WO2020079438A1

WO2020079438A1 - Skin probe for sampling a biological fluid

Info

Publication number: WO2020079438A1
Application number: PCT/GB2019/052965
Authority: WO
Inventors: Neville Freeman
Original assignee: Nanoflex Limited
Priority date: 2018-10-19
Filing date: 2019-10-17
Publication date: 2020-04-23
Also published as: GB201817090D0

Abstract

Skin probe for sampling a biological fluid (eg sweat) on skin comprising a sensor element housing which has a first housing part with a convex or apical profile and a second housing part, wherein the first housing part includes a sensor element window, wherein in use the first housing part is impinged on the skin and the convex or apical profile serves to promote movement of the biological fluid on the skin at or near to the sensor element window; and a sensor element of a sensor for determining the presence or amount of an analyte of interest in the biological fluid, wherein the sensor element is housed in the first housing part exposed in or from the sensor element window. During skin impingement, the convex or apical profile creates a differential pressure gradient which promotes movement of the biological fluid on the skin. The skin probe is able to work efficiently with very small volumes of sweat and manage the flow to ensure that fresh sweat is being monitored continuously.

Description

SKIN PROBE FOR SAMPLING A BIOLOGICAL FLUID

The present invention relates to a skin probe for sampling a biological fluid (eg sweat) on skin.

There are many examples of analytical measurement where an extremely limited volume of sample has a profound impact on the result. For clinical measurements, there are factors such as the comfort, compliance and condition of the patient which also need to be taken into consideration. In the case of the measurement of blood glucose concentration for example, there have been significant efforts invested in seeking to reduce the sample size to ensure patient comfort whilst still obtaining a reliable outcome.

In recent years, there has been increased interest in the measurement of biological materials in sweat. The measurement of biological materials in sweat is particularly difficult. Under ambient conditions, the average flow rate per gland is only a few nanolitres per minute and may vary with temperature, humidity and work load by a factor of 20 or more. Furthermore the density of sweat glands is relatively low (typically less than one hundred glands per centimetre square) and the act of occluding the skin can alter the behaviour of the sweat glands.

One simple approach to improving the measurement of an analyte in sweat is to fix the sensor directly on the skin by using a band (eg an elasticated head or wrist band or a watch or chest band) or a pressure pad. A comparison of a normalised blood glucose response with the response obtained from sweat by a sensor held in place with an elasticated head band and pressure pad is shown in Figure 1. The "Sensor" trace is the sweat-based glucose measurement and the "Blood Glc" trace is the blood glucose measurement. "Lunch" marks where lunch began and "Glucose Drink" marks where a glucose drink was taken. Data from the sensor is in very close temporal proximity (almost coincident) with the blood glucose measurements in the first half of the experiment with very little delay in monitoring the prandial increase in blood glucose levels. However during the second half of the experiment, the sweat measurement is 45 minutes behind the blood glucose measurement. This appears to be due either to slight shifts in the sensor position or minute pooling of sweat under the sensor itself. It is clear that this approach does not offer a practicable solution for real time measurement of analytes in sweat. Indeed the consequences of the delay are potentially fatal and rule out the use of the device for glucose measurement.

Techniques for sampling sweat include exercise to induce sweating at elevated rates or administration of stimulants such as pilocarpine which induce temporarily elevated rates of sweating. Neither of these techniques are suitable for general use. Sweat can also be sampled using a device equipped with channels, chambers, microfluidics or absorbents. However the levels of sweat available under ambient conditions in a sedentary subject provide insufficient throughput. The volume of sweat which reaches the sensor is often referred to as the "dead volume". The dead volume needs to be significantly lower than the volume of sweat produced. In order to achieve a practicable device for use with a sedentary subject under ambient conditions, a sensor needs to be operable when the dead volume of sweat is extremely low.

The present invention seeks to improve the sampling of extremely small volumes of biological fluid where the flow rate may be extremely slow and vary by up to an order of magnitude. In particular, the present invention relates to a skin probe which serves to manage fluid flow effectively and precisely for the purposes of collection and/or measurement.

Thus the present invention provides a skin probe for sampling a biological fluid on the skin comprising:

a sensor element housing which has a first housing part with a convex or apical profile and a second housing part, wherein the first housing part includes a sensor element window, wherein in use the first housing part is impinged on the skin and the convex or apical profile serves to promote movement of the biological fluid on the skin at or near to the sensor element window; and

a sensor element of a sensor for determining the presence or amount of an analyte of interest in the biological fluid, wherein the sensor element is housed in the first housing part exposed in or from the sensor element window.

The skin probe according to the invention is capable of effectively sampling (for example) sweat in a sedentary individual under ambient conditions and therefore to facilitate measurement of data which is meaningful in real time. The skin probe is able to work efficiently with very small volumes of sweat and manage the flow to ensure that fresh sweat is being monitored continuously.

During skin impingement, the convex or apical profile creates a differential pressure gradient which promotes movement of the biological fluid on the skin {ie a mechanical inducement of fluid flow). The sensor element window may be at the point of maximum pressure or placed in a region where biological fluid flow is affected by the differential pressure gradient.

The convex or apical profile may be the profile of a portion (or the whole) of an exterior face of the first housing part.

Preferably in use the first housing part is impinged on the skin coincident with the sensor element window.

The first housing part may be adapted to promote movement of the biological fluid on the skin across the sensor element window. Preferably the sensor element window is positioned at or near to an extremity, tip, pole or apex of the first housing part.

The sensor element window may be substantially coincident with the principal axis of the first housing part.

In a preferred embodiment, the sensor element housing has a first housing part with a convex profile. The convex profile may be substantially spherical or aspherical. The sensor element window may be at or near to the centre of curvature of the convex profile.

The profile of the sensor element housing may be substantially hemispherical (such as a dome or half-dome), substantially hemicylindrical, triangular or substantially

trapezoidal.

In a preferred embodiment, the convex or apical profile is formed by a feature which resides in or is prominent from the sensor element window. Particularly preferably the feature is a part of the sensor element.

In this embodiment, the sensor element is typically flexible. For example, the sensor element may comprise a flexible substrate. Preferably the second housing part comprises a convex structure (eg a convex saddle) which causes the flexible sensor element to flex into the convex profile in the sensor element window.

The first housing part may be further adapted functionally, configurationally or compositionally to promote movement of the biological fluid on the skin at or near to the sensor element window.

The first housing part may be composed of materials with different compressibility. For example, the first housing part may be composed of a low compressible material (eg near to the sensor element window) and a high compressible material (eg remote from the sensor element window such as on the periphery of the first housing part).

Alternatively the first housing part may be composed of a low compressible material (eg near to the sensor element window) and the second housing part may be composed of a high compressible material.

The first housing part may be composed of materials with different hydrophobicity or hydrophilicity.

Preferably the first housing part is composed of a hydrophobic material (eg near to the sensor element window) and a hydrophilic material (eg remote from the sensor element window such as on the periphery of the first housing part). The presence of a hydrophobic material near to the sensor element window and a hydrophilic material remote from the sensor element window advantageously produces a chemical potential gradient which urges sweat away from the sensor element window. Alternatively the first housing part may be composed of a hydrophobic material (eg near to the sensor element window) and the second housing part may be composed of a hydrophilic material.

Preferably the sensor element is provided with a hydrophobic surface (eg a screen- printed hydrophobic surface) and the first housing part is composed of a hydrophilic material (eg remote from the sensor element window such as on the periphery of the first housing part).

Preferably the first housing part is composed of a wicking material remote from the sensor element window (eg on the periphery of the first housing part). Alternatively or additionally the second housing part may be composed of a wicking material. The presence of a wicking material remote from the sensor element window advantageously urges sweat away from the sensor element window and serves to ensure that excess sweat does not flow towards the sensor element window.

The first housing part may be provided with a bund (eg a rail) at or near to the periphery of the sensor element window. The bund may partly or fully border the sensor element window. The bund serves to deflect excess sweat away from the sensor element window. The bund may be made of a soft elastomeric material such as silicone.

Preferably the first housing part contains a vibrational actuator. The vibrational actuator may actuate periodically or continuously.

The first housing part may contain a wave generator. The wave generator may generate a wave in the wall of the first housing part or in the region of the skin impinged by the first housing part.

The first housing part may contain an electric field generator. The electric field generator may be a plurality of electrodes in contact with the skin.

The second housing part may be elongate and non-convex. The sensor element may be an electrochemical sensor element (eg an electrode), a colorimetric indicator, an optical sensor element or a mass balance sensor element. The sensor may be an electrochemical sensor, a colorimetric indicator, an optical sensor or a mass balance sensor.

The sensor element may be a sensor element of a biosensor. Preferably the biosensor is a glucose biosensor.

The biosensor may deploy a biological component such as an enzyme or antibody.

Preferably the sensor element is an electrode assembly (eg a nanoelectrode assembly). The sensor element may be an electrode assembly upon which is immobilized glucose oxidase. The immobilised glucose oxidase may be mediator-free (ie free of an exogenous mediator). The nanoelectrode assembly is operable as a working electrode and forms part of an electrochemical sensor (eg an electrochemical biosensor) which further comprises a reference electrode. The electrochemical sensor is typically amperometric, potentiometric or impedance-based. Preferably the electrochemical sensor is amperometric. The electrochemical sensor may further comprise a counter electrode.

The nanoelectrode assembly may have a laminate structure comprising: a first insulating capping layer; a first conducting layer capped by the first insulating capping layer and substantially sandwiched or encapsulated by at least the first insulating capping layer such as to leave exposed only an electrical contact surface; and an array of etched voids extending through at least the first insulating capping layer and the first conducting layer, wherein each void is partly bound by a surface of the first conducting layer which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase, wherein in use the biological fluid passes into the etched voids for exposure to the immobilised glucose oxidase.

The nanoelectrode assembly may be free of any system which is glucose flux-limiting or glucose diffusion-controlling {eg a glucose membrane).

The electrical contact surface may be part of the first conducting layer or may be connected to the first conducting layer. The electrical contact surface may be a peripheral contact edge such as a square contact edge of the conducting layer. The electrical contact surface may be a wide area electrical contact surface (eg the electrical contact surface may extend along substantially the entire length of the periphery of the nanoelectrode assembly). The electrical contact surface may be substantially T-shaped. The electrical contact surface may be an electrical contact lip. The electrical contact surface allows simple and reliable connection of each internal submicron electrode to external instrumentation eg external circuitry such as a potentiostat, handheld meter or monitoring device for example.

Typically the nanoelectrode assembly has at least one dimension (eg one or two dimensions) on the nanometre scale. The critical dimension may be lOOnm or less.

The layers of the laminate structure may be successively fabricated (eg cast, spun, sputtered, grown, deposited or printed (eg screen printed)) layer-by-layer according to standard techniques.

Preferably the nanoelectrode assembly comprises: a plurality of conducting layers (which may be the same or different) including the first conducting layer and a plurality of insulating capping layers (which may be the same or different) including the first insulating capping layer, wherein the plurality of conducting layers and the plurality of insulating capping layers are alternating in the laminate structure, wherein each conducting layer is sandwiched or encapsulated to leave exposed only an electrical contact surface and the array of etched voids extends through the plurality of insulating capping layers and the plurality of conducting layers, wherein each void is partly bound by a surface of each of the plurality of conducting layers which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase.

The number of internal submicron electrodes in each void may be three, four or five (or more). Such embodiments may be formed by successive lamination (eg deposition or growth) of the conducting layers and insulating capping layers. The dimensions and absolute spatial locations within the void and relative spatial locations of each of the internal submicron electrodes may be precisely defined.

Preferably the nanoelectrode assembly further comprises: a second conducting layer, wherein the first conducting layer is sandwiched or encapsulated to leave exposed only a first electrical contact surface and the second conducting layer is sandwiched or encapsulated to leave exposed only a second electrical contact surface, wherein the array of etched voids extends through the first conducting layer, the first insulating capping layer and the second conducting layer, wherein each void is partly bound by a surface of the first conducting layer which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase and/or by a surface of the second conducting layer which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase. The first conducting layer and second conducting layer may be substantially coplanar (eg laterally spaced apart). The first conducting layer and second conducting layer may be non-coplanar (eg axially spaced apart (preferably substantially co-axially spaced apart) or radially spaced apart (preferably concentrically radially spaced apart)). This may require multilevel metal interconnect.

Preferably the nanoelectrode assembly comprises: a second conducting layer and a second insulating capping layer, wherein the first conducting layer is sandwiched or encapsulated to leave exposed only a first electrical contact surface and the second conducting layer is sandwiched or encapsulated to leave exposed only a second electrical contact surface, wherein the array of etched voids extends through the first conducting layer, the first insulating capping layer, the second conducting layer and the second insulating capping layer, wherein each void is partly bound by a surface of the first conducting layer which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase and/or by a surface of the second conducting layer which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase. The first conducting layer and second conducting layer may be substantially coplanar (eg laterally spaced apart). The first conducting layer and second conducting layer may be non-coplanar (eg axially spaced apart (preferably substantially co-axially spaced apart) or radially spaced apart (preferably concentrically radially spaced apart)). This may require multilevel metal interconnect.

Preferably the array of etched voids is a plurality of discrete sub-arrays of etched voids. The array (or each sub-array) may be a linear or staggered (eg herringbone) pattern. The array (or each sub-array) may be a cubic pattern. The array (or each sub-array) may be a multi-dimensional (eg bi-dimensional) array.

The array of voids may be physically, mechanically or chemically etched. For example, the array of voids may be may be etched by a laser or by mechanical indentation or piercing. Each void may be an aperture, through-hole, well, tube, capillary, pore, bore or trough. Preferably each etched void is a well. The well may terminate in an insulating capping layer or insulating substrate layer. The well may terminate in a conducting layer which provides an internal submicron electrode in the base of the well.

The lateral dimension ( d_w ) and shape of a void determines the distance between opposite faces of the internal submicron electrode. The cross-sectional shape of the void may be regular. For example, the cross-sectional shape of the void may be substantially circular and the lateral dimension is the diameter. For example, the cross-sectional shape of the void may be substantially square and the lateral dimension is the width.

The lateral dimension d_w {eg width or diameter) of each void (which may be the same or different) is typically lOOnm or more.

The depth of the void is the etch depth (d_d). The position of the n^th internal submicron electrode at a specified depth (d_n) in the void (ie the distance from the aperture opening to the closest edge of the n^th electrode) is determined by the width of the insulating capping layer(s). The thickness of the internal submicron electrode ( w_n ) and its position within the void (defined by d_n, d and w_n) can be independently controlled on the nanoscale.

The etch depth (d_d) of each void (which may be the same or different) is typically 10000 microns or less, preferably 0.0003 to 1000 microns, particularly preferably 0.05 to 100 microns, more preferably 0.01 to 10 micron.

The plurality of voids can be arranged in an array with a precisely defined separation or pitch (x and y which may be the same or different). The pitch is typically lOOnm or more.

The (or each) conducting layer may be a substantially planar or cylindrical conducting layer.

Preferably the (or each) conducting layer is a substantially planar conducting layer.

The (or each) conducting layer may be substantially T-shaped, serpentine or digitated.

The (or each) conducting layer may be metallic. The conducting layer may be composed of a noble metal such as gold, platinum or silver or a metal nitride (eg titanium nitride). The (or each) conducting layer may be functionalised (eg chemically or biologically functionalised). The (or each) conducting layer may be a composite (eg a composite of a nanoparticle, nanowire or nanoconnector). For example, the (or each) conducting layer may comprise (or consist of) carbon nanotubes or metal (eg gold) nanoparticles.

The thickness (w_n) of the n^th conducting layer may be determined by fabrication at atomic scale resolution (where atomic scale means a thickness of at least an atom or more). The thickness (w_n) of the (or each) conducting layer (which may be the same or different) may be O.lOnm or more, preferably in the range 0.10 to 990nm, particularly preferably 0.10 to 500nm, more preferably 0.10 to 250nm, even more preferably 0.10 to lOOnm.

The (or each) insulating capping layer may be polymeric. The thickness of the (or each) insulating capping layer (which may be the same or different) may be O.lOnm or more, preferably in the range 0.10 to 5000nm, particularly preferably 0.10 to 2000nm, more preferably 0.10 to 990nm, most preferably 0.10 to 500nm.

The depth of the first internal submicron electrode ( ie the internal submicron electrode closest to the hole edge) ( di ) is typically 1000 microns or less, preferably 0.0001 to 100 microns, particularly preferably 0.0001 to 10 microns, more preferably 0.0001 to 1 micron, most preferably 0.0001 to 0.5 microns.

The (or each) internal submicron electrode is typically partly or wholly annular.

In a first embodiment, the first conducting layer is substantially sandwiched or encapsulated by only the first insulating capping layer such as to leave exposed only an electrical contact surface of the first conducting layer, wherein the array of etched voids extends through only the first insulating capping layer and the first conducting layer.

In a second embodiment, the electrode further comprises:

an insulating substrate layer, wherein the first conducting layer is fabricated on the insulating substrate layer and is substantially sandwiched or encapsulated by the first insulating capping layer and the insulating substrate layer such as to leave exposed only an electrical contact surface of the first conducting layer.

In a third embodiment, the electrode further comprises:

an insulating substrate layer;

a second insulating capping layer fabricated on the insulating substrate layer, wherein the first conducting layer is fabricated on the second insulating capping layer and is substantially sandwiched or encapsulated by the first insulating capping layer and the second insulating capping layer such as to leave exposed only an electrical contact surface of the first conducting layer.

In a fourth embodiment, the electrode further comprises:

an insulating substrate layer; a second insulating capping layer,

wherein the first conducting layer is fabricated on the second insulating capping layer and is substantially sandwiched or encapsulated by the first insulating capping layer and the second insulating capping layer such as to leave exposed only an electrical contact surface of the first conducting layer;

a second conducting layer,

wherein the second conducting layer is fabricated on the insulating substrate layer and is substantially sandwiched or encapsulated by the second insulating capping layer and the insulating substrate layer such as to leave exposed only an electrical contact surface of the second conducting layer,

wherein the array of etched voids extends through at least the first insulating capping layer, the first conducting layer and the second insulating capping layer, wherein each void is partly bound by a surface of the first conducting layer which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase.

Preferably the array of etched voids extends through only the first insulating capping layer, the first conducting layer and the second insulating capping layer.

Preferably the array of etched voids extends through the first insulating capping layer, the first conducting layer, the second insulating capping layer and the second conducting layer, wherein each void is partly bound by a surface of the first conducting layer which acts as a first internal submicron electrode upon or adjacent to which is immobilised glucose oxidase and by a surface of the second conducting layer which acts as a second internal submicron electrode optionally (but preferably) upon or adjacent to which is immobilised glucose oxidase.

In a fifth embodiment, the electrode further comprises:

an insulating substrate layer;

a second conducting layer,

wherein the first conducting layer is digitated and the second conducting layer is digitated, wherein the first conducting layer and the second conducting layer are interdigitally fabricated on the insulating substrate layer and are substantially sandwiched or

encapsulated by the first insulating capping layer and the insulating substrate layer such as to leave exposed only an electrical contact surface of the first conducting layer and an electrical contact surface of the second conducting layer,

wherein the array of etched voids extends through the first insulating capping layer, the first conducting layer and the second conducting layer, wherein each void is partly bound by a surface of the first conducting layer which acts as a first internal submicron electrode upon or adjacent to which is immobilised glucose oxidase and is partly bound by a surface of the second conducting layer which acts as a second internal submicron electrode optionally (but preferably) upon or adjacent to which is immobilised glucose oxidase.

In a sixth embodiment, the electrode further comprises:

an insulating substrate layer;

a second conducting layer,

wherein the second conducting layer is substantially coplanar with the first conducting layer, wherein each of the first conducting layer and the second conducting layer is capped by the first insulating capping layer and is substantially sandwiched or encapsulated by at least the first insulating capping layer such as to leave exposed only an electrical contact surface of the first conducting layer and an electrical contact surface of the second conducting layer respectively,

wherein one or more first etched voids extend through the first insulating capping layer and the first conducting layer and one or more second etched voids extend through the first insulating capping layer and the second conducting layer, wherein each first etched void is partly bound by a surface of the first conducting layer which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase and each second etched void is partly bound by a surface of the second conducting layer which acts as an internal submicron electrode upon or adjacent to which is immobilised glucose oxidase.

Preferably each of the first conducting layer and the second conducting layer is substantially sandwiched or encapsulated by only the first insulating capping layer such as to leave exposed only an electrical contact surface of the first conducting layer and an electrical contact surface of the second conducting layer respectively.

The insulating substrate layer is typically composed of silicon, silicon dioxide, silicon nitride or a polymeric material.

The laminate structure may be substantially planar, cylindrical, hemispherical or spherical. A cylindrical, hemispherical or spherical laminate structure may have a hollow or solid core. For example, the laminate structure may be a fibre which may have a hollow or solid core with a diameter of 1 micron or more. For example, the laminate structure may be a slide, taper, plate or tape which may have a width of 1 micron or more.

Preferably the biological fluid is sweat.

The analyte of interest may be biological, biochemical or chemical.

The analyte of interest may be a metabolite, biomarker, therapeutic agent or toxic agent.

The analyte of interest may be glucose, lactate, uric acid, creatine or creatinine. Preferably the analyte of interest is glucose. The analyte of interest may be acetaminophen (paracetamol), acetyl salicylic acid (aspirin), ibuprofen, warfarin, a statin, an alcohol (eg ethanol), ascorbic acid (vitamin C), a vitamin, a mineral or a hormone.

The present invention will now be described in a non-limitative sense with reference to Figures 2 to 11 in which:

Figure 2. A schematic illustration of a first embodiment of the skin probe of the invention.

Figure 3. A schematic illustration of a second embodiment of the skin probe of the invention.

Figure 4. A schematic illustration of a third embodiment of the skin probe of the invention.

Figure 5. A schematic illustration of a fourth embodiment of the skin probe of the invention.

Figure 6. A schematic illustration of a fifth embodiment of the skin probe of the invention.

Figure 7. Data obtained by the skin probe of Figure 10 worn by a type-one insulin- dependent diabetic (at rest).

Figure 8. Data obtained by the skin probe of Figure 10 worn by a non-diabetic (at rest).

Figure 9. Data obtained by the skin probe of Figure 10 worn by a pre-diabetic (at rest).

Figure 10. An exploded view of a sixth embodiment of the skin probe of the invention.

Figure 11. Quantified blood glucose measurements using the skin probe of Figure 10 (data outage on right arm at approximately 21:30).

Figure 2 is a schematic illustration of a first embodiment of the skin probe of the invention 100. The skin probe 100 comprises a substantially hemicylindrical housing 1 with a convex housing part la and a non-convex housing part lb. A sensor element 2 is mounted at the tip of the convex housing part la and is exposed through a sensor element window lc.

In use, the skin probe 100 impinges the skin 3 at the tip and the sensor element window lc coincides with the point of maximum pressure. This mechanical action causes sweat to move away from the sensor element window lc and is aided by the natural movement of the wearer and the elasticity of the skin 3. The action can be enhanced by rocking the skin probe 100 on the skin 3.

The sensor assembly 2 is a nanoelectrode assembly operable as a working electrode and forms part of an electrochemical biosensor which further comprises a reference electrode and counter electrode (not shown). The electrochemical biosensor is

amperometric.

Figure 3 is a schematic illustration of a second embodiment of the skin probe of the invention 200. The second embodiment is similar to the first embodiment but a

hydrophobic surface 5 (DuPont 5036) is screen-printed onto the sensor element 2 and the surface of the convex housing part lc is hydrophilic. Sweat is aqueous and is therefore driven away from the sensor element 2 by a chemical potential.

Figure 4 is a schematic illustration of a third embodiment of the skin probe of the invention 300. The third embodiment is similar to the second embodiment but the non- convex housing part lb is composed of a wicking material (cellulose acetate). The wicking material aids the removal of excess sweat from the region of the sensor element 2.

Figure 5 is a schematic illustration of a fourth embodiment of the skin probe of the invention 400. The fourth embodiment is similar to the first embodiment but the non- convex housing part lb is composed of a wicking material (cellulose acetate) as described for the third embodiment.

Figure 6 is a schematic illustration of a fifth embodiment of the skin probe of the invention 500. The fifth embodiment is similar to the first embodiment but further comprises a spring-loaded tensioner 7. The spring-loaded tensioner serves to induce translocation of sweat.

Figure 10 is an exploded view of a sixth embodiment of the skin probe of the invention 600. The skin probe 600 comprises a sensor element housing in two housing parts. The first housing part is a plate 607 which incorporates a sensor element window 608. The plate 607 is seated on and fixed to a second housing part. The second housing part is an enclosure 601 which contains auxiliary components such as electronics and batteries and incorporates an aperture 603 in an upper face 610 to allow access to the auxiliary components. A convex saddle 604 on the upper face 610 is adjacent to and spaced apart from the aperture 603. The convex saddle 604 is coincident with the sensor element window 608.

An electrochemical sensor 605 is mounted between the plate 607 and the enclosure 601 such that it is coincident with the aperture 603 and the sensor element window 608. The electrochemical sensor 605 comprises an elongate flexible substrate which terminates in a contact means 606. During assembly, the plate 607 urges the electrochemical sensor 605 on to the convex saddle 604 to cause it to flex into a convex profile which resides in the sensor element window 608 of the plate 607 from where it can make contact with the skin of a user. The contact means 606 is adjacent to the aperture 603 where it makes effective contact with the auxiliary components.

Experimental Results

Experiments were carried out to compare the blood glucose response with the response obtained from sweat using the sixth embodiment of the skin probe of the invention (Figure 10). The subjects were a type-one insulin-dependent diabetic (at rest), a non-diabetic (at rest) and a pre-diabetic (at rest) and the respective results are shown in Figures 7 to 9. The sweat glucose measurement (marked as "Sensor") was consistently about 6-7 minutes behind the blood glucose measurement (marked as "Blood Glucose " or "BLG”) which is a significant improvement on conventional sampling techniques (see Figure 1). Furthermore it can be seen that the drop out/delay observed for the flat mounted device in Figure 1 is no longer evident. This approach therefore offers a significant improvement on sweat sampling as a consequence of better management of the fluid flow in the sensing area.

The data from Figures 7 to 9 can be quantified to provide blood glucose values which are in good agreement with conventional estimates using finger prick testing (see Figure 11). It should be noted that the temporal disjunction observed during the second prandial event in Figure 1 is not observed in Figure 11. The data is very closely correlated both in terms of the blood glucose concentration and timing of the changes in concentration. At the end of the test period both left and right arm blood glucose measurements were within 10% of the measured blood glucose test.

Claims

1. A skin probe for sampling a biological fluid on the skin comprising:

2. A skin probe as claimed in claim 1 wherein in use the first housing part is impinged on the skin coincident with the sensor element window.

3. A skin probe as claimed in claim 1 or 2 wherein the sensor element window is positioned at or near to an extremity, tip, pole or apex of the first housing part.

4. A skin probe as claimed in any preceding claim wherein the sensor element housing has a first housing part with a convex profile.

5. A skin probe as claimed in any preceding claim wherein the profile of the sensor element housing is substantially hemicylindrical.

6. A skin probe as claimed in claim 1 or 2 wherein the convex or apical profile is formed by a feature which resides in or is prominent from the sensor element window.

7. A skin probe as claimed in claim 6 wherein the feature is a part of the sensor element.

8. A skin probe as claimed in claim 6 or 7 wherein the sensor element is flexible and the second housing part comprises a convex structure which causes the flexible sensor element to flex into the convex profile in the sensor element window.

9. A skin probe as claimed in any preceding claim wherein the first housing part is composed of a hydrophobic material near to the sensor element window and a hydrophilic material remote from the sensor element window.

10. A skin probe as claimed in any preceding claim wherein the sensor element is provided with a hydrophobic surface and the first housing part is composed of a hydrophilic material remote from the sensor element window.

11. A skin probe as claimed in any preceding claim wherein the first housing part is composed of a wicking material remote from the sensor element window.

12. A skin probe as claimed in any preceding claim wherein the first housing part contains a vibrational actuator.

13. A skin probe as claimed in any preceding claim wherein the sensor element is a sensor element of a glucose biosensor.

14. A skin probe as claimed in any preceding claim wherein the sensor element is a nanoelectrode assembly operable as a working electrode, wherein the nanoelectrode assembly forms part of an electrochemical sensor which further comprises a reference electrode.

15. A skin probe as claimed in any preceding claim wherein the biological fluid is sweat.

16. A skin probe as claimed in any preceding claim wherein the analyte of interest is glucose.