material and comprises a plurality of marks 572 such as color marks or knots distributed thereon for indicating the distance from the shell 102. The string 570 may also have a handle 574 at the opposite end thereof.

[0374] In a sampling and/or health-related-substance-delivery process, the ingestible apparatus 100′ is ingested by a user 522 and goes through the GI tract 576 as described above. With the movement of the ingestible apparatus 100′ in the GI tract 576, the string 570 is extended into the mouth of the user 522. By monitoring the marks of the string 570 remaining outside the user's mouth, the location of the ingestible apparatus 100′ in the GI tract 576 may be monitored.

[0375] When the shell 102 of the ingestible apparatus 100′ is dissolved, the string 570 is separated from the delivery structure 110 and may be pulled out from the user's mouth. Thus in these embodiments, the string 570 may be made of an undissolvable material.

[0376] In some embodiments, the string 570 may be made of a dissolvable material and may be coupled to the shell 102 or the housing 112. When the shell 102 of the ingestible apparatus 100′ is dissolved, the string 570 may be left in the user's GI tract and dissolve. In these embodiments, a portion of the string 570 adjacent the handle 574 may be made of an undissolvable material.

[0377] In some embodiments wherein the ingestible apparatus 100 is configured for sampling, the ingestible apparatus 100 may be used for collecting other mucosal-layer samples than mucosal-layer samples.

[0378] FIG. 43 shows an ingestible apparatus 100 in some embodiments. The ingestible apparatus 100 in these embodiments is similar to that shown in FIG. 7 except that the piston mandrel 144 is rotatable about a longitudinal axis thereof. The piston mandrel 144 is coupled to a torsion structure such as a twisted torsion-spring 602 retained in a dissolvable block 604 such that the torsion structure would not release the energy stored therein before the dissolvable block 604 is substantively deformed.

[0379] When the ingestible apparatus 100 is ingested in the GI tract and the shell 102 and coating 104 are substantively deformed, gastrointestinal content enters the compartment 126 via the port 302. Consequently, the dissolvable block 604 starts to dissolve. When the dissolvable block 604 is substantively deformed, the twisted torsion-spring 602 starts to release the energy stored therein and applies a torque to the piston mandrel 144 to cause the piston mandrel 144 and the mucosal-layer brush 308 thereon to rotate, thereby providing an improved mucosal-lining-sampling performance.

[0380] FIG. 44 shows an ingestible apparatus 100, according to some embodiments of this disclosure. The ingestible apparatus 100 in these embodiments is similar to that shown in FIG. 43 except that the piston mandrel 144 is not rotatable. Rather, the mucosal-layer brush 308 is coupled to a sleeve 606 which is coupled to the piston mandrel 144 and is rotatable about a longitudinal axis thereof. The rotatable sleeve 606 is coupled to a torsion structure such as a twisted torsion-spring 602 retained in a dissolvable block 604 such that the torsion structure would not release the energy stored therein before the dissolvable block 604 is substantively deformed.

[0381] When the ingestible apparatus 100 is ingested in the GI tract and the shell 102 and coating 104 are substantively deformed, gastrointestinal content enters the compartment 126 via the port 302. Consequently, the dissolvable block 604 starts to dissolve. When the dissolvable block 604 is substantively deformed, the twisted torsion-spring 602 starts to release the energy stored therein and applies a torque to the rotatable sleeve 606 to cause the rotatable sleeve 606 and the mucosal-layer brush 308 thereon to rotate, thereby providing an improved mucosal-lining-sampling performance.

[0382] In above embodiments, the ingestible apparatus 100 comprises a dissolvable shell 102 coated with a dissolvable coating 104. In some alternative embodiments, the ingestible apparatus 100 does not comprise any dissolvable shell 102 or dissolvable coating 104.

[0383] For example, in an embodiment shown in FIG. 45, the ingestible apparatus 100 only comprises a collection structure 110 which in this example is similar to the delivery structure 110 shown in FIG. 1A. However, for safety considerations, the housing 112 is further rearwardly extended to receive the entire piston 124 therein. The housing 112 also comprises an opening 642 about the rear end thereof to allow the gastrointestinal content to flow therein.

[0384] In this embodiment, the first set of electrodes 166 may be isolated from the gastrointestinal content by a dissolvable block 644.

[0385] When the ingestible apparatus 100 is ingested into a user's GI tract, gastrointestinal content flows into the rear portion of the housing via the opening 642 causing the dissolvable block 644 and the dissolvable latch 164 to dissolve. The dissolvable block 644 may be designed to dissolve faster than the dissolvable latch 164 in the gastrointestinal content. As a result, the first switch S.sub.1 formed by the first set of electrodes 166 is first configured to a closed or on configuration after the dissolvable block 644 is substantively deformed, causing the transmission of a RF signal. Then, after the dissolvable latch 164 is substantively deformed, the piston 124 is actuated and the second switch S.sub.2 (formed by the second set of electrodes 168 and the electrically conductive shoulder 150) is configured to a closed or on configuration thereby stopping the transmission of the RF signal.

[0386] Also shown in FIG. 45, all exterior edges and corners of the housing 112 are smooth or curved edges and corners for safety considerations. Similarly, the housing 112 in above-described embodiments and shown in FIGS. 1A to 44 may only comprise smooth or curved edges and corners for safety considerations.

[0387] In some embodiments, the circuit structure 118 of the ingestible apparatus 100 does not comprise a RF-signal transmitter. Rather, the circuit structure 118 comprises a timer and a memory. The circuit structure 118 uses the timer for recording the time instant of the occurrence of each state of the ingestible apparatus 100 and stores the recorded time instants in the memory. The stored time instants may be later retrieved for processing after the ingestible apparatus 100 is discharged from the user's body.

[0388] In some embodiments, the circuit structure 118 of the ingestible apparatus 100, such as the first and second detection circuits may be MEMS chips.

[0389] In an embodiment similar to that shown in FIG. 30, the dissolvable latch 164 is substantively deformed and the mucosal-layer brush 308 is extended out of the compartment 126 for collecting mucosal-cell samples, with or without discharging a health-related substance from the compartment 126. The method of containing and then extending the mucosal-layer brush with the action of the spring may be used to enact the outward extension of the mucosal-layer brush and enable the bristles to fully contact the mucosal lining.

[0390] In this embodiment, the mucosal-layer brush comprises bristles that are spring loaded and contained within the compartment 126. With extension of the piston, the bristles are allowed to extend radially outward beyond the edge of the housing to ensure contact with the mucosal lining.

[0391] In some embodiments, the mucosal-layer brush may comprise bristles which are formed from fluid-absorbent material such as hydrophilic fibers (e.g., poly-vinyl alcohol (PVA)). The fluid-absorbent material of the bristles may be used either to improve the collection of the gastrointestinal content or to deliver health-related substances to the mucosal layer through the bristles of the mucosal layer brush. Optionally, the bristles may change their properties with the absorbance of the fluid such that contact with the mucosal layer is further improved. For example, with contact with the gastrointestinal fluid the bristles may absorb fluid and become stiffer.

[0392] For example, FIG. 46 shows an ingestible apparatus 100 in some embodiments. The ingestible apparatus 100 in these embodiments comprises a dissolvable shell 102 and optionally an enteric-targeted coating 104 as described above. The dissolvable shell 102 receives therein a housing 112 having one or more openings 800 on one or more sidewalls thereof at a distance to a front wall 802.

[0393] A piston 124 movably extends into the housing 112 from a rear wall 804 thereof. The piston 124 comprises a piston plate 142 and a piston mandrel 144 extending rearwardly from the piston plate 142 out of the housing 112 to an end piece 148. The piston 124 engages a compressed spring 806 located in the housing 112 between the rear wall 804 and the piston plate 142.

[0394] At an initial state T.sub.A, the piston 124 is located adjacent the rear wall 804 and is retained thereto by a dissolvable latch 164 sandwiched between and engaging with the end piece 148 and the rear wall 804 of the housing 112. At the initial state T.sub.A, the piston plate 142 is located between the openings 800 and the rear wall 804.

[0395] A mucosal-layer brush 808 is coupled to the piston plate 142 on a side opposite to the side that the piston mandrel is coupled thereto. The mucosal-layer brush 808 comprises a plurality of bristles 810 and one or more fluid-absorbent materials 812 folded or otherwise compacted in the housing 112 at a location between the openings 800 and the piston plate 142.

[0396] In a sampling process, the ingestible apparatus 100 may be ingested by a user. When the ingestible apparatus 100 arrives the target area, the dissolvable shell 102 and the enteric-targeted coating 104 are dissolved, as shown in FIG. 47.

[0397] Then, the dissolvable latch 164 is in contact with the gastrointestinal content and starts to dissolve. As shown in FIG. 48, with the dissolution of the latch 164, the spring 806 pushes the piston 124 towards the openings 800 and the front wall 802. As a result, the compacted bristle 810 and fluid-absorbent materials 812 are radially or laterally extended via the openings 800 out of the housing 112 and unfolded or otherwise fully expanded to collect the gastrointestinal content.

[0398] As shown in FIG. 49, the spring 806 continues to push the piston 124 towards the front wall 802 with the dissolution of the latch 164. The bristles 810, fluid-absorbent materials 812, and the gastrointestinal samples collected thereon (not shown) are then retracted into the housing 112.

[0399] When the piston plate 142 passes the openings 800, the bristles 810, fluid-absorbent materials 812, and the gastrointestinal samples collected thereon are then sealed in the sealed compartment 814 between the front wall 802 of the housing 112 and the piston plate 142.

[0400] In some embodiments wherein the ingestible apparatus 100 comprises a mucosal-layer brush initially received in the housing 112 (e.g., in the embodiments similar to those shown in FIGS. 28 and 46), health-related substance (such as health-related substance in a powder form) may be initially attached to the bristles of the mucosal-layer brush. When the mucosal-layer brush is extended out of the housing 112 as described above, the health-related substance attached thereon is also extended out of the housing, thereby being delivered (or “painted”) into the target area.

[0401] In some embodiments wherein the ingestible apparatus 100 comprises a mucosal-layer brush outside the housing and initially within the dissolvable shell 102 (e.g., in the embodiments similar to those shown in FIGS. 7, 43, and 44), health-related substance (such as health-related substance in a powder form) may be initially attached to the bristles of the mucosal-layer brush. When the dissolvable shell 102 is dissolved as described above, the health-related substance attached on the bristles of the mucosal-layer brush may be delivered (or “painted”) into the target area.

[0402] Referring now to FIGS. 50A to 60B, an ingestible apparatus 100 according to various implementations are shown. The ingestible apparatus includes a housing 112 defining a sample compartment 414, where the housing 112 includes a sealing surface 420 having an access port 302 formed therein. The sample compartment 414 is communicable with the access port 302 and is of a set volume, defined by the boundary of the sealing surface 420 and the access port 302. Additionally, the housing 112 further includes at least one inlet port 404 communicable with an exterior environment. This disclosure contemplates that the housing 112 can include a plurality of inlet ports, e.g., two, three, four, etc. inlet ports. The inlet port 404 is communicable with the access port 302 such that gastrointestinal content of the GI tract 222 of the subject can flow from the exterior environment through the inlet port 404 and then through the access port 302 into the sample compartment 414. A larger size of opening may be desirable, for example one or more openings of greater than about 2 mm. In some embodiments, there are 4 openings radially distributed about the housing, with a total of over 50% of the housing perimeter as an opening. This provides for an effective flow of the gastrointestinal content of the GI tract to flow to the access port 302 of the sample compartment 414. The shape of the opening may also be selected to promote an effective flow of gastrointestinal content. In some embodiments, the inlet ports are square or rectangle, to maximize the opening toward the access port. The ingestible apparatus 100 also includes a stopper 406 configured to seal the access port 302, and an actuation assembly connected to the stopper 406. In some embodiments the inlet port 404 is the full perimeter of the apparatus, with only a central actuation assembly connecting one end of the housing with the other. In some embodiments, the one end of the housing 112 is the stopper 406 and the other end of the housing is a sample compartment 414.

[0403] The ingestible apparatus also includes a stopper 406 configured to seal the access port 302, and an actuation assembly connected to the stopper 406. In some embodiments, the actuation assembly includes a piston 425 (e.g., a piston plate and/or piston mandrel). The piston 425 can be rigid or flexible. Alternatively or additionally, in some embodiments, the actuation assembly includes an actuation structure such as a biased spring (e.g., spring 464A or 464B in FIGS. 50A-50C, which are also referred to herein individually or collectively as spring 464), elastic material (e.g., elastic member 462 in FIG. 51), or other element capable of moving the actuation assembly between the first and second working positions (as described in detail below). As described below, the actuation assembly is movable between a first working position where the access port 302 is open and a second working position where the access port 302 is sealed with the stopper 406. It should be understood that the components of the actuation assemblies in the figures below (e.g., pistons, springs, and/or elastic members) are provided only as examples. This disclosure contemplates using different components (e.g., single or multiple components) in the actuation assembly. Additionally, this disclosure contemplates using more than one actuation assembly (see e.g., the ingestible apparatus shown in FIGS. 55A-55D).

[0404] The ingestible apparatus further includes a delay structure. As described herein, a delay structure may include one or more of a dissolvable coating, a dissolvable shell, and a dissolvable block. In some implementations, the delay structure is a dissolvable block 470 configured to prevent the actuation assembly from moving between the first and second working positions until the ingestible apparatus is within a target area of the GI tract of the subject. As described herein, the ingestible apparatus optionally further includes an isolating structure 102 (sometimes referred to herein as a “dissolvable shell”) such as a shell. The isolating structure is configured to dissolve in a gastrointestinal content of the GI tract of the subject. Additionally, the isolating structure or shell may be coated with an enteric-targeted coating 104 to enable the shell to dissolve at the target area.

[0405] The actuation assembly can include one or more actuation structures such as springs. In some implementations, the actuation assembly includes a compression spring, where the compression spring is in a first compressed state in the first working position and a second compressed state in the second working position. A potential energy associated with the second compressed state is greater than zero and less than a potential energy associated with the first compressed state. In other words, as described in further detail below, the compression spring is capable of applying spring force in both the first and second compressed states (for example refer to spring 464A and 464B of FIGS. 50A-50C). In other implementations further described below, the actuation assembly includes an extension spring, where the extension spring is in a first extension state in the first working position and a second extension state in the second working position. A potential energy associated with the second extension state is greater than zero and less than a potential energy associated with the first extension state. In other words, as described in further detail below, the extension spring is capable of applying spring force in both the first and second states of extension. Optionally, the actuation assembly includes a plurality of springs (e.g., two or more compression springs, expansion springs, or combinations thereof).

[0406] Now referring specifically to FIGS. 50A-50C, an ingestible sample apparatus according to one implementation of this disclosure is shown. FIG. 50A is a cross sectional view of an ingestible apparatus 100 where the housing 112 is contained within an isolating structure 102 coated with an enteric coating 104. A sample compartment 414 is formed within the housing and a compression spring 464 is held in a first compressed state (see spring 464A in FIG. 50A) by a piston 425 configured to be held by a dissolvable block 470. In this implementation, the actuation assembly includes the piston 425 and the compression spring 464. The first compressed state provides a first working position for the actuation assembly such that the stopper 406 that is held so that the access port 302 is open and in fluid communication with the inlet ports 404. As described herein, the number, size, and/or shape of the inlet ports 404 may be different than shown in FIG. 50A. In FIG. 50B, the isolating structure 102 has partially dissolved due to exposure to the gastrointestinal content 222 within a targeted area of the GI tract. The inlet ports 404 are in communication with the gastrointestinal content which is able to flow through the access port 302 and into the sample compartment 414. At the same time, the gastrointestinal content has come into contact with the dissolvable block 470. The dissolvable block is holding the stopper 406 in a first working position. The stopper is connected to a piston 425 that is designed to engage with the dissolvable block 470 to hold the compression spring 464 in a first compressed state (see spring 464A in FIG. 50A). In FIG. 50A to FIG. 50C, the piston 425 is a rigid post directly connected to the stopper 406. In other embodiments, the piston can also be a flexible component, such as a cable or other form that is able to hold the stopper in a first working position.

[0407] With time, the dissolvable block 470 begins to soften and/or dissolve and the compression spring 464 expands to a second compressed state (see spring 464B in FIG. 50C). Accordingly, the piston 425 and stopper 406 configuration are released and move past the first working position to a second working position where the stopper 406 makes contact with the sealing surface 420 surrounding the access port 302. In FIG. 50C, the stopper 406 is now in the second working position. The second working position is a position less extended than the full extension of the spring. Specifically, in a configuration where the sealing surface 420 had not been positioned within the actuation length of the spring, the spring extension would have continued and the final position of the stopper 406 would be at a distance beyond the position of the sealing surface 420.

[0408] The actuation assembly is therefore configured in this embodiment, in the second working position, to apply a linear force at an interface between the stopper 406 and the sealing surface 420 to seal the access port 302 with the stopper 406. For example, a direction of the linear force applied by the actuation assembly, in the second working position, is approximately perpendicular to the interface between the stopper and the sealing surface. This is shown by arrows 468 in FIG. 50C. Specifically, in the case where the actuation assembly is a spring, the stopper is able to exert and maintain a force equal to the spring force against the sealing surface 420 in order to ensure an adequate seal. It is desirable to maintain such spring force while the ingestible apparatus transits through the subject's GI tract, which may be for example 72 hours. It should be understood that the sample may become contaminated as a result of inadequate seal. The actuation assembly described herein addresses this problem by applying the linear force at the interface between the stopper 406 and sealing surface 420. This disclosure contemplates that the direction of force may deviate from being perpendicular to the interface between the stopper 406 and the sealing surface 420. It should be understood that the magnitude and direction of the force should be sufficient to maintain the seal.

[0409] Alternatively or additionally, in the series of FIGS. 50A to 50C, the dissolvable block 470 is not arranged between the stopper 406 and the sealing surface 420. This embodiment ensures that the remains of the dissolvable block 470, which is not likely to fully dissolve prior to the release of the spring 464, does not interfere with the stopper 406 forming a seal with the sealing surface 420. Further, it may be desirable to ensure that the material of the dissolvable block 470 does not enter into the sample compartment 414 through the access port 302 and contaminate the collected sample.

[0410] As described below for some embodiment, and as shown in FIG. 50C, a surface area of the stopper 406 at the interface between the stopper 406 and the sealing surface 420 is larger than an area of the access port 302. In other words, the stopper 406 is designed to completely cover the opening presented by the access port 302. In some embodiments, at least a portion of the surface area of the stopper 406 overlaps with and contacts at least a portion of the sealing surface 420 at the second working position of the actuation assembly. In some embodiments, the surface area of the stopper 406 extends beyond the sealing surface 420 at the second working position. In some embodiments the outer dimension of the stopper 406 may be approximately the same dimension as the inner dimension of the housing 112. In this way, the housing 112 acts as a guide to direct the stopper 406 once the piston 425 is released. It may, however, be desirable in some implementations that the fit allow for easy movement of the stopper 406 within the housing 112. Alternatively or additionally, the ingestible apparatus can therefore optionally further include a recess 430 arranged at least partially around a perimeter of the sealing surface 420. The recess 430 is configured to enhance a seal between the stopper 406 and the sealing surface 420 at the second working position of the actuation assembly. The recess 430 provides a configuration where the sealing surface area can be optimized to ensure a good sealing pressure between the sealing surface 420 and the stopper 406 based on the spring force provided while maintaining an access port 302 centralized to ensure that the seal does not rely on precise alignment. For example, with this configuration, the edge 301 of the access port 302 can be maintained central without the sealing surface 420 extending all the way to the edge of the housing 112. Alternatively or additionally, the recess 430 can be used to interrupt the capillary action that could otherwise be created along the interface between the stopper 406 and the housing 112 or the stopper 406 and the sealing surface 420. For example, gastrointestinal content such as luminal fluid drawn in along the housing 112 and the stopper 406 will pool in the recess 430 rather than continue along the sealing surface towards the access port 302.

[0411] The ingestible apparatus can optionally further include a gasket 408 arranged between the stopper and the sealing surface. The gasket can be made a deformable material such as a silicone elastomer or rubber. The gasket 408 is used to promote an effective seal between the stopper 406 and the sealing surface 420. Additionally, the gasket 408 may extend up the sides of the stopper 406 away from the sealing surface 420. In this way, when the stopper 406 is exerting a closing pressure against the sealing surface 420 in the second working position, the gasket 408 may bulge outward to increase contact with the housing wall 111 and further enhance the effectiveness of the seal to prevent gastrointestinal contents to access the access port 302 in the second working position. Alternatively or additionally, the gasket 408 and the recess 430 can optionally be used together to form an effective seal.

[0412] In FIG. 51, an alternative embodiment is shown where the actuation assembly comprises an elastic member 462 (e.g., an extension spring) made of an elastic material. The elastic member is attached at one end 466A to the housing 112 and the opposite end 466B to the stopper 406. The figure is depicted with an elastic cable, however, a coil spring or other form of elastic member may also be used. For example, the elastic member 462 can optionally be a cable, band, metal or plastic coil, or other material with an elastic spring force capable of acting on a stretched/compressed object to return it to its original length. The ingestible device includes a shell as an isolating structure 102, where the shell is preventing the gastrointestinal contents 222 from contacting the dissolvable block 470 and is preventing fluid from enter the inlet port 404 before the device is in the target area along the GI tract. The dissolvable block 470 is holding the stopper 406 in a first working position with the actuation assembly is in a first extension state. Once the isolation structure 102 is dissolved within the target area and the dissolvable block 470 dissolves or softens, the actuation assembly pulls the end piece 148, which is connected to the stopper 406, through the access hole (or opening) 412 in the rear housing 112 to the second extension state where it will rest against the sealing surface 420 at the second working position. The potential energy associated with the second extension state is greater than zero and less than a potential energy associated with the first extension state. Similarly as described above, the actuation assembly is therefore configured in this embodiment, in the second working position, to apply a linear force at an interface between the stopper 406 and the sealing surface 420 to seal the access port 302 with the stopper 406. For example, a direction of the linear force applied by the actuation assembly, in the second working position, is approximately perpendicular to the interface between the stopper 406 and the sealing surface 420. Specifically, in the case where the actuation assembly is a spring, the stopper is able to exert and maintain a force equal to the spring force against the sealing surface in order to ensure an adequate seal. In FIG. 51 it is further depicted with the stopper 406 not having a close fit with the housing 112 such that with the movement for the stopper 406 to seal the access port the alignment may not be precise. To ensure a complete seal, the stopper surface area is greater than the access port 302 and the position of the access port 302 within the path of the stopper 406 is positioned to ensure a complete seal. To ensure an adequate sealing pressure, the recess 430 is used to minimize the surface area of the sealing surface 420 resulting in the stopper surface area exceeding that of the access port 302.

[0413] In some embodiments, ingestible apparatus includes a mucosal-layer brush 308 configured for collecting a sample that includes mucosal cells. The mucosal layer brush 308 includes one or more bristles (e.g., bristles 410A, 410B, 410C shown in FIGS. 52A-52C, which are individually and collectively referred to herein as bristles 410). The bristles may be made of absorbent material to absorb the fluid of the gastrointestinal contents and to promote adherence of the mucosal cells. Alternatively or additionally, the bristles may be arranged to enable the collection of mucosal cells and luminal fluid through trapping of the gastrointestinal contents within the structure. In some implementations shown in the figures, a bristle is an elongate member such as a relatively stiff cable, wire-like or rod-like member, for example, as found on a tool such as a brush or broom. Alternatively or additionally, in some implementations, the bristles are arranged to form a web, mesh, foam or lattice. For example, the bristles may be a sponge or multiple sponges. For example, the mucosal-layer brush 308 may be formed of a polyurethane sponge, or a foam such as reticulated vitreous carbon. It should be understood that the mucosal-layer brush 308 may include one or more bristles, or it may include a plurality of bristles. The bristles 410, either as elongated structures or mesh like structures can be arranged about a central stem 411, or as tree like bristles as depicted in the figures to follow. In some embodiments, the bristles may be attached directly to the stopper 406 or piston. As described herein, the bristles are of sufficient length to extend beyond the outer extent of the stopper 406 and outside of the housing 112 when the actuation structure is in the first working position. Optionally, in some implementations, the bristles are of sufficient length to extend beyond the outer extent of the isolation structure 102 (e.g., shell) when the actuation structure is in the first working position. In either implementations, it should be understood that the isolation structure, which encapsulates the housing, may compress or spring load the bristles, preventing them from extending beyond its boundaries until the isolation structure 102 is dissolved. When the isolation structure 102 dissolves, the bristles extend outward beyond the stopper 406 and/or the housing 112 such that the mucosal-layer brush 308 can collect a sample. It should also be understood that the type of mucosal-layer brush shown in the figures below (e.g., rod-like bristles, sponge, etc.) are provided only as examples. This disclosure contemplates using any type of mucosal-layer brush with the embodiments described herein.

[0414] In FIG. 52A to FIG. 52C an ingestible apparatus 100 is depicted with a mucosal layer brush 308 contained within a housing 112 and further contained within an isolating structure 102. The rod-like bristles 410 are attached directly to the stopper 406 and are partially contained within the housing 112 extending out through an inlet port 404. It should be understood that alternative arrangements where the bristles can be connected to a piston and fully contained within the housing 112 are also contemplated. The one or more bristles 410A are initially compressed or spring-loaded by the isolating structure 102 as shown in FIG. 52A. In this way when the isolating structure 102 or shell is dissolved in the target area the bristles 410B are able to extend beyond the perimeter of the housing 112 and/or shell as shown in FIG. 52B. This configuration provides an ingestible capsule of suitable size for ingestion while maximizing the reach of the mucosal layer brush 308 as it travels through the gastrointestinal tract. In FIG. 52B, the dissolvable block 470 begins to dissolve and as previously described, the stopper 406 attached to a rigid piston 425 travels through the opening 412 from a first position with a spring 464A compressed to a first state to a final position depicted in FIG. 52C with a spring 464C in a fully extended state (e.g., there may be zero potential energy depending on the sample volume). In this embodiment, the concave shape of the stopper 406 provides for the bristles 410C of the mucosal-layer brush 308 to be retracted back through the inlet port 404 into the compartment 414 of the housing 112 without interference with the seal formed by the stopper 406 and optionally a gasket 408 contacting the walls of the housing 112. In other words, the spring 464C may not provide a spring force creating the seal in this embodiment.

[0415] Referring now to FIGS. 53A to 53E, an ingestible apparatus 100 according to another implementation is shown. The ingestible apparatus includes a housing 112 defining a sample compartment 414, where the housing includes a sealing surface 420 having an access port 302 formed therein. The sample compartment 414 is communicable with the access port 302. The ingestible apparatus also includes a stopper 406 configured to seal the access port 302, and an actuation assembly connected to the stopper 406. In FIGS. 53A-53E, the actuation assembly is an elastic member 462. The actuation assembly is movable between a first working position where the access port 302 is open and a second working position where the access port 302 is sealed with the stopper 406. The ingestible apparatus further includes a mucosal-layer brush 308, where the mucosal-layer brush extends beyond a perimeter of the stopper 406 at the first working position of the actuation assembly. Optionally, the mucosal-layer brush 308 extends beyond a perimeter of the housing 112 at the first working position of the actuation assembly.

[0416] The actuation assembly is an elastic member 462 held in a first extension state in the first working position and contained within the sample compartment 414. The actuation assembly connects directly to the stopper 406 and the mucosal layer brush 308 connects directly to the actuation assembly. Alternatively or additionally, the mucosal-layer brush 308 may connect directly to the stopper 406. For example, where the mucosal-layer brush 308 comprises a sponge fixed directly to the stopper. Or, alternatively or additionally, the mucosal-layer brush 308 may connect to a piston that connects the actuation assembly to the stopper 406, or where the piston is to be considered the stem 411 of the mucosal layer brush 308. Similar to previous embodiments, the mucosal layer brush 308 is positioned between the sample compartment 414 and the stopper 406 at the first working position of the actuation assembly. The first working position is maintained by a configuration that includes a flexible wire 463 held by one or more dissolvable blocks 470. In FIG. 53A the mucosal layer brush 308 is shown to be contained within the isolating structure 102. In FIG. 53B, after the dissolution of the isolating structure 102 in the gastrointestinal fluid the bristles of the brush 410 are shown to extend past the perimeter of the housing 112/sample compartment 414 and past the perimeter of the stopper 406. The extension may be enabled by the spring-loaded material of the bristles 410 or may be assisted by a swelling of the bristles due to absorption of fluid from the gastrointestinal contents. The mucosal-layer brush 308 extends past the dimension of the stopper 406 and/or the housing 112 radially around the perimeter of the housing 112. The radial extension may be partial, or in the configuration with a central actuation assembly it may extend past around the full perimeter. FIG. 53C depicts a top view of the stopper 406 and the mucosal-layer brush 308 first contained within the isolating structure 102, and then in FIG. 53D after the dissolution of the isolating structure the mucosal-layer brush 308 extends out past the original perimeter of the ingestible apparatus in a radial manner.

[0417] In FIG. 53E the mucosal-layer brush 308 is retracted inside the housing 112 through the access port 302 at the second working position of the actuation assembly. In other words, the elastic member 462 transitions from the first extension state to a second extension state, a potential energy associated with the second extension state is greater than zero and less than a potential energy associated with the first extension state. This configuration is achieved following the dissolution of the dissolvable blocks (e.g., dissolvable blocks 470 in FIGS. 53A and 53B) which enable the elastic member 462 held in extension to retract, thereby pulling the stopper 406 and the connected mucosal-layer brush 308 and sponge like bristles 410 through the access port 302 and into the housing 112. The spring-loaded property of the bristles 410 allowed the mucosal-layer brush 308 to be retracted through an access port 302 that was smaller than the full extension of the bristles in the first working position. As previously described, in the second working position of the actuation assembly, the stopper 406 is held against the sealing surface 420, and a linear force is applied at an interface between the stopper 406 and the sealing surface 420 to seal the access port 302 with the stopper 406 (see arrows 468). The stopper 406 is configured with a surface area greater than the access port 302 and the position of the access port 302 within the path of the stopper 406 is positioned to ensure a complete seal. A recess 430, previously used to position the dissolvable block 470 in top surface of the sample compartment is used to optimize the sealing surface 420 for the spring force of the actuation assembly at the second working position to ensure an effective seal.

[0418] Referring now to FIG. 54A to FIG. 54B, an ingestible apparatus 100 according to another embodiment is shown. The ingestible apparatus includes a housing 112 defining a sample compartment 414, where the housing includes a sealing surface 420 having an access port 302 formed therein. The sample compartment 414 is communicable with the access port 302. The ingestible apparatus also includes a stopper 406 configured to seal the access port 302, and an actuation assembly connected to the stopper 406. The actuation assembly comprises a plurality of elastic members 462 held in extension to a single flexible piston 425. The dissolvable block 470 extends across the sealing surface and acts to hold the actuation structure in the first extension position. In this embodiment, the ingestible apparatus includes a mucosal-layer brush 308. The bristles 410 are rod-like structures connected to a piston 425 and held within the isolation structure 102. In FIG. 54B, after the dissolution of the isolation structure 102 the bristles 410 extend past the perimeter of the sample compartment 414, the access port 302 the housing 112 and the stopper 406. The piston 425 in this embodiment is a flexible cable, and allows mucosal-layer brush 308 to flex and bend within the gastrointestinal tract in the first working position. Once the dissolvable block 470 is dissolved, the access port 302 is opened and the actuation assembly is moved between the first working position where the access port 302 has been opened and a second working position where the access port 302 is sealed with the stopper 406. As described herein, a linear force is applied at an interface between the stopper 406 and the sealing surface 420 to seal the access port 302 with the stopper 406 when the actuation assembly is in the second working position.

[0419] Alternatively or additionally, in FIG. 55A and FIG. 55B an embodiment is depicted with a plurality of actuation assemblies and dissolvable blocks 470. As described below, the actuation assemblies include pistons 425, which are rigid, and elastic members 462A and 462B (referred to herein individually and collectively as elastic member 462). The sample compartment 414 is contained within the housing 112, and at least two actuation assemblies are held in extension each by a dissolvable block 470B. The dissolvable blocks 470B are positioned so that they are not between the stopper 406 and the sealing surface 420. The ingestible apparatus 100 includes a mucosal-layer brush 308, positioned outside of the sample compartment 414 and between the sealing surface 420 and the stopper 406. The bristles 410 of the mucosal-layer brush 308 extend beyond the perimeter of the access port 302 and are contained by an isolation structure 102 as shown in FIG. 55A. In this embodiment, the isolation structure 102 surrounds the perimeter of the ingestible apparatus and isolates the dissolvable blocks 470 and the fluid access to the access port 302 but does not act as a shell around the entire ingestible apparatus. The stopper 406 is held in a first working position away from the sealing surface 420 and access port 302 by pistons 425 near the periphery of the device that rest on the dissolvable blocks 470B, each of which is connected to an elastic member 462B held in extension. The stopper 406 is also connected to an elastic member 462A held in extension. In FIG. 55B it is shown where the isolation structure 102 has been dissolved and the bristles 410 of the mucosal layer brush 308 move to extend past the housing 112 and the stopper 406. In FIG. 55C a top view depicts that the bristles 410 extend radially around a portion of the perimeter of the housing 112 as a consequence of the pistons 425 extending up near the periphery. The mucosal-layer brush 308 is also shown to be depicted as a plurality of sponge like bristles 410. The partial radial distribution, and/or plurality of bristles may also serve to facilitate the retraction of the mucosal-layer brush within the sample compartment. The different elastic members 462A and 462B work in a two-part retraction and sealing process. The first dissolvable block 470A is attached to the stopper 406 and is configured to dissolve faster than the second dissolvable blocks 470B. Upon its dissolution, the elastic member 462A is released and retracts the mucosal-layer brush 308 into the sample compartment 414. The second dissolvable blocks 470B will dissolve thereafter and the second series of elastic members 462B will retract from a first working position and first extension state to a second working position and second extension state, pulling the pistons 425 into a channel formed between the housing 112 and the sample compartment 414. As shown in FIGS. 55A and 55B, each of the elastic members 462A and 462B is arranged in a channel. The potential energy associated with the second extension state is greater than zero and less than a potential energy associated with the first extension state thereby creating an effective seal between the stopper 406 and the sealing surface 420. An alternate embodiment for the positioning of the dissolvable blocks 470B is shown in FIG. 55D in a cut away image, where the piston 425 is thread through a guide 421 on the sealing surface 420 and the dissolvable block 470B is held below between the walls of the sample compartment 414 and the housing 112. As described herein, a linear force is applied at an interface between the stopper 406 and the sealing surface 420 to seal the access port 302 with the stopper 406 when the actuation assembly is in the second working position.

[0420] Alternatively or additionally, in FIG. 56A and FIG. 56B an embodiment is depicted where a mucosal-layer brush 308 is partially contained within a housing 112. The mucosal-layer brush 308 includes bristles 410 that are connected to a flexible, spring-loaded stem 411, such that that upon the dissolution of the isolation structure 102 in FIG. 56B the bristles 410 extend out the inlet port 404 and past the perimeter of the housing 112. The actuation assembly consists of a spring 464 in compression at a first compressive state. The actuation assembly holds the stopper 406 and mucosal-layer brush 308 at a first working position. Once the dissolvable block 470 is dissolved and the actuation assembly moves from a first working position to a final working position the mucosal-layer brush 308 is retracted into the sample compartment 414 at the rear of the housing 112 as a result of the rigid piston 425 combined with the flexible, spring-loaded stem 411 of the mucosal-layer brush 308. In this configuration, it is shown that the compressed spring 464 is able to extend to its full length and its movement is not constrained by a sealing surface 420. Therefore, the potential energy of the spring in the final working position may be zero and the seal is maintained by the contact of the stopper 406 with the walls of the housing 112.

[0421] Alternatively or additionally, in FIG. 57 another embodiment is shown with a curved housing 112 where the actuation assembly is held in an extended first position on the opposite side as the inlet port 404. The bristles 410 are connected to a piston 425, which is flexible, that is wrapped around a pulley within the curved housing 112. The bristles 410 extend through the inlet port 404 and beyond the perimeter of the housing 112. Upon the dissolution of the dissolvable block 470 the spring 464, which is the actuation assembly, moves from its first extension state to a second extension state, where the potential energy at the second extension state is less than the first and greater than zero. The mucosal-layer brush 308 is retracted through the access port 404 and the stopper 406 is pulled to a second working position and forms a seal against the sealing surface 420. As described herein, a linear force is applied at an interface between the stopper 406 and the sealing surface 420 to seal the access port 302 with the stopper 306 when the actuation assembly is in the second working position. The dissolvable block 470 is positioned between the stopper 406 and the sealing surface 420. An alternative embodiment is shown in FIG. 58 where the stopper 406 is formed to push the mucosal-layer brush 308 through the access port 404 and form a seal against the wall of the housing 111.

[0422] Another embodiment is shown in FIG. 59 where a series of inlet ports 404A and 404B and stoppers 406A, 406B, and 406C are used to collect a luminal fluid sample by passive wicking and retract a mucosal-layer brush 308 in separate compartments. Upon dissolution of the isolation structure surrounding the ingestible apparatus (not depicted) fluid is collected through the first inlet port 404A and may be assisted by absorbent material 324 placed in the first sample compartment 414A. The bristles 410 of the mucosal-layer brush 308 extend out a second inlet port 404B. The gastrointestinal contents act on the dissolvable block 470 and upon dissolution and/or softening of the dissolvable block 470 a spring 464, which is the actuation assembly, held in place by a piston 425, which is flexible cable, connected to the dissolvable block 470, is released from a first extension position to a second extension position, where the potential energy at the second extension position is greater than zero and less than the first extension position. As described herein, a linear force is applied at an interface between each of the stoppers 406A and 406B and each of the sealing surfaces 420A and 420B to seal the access ports 302A and 302B with the stoppers 406A and 406B, respectively, when the actuation assembly is in the second working position. By the movement of the spring 464 and connected piston 425, the mucosal-layer brush 308 is retracted, the first stopper 406A is moved to seal the access port 302A which is in fluid communication with the first inlet port 404A and the second stopper 406B is moved along by the same piston 425 to seal the access port 302B which is in fluid communication with the second inlet port 404B. The mucosal-layer brush 308 is thereby retracted into a sample compartment 414B and sealed within the housing by the second stopper 406B on the one side and a third stopper 406C, connected to the same piston 425, on the other side.

[0423] Referring now to FIG. 60A, it is shown that the housing 112 optionally includes a first portion 440 that houses the stopper 406 and a second portion 450 that defines the sample compartment 414. The first portion 440 is configured to removably couple with the second portion 450. The collected sample is contained within the sample compartment 414 of the removable second portion 450. Optionally the sample compartment 414 of the second portion may contain absorbent material 324 (as shown in FIG. 60B) or a retracted mucosal-layer brush. It is important that the removable configuration not compromise the effectiveness of the seal along the sealing surface and the stopper. In some implementations, the first portion 440 includes a first wall section 441 and the second portion 450 includes a second wall section 451, where the first and second wall sections are in an overlapping condition (which creates an overlapping portion 445) when the first portion is coupled with the second portion. The overlapping condition prevents ingress of a gastrointestinal content of the GI tract of the subject when the first portion is coupled with the second portion and/or prevents contamination of the sample during separation of the first and second portions. Optionally, the overlapping condition of the first and second wall sections extends for about 20-25% of a total length of the housing. It should be understood that an overlapping condition of 20-25% of total length is provided only as an example. This disclosure contemplates that the overlapping condition may amount to more or less than this amount, for example, a larger percentage of the total length. In some implementations, the first and second wall sections are coupled by interference fit. In other implementations, the first and second wall portions are coupled by threading. FIG. 60B depicts a sample compartment 414 (second portion 450) removed from the housing 112 (first portion 440) after the fluid has been collected and the ingestible apparatus has been retrieved from the patient or user. The coupling, here shown as threading 436, is shown to extend the full length of the overlapping portion 445 in FIG. 60B. Although interference fit and threading are provided as examples, this disclosure contemplates using other means to removably couple the first and second portions of the housing. Optionally, the coupling extends only a portion 434 of the overlapping portion 445, as is depicted in FIGS. 60A and 60C where the threading 436 is positioned on the coupled portion 434 of the overlapping portion 445. Additionally, as discussed above, the ingestible apparatus can optionally further include a recess 430 arranged at least partially around a perimeter of the sealing surface 420. The recess 430 is visible in the sample compartment 414 that has been removed from the housing. In FIG. 60C it is shown that the recess 430 can be located in the region where the first and second wall sections overlap with each other. The recess 430 acts to prevent the capillary action from drawing up the fluid along the overlapping portion, and the recess prevents such capillary action from drawing fluid all the way to the sealing surface 420. In some embodiments as depicted in FIG. 60A to FIG. 60C, the sealing surface 420 is formed from the top surface of the removable second portion 450 or sample compartment 414. Optionally, the sealing surface that is in contact with the stopper under a sealing pressure may be formed within the first portion, connected to the housing. In this configuration the sealing pressure of the stopper 406 is maintained while the second portion is removed. The prevention of contamination entering the access port of the sample compartment 414 is therefore dependent in the one path from the inlet port by the seal of the stopper 406 against the sealing surface 420 and along the second path by the fit and design of the overlapping portion 445 of the first and second portions 440, 450 of the housing 112.

[0424] In some embodiments, the mechanical components of the ingestible apparatus 100 can be made of suitable conductive materials to be utilized as structural electronic components of the antenna to save the space within the capsule and bring down the cost per capsule. Referring to FIG. 61A a coil spring 464A held in compression demonstrates the use of the structural component as an electrical component in the RFID circuit 490. The spring is electrically connected to the RFID circuit 490 at the two ends 492 and 494 of the spring 464A. However, the spring 464A is still in the compressed state, and the two surface electrodes 496, which are serving as a switch of the RFID circuit, are not electrically connected. Therefore, the RFID circuit 490 is turned off.

[0425] FIG. 61B shows the spring 464B in its extended state. The metal screw 498 moves to a position where it engages with the two surface electrodes 496 and forms a closed loop of the RFID circuit 490, and the coil shape of the spring enables inductive powering of passive RFID circuit 490 through electromagnetic coupling of an external antenna (not shown in the diagram) with a certain distance and sending data in the form of radio waves.

[0426] In some embodiments, the RF-signal transmitter has an antenna that consists of a coil only.

[0427] In some embodiments, the RF-signal transmitter has an antenna that consists of a bar made of ferrite which is an iron based magnetic material, and a coil wound around the ferrite bar. With the addition of the ferrite bar, the magnetic component of the RF waves through the coil becomes more concentrated and the antenna with the ferrite rod has a much greater level of sensitivity than if the coil had been used on its own.

[0428] Referring now to FIGS. 62A and 62B the spring 464 is utilized as the conductive wire to connect the RFID chip 490 with a separate antenna (not shown). The spring 464 is electrically connected to the RFID circuit 490 at the two ends 492 and 494 of the spring 464. In some embodiments, the spring 464 can also be utilized as the ferrite bar of the antenna. In some embodiments, the piston 124 can be made of ferrite and therefore utilized as the ferrite bar of the antenna. In FIG. 62A the spring 464 is in compression and the RFID circuit 490 is in the on configuration. The piston 124 made of ferrite is acting to amplify the RFID circuit signal. In FIG. 62B, the spring 464 is in extension and the RFID circuit is in the off configuration.

[0429] In some embodiments, the mandrel can be made of conductive material and utilized as the conductive wire to connect the RFID chip with a separate antenna.

[0430] In some embodiments, the RFID chip contains information about the specification of the ingestible apparatus that can be pre-programmed prior to assembly of the apparatus. For example, the RFID chip could be coded with unique identifiers which correspond to the design and manufacturing specifications of a capsule, for example, a specific coating material and a specific dissolvable latch. In a scenario where one patient ingests multiple capsules and later excretes the capsules during the same bowel movement, each RFID chip from the capsule could be activated remotely and the unique identifiers from the RFID readout could be analyzed in order to identify and distinguish the design and manufacturing specifications of each excreted capsule.

EXAMPLES

[0431] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. or is at ambient temperature, and pressure is at or near atmospheric.

Methods:

[0432] Ingestible apparatus (capsules) (n=16) were placed in sterile PBS solution without the exterior shell. The dissolvable latch was exposed to the fluid in a manner intended to stimulate exposure to the contents of the gastrointestinal tract (3 hours at 37° C. and 100 rpm of mixing) to promote its dissolution the same manner as would occur in vivo. Upon dissolution of the dissolvable latch, the sample compartment was sealed with sterile PBS solution contained therein. Control samples were taken from the PBS solution following the dissolution procedure. The capsules were provided within a shell to two participants (eight capsules each participant). The participants ingested the sealed ingestible apparatus and they were allowed to normally transit the full gastrointestinal tract. The capsules were later retrieved from the feces and returned for analysis. The total transit time was recorded. The transit time of the capsules for participant A and B was 24±2 and 35±11, respectively. Following the retrieval of the capsules, the capsules were put in room temperature for storage. For each participant, samples from four validation capsules were removed after they were in storage for 48 hours, and four others were removed after they were in storage for 96 hours, to resemble different delivery time spans. The collected samples were carefully removed from the capsules after cleaning the capsule surface with 70% ethanol and DNA away. Evidence of contamination was evaluated via DNA extraction using QIAamp Fast DNA Stool Mini Kit and 16S qPCR by assessing samples from the kit control (including DNA extraction reagents, and qPCR reagents), the pre-ingestion PBS samples, and the 16 samples from the PBS solution extracted from the 16 post-ingestion SIMBA capsules.

Results:

[0433] Out of 16 validation samples, one was contaminated to feces due to a manufacturing non-conformity and was removed from this study. After DNA extraction, the DNA concentration was assessed using Qubit and all the validation samples showed less than 10 μg/μL DNA in the sampling chamber. The DNA samples were then processed using qPCR technique targeting the microbial-specific 16S rRNA gene. Both pre-ingestion and post-ingestion PBS samples show less contamination comparing with the samples from the kit control by presenting a higher Ct number in the qPCR result (FIG. 63). The post-ingestion PBS samples show slightly less contamination than the pre-ingestion PBS samples, indicating there is no contamination to the PBS solution inside the sealed SIMBA capsules during the gut transit and the storage time.

[0434] Although embodiments have been described above with reference to the accompanying drawings, those of skill in the art will appreciate that variations and modifications may be made without departing from the scope thereof as defined by the appended claims.