Method and system for collecting body fluid from a subject

Abstract

The present invention relates to a method for collecting bodily fluid from the skin of a subject using a collection system, the method comprising: a) placing (201) a rim of a microneedle assembly in contact with the skin of the subject, thereby sealing the interior of the housing from the ambient atmosphere; b) applying (202) a negative penetration pressure to the fluid port and thereby the interior of the housing using a pump, the negative penetration pressure being maintained during a penetration time, causing the plurality of microneedles to penetrate the skin of the subject; c) lifting off (203), wherein the plurality of microneedles are removed from the skin during a lift-off time, and the interior of the housing is at least atmospheric pressure; and d) applying (204) a negative extraction pressure using a pump during an extraction time, causing bodily fluid expelled from the skin to flow toward the fluid port and be collected in a sample volume.

Description

[Technical Field]

[0001] The present disclosure relates generally to the field of withdrawing fluids from a subject, and more particularly to the field of withdrawing bodily fluids using microneedle arrays. [Background technology]

[0002] In modern analysis of subjects, such as humans or animals, there is great interest in analyzing various body fluids and mixtures thereof. Traditionally, a diabetic patient wishing to measure their blood glucose level would have their skin pricked with a lancet, a small amount of blood extracted from the skin opening, and a test strip applied to the blood that had bled from the skin at the point where the lancet had penetrated the skin. In recent years, there has been interest in obtaining other body fluids that can be extracted from the subject's skin without causing any damage or pain to the subject's skin.

[0003] A common problem with collecting body fluids is that the volume of body fluid is very small and difficult to extract efficiently.

[0004] Efficient extraction of bodily fluids from subjects has been attempted by producing localized edema, which is used to collect bodily fluids, as disclosed, for example, in US20200315502. This method is painful and results in long-lasting skin discoloration. Therefore, it would be of great interest to identify alternative methods.

[0005] Therefore, it would be highly desirable to provide a more effective method for collecting body fluids that can be efficiently extracted without causing localized edema. Summary of the Invention

[0006] SUMMARY OF THE DISCLOSURE It is an object of the present disclosure to mitigate, alleviate or eliminate one or more of the above mentioned deficiencies and disadvantages in the prior art singly or in any combination, and to provide an improved harvesting method.

[0007] It is a further object of the present disclosure to provide an improved collection system.

[0008] An object of the present invention is to provide a method for collecting bodily fluid from the skin of a subject using a collection system, the collection system comprising: a fluid pump; a microneedle assembly; and a conduit connecting the fluid pump and the microneedle assembly, the microneedle assembly comprising: a housing including a fluid port connected to the fluid pump via the conduit; and a microneedle array in fluid communication with the fluid port, the microneedle array being formed on a substrate and having a plurality of microneedles extending from a first side of the substrate, each microneedle having a proximal end connected to the first side of the substrate and a distal end, the distal end having a chamfer, each needle having a hole extending from the proximal end to the distal end, each hole extending into a corresponding hole in the substrate, the plurality of microneedles providing a fluid pathway from the distal end to the fluid port; and a rim extending around the microneedle assembly, the rim intended to define a seal between the ambient atmosphere and the interior of the housing when in contact with the skin of the subject, the method comprising the steps of: a) placing the rim of the microneedle assembly in contact with the skin of the subject to seal the interior of the housing from the ambient atmosphere; b) applying a negative penetration pressure to the fluid port and thereby to the interior of the housing using a pump, the negative penetration pressure being maintained during a penetration time so that the multiple microneedles penetrate the skin of the subject; c) lifting off, where the multiple microneedles are removed from the skin during a lift-off time and the interior of the housing is at at least atmospheric pressure; and d) applying a negative extraction pressure using the pump during an extraction time so that bodily fluid expelled from the skin flows towards the fluid port and is collected in the sample volume.

[0009] An object of the present invention is to provide a collection system for collecting bodily fluid from the skin of a subject, the collection system comprising: a fluid pump; a microneedle assembly; and a conduit connecting the fluid pump and the microneedle assembly, the microneedle assembly comprising a housing including a fluid port connected to the fluid pump via the conduit; and a microneedle array in fluid communication with the fluid port, the microneedle array having a plurality of microneedles formed on a substrate and extending from a first side of the substrate, each microneedle having a proximal end connected to the first side of the substrate and a distal end, the distal end having a chamfer, and each needle having The device comprises: a microneedle array having holes extending from a proximal end to a distal end, each hole extending to a corresponding hole in a substrate, the plurality of microneedles providing a fluid path from the distal end to a fluid port; a rim extending around the microneedle array, the rim intended to define a seal between the ambient atmosphere and the interior of the housing when in contact with the skin of a subject; and a control unit configured to control the fluid pump and including a pressure sensor arranged to measure pressure in the flow path through the conduit, the control unit configured to perform the method described in the embodiments disclosed herein. [Brief explanation of the drawings]

[0010] The foregoing will become apparent from a more particular description of the embodiments, as illustrated in the accompanying drawings, in which like reference numerals refer to like parts in different drawings, and in which the drawings are not necessarily to scale, emphasis instead being placed upon illustrating exemplary embodiments.

[0011] [Figure 1] 1 is a schematic block diagram of a collection system according to an embodiment of the present invention. [Figure 2] FIG. 2 is a flow diagram illustrating an embodiment of a method according to an embodiment of the present invention. [Figure 3] FIG. 1 is a pressure versus time diagram illustrating one embodiment of the present invention. [Figure 4] FIG. 2 is a schematic block diagram of a control unit according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0012] Aspects of the present disclosure are described in more detail below with reference to the accompanying drawings. However, the apparatus and methods disclosed herein may be embodied in many different forms and should not be construed as limited to the aspects set forth herein. Like reference numerals in the drawings refer to like elements throughout.

[0013] The terminology used herein is for the purpose of describing particular aspects of the disclosure only and is not intended to be limiting of the present invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0014] In the present disclosure, the term "body fluid" should be interpreted as a fluid extracted from the skin of a subject, which may be, for example, interstitial fluid or a mixture of interstitial fluid and other fluids present in the skin, such as plasma or intracellular fluid.

[0015] In this disclosure, the term "subject" should be construed to encompass humans and animals, as well as ex vivo tissue for experimental purposes.

[0016] Some of the exemplary embodiments presented herein relate to methods for sampling bodily fluids. As part of the development of the exemplary embodiments presented herein, a problem is first identified and discussed.

[0017] Previous attempts to extract bodily fluids using microneedle arrays (MNAs) have involved applying negative pressure to the fluid channels of the MNA to provide a suction effect. The inventors have experimented with various negative pressures to improve the flow of bodily fluids from subjects. However, none of these experiments were successful, and only limited sample volumes were extracted.

[0018] The inventors have realized that these problems can be minimized or eliminated by introducing a pressure sequence into the MNA, beginning with a penetration step in which a negative penetration pressure is applied to the MNA. This step is followed by a lift-off step in which the MNA is mechanically lifted from the skin by positive pressure or by ventilation under pressure. This lift-off step is followed by an extraction step in which negative pressure is applied. This sequence unexpectedly and surprisingly increases the flow of fluid from the skin.

[0019] 1, 2, and 3, a method of collecting bodily fluid from the skin of a subject using a collection system 100 is disclosed. The collection system 100 includes a fluid pump 102, a microneedle assembly 103, and a conduit 104 connecting the fluid pump 102 and the microneedle assembly 103.

[0020] The microneedle assembly 103 comprises a housing 105 including a fluid port 106 connected to the fluid pump 102 via a conduit 104 , and a microneedle array 107 in fluid communication with the fluid port 106 .

[0021] The microneedle array 107 is formed on a substrate and comprises a plurality of microneedles extending from a first side of the substrate 108, each microneedle 109 having a proximal end connected to the first side of the substrate 108 and a distal end. The distal ends have a chamfer, and each needle has a hole extending from the proximal end to the distal end, each hole extending to a corresponding hole in the substrate. The plurality of microneedles provide a fluid pathway from the distal end to a fluid port.

[0022] The microneedle assembly 103 further comprises a rim 110 extending around the microneedle array 107, the rim intended to define a seal between the ambient atmosphere and the interior of the housing 111 when in contact with the subject's skin.

[0023] In FIG. 2, the method, generally designated 200, includes the following steps. Step a) Placing 201 the rim of the microneedle assembly in contact with the skin of the subject, thereby sealing the interior 111 of the housing 105 from the ambient atmosphere. Step b) applying 202 a negative penetration pressure PP to the fluid port and thereby to the interior of the housing using a pump, the negative penetration pressure PP being maintained during a penetration time tP, causing the multiple microneedles to penetrate the skin of the subject. Step c) Lifting off 203, wherein the plurality of microneedles are removed from the skin during a lift-off time tL, and the interior of the enclosure is at least atmospheric pressure. Step d) A negative extraction pressure PE is applied 204 using a pump during an extraction time tE, causing body fluid expelled from the skin to flow towards the fluid port and be collected in the sample volume 112.

[0024] The negative penetration pressure PP is between -30 kPa and -45 kPa.

[0025] The penetration time tP is between 10 and 60 seconds.

[0026] The negative extraction pressure PE is between -10 kPa and -30 kPa.

[0027] The negative extraction pressure PE is between -20 kPa and -30 kPa. In one embodiment, the negative extraction pressure is -25 kPa.

[0028] Optionally, step d) 204 further comprises step d1) 205 of reducing the pressure in the volume to a negative extraction pressure during lift-off at a pressure differential rate of less than 1 kPa / sec.

[0029] Referring again to FIG. 1, the collection system 100 comprises a control unit 113 configured to control the fluid pump and including a pressure sensor positioned to measure the pressure PS in the flow path through the conduit 104, the control unit 113 being configured to perform the method 200 described in the embodiments disclosed herein.

[0030] FIG. 4 illustrates an exemplary implementation of the control unit 113 in programmable signal processing hardware. The signal processing device 400 shown in FIG. 4 includes an input / output (I / O) section 410 that receives the measured pressure and sends a control signal CS to the pump 102. The signal processing device 400 includes a processor 420, a working memory 430, and an instruction store 440 that stores computer-readable instructions. The instruction store 440, when executed by the processor 420, causes the processor 420 to perform the processing operations described herein for controlling the collection system 100. The instruction store 440 may include a ROM preloaded with computer-readable instructions. Alternatively, the instruction store 440 may include a RAM or similar type of memory, and the computer-readable instructions may be input from a computer program product, such as a computer-readable storage medium 450, such as a CD-ROM, or a computer-readable signal 460 carrying the computer-readable instructions.

[0031] In this embodiment, a combination of hardware components 470 shown in FIG. 4, comprising a processor 420, a working memory 430, and an instruction store 440, is configured to implement the functionality of the control unit 113 described above.

[0032] The present disclosure provides a method for collecting bodily fluid from the skin of a subject using a collection system, the collection system comprising: a fluid pump; a microneedle assembly; and a conduit connecting the fluid pump and the microneedle assembly, the microneedle assembly comprising: a housing including a fluid port connected to the fluid pump via the conduit; a microneedle array in fluid communication with the fluid port, the microneedle array being formed on a substrate and having a plurality of microneedles extending from a first side of the substrate, each microneedle having a proximal end connected to the first side of the substrate and a distal end, the distal end having a chamfer, each needle having a hole extending from the proximal end to the distal end, each hole extending into a corresponding hole in the substrate, the plurality of microneedles providing a fluid path from the distal end to the fluid port; and a microneedle array having a periphery of the microneedle array. and a rim extending around the housing, the rim intended to define a seal between the ambient atmosphere and the interior of the housing when in contact with the skin of the subject, the method comprising the steps of: a) sealing the interior of the housing from the ambient atmosphere by placing the rim of the microneedle assembly in contact with the skin of the subject; b) applying a negative penetration pressure to the fluid port and thereby to the interior of the housing using a pump, the negative penetration pressure being maintained during a penetration time so that the multiple microneedles penetrate the skin of the subject; c) lifting off, where the multiple microneedles are removed from the skin during a lift-off time and the interior of the housing is at least atmospheric pressure; and d) applying a negative extraction pressure using the pump during an extraction time so that bodily fluid expelled from the skin flows towards the fluid port and is collected in the sample volume.

[0033] According to some embodiments, the negative penetration pressure is between -30 kPa and -45 kPa.

[0034] According to some embodiments, the penetration time is between 10 and 60 seconds.

[0035] According to some embodiments, the negative extraction pressure is between -10 kPa and -30 kPa.

[0036] According to some embodiments, the negative extraction pressure is between -20 kPa and -30 kPa.

[0037] According to some embodiments, step d) further comprises a step d1) of reducing the pressure in the volume to a negative extraction pressure during lift-off at a pressure differential rate of less than 1 kPa / s.

[0038] The present disclosure also relates to a collection system for collecting bodily fluid from the skin of a subject. The collection system comprises a fluid pump, a microneedle assembly, and a conduit connecting the fluid pump and the microneedle assembly, the microneedle assembly comprising: a housing including a fluid port connected to the fluid pump via the conduit; a microneedle array in fluid communication with the fluid port, the microneedle array being formed on a substrate and having a plurality of microneedles extending from a first side of the substrate, each microneedle having a proximal end connected to the first side of the substrate and a distal end, the distal end having a chamfer, each needle having a hole extending from the proximal end to the distal end, each hole extending into a corresponding hole in the substrate, the plurality of microneedles providing a fluid path from the distal end to the fluid port; a rim extending around the microneedle array, the rim intended to define a seal between the ambient atmosphere and the interior of the housing when in contact with the subject's skin; and a control unit configured to control the fluid pump and including a pressure sensor positioned to measure pressure in the flow path through the conduit, the control unit being configured to perform the methods described in the embodiments disclosed herein.

[0039] In the drawings and specification, illustrative embodiments have been disclosed. However, many variations and modifications of these embodiments are possible. Accordingly, although specific terms may be used, such terms are not intended to be limiting but are used in a generic and descriptive sense only, and the scope of the embodiments is defined by the following claims.

[0040] The description of the exemplary embodiments set forth herein has been presented for illustrative purposes. This description is not intended to be exhaustive or to limit the exemplary embodiments to the precise form disclosed, as modifications and variations are possible in light of the above teachings and may result from practicing various alternatives to the provided embodiments. The examples described herein have been chosen and described to explain the principles and properties of various exemplary embodiments and their practical applications, and to enable those skilled in the art to utilize the exemplary embodiments in various ways and with various modifications suited to the particular use envisioned. Features of the embodiments described herein may be combined in all possible combinations of methods, apparatus, modules, systems, and computer program products.

[0041] It should be understood that the exemplary embodiments presented herein may be implemented in any combination with each other. It should be noted that "comprising" does not necessarily exclude the presence of other elements or steps than those listed, and that "a" or "an" before an element does not necessarily exclude the presence of a plurality. It should also be noted that any reference signs do not limit the scope of the claims, and that the exemplary embodiments may be implemented, at least in part, by both hardware and software, and that the same item of hardware may refer to multiple "means," "units," or "devices."

Claims

1. A method (200) of collecting bodily fluid from the skin (101) of a subject using a collection system (100), comprising: The collection system (100) comprises a fluid pump (102), a microneedle assembly (103), and a conduit (104) connecting the fluid pump (102) and the microneedle assembly (103); The microneedle assembly (103) comprises: a housing (105) including a fluid port (106) connected to the fluid pump (102) via the conduit (104); a microneedle array (107) in fluid communication with the fluid port (106), the microneedle array (107) being formed on a substrate (108) and having a plurality of microneedles extending from a first side of the substrate, each microneedle (109) having a proximal end connected to the first side of the substrate (108) and a distal end, the distal end having a chamfer, each needle having a hole extending from the proximal end to the distal end, each hole extending into a corresponding hole in the substrate, the plurality of microneedles providing a fluid path from the distal ends to the fluid port; a rim (110) extending around the microneedle array (107), the rim (110) intended to define a seal between the ambient atmosphere and the interior of the housing (111) when in contact with the skin of the subject; The method (200) comprises the following steps: a) placing (201) the rim of the microneedle assembly in contact with the skin of the subject, thereby sealing the interior (111) of the housing (105) from the ambient atmosphere; b) applying (202) a negative penetration pressure (PP) to the fluid port, and thereby to the interior of the housing, using the pump, wherein the negative penetration pressure (PP) is maintained during a penetration time (tP) to cause the plurality of microneedles to penetrate the skin of the subject; c) lifting off (203), wherein the plurality of microneedles are removed from the skin during a lift-off time (tL) and the interior of the housing is at least atmospheric pressure; d) applying (204) a negative extraction pressure (PE) using the pump during an extraction time (tE), causing the body fluid expelled from the skin to flow towards the fluid port and be collected in a sample volume (112); A method (200) comprising:

2. The method (200) of claim 1, wherein the negative penetration pressure (PP) is between -30 kPa and -45 kPa.

3. 3. The method (200) of claim 1 or 2, wherein the penetration time (tP) is between 10 and 60 seconds.

4. The method (200) of any one of claims 1 to 3, wherein the negative extraction pressure (PE) is between -10 kPa and -30 kPa.

5. The method (200) of any one of claims 1 to 4, wherein the negative extraction pressure (PE) is between -20 kPa and -30 kPa.

6. 6. The method (200) of any one of claims 1 to 5, wherein step d) (204) further comprises step d1 (205) of reducing the pressure in the volume to the negative extraction pressure at a pressure differential rate of less than 1 kPa / sec during lift-off.

7. A collection system (100) for collecting bodily fluid from the skin of a subject, comprising: a fluid pump (102); a microneedle assembly (103); a conduit (104) connecting the fluid pump (102) and the microneedle assembly (103); The microneedle assembly (103) comprises: a housing (105) including a fluid port (106) connected to the fluid pump (102) via the conduit (104); a microneedle array (107) in fluid communication with the fluid port (106), the microneedle array (107) being formed on a substrate (108) and having a plurality of microneedles extending from a first side of the substrate, each microneedle (109) having a proximal end connected to the first side of the substrate (108) and a distal end, the distal end having a chamfer, each needle having a hole extending from the proximal end to the distal end, each hole extending into a corresponding hole in the substrate, the plurality of microneedles providing a fluid path from the distal ends to the fluid port; a rim (110) extending around the microneedle array (107), the rim (110) intended to define a seal between the ambient atmosphere and the interior of the housing (111) when in contact with the skin of the subject; a control unit (113) configured to control the fluid pump and including a pressure sensor arranged to measure a pressure (PS) in a flow path through the conduit (104), configured to place (201) the rim of the microneedle assembly in contact with the skin of the subject, sealing the interior (111) of the housing (105) from the ambient atmosphere; a) applying (202) a negative penetration pressure (PP) to the fluid port, and thereby to the interior of the housing, using the pump, the negative penetration pressure (PP) being maintained during a penetration time (tP) to cause the plurality of microneedles to penetrate the skin of the subject; b) increasing the pressure in the volume to cause lift-off (203), wherein the plurality of microneedles are removed from the skin during a lift-off time (tL) and the interior of the housing is at least atmospheric pressure; d) applying (204) a negative extraction pressure (PE) using the pump during an extraction time (tE), causing the body fluid expelled from the skin to flow towards the fluid port and be collected in a sample volume (112); a control unit (113) configured to: A collection system (100) comprising:

8. The collection system (100) of claim 7, wherein the negative penetration pressure (PP) is between -30 kPa and -45 kPa.

9. 9. The collection system (100) of claim 7 or 8, wherein the penetration time (tP) is between 10 and 60 seconds.

10. The collection system (100) of any one of claims 7 to 9, wherein the negative extraction pressure (PE) is between -10 kPa and -30 kPa.

11. The collection system (100) of any one of claims 7 to 10, wherein the negative extraction pressure (PE) is between -20 kPa and -30 kPa.

12. 12. The collection system (100) of any one of claims 7 to 11, wherein step d) (204) further comprises step d1 (205) of reducing the pressure in the volume to the negative extraction pressure at a pressure differential rate of less than 1 kPa / sec during lift-off.

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