Method for sampling bodily fluid from test subject and sampling system

Abstract

The invention relates to a method (200) for sampling bodily fluids from the skin (101) of a test subject by means of a sampling system (100). The method (200) comprises the steps of: a) placing (201) the rim of the microneedle assembly in contact with the skin of the test 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 by means of the pump and thereby to the interior of the housing, where the negative penetration pressure (PP) is maintained during a penetration time (tP), whereby the plurality of microneedles penetrate the skin of the test subject; c) exfoliation (203) wherein the plurality of microneedles are removed from the skin during an exfoliation time (tL) wherein the interior of the housing is at least atmospheric pressure; and d) applying (204) a negative extraction pressure (PE) with the pump during the extraction time (tE), whereby the bodily fluid released from the skin flows towards the fluid port and is collected in the sample volume (112). The invention also relates to a sampling system (100).

Description

Technical Field

[0001] The present disclosure generally relates to the field of sampling fluids from a test subject, and more particularly to the field of sampling body fluids using a microneedle array. Background Art

[0002] In modern analysis of a test subject, such as a human or an animal for example, there is great interest in analyzing different body fluids and their mixtures. Traditionally, for a diabetic patient who wants to test their blood glucose level, a lancet is used to pierce the skin and extract a small amount of blood through the opening in the skin, and then a test strip is exposed to the blood that comes out of the skin at the site where the lancet entered the skin. In recent years, there has been great interest in sampling other body fluids that can be extracted from the skin of a test subject without causing damage to the skin and pain to the test subject.

[0003] A common problem associated with sampling body fluids is that the volume of the body fluid is quite small, and it is troublesome to extract it in an effective manner.

[0004] Some attempts have been made to efficiently extract body fluids from a test subject by inducing local edema, which is used for sampling body fluids. This is disclosed, for example, in US20200315502. This method is both painful and causes the skin to change color permanently. Therefore, it would be very interesting if an alternative method could be found.

[0005] Therefore, it is very interesting to provide a method for sampling body fluids that can efficiently extract body fluids without inducing local edema and still be effective. Summary of the Invention

[0006] An object of the present disclosure is to provide a sampling method that seeks to mitigate, alleviate or eliminate one or more of the above-mentioned deficiencies and drawbacks in the art, either individually or in any combination, and to provide an improved sampling method.

[0007] Another object of the present disclosure is to provide an improved sampling system.

[0008] The object is achieved by a method for sampling a body fluid from the skin of a test subject with the aid of a sampling system, wherein the sampling system comprises: a fluid pump; a microneedle assembly; a catheter connecting the fluid pump to the microneedle assembly; the microneedle assembly comprises: a housing comprising a fluid port connected to the fluid pump via the catheter; a microneedle array, the microneedle array being in fluid communication with the fluid port, wherein the microneedle array is formed on a substrate and comprises a plurality of microneedles extending from a first side of the substrate, each microneedle having a distal end and a proximal end connected to the first side of the substrate, wherein the distal end has a bevel, and wherein each needle has a hole extending from its proximal end to its distal end, and wherein each hole extends into a corresponding hole of the substrate, wherein the plurality of microneedles provide a fluid path from the distal end to the fluid port; an edge , the rim extending around the microneedle array, wherein the rim is intended to define a seal between the ambient atmosphere and the interior of the housing when the rim is in contact with the skin of a test subject; wherein the method comprises the steps of: a) placing the rim of the microneedle assembly in contact with the skin of the test subject, thereby sealing 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 by means of a pump, wherein the negative penetration pressure is maintained during a penetration time, thereby a plurality of microneedles penetrate the skin of the test subject; c) stripping, wherein the plurality of microneedles are removed from the skin during the stripping time, wherein the interior of the housing is at least at atmospheric pressure; and d) applying a negative extraction pressure using a pump during an extraction time, thereby body fluid released from the skin flows toward the fluid port and is collected in a sample volume.

[0009] The object is also achieved by a sampling system for sampling body fluids from the skin of a test subject, wherein the sampling system comprises: a fluid pump; a microneedle assembly; a catheter connecting the fluid pump to the microneedle assembly; the microneedle assembly comprises: a housing comprising a fluid port connected to the fluid pump via the catheter; a microneedle array, the microneedle array being in fluid communication with the fluid port, wherein the microneedle array is formed on a substrate and comprises a plurality of microneedles extending from a first side portion of the substrate, each microneedle having a distal end and a proximal end connected to the first side portion of the substrate, wherein the distal end has a bevel, and wherein each The needle has a hole extending from its proximal end to its distal end, and wherein each hole extends into a corresponding hole in the substrate, wherein the plurality of microneedles provide a fluid path from the distal end to the fluid port; a rim extending around the microneedle array, wherein the rim is intended to define a seal between the surrounding atmosphere and the interior of the housing when the rim is in contact with the skin of a test subject; a control unit configured to control a fluid pump and including a pressure sensor arranged to measure pressure in a flow path through the conduit, wherein the control unit is configured to perform the method as set forth in the embodiments disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0011] Figure 1 is a schematic block diagram of a sampling system according to one embodiment of the present invention.

[0012] Figure 2 is a flow chart illustrating an embodiment of a method according to one embodiment of the present invention.

[0013] Figure 3 is a graph illustrating pressure versus time according to an embodiment of the present invention.

[0014] Figure 4 is a schematic block diagram of a control unit according to one embodiment of the present invention. DETAILED DESCRIPTION

[0015] Various aspects of the present disclosure will be described more fully below with reference to the accompanying drawings. However, the devices and methods disclosed herein can be implemented in many different forms and should not be construed as limited to the aspects set forth herein. The same reference numerals in the accompanying drawings always represent the same elements.

[0016] The terms used herein are for the purpose of describing specific aspects of the present disclosure only and are not intended to limit 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.

[0017] In the present disclosure, the term "body fluid" should be interpreted as a fluid extracted from the skin of a test subject. The fluid 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.

[0018] In this disclosure, the term "test subject" should be interpreted to cover both humans and animals, as well as in vitro tissues used for experimental purposes.

[0019] Some of the example embodiments presented herein relate to a method for sampling a body fluid.As part of the development of the example embodiments presented herein, a problem will first be identified and discussed.

[0020] In some early attempts to extract body fluids using microneedle arrays (MNAs), a low pressure was applied to the fluid channels of the MNAs to provide a suction effect. The inventors tried many different low pressures to improve the flow of body fluids from the test subject. However, none of these experiments proved successful, and only limited sample volumes were extracted.

[0021] The inventors have recognized that these problems can be minimized or even eliminated by introducing a pressure sequence to the MNA beginning with a penetration step in which a negative penetration pressure is applied to the MNA. This step is followed by a stripping step in which the MNA is stripped from the skin by positive pressure or by venting a lower pressure and mechanically stripping the MNA from the skin. The stripping step is then followed by an extraction step in which a lower pressure is applied. This sequence provides an unexpected and surprisingly increased flow of body fluids from the skin.

[0022] Now refer to Figure 1 and Figure 2 as well as Figure 3 , a method for sampling body fluid from the skin of a test subject by means of a sampling system will be disclosed. The sampling system 100 comprises: a fluid pump 102; a microneedle assembly 103; and a catheter 104, which connects the fluid pump 102 to the microneedle assembly 103.

[0023] The microneedle assembly 103 includes a housing 105 including a fluid port 106 connected to a fluid pump 102 via a conduit 104 ; and a microneedle array 107 in fluid communication with the fluid port 106 .

[0024] The microneedle array 107 is formed on a substrate 108 and includes a plurality of microneedles extending from a first side of the substrate, each microneedle 109 having a distal end and a proximal end connected to the first side of the substrate 108. The distal end has a bevel, and wherein each needle has a hole extending from its proximal end to its distal end, and wherein each hole extends into a corresponding hole of the substrate. The plurality of microneedles provide a fluid path from the distal end to the fluid port.

[0025] The microneedle assembly 103 also includes a rim 110 extending around the microneedle array 107, wherein the rim is intended to define a seal between the surrounding atmosphere and the interior 111 of the housing when the rim is in contact with the skin of a test subject.

[0026] exist Figure 2 The method generally indicated at 200 comprises the following steps:

[0027] Step a) The rim of the microneedle assembly is placed 201 in contact with the skin of a test subject, thereby sealing the interior 111 of the housing 105 from the surrounding atmosphere.

[0028] In step b), a negative piercing pressure PP of 202 is applied to the fluid port by means of a pump and thus a negative piercing pressure PP of 202 is applied to the interior of the housing, wherein the negative piercing pressure PP is maintained during the piercing time tP, whereby a plurality of microneedles pierce the skin of the test subject.

[0029] In step c), peeling 203 is performed, wherein a plurality of microneedles are removed from the skin during the peeling time tL, wherein the interior of the housing is at least at atmospheric pressure; and

[0030] In step d), a negative extraction pressure PE of 204 is applied by means of a pump during the extraction time tE, whereby the body fluid released from the skin flows towards the fluid port and is collected in the sample volume portion 112.

[0031] The negative piercing pressure PP is in the range from -30 kPa to -45 kPa.

[0032] The piercing time tP is in the range from 10 s to 60 s.

[0033] The negative extraction pressure PE is in the range from -10 kPa to -30 kPA.

[0034] The negative extraction pressure PE is in the range from -20 kPa to -30 kPa. In one embodiment, the negative extraction pressure is -25 kPa.

[0035] Optionally, step d) 204 further includes step d1) 205 of reducing the pressure in the volume portion to the negative extraction pressure at a differential pressure rate of less than 1 kPa / s during peeling.

[0036] Now referring again to Figure 1 , the sampling system 100 further includes a control unit 113, which is configured to control the fluid pump and includes a pressure sensor, which is arranged to measure the pressure PS in the flow path through the conduit 104, wherein the control unit 113 is configured to perform the method 200 as described in the embodiments disclosed herein.

[0037] Figure 4 An exemplary implementation of the control unit 113 in programmable signal processing hardware is shown. Figure 4The signal processing device 400 shown in 400 includes an input / output (I / O) portion 410 for receiving the measured pressure and transmitting the control signal CS to the pump 102. The signal processing device 400 also includes a processor 420, a working memory 430, and an instruction memory 440 storing computer-readable instructions, which, when executed by the processor 420, causes the processor 420 to perform the processing operations described herein to control the sampling system 100. The instruction memory 440 may include a ROM preloaded with computer-readable instructions. Alternatively, the instruction memory 440 may include a RAM or a similar type of memory, and the computer-readable instructions may be input to the instruction memory 440 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 computer-readable instructions.

[0038] In this embodiment, Figure 4 The combination 470 of hardware components including the processor 420 , the working memory 430 , and the instruction memory 440 shown in FIG. 4 is configured to implement the functionality of the aforementioned control unit 113 .

[0039] The present disclosure relates to a method for sampling a body fluid from the skin of a test subject with the aid of a sampling system, wherein the sampling system comprises: a fluid pump; a microneedle assembly; a catheter connecting the fluid pump to the microneedle assembly; the microneedle assembly comprises: a housing comprising a fluid port connected to the fluid pump via the catheter; a microneedle array, the microneedle array being in fluid communication with the fluid port, wherein the microneedle array is formed on a substrate and comprises a plurality of microneedles extending from a first side portion of the substrate, each microneedle having a distal end and a proximal end connected to the first side portion of the substrate, wherein the distal end has a bevel, and wherein each needle has a hole extending from its proximal end to its distal end, and wherein each hole extends into a corresponding hole of the substrate, wherein the plurality of microneedles provide a fluid path from the distal end to the fluid port; an edge, The rim extends around the microneedle array, wherein the rim is intended to define a seal between the ambient atmosphere and the interior of the housing when the rim is in contact with the skin of a test subject; wherein the method comprises the steps of: a) placing the rim of the microneedle assembly in contact with the skin of the test subject, thereby sealing 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 with the aid of a pump, wherein the negative penetration pressure is maintained during a penetration time, thereby the plurality of microneedles penetrate the skin of the test subject; c) stripping, wherein the plurality of microneedles are removed from the skin during the stripping time, wherein the interior of the housing is at least at atmospheric pressure; and d) applying a negative extraction pressure using a pump during an extraction time, thereby body fluid released from the skin flows toward the fluid port and is collected in a sample volume.

[0040] According to some embodiments, the negative penetration pressure is in the interval from -30 kPa to -45 kPa.

[0041] According to some embodiments, the piercing time is in the interval from 10 s to 60 s.

[0042] According to some embodiments, the negative extraction pressure is in the interval from -10 kPa to -30 kPa.

[0043] According to some embodiments, the negative extraction pressure is in the interval from -20 kPa to -30 kPa.

[0044] According to some embodiments, step d) further comprises a step d1) of reducing the pressure in the volume during stripping to a negative extraction pressure at a pressure differential rate of less than 1 kPa / s.

[0045] The present disclosure also relates to a sampling system for sampling a body fluid from the skin of a test subject. The sampling system comprises: a fluid pump; a microneedle assembly; a catheter connecting the fluid pump to the microneedle assembly; the microneedle assembly comprises: a housing comprising a fluid port connected to the fluid pump via the catheter; a microneedle array, the microneedle array being in fluid communication with the fluid port, wherein the microneedle array is formed on a substrate and comprises a plurality of microneedles extending from a first side of the substrate, each microneedle having a distal end and a proximal end connected to the first side of the substrate, wherein the distal end has a bevel, and wherein each needle has a hole extending from its proximal end to its distal end, and wherein each hole extends into a corresponding hole of the substrate, wherein the plurality of microneedles provide a fluid path from the distal end to the fluid port; a rim extending around the microneedle array, wherein the rim is intended to define a seal between the ambient atmosphere and the interior of the housing when the rim is in contact with the skin of a test subject; a control unit configured to control the fluid pump and comprising a pressure sensor arranged to measure pressure in a flow path through the catheter, wherein the control unit is configured to perform the method as set forth in the embodiments disclosed herein.

[0046] In the drawings and description, exemplary embodiments have been disclosed. However, many variations and modifications may be made to these embodiments. Therefore, although specific terms are employed, these terms are used only in a general and descriptive sense and not for the purpose of limitation, and the scope of the embodiments is defined by the appended claims.

[0047] The description of the example embodiments provided herein is presented for illustrative purposes. The description is not intended to be exhaustive or to limit the example embodiments to the precise form disclosed, and modifications and variations are possible in light of the above teachings, or may be obtained from practice of various alternatives of the provided embodiments. The example discussed herein are selected and described in order to explain the principles and nature of the various example embodiments and their practical application so that those skilled in the art may use the example embodiments in various ways and with various modifications as are suited to the particular use contemplated. The features of the embodiments described herein may be combined in all possible combinations in methods, apparatus, modules, systems, and computer program products.

[0048] It should be understood that the example embodiments presented herein may be practiced in any combination with each other. It should be noted that the word "comprising" does not necessarily exclude the presence of other elements or steps than those listed, and the word "a" or "an" preceding an element does not exclude the presence of a plurality of such elements. It should also be noted that any reference signs do not limit the scope of the claims, and the example embodiments may be implemented at least in part by both hardware and software, and several "means", "units" or "devices" may be represented by the same item of hardware.

Claims

1. A method (200) for sampling a body fluid from the skin (101) of a test subject by means of a sampling system (100), in, The sampling system (100) comprises: Fluid pump (102); Microneedle assembly (103); a catheter (104), the catheter (104) connecting the fluid pump (102) to the microneedle assembly (103); The microneedle assembly (103) comprises: a housing (105), the housing (105) comprising 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), wherein the microneedle array (107) is formed on a substrate (108) and comprises a plurality of microneedles extending from a first side of the substrate, each microneedle (109) having a distal end and a proximal end connected to the first side of the substrate (108), wherein the distal end has a bevel, and wherein each needle has a hole extending from its proximal end to its distal end, and wherein each hole extends into a corresponding hole of the substrate, wherein the plurality of microneedles provide a fluid path from the distal end to the fluid port; a rim (110) extending around the microneedle array (107), wherein the rim is intended to define a seal between the surrounding atmosphere and an interior (111) of the housing when the rim is in contact with the skin of the test subject; The method (200) comprises the following steps: a) placing (201) the rim of the microneedle assembly in contact with the skin of the test subject, thereby sealing the interior (111) of the housing (105) from the surrounding atmosphere; b) applying (202) a negative penetration pressure (PP) to the fluid port and thereby to the interior of the housing by means of the pump, wherein the negative penetration pressure (PP) is maintained during a penetration time (tP), Thereby the plurality of microneedles penetrate the skin of the test subject; c) peeling (203), wherein the plurality of microneedles are removed from the skin during a peeling time (tL), wherein the interior of the housing is at least at atmospheric pressure; and d) applying (204) a negative extraction pressure (PE) using the pump during an extraction time (tE), whereby the body fluid released from the skin flows towards the fluid port and is collected in a sample volume (112).

2. The method (200) according to claim 1, in, The negative penetration pressure (PP) is in the range from -30 kPa to -45 kPa.

3. The method (200) according to claim 1 or 2, in, The penetration time (tP) is in the range from 10 s to 60 s.

4. The method (200) according to any one of the preceding claims, in, The negative extraction pressure (PE) is in the range from -10 kPa to -30 kPa.

5. The method (200) according to any one of the preceding claims, in, The negative extraction pressure (PE) is in the interval from -20 kPa to -30 kPa.

6. The method (200) according to any one of the preceding claims, in, Step d) (204) further comprises a 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 / s during stripping.

7. A sampling system (100) for sampling a body fluid from the skin of a test subject, in, The sampling system (100) comprises: Fluid pump (102); Microneedle assembly (103); a catheter (104), the catheter (104) connecting the fluid pump (102) to the microneedle assembly (103); The microneedle assembly (103) comprises: a housing (105), the housing (105) comprising a fluid port (106) connected to the fluid pump (102) via the conduit (104); A microneedle array (107), wherein the microneedle array (107) and the fluid port (106) are Fluid communication, wherein the microneedle array (107) is formed on a substrate (108) and includes a plurality of microneedles extending from a first side of the substrate, each microneedle (109) having a distal end and a proximal end connected to the first side of the substrate (108), wherein the distal end has a bevel, and wherein each needle has a hole extending from its proximal end to its distal end, and wherein each hole extends into a corresponding hole of the substrate, wherein the plurality of microneedles provide a fluid path from the distal end to the fluid port; a rim (110) extending around the microneedle array (107), wherein the rim is intended to define a seal between the surrounding atmosphere and an interior (111) of the housing when the rim is in contact with the skin of the test subject; a control unit (113) configured to control the fluid pump and comprising a pressure sensor arranged to measure a pressure (PS) in the flow path through the conduit (104), wherein the control unit (113): configured to, when the rim of the microneedle assembly is placed (201) in contact with the skin of the test subject, thereby sealing the interior (111) of the housing (105) from the surrounding atmosphere: a) applying (202) a negative penetration pressure (PP) to the fluid port and thereby to the interior of the housing by means of the pump, wherein the negative penetration pressure (PP) is maintained during a penetration time (tP), Thereby the plurality of microneedles penetrate the skin of the test subject; b) increasing the pressure in the volume, peeling (203), wherein the plurality of microneedles are removed from the skin during a peeling time (tL), wherein the interior of the housing is at least at atmospheric pressure; and d) applying (204) a negative extraction pressure (PE) using the pump during an extraction time (tE), whereby the body fluid released from the skin flows towards the fluid port and is collected in a sample volume (112).

8. The sampling system (100) according to claim 7, in, The negative penetration pressure (PP) is in the range from -30 kPa to -45 kPa.

9. The sampling system (100) according to claim 7 or 8, in, The penetration time (tP) is in the range from 10 s to 60 s.

10. The sampling system (100) according to any one of claims 7 to 9, in, The negative extraction pressure (PE) is in the range from -10 kPa to -30 kPa.

11. The sampling system (100) according to any one of claims 7 to 10, in, The negative extraction pressure (PE) is in the interval from -20 kPa to -30 kPa.

12. The sampling system (100) according to any one of claims 7 to 11, in, Step d) (204) further comprises a 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 / s during stripping.

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