Needle-based device with temperature sensing function

Abstract

An electrochemical sensor device for introduction into the skin of a subject of a needle-type electrode to contact a biological fluid or tissue of the subject and detect a target analyte. The device has a movable portion that urges the needle electrode to enter the skin of the subject and the thermal energy sensor to determine the temperature of the biological fluid or tissue.

Description

Technical Field

[0001] The present invention generally relates to a device for introducing a needle into the skin of a subject, the needle being held in place. The needle contacts a biological fluid in the subject and detects a target analyte therein. The device is designed to be relatively unobtrusive to the subject in a simple, lightweight and low-profile form. Additionally, the device has a temperature sensing function to improve the accuracy of target analyte detection. Background Art

[0002] The evolution of microfabrication technology in the 1990s has allowed for the mass production of micro-needle devices for medical use.

[0003] A single micro-needle typically has a length of 150 to 1500 μm, a width of 50 to 250 μm, and a tip thickness of 1 to 25 μm. In the context of a biosensor device, the micro-needle may be conductive and act as a working electrode, a counter electrode, or a reference electrode.

[0004] As a working electrode in an electrochemical biosensor, the micro-needle may be coated with a detection element, such as a redox-modified aptamer or an enzyme, to sense a specific target analyte, such as interstitial fluid or blood, in a biological fluid. Typically, the biosensor is used by applying an electric potential (e.g., square wave voltammetry). The peak current passing through the working electrode is measured, and this value is used to determine the quantity of the analyte present at the working electrode.

[0005] The prior art discloses a number of devices for inserting micro-needles into the skin of a subject. These devices are typically used to facilitate the application of micro-needles by the subject in a non-clinical setting, such as at home. The key objectives of these devices are ease of use and replicability.

[0006] Some devices are dedicated solely to the application of micro-needles and are removed along with the micro-needles once their function is completed. Other prior art devices are designed to separate from the micro-needle, thus allowing the micro-needle to remain in place in the skin for a period of time after insertion. While in the skin, the micro-needle can sense fluctuations in the concentration of analytes in the interstitial fluid.

[0007] There is a further type of prior art device used for introducing micro-needles, where the device and the micro-needle remain in place in the subject for a period of time. While these devices provide simplicity in the subject's use of the device, they have some problems.

[0008] One problem is that these devices are generally noticeable and easily drawn to the attention of the subject. The device may be caught by clothing or other nearby objects, causing complete or partial displacement. These devices may need to be worn overnight, and there will be obvious discomfort when the subject rolls over the device.

[0009] A further problem is that prior art devices are complex and have a large number of individual components. This increases the cost of the device and the tendency to fail. The large number of components also increases the weight of the device, thus increasing the detectability by the subject. Proportionally to the period of wear, the perceived discomfort regarding weight increases. In some applications (such as hormone monitoring), continuous real-time data may be required for a period of several weeks. When the device may need to be replaced several times during this period, the problem of the subject wearing a heavy device for a long time still exists.

[0010] A further problem occurs when the subject may be unsure whether the microneedles penetrate the skin properly in the first instance and further whether the microneedles remain properly embedded in the skin during the period. Prior art devices typically include a housing, the lower surface of which sits flush with the surface of the skin. Given the presence of the outer shell, it makes it difficult, if not impossible, for the user to see the surface of the skin and check whether the microneedles are properly embedded. If there is any doubt, the device may be removed and a new one applied to the skin. When the microneedles have been properly inserted, the replacement of the device may be wasteful.

[0011] In a microneedle-based biosensor device as described above, generally in these cases, problems arise in the temperature-dependent interaction of the target analyte with the working electrode. For example, the structure or configuration of the sensing element may be adjusted according to temperature, especially when the sensing element is a biomolecule such as a protein or nucleic acid. This change in structure or configuration may change the binding kinetic energy of the target analyte. When the sensing element is an enzyme, the catalytic rate reaction to temperature may increase or decrease.

[0012] In any case, the calibration curve or other criteria used to evaluate the sensor output will not provide a correct reference, as the criteria have been established at different temperatures at which the test samples were read at that time. Of course, an incorrect reference will be converted into an incorrect analyte concentration value.

[0013] The problem of temperature dependence may not occur in laboratory-grade analysis, when the temperature of the sample can be strictly controlled to be the same or similar to the temperature of the relevant standard.

[0014] However, in many applications, the sample temperature cannot be controlled and temperature dependence is very likely to exist between the standard and the test sample. A significant case is when the test sample is a biological fluid in situ. When the normal human body temperature is approximately 37.5 degrees Celsius, the human body temperature fluctuates significantly during the course of a day in an individual, with large variations observed during infection events or even in response to environmental temperature. Even, significant variations are observed between individuals under the same test conditions. It has been found that when the test sample is within the expected range of human body temperature changes, these changes are sufficient to cause the standard performed at 37.5 degrees Celsius to provide an incorrect output.

[0015] The prior art provides for the use of mathematical correction factors to calculate any temperature differences between a standard sample and a test sample. While these means are generally effective in improving the accuracy of sensor output, they still rely on the correct determination of the temperature of the test sample. Specific challenges arise when the test sample is in an in-situ biological fluid and accurate temperature readings are not easily obtained because the liquid is inaccessible to the temperature probe.

[0016] One aspect of the present invention provides an improved micro-needle-based biosensor over the prior art. This improvement may be in any one or more of detectability, size, weight, complexity, cost, the ability to monitor incorrect insertion, or accuracy. This improvement or these improvements may be provided by only one embodiment of the present invention. In some instances, the present invention may provide no improvement and instead only provide a useful alternative to prior art devices.

[0017] The discussion of documents, acts, materials, devices, articles and the like included in this specification is for the purpose of providing a context for the present invention only. It is not implied or represented that any or all of these matters form part of the basis of the prior art or are common general knowledge in the field related to the present invention because they existed prior to the priority date of each claim of this application. Summary of the Invention

[0018] In a first aspect, but not necessarily the broadest aspect, the present invention provides an electrochemical sensor device for long-term contacting one or more protrusions with a biological fluid or a tissue under the skin of a subject, the device comprising: one or more protrusions, each for penetrating the skin; a skin contact portion defining a skin contact surface and allowing one or more spaces for the one or more protrusions to extend therethrough; a movable portion for moving the one or more protrusions from a first position behind the skin contact surface to a second position protruding from the skin contact surface; optionally a maintaining portion for maintaining the skin contact surface in contact with the skin during use; and a thermal energy sensor for determining the temperature of the biological fluid or tissue when the one or more protrusions contact the biological fluid or tissue, wherein the movable portion is for moving from the first position to the second position.

[0019] In an embodiment of the first aspect, the movable portion moves along a generally arcuate path or along other types of non-linear paths.

[0020] In an embodiment of the first aspect, the movable portion has a connecting end and a free end.

[0021] In an embodiment of the first aspect, the free end moves a longer distance relative to the connecting end.

[0022] In one embodiment of the first aspect, the non-linear path is described with reference to the free end.

[0023] In one embodiment of the first aspect, the non-linear path is less than about 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, or 3 mm.

[0024] In one embodiment of the first aspect, the angular measurement of the arc is less than about 45 degrees, 40 degrees, 35 degrees, 30 degrees, 25 degrees, 20 degrees, 15 degrees, 14 degrees, 13 degrees, 12 degrees, 11 degrees, 10 degrees, 9 degrees, 8 degrees, 7 degrees, 6 degrees, or 5 degrees.

[0025] In one embodiment of the first aspect, the movable part has a pivot part, a hinge part, a bending part, or a joint part.

[0026] In one embodiment of the first aspect, the movable part is associated with a fixed part.

[0027] In one embodiment of the first aspect, in use, the fixed part is fixed, and the movable part is movable relative to the fixed part.

[0028] In one embodiment of the first aspect, the fixed part includes a part that allows the movable part to pivot, articulate, bend, or join.

[0029] In one embodiment of the first aspect, the fixed part is in a fixed spaced relationship with the skin contact surface.

[0030] In one embodiment of the first aspect, the spacing between the fixed part and the skin contact surface is less than about 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, or 2 mm.

[0031] In one embodiment of the first aspect, the fixed part is generally lateral to the movable part.

[0032] In one embodiment of the first aspect, the device further includes a user-activatable release part for maintaining the movable part in the first position until the user activates the release part, while the movable part is released and caused or allowed to move to the second position.

[0033] In one embodiment of the first aspect, the device includes a locking part for locking the movable part when in the second position.

[0034] In one embodiment of the first aspect, for the device to move the movable part from the first position to the second position, a motive force is required from within and / or outside the device.

[0035] In one embodiment of the first aspect, the motive power is derived from a spring, an elastically deformable component, a shape memory element, or other biasing means within the device; and the motive power is derived from a user outside the device.

[0036] In one embodiment of the first aspect, the device does not have an internal motive power generator for moving the movable part from the first position to the second position.

[0037] In one embodiment of the first aspect, the maintaining part is or includes a dermatologically acceptable composition located near or in contact with the skin contact surface.

[0038] In one embodiment of the first aspect, the dermatologically acceptable composition is an adhesive or a functionally equivalent thereof.

[0039] In one embodiment of the first aspect, the maintaining part is used to mechanically hold the skin contact surface in contact with the skin.

[0040] In one embodiment of the first aspect, the maintaining part is selected from any one or more of the following: a belt, a strip, a strap, a clip, a handle, a peg, a buckle, a sleeve, a housing, a sock, a glove, a cover, a cap, underwear, a singlet, a shirt, a bra, a top, trousers, a scarf, a ring, glasses, or a collar.

[0041] In one embodiment of the first aspect, one or more protrusions are mechanically directly or indirectly connected to the movable part.

[0042] In one embodiment of the first aspect, one or more protrusions are wires, needles, and / or microneedles.

[0043] In one embodiment of the first aspect, one or more protrusions form an array.

[0044] In one embodiment of the first aspect, one or more protrusions have a sufficient length to contact the epidermal layer, dermal layer, or hypodermal layer of the subject.

[0045] In one embodiment of the first aspect, the function of one or more protrusions during use is to: introduce current into the skin or conduct current out of or through the skin, introduce sound waves into the skin or conduct sound waves out of or through the skin, introduce light into the skin or conduct light out of or through the skin, introduce heat into the skin or conduct heat out of or through the skin, sample liquid or tissue from the skin, or deliver a bioactive substance to the skin, or introduce an analyte sensing substance to the skin.

[0046] In one embodiment of the first aspect, each of the one or more protrusions is a conductor, and the device further includes a circuit having a sound, visual, or tactile indicator, and the circuit is used to activate the indicator when the one or more protrusions contact a conductive liquid naturally present in the skin.

[0047] In an embodiment of the first aspect, the circuit includes at least two protrusions and the circuit is configured to be completed by contacting the conductive liquid naturally present in the skin through the at least two protrusions so as to actuating the indicator.

[0048] In an embodiment of the first aspect, the circuit includes a protrusion and at least one conductive pad is placed on the skin, and the circuit is used to complete electrical communication with the conductive liquid naturally present in the skin through the protrusion and the conductive pad to activate the indicator.

[0049] In an embodiment of the first aspect, the device includes a housing sized such that when the device is applied to the skin and the movable part is in the second position, and any part of each one or more protrusions protruding from the skin contact surface is embedded in the skin, the housing extends over most or substantially all of the skin, no more than about 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm.

[0050] In an embodiment of the first aspect, a long time is greater than about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours or 96 hours.

[0051] In an embodiment of the first aspect, the device is configured such that the one or more protrusions are inseparable from the device, or inseparable without the assistance of tools.

[0052] In an embodiment of the first aspect, the movable part and the fixed part are integral.

[0053] In an embodiment of the first aspect, the integral movable part and the fixed part are made of an elastically deformable material.

[0054] In an embodiment of the first aspect, the integral movable part and the fixed part are part of the circuit board of the device.

[0055] In an embodiment of the first aspect, the movable part is biased towards the second position and maintained in the first position, through the user-activatable release part resisting the bias until the release part is activated, at which time the movable part is released and allowed to move to the second position.

[0056] In an embodiment of the first aspect, the user-activatable release part is a flange for holding the movable part in the first position, and the flange and / or the movable part is deformed by the driving force provided by the user to allow the movable part to be released from the flange and move to the second position.

[0057] In an embodiment of the first aspect, the movable part is hingedly associated with the skin contact part.

[0058] In an embodiment of the first aspect, the hinge is located at or towards the peripheral region of the movable part and the skin contact part.

[0059] In an embodiment of the first aspect, the release part includes components for maintaining the movable part in a first position, but which are removable or deformable by the user to allow the movable part to move to a second position.

[0060] In an embodiment of the first aspect, the components are removable by sliding generally across the skin contact part.

[0061] In an embodiment of the first aspect, the components are generally wedge-shaped, and the device includes a hinge to associate the movable part with the skin contact part, with the thin part of the wedge being located approximately at the hinge and the thick part of the wedge being located remotely from the hinge.

[0062] In an embodiment of the first aspect, the release part is removable from the device and includes a handle to assist with manual removal.

[0063] In an embodiment of the first aspect or the third aspect, one or more protrusions have analyte detection elements associated with the one or more protrusions.

[0064] In an embodiment of the first aspect or the third aspect, one or more protrusions are configured to act as working electrodes.

[0065] In an embodiment of the first aspect or the third aspect, one or more protrusions have a reference solution in electrical communication therewith and are used to act as reference electrodes.

[0066] In an embodiment of the first aspect or the third aspect, one or more protrusions are configured to act as counter electrodes to the working electrodes.

[0067] In an embodiment of the first aspect or the third aspect, one or more protrusions are specifically configured to determine the temperature of biological fluid or tissue around the one or more protrusions when the one or more protrusions are inserted into the skin of a subject.

[0068] In an embodiment of the first aspect or the third aspect, the device includes a thermal insulation material for retaining thermal energy within the one or more protrusions.

[0069] In an embodiment of the first aspect or the third aspect, the thermal insulation material surrounds a terminal portion of the one or more protrusions, the terminal portion being distal to a portion of the one or more protrusions inserted into the skin.

[0070] In an embodiment of the first or third aspect, the thermal insulation material forms a cover over a terminal portion of one or more protrusions, which is distal to a portion of one of the one or more protrusions inserted into the skin.

[0071] In an embodiment of the first or third aspect, the thermal insulation material surrounds the thermal energy sensor and one or more protrusions.

[0072] In an embodiment of the first or third aspect, at least a portion of the one or more protrusions is made of metal, metal alloy, metal composition, or ceramic.

[0073] In an embodiment of the first or third aspect, the metal, metal alloy, metal in the metal composition, or ceramic has a thermal conductivity k of at least 200, 300, or 400 W / mK.

[0074] In an embodiment of the first or third aspect, the metal, metal alloy, or metal in the metal composition is or includes any one or more of copper, steel, silver, nickel, tin, zinc, lead, aluminum, and silicon.

[0075] In an embodiment of the first or third aspect, the thermal energy sensor is used to detect thermal energy in one of the one or more protrusions.

[0076] In an embodiment of the first or third aspect, the thermal energy sensor is applied to or directly oriented towards one or more protrusions.

[0077] In an embodiment of the first or third aspect, the thermal energy sensor contacts one or more protrusions or is otherwise in thermal communication therewith.

[0078] In an embodiment of the first or third aspect, the thermal communication is through a thermally conductive flowable substance located between the thermal energy sensor and one of the one or more protrusions.

[0079] In an embodiment of the first or third aspect, the thermal energy sensor is a thermocouple, a thermistor, or an infrared sensor.

[0080] In an embodiment of the first or third aspect, one of the one or more protrusions forms part of a thermocouple or a thermistor.

[0081] In an embodiment of the first or third aspect, the one or more protrusions include a cavity.

[0082] In an embodiment of the first or third aspect, at least a portion of the thermal energy sensor is located within the cavity or acts at least in part through the cavity.

[0083] In an embodiment of the first aspect or the third aspect, the cavity holds a thermally conductive flowable substance to form thermal communication between the thermal energy sensor and the surface of the cavity.

[0084] In an embodiment of the first aspect or the third aspect, the thermal energy sensor is used to detect the thermal energy of tissue adjacent to one of the one or more protrusions.

[0085] In an embodiment of the first aspect or the third aspect, the thermal energy sensor is applied or directly oriented towards the skin surface.

[0086] In an embodiment of the first aspect or the third aspect, the thermal energy sensor contacts the skin or otherwise has thermal communication with the skin.

[0087] In an embodiment of the first aspect or the third aspect, the thermal communication is through a thermally conductive solid material that has thermal communication with the thermal energy sensor on a first side and with the skin on a second side.

[0088] In an embodiment of the first aspect or the third aspect, the thermally conductive solid material is metal or plastic, or plastic with a filler.

[0089] In an embodiment of the first aspect or the third aspect, the filler is graphite, graphene, carbon fiber, or other carbon-based material.

[0090] In an embodiment of the first aspect or the third aspect, the thermally conductive solid material has a thickness less than about 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm.

[0091] In an embodiment of the first aspect or the third aspect, the thermal energy sensor is a thermocouple, a thermistor, or an infrared sensor.

[0092] In an embodiment of the first aspect or the third aspect, the one or more protrusions and the thermal energy sensor are included in a housing or otherwise associated with the housing.

[0093] In an embodiment of the first aspect or the third aspect, the analyte detection element is an aptamer.

[0094] In an embodiment of the first aspect or the third aspect, an oxidation-reduction active species associated with the aptamer is included and is used to act as a reporter for the interaction of the target analyte with the aptamer.

[0095] In a second aspect, the present invention provides a method for bringing one or more protrusions of an electrochemical sensing device into contact with a biological fluid or tissue under the skin of a subject. The method includes the steps of providing a device according to any embodiment of the first aspect, bringing the skin contact surface of the device into contact with the subject, and causing or allowing the movable part to move from a first position to a second position, and causing or allowing a thermal energy sensor to determine the temperature of the biological fluid or tissue.

[0096] In one embodiment of the second aspect, the device is maintained in contact with the skin for a period greater than about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, or 96 hours.

[0097] In a third aspect, the present invention provides an electrochemical sensor device for bringing one or more protrusions into contact with a biological fluid or a tissue under the skin of a subject. The device includes: one or more protrusions, each for penetrating the skin; a skin contact part, defining a skin contact surface and one or more spaces allowing the one or more protrusions to extend therethrough; a movable part for moving the one or more protrusions from a first position behind the skin contact surface to a second position protruding from the skin contact surface; a maintaining part for maintaining the skin contact surface in contact with the skin during use; a user-activatable release part for maintaining the movable part in the first position until the user activates the release part, while the movable part is released and caused or allowed to move to the second position; and a thermal energy sensor for determining the temperature of the biological fluid or tissue when the one or more protrusions are in contact with the biological fluid or tissue.

[0098] In one embodiment of the third aspect, the release part includes components for maintaining the movable part in the first position, but which are removable or deformable by the user to allow the movable part to move to the second position.

[0099] In one embodiment of the third aspect, the components are removable by sliding substantially across the skin contact part.

[0100] In one embodiment of the third aspect, the components are substantially wedge-shaped, and the device includes a hinge connecting the movable part to the skin contact part, with the thin part of the wedge approximately located at the hinge and the thick part of the wedge located remotely from the hinge.

[0101] In one embodiment of the third aspect, the release part is removable from the device and includes a handle to assist in manual removal.

[0102] In a fourth aspect, the present invention provides a method of bringing one or more protrusions into contact with a biological fluid or tissue under the skin of a subject, the method comprising the steps of providing a device according to any embodiment of the third aspect, bringing the skin contact surface of the device into contact with the subject, and activating a user-activatable release portion to cause or allow a movable portion to move from a first position to a second position, and causing or allowing a thermal energy sensor to determine the temperature of the biological fluid or tissue.

[0103] For a better understanding of the above and other aspects of the present invention, the following specific embodiments are given and described in detail in conjunction with the accompanying drawings as follows: Description of the Drawings

[0104] FIG. 1 shows a height schematic and side view of the microneedle insertion device of the present invention. This embodiment is based on a biasing means to provide motive force for the insertion of the microneedles into the skin. The arm 20a shown in the first position, as it appears to the user, and its position 20b when the microneedles are inserted into the skin. The curvature of the movable arm is shown as deliberately exaggerated to better illustrate the operation of the embodiment as a whole. While this curvature will be operable (and thus not excluded from the scope of the present invention), this curvature will generally be on a materially lower scale.

[0105] FIG. 2A shows a further height schematic and side view of the microneedle insertion device of the present invention. This embodiment is based on the user providing motive force for the insertion of the microneedles into the skin. The arm 205a shown in the first position, as it appears to the user, and its position 205b when the microneedles are inserted into the skin.

[0106] FIG. 2B shows a variation of the embodiment of FIG. 2A without the upper housing.

[0107] FIG. 3A shows a top view of an embodiment of the present invention using a printed circuit board (PCB) as a biasing means to provide motive force for the insertion of the microneedles into the skin. The arm 20 shown in the first position, as it appears to the user, and before the microneedles are inserted into the skin.

[0108] FIG. 3B shows a bottom view of the embodiment of FIG. 3A.

[0109] FIG. 4 shows a top view of the microneedle insertion device of the present invention. This embodiment is based on the user providing motive force for the insertion of the microneedles into the skin. The arm shown in the first position, as it appears to the user, and before the microneedles are inserted into the skin.

[0110] FIG. 5A shows a bottom view of the embodiment of FIG. 4.

[0111] FIG. 5B shows a top view of the embodiment of FIG. 4.

[0112] Figure 6 shows a bottom view of the embodiment of Figure 4 with the removable elastomeric layer moved to expose the dermatologically acceptable adhesive more fully.

[0113] Figure 7 shows a bottom view of the microneedle insertion device of Figure 4 with the removable elastomeric layer moved to expose the dermatologically acceptable adhesive.

[0114] Figure 8 shows a bottom view of the microneedle insertion device of Figure 7 with the microneedles in the extended position as required for insertion into the skin of a subject.

[0115] Figure 9 shows a further microneedle device of the present invention incorporating a temperature sensor. This device is further adapted to prevent outward extension of the microneedles until the device is applied to the skin surface. The central region of the figure shows a side view of the components of the device and in the deployed form. Each component is shown in perspective in the peripheral region of the illustration.

[0116] Figure 10 shows a schematic and sectional view of a needle of the present invention having an associated temperature sensor in the form of a thermistor or thermocouple in contact with the needle.

[0117] Figure 11 shows a schematic and sectional view of a needle of the present invention having an associated temperature sensor in the form of an infrared sensor directed towards the needle.

[0118] Figure 12 shows a schematic and sectional view of a needle of the present invention having an associated temperature sensor in the form of a thermistor or thermocouple in contact with the needle and an isolation cover covering the needle and the temperature sensor.

[0119] Figure 13 shows a schematic and sectional view of a needle of the present invention having an associated temperature sensor in the form of an infrared sensor directed towards the needle and an isolation cover covering the needle but having a window formed therein to allow the target surface of the needle to be exposed.

[0120] Figure 14 shows a schematic and sectional view of a needle of the present invention having a cavity in which a temperature sensor in the form of a thermistor or thermocouple is located.

[0121] Figure 15 shows a schematic and sectional view of a needle of the present invention having a needle acting as the first metal in a thermocouple and a needle extending through the cavity to act as the second metal in the thermocouple.

[0122] Figure 16 shows a schematic and sectional view of a wearable device incorporating an electrochemical sensor and a temperature sensor.

[0123] Figure 17 shows a schematic diagram of the basic circuit of an electrochemical sensor having a temperature sensor providing input to a processor for determining the concentration of a target analyte.

[0124] Unless otherwise specified herein, when used in different figures, features of figures labeled with the same number are considered to be the same features, or at least features that are functionally similar.

[0125] The figures are not prepared in accordance with any specific scale or size and do not provide a completely accurate representation of several embodiments. Detailed Description

[0126] After considering this specification, those of ordinary skill in the art will clearly understand how the present invention can be implemented in several alternative embodiments and alternative applications. However, although several embodiments of the present invention will be described herein, it will be understood that these embodiments are presented only by way of example and are not to be considered limiting. As such, the description of several alternative embodiments should not be construed as a limitation on the scope and breadth of the present invention. Furthermore, the description of advantages or other aspects applies to specific exemplary embodiments and does not necessarily apply to all embodiments, or any embodiments that are actually covered by the claims.

[0127] In all descriptions of this specification and the claims, the word "comprise" and variations of this word, such as "comprising" and "comprises", are not intended to exclude other additives, components, integers, or steps.

[0128] References throughout this specification to "one embodiment" or "an embodiment" mean that the particular features, structures, or characteristics described in connection with the embodiment are included in at least one embodiment of the present invention. Thus, the phrases "in one embodiment" or "in an embodiment" that appear in several places throughout this specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment.

[0129] As used herein, positional terms such as "lateral", "across", "above", "over", "below", "higher", "lower", "upward", "downward", "plan view", and others are considered with reference to the device of the present invention, such as the upper surface of a human thigh when a human is sitting on a chair. It can be understood that the regions of the skin to which this device can be applied have different orientations with respect to the upright direction, and are only defined in cases where those of ordinary skill in the art are fully enabled to reassign the foregoing positional terms.

[0130] The term "subject" is used to refer to an animal (including a human or non-human animal) to which the present device may be applied. The term "user" is used to refer to a human who applies the device to a human or non-human animal. The subject and the user may be the same human subject, but this is not necessarily the case.

[0131] "Biological fluid" can be any biological fluid of the subject, including but not limited to interstitial fluid, blood, saliva, lacrimal secretions, lactation secretions, nasal secretions, tracheal secretions, bronchial secretions, alveolar secretions, gastric secretions, gastric contents, glandular secretions, vaginal secretions, uterine secretions, prostatic secretions, semen, urine, sweat, cerebrospinal fluid, glomerular filtrate, hepatic secretions, bile or exudates, any of the above biological fluids contacting the needle electrode of the in-vivo electrochemical sensor during use. "Tissue" includes a volume having one or more cells.

[0132] Unless the contrary intention is apparent from the context in which it is used, the terms "needle", "microneedle" and "wire" may be used interchangeably. They are each functionally the same or similar and can be inserted into the skin of the subject to contact biological fluid or tissue.

[0133] Various different embodiments of the present invention are disclosed herein (whether through the drawings or written description), these embodiments having one or more features disclosed in their context. It is understood that it is not intended to limit the application to the specific features or combinations of features used in the disclosed embodiments. For example, a first embodiment may be disclosed as including features A and B, while a second embodiment is disclosed as including features C and D. It is intended to include embodiments having any possible combination of any one, two, three or four of the features A, B, C and D within the scope of the present invention.

[0134] However, certain combinations are disadvantageous or actually inoperable, which will be apparent to those skilled in the art. For example, when feature B requires feature A to operate, an embodiment including the combination of features B, C and D may not function.

[0135] The present invention is at least in part described as the discovery of an improved or alternative sensor device, wherein a temperature sensing function is provided to improve the accuracy of the device output. Further details of the temperature sensing function are provided below.

[0136] The device includes a movable part that urges the microneedles into the skin of a subject and moves along a non-linear path. Additionally, the non-linear path can be of a finite length and be an arc with a finite angle. Through this configuration, the main moving part of the device only needs to have a limited range of motion in the vertical direction to press and insert the microneedles into the skin of the subject. When viewed laterally, the limited range of motion allows the housing of the device to present a relatively low-profile appearance. Thus, the device protrudes a relatively low height above the skin and is therefore less obtrusive to the subject.

[0137] Furthermore, the non-linear path of the movable part allows for the use of simplified mechanisms. For example, the movable part can be moved by means of simple bending or hinging mechanisms. These mechanisms require a relatively small number of components, allowing for the development of a device that is overall smaller, lighter, simpler, more reliable, and less expensive.

[0138] Specific embodiments of the present invention have further features which, when taken alone or in combination with other features, provide further advantages or further useful alternatives to the prior art. This embodiment will be fully described by reference to the non-limiting preferred embodiments described below.

[0139] Referring to FIG. 1, there is shown the basic form of the device 10 having a microneedle array (designating a microneedle 15) engaged to a movable part. The movable part in this embodiment is an elastically deformable arm 20. The arm 20 is biased to assume a linear position 20b, although it is initially presented to the user as the arm 20a bent upward as represented by the dashed line.

[0140] The device 10 includes a rigid housing 25 having a skin contact portion 30 on its lower side, defining a downward-facing skin contact surface 35. The surface 35 is placed on the skin of the subject and is held thereon by dermatologically acceptable adhesives 40a and 40b. Suitable adhesives are typically waterproof to allow the subject to bathe normally. The adhesives generally have sufficient tack to limit separation caused by daily activities such as dressing, undressing, sleeping, doing housework, light to moderate-intensity exercise, rubbing against objects while walking, and others similar. The strength of the adhesives is generally not too high to cause any difficulty, unpleasant sensation, pain, annoyance, or skin damage upon removal of the device.

[0141] Example adhesives are synthetic rubber adhesives or pressure-sensitive acrylic adhesives used for medical tapes. A medical double-sided tape can be used, such as 3M TM 1577 tape, with one side adhered to the device and the other side adhered to the skin of the subject.

[0142] The skin contact portion 30 includes a space 45, the edges of which are designated as edges 45a and 45b. The space 45 provides a corresponding passage for the microneedles 15 to pass through, allowing the terminal region of the microneedles to pass through and embed into the underlying skin 50 when the arm 20 is in the linear position 20b.

[0143] The arm 20 is maintained in a bent state by the flange 55 which acts as a release means. When the user wishes to insert the microneedle 15 into the skin 50, the button 60 is pressed as shown by the arrow. The lower surface of the button 60 abuts against the flange 55, and since the flange 55 has some ability to deform (made of a rubber-like material or formed by an elastic protrusion from the inner surface of the exemplary housing 25), it bends downward under the force to release the edge of the arm 20a. The elastic properties of the arm 20a cause it to quickly return to its biased position 20b, thus applying a force to the microneedle 15 to enter the underlying skin 50. The flange 55 is used to exhibit sufficient elasticity to resist the biasing force of the arm 20a, however its elasticity is not sufficient to resist the downward force applied when the button 60 is pressed.

[0144] In the embodiment of FIG. 1, the arm 20 is fixed to the housing 25 at one end by a fastener 5. When the arm 20 is elastic, the elasticity is not too strong such that it easily moves away from the position 20b when on the subject's skin 50. It can be appreciated that any movement of the arm 20 away from the position 20b may cause the microneedle 15 to be withdrawn from the skin 50. Considering the biasing of the arm 20 towards the position 20b, it may not require a locking mechanism to hold the arm in the position 20b. However, if a suitable locking mechanism is desired, it is described below in the embodiment of FIG. 2A.

[0145] FIG. 2A shows an alternative basic form of the device 200, where the arm 205 is rigid and hinged to the housing 25 by a hinge pin 210. The embodiment of FIG. 2A operates similarly to the embodiment of FIG. 1, with the flange 55 acting as the release means. However, in the embodiment of FIG. 2A, the button 215 acts on the rigid arm 205a. The rigid arm 205 transmits the force of the button to the deformable flange 55, causing the flange 55 to bend and thus release the free end of the arm 205a. The button 215 is continuously pressed by the user until the arm reaches the position 205b, and at this position the microneedle 15 is embedded in the skin 50. Again, a point on the free end of the arm 205a moves along a non-linear path, which in this embodiment is an arc, a segment of a circle with the center located at the hinge pin 210.

[0146] It will be appreciated that when the device is worn, the articulated configuration of the embodiment of FIG. 2A provides no resistance to the arm 205 pivoting away from the pivoted-away position 205b. The microneedles 15 are withdrawn from the skin 50 while remaining in place, thus presenting a danger. Accordingly, a locking mechanism is provided to maintain the arm in the position 205b. The mechanism includes a deformable latch 220, for example made of a partially elastic material or formed by an inward projection from the material of the housing 25. The latch 220 has an inclined upper surface, and when in contact with the rigid arm 205, the entire latch 220 is forced to bend to the left (as shown) when a force is applied by the user through the button 215 and the inclined upper surface. When the terminal of the arm 205 passes under the lower corner of the inclined upper surface, the latch 220 returns to its normal upright position (as shown), and the free end of the arm 205 is fixedly located in the groove at the base of the latch 220.

[0147] An alternative to the embodiment of FIG. 2A is shown in FIG. 2B. In FIG. 2B, the device 200 does not have an upper housing. The arm 205a is removable by the user through a release means such as a flange 55, in this embodiment when the device 200 is applied to the subject. After removing the release means such as the flange 55, the arm 205 is pressed downward by the user so that it reaches the position 205b.

[0148] It is worth noting that in the embodiments of FIGS. 1, 2A, and 2B, when released from the flange 55, the free end of the arm 20 or 205 moves in a non-linear manner to return to its biased position 20b. If a single point on the free end of the arm 20 or 205 is considered, the movement of this point along the non-linear path is described as arcuate. In the context of the present invention, the terms "arc", "arcuate", and other similar terms refer to a curve joining two points. The term "arc" should not be construed restrictively as meaning only a segment of a circle, although in some embodiments it is a segment of a circle (e.g., referring to the embodiment of FIG. 2A).

[0149] It can be clearly seen from the basic embodiments of FIGS. 1, 2A, and 2B that in each case, when transferred from the first position to the second position, the arm 20 or 205 moves a relatively small distance. In fact, in these embodiments (and certain other embodiments), the device is intentionally configured such that the arm cannot move along any path other than between the first and second positions. That is to say, the device can be configured such that the arm cannot move along any path other than the shortest distance between the first and second positions.

[0150] By restricting the path along which the arm can move, the height of the device (as shown in the vertical direction) is also restricted, which provides an advantage here. Accordingly, the device can present a low profile (in terms of size perception) and extend a relatively short distance over the subject's skin.

[0151] Referring now to FIGS. 3A and 3B, there is shown a preferred apparatus having generally the same construction and the same operation as FIG. 1. The arm is integrally formed with the PCB 65, which carries a variety of electronic components required for the operation of the device. The PCB material is elastically deformable, allowing the arm (with the terminal engaging the microneedle) to bend upward, such as when the arm is positioned in the first position, but when released, it reaches the second position due to the biasing characteristic towards the second position in the arm.

[0152] The arm 20 is held in the first position through the terminal of the arm 20 on the flange 55, as most clearly shown in FIG. 1A. In this position, the microneedle 15 is maintained within the device, with no part extending out of the space 45. The device is provided in this configuration for use, and in this configuration, the device is applied to the skin of the subject.

[0153] The arm 20 is connected to the microneedle and supports the microneedle at the fixed block 70. The fixed block 70 also includes conduits (not shown in the figure) to carry current from each microneedle 15 to one of several connection points 75 on the PCB 65. Through this configuration, electrical signals can be transmitted to and / or from the microneedles embedded in the skin of the subject. For example, the device can be used as a sensor with the microneedles to contact biological fluids or tissues in the body of the subject to detect analytes therein. The biological fluid can be, but is not limited to, interstitial fluid, blood, or a mixture thereof. The electrical signals are transmitted from the microneedles to the PCB for amplification, filtering, encoding, analysis, transmission, or other electrical or electronic processing.

[0154] In this embodiment, the PCB provides a dual function of carrying the electronics of the device and also serving as a means of moving the microneedles from a position within the device to a position outside the device. The PCB material has been found to be well-suited to provide a limited range of better movement to the arm of the device. Through this configuration, the number of components in the device is reduced.

[0155] The upper surface of the housing 25 presents an arcuate surface of the button 215, which is pressable through the finger of the user. The button 215 is biased upward (as shown) through a spring or because it is integrally formed in the housing 25 material. In the latter form of biasing, the button 215 can be fixed to the arm, integrated in the housing material and biased such that the upper surface of the button 215 is coplanar with the housing 25.

[0156] The lower part (not visible) of the button 215 abuts against the upper surface of the arm 20, which is the rear surface of the PCB 65, such that pressing the button 215 causes the arm 20 to move downward to release from the flange 55 and reach the second position. In the second position, it can be understood that the microneedles will extend through the corresponding space 45 and embed into the underlying skin (such as the epidermis, dermis, or hypodermis of the subject).

[0157] The biasing characteristic of the PCB 65 material towards the second position is strong enough for the arm such that it remains in the second position without the need for any means of locking the arm in the second position. Accordingly, the microneedles 15 can be maintained embedded in the subject's skin for an extended period of time.

[0158] In an alternative embodiment, the arm 20 has a curved configuration when in the second position and is naturally biased away from the second position. In another embodiment, the biasing of the arm 20 towards the second position is not strong enough to prevent any movement away from the second position. In this embodiment (and in many other embodiments), a locking mechanism can be provided to prevent movement away from the second position, such that the microneedles 15 do not retract back into the device and remain inserted in the skin. Suitable locking mechanisms are the latch mechanisms associated with many other embodiments as described herein. Other locking mechanisms will be apparent to those of ordinary skill in the art with the benefit of the present invention.

[0159] The housing 25 includes opposing depressions 80 to facilitate gripping between the user's thumb and forefinger and to hold the device against the skin surface. The user's thumb can freely activate the button 215 to embed the microneedles 15 into the underlying skin.

[0160] The skin contact surface 35 can have a dermatologically acceptable adhesive layer (not shown in the figures) applied thereto to hold the device in place on the subject's skin for an extended period of time. The adhesive layer can cover some or substantially all of the skin contact surface 35. A manually releasable elastomeric layer can cover the adhesive until the device is applied to the skin, as described for other embodiments of the device herein.

[0161] Now referring to FIGS. 4, 5A, 5B, 6, and 7, which illustrate a preferred device construction and operation that is generally the same as the embodiment of FIG. 2B.

[0162] This embodiment includes an upper housing 25 and a skin contact portion 30. A removable elastomeric layer 90 is also provided and is graspable by means of a tab 95. Removal of the removable elastomeric layer 90 exposes the dermatologically acceptable adhesive on the skin contact surface 35. As explained above, the adhesive is for the purpose of holding the device on the subject's skin for an extended period of time. The elastomeric layer 90 serves to prevent the adhesive from curing or drying out and to prevent contamination of the adhesive layer by cured or dried adhesive, and from premature bonding of the adhesive to the packaging or other surfaces prior to use. Particularly in the preferred embodiment, in addition to covering the adhesive layer, the elastomeric layer 90 extends over the space 45 to prevent contamination of the microneedles 15 and also helps to prevent accidental needle stick injuries to the user.

[0163] The device can have a retention portion that serves to retain the device on the skin such that the protrusions maintain contact with the subject's biological fluid or tissue. The retention portion can be dedicated to this function or can perform other functions.

[0164] Among the numerous results, it would be useful for the retention portion to be or include a dermatologically acceptable adhesive. The adhesive allows for the simplification of the device application by the user, typically only requiring the removal of the protective backing to expose the adhesive and then contacting the exposed adhesive to the skin. This method of application is similar to the application of a sticking plaster and is a process already familiar to the user.

[0165] As an alternative to the use of an adhesive, the retention portion can be some mechanical means to maintain the device in the desired position on the skin. For example, the device can include a dedicated strap contacting the limb, which is adjustable to keep the device firmly applied to the subject. Alternatively, the device can cooperate with a wearable item, such as a glove or a shirt, or a jewelry item such as a ring, which serves to maintain the device in position. The device can be used to engage and disengage the wearable item (e.g., through interlocking hook and loop means), or can be integrated into the wearable item.

[0166] In some embodiments, the device is simply retained against the housing by a wearable item. For example, the retention portion can be a tightly fitting elastic glove worn over the device.

[0167] In some embodiments, the retention portion is any surface or part of the device contacting the subject's skin, with the characteristics of the subject being at least partially responsive to maintaining the device in position on the subject. For example, the device can be used to be retained between two normally closely juxtaposed parts of the body, or retained within an existing anatomical structure. The shape and / or size of the device is defined to be retained between the toes, between the buttocks, in the groin, in the buccal cavity, in the nostrils, in the ear canal, or in the navel.

[0168] In a number of other embodiments, the shape and / or size of the device housing is defined to fit closely, for example, to a finger, a toe, or an ear. The device housing can be elastically deformable, for example, a combination of rubberized materials, and is used to be stretched over any anatomical part (such as a finger).

[0169] Each of the foregoing embodiments is considered to be a retention portion within the context of the present invention.

[0170] The device further includes a release assembly 100, having a gripping portion 105 and a wedge portion 110, the functions of which will be described more fully below.

[0171] Now referring to the exploded views of FIGS. 5A and 5B, components similar to those in the previous figures will be immediately apparent.

[0172] In this embodiment, the driving force that causes the microneedles 15 to penetrate the underlying skin is provided by the user's driving force responsible for moving the arm 205. In use, the user places a finger on the upper housing 25 and pushes downward. Further, the arm 205 is movable through a hinged configuration.

[0173] The articulated configuration is provided through opposing lugs 115 extending from the skin contact portion 30, each lug including an opening. The arm 205 includes opposing laterally extending disks 122, each disk being located within the opening of a respective lug 115. The visible arm 205 is pivotally hinged relative to the skin contact portion 30 to permit movement from a first position to a second position.

[0174] The arm 205 presented to the user has the arm in the first position. The arm 205 is held in the first position by the wedge portion 110 of the release assembly 100. Prior to removal of the release assembly 100, the wedge portion is inserted between the skin contact portion 30 and the arm 205, thereby retaining the microneedles within the device.

[0175] When intending to apply the device to the skin of a subject, the user removes the elastic layer 90 by pulling on the tab 95 to expose the adhesive layer at the skin contact surface 35. The device is then applied to the skin, with the adhesive maintaining it in place over time.

[0176] Once the device is applied to the skin, the user grasps the gripping portion 105 and pulls laterally to the left (as shown) to completely remove the release assembly 100. The release assembly 100 has no further function and is discarded at this time. By removing the release assembly 100, the arm 205 is released from the first position and is permitted to move (under the downward force applied by the user) to the second position, such that the lower surface of the arm 205 contacts the upper surface of the skin contact portion 30. In the second position, the microneedles 15 extend through the space 45 and into the underlying skin.

[0177] It will be understood that the release assembly 100 can be used to prevent the upper housing 25 of the device from closing onto the skin contact portion 30 when the user does not intend it to. The release assembly 100 is inserted or otherwise positioned between the upper housing 25 and the skin contact portion 30 to prevent the upper housing 25 from closing towards the skin contact portion 30 sufficiently to permit the tip (e.g., projection) of the microneedles to project from the bottom of the opening in the skin contact portion 30. Preventing closure also prevents the arm 205 from moving from the first position to the second position. Thus, when the release assembly 100 is in position, the tip of the microneedles cannot be inadvertently touched to cause microneedle contamination or injury. When using the device, as a step in the usage process, the user removes the release assembly 100. In a preferred embodiment of device use, the user first adheres the device to the skin of the subject and then removes the release assembly 100 before pressing on the upper housing 25 to insert the microneedles into the skin.

[0178] Before being removed by the user, the release assembly 100 is maintained in position by any of a variety of features. In one example, the release assembly 100 includes a protrusion adapted to fit into a groove in the upper housing 25, the skin contact portion 30, or both the upper housing 25 and the skin contact portion 30 to help maintain it in position until intentionally removed. In another example, the release assembly 100 is designed to be slidably assembled to the skin contact portion 30 or the upper housing 25, and the frictional force between the release assembly 100 and the upper housing 25 or the skin contact portion 30 helps to keep it in position until intentionally removed. In yet another example, magnetic force can be used to help hold the release assembly 100 in position. In one embodiment of the present invention, when the release assembly 100 is in position, the magnet fixed within the release assembly 100 is positioned such that it is close to a Hall effect sensor located in the upper housing 25 or the skin contact portion 30. According to this embodiment, when the release assembly 100 is removed by the user, the Hall effect sensor detects the removal of the magnet, causing some actuation of the device, such as powering on an electronic circuit ready for use and switching it from a sleep mode to a startup mode. It should be understood that the foregoing are examples of possible methods for helping to hold the release assembly 100 in position before intentional removal, which may be used alone or in combination, and other known methods in the art may also be used alone or in combination in a given example.

[0179] In some embodiments of the present invention, the release assembly 100 can also act as a covering assembly for covering the microneedles after the device has been removed from the subject. In a preferred example of this embodiment, a locking assembly is located on the upper housing 25 and extends downwardly towards the skin contact portion 30. The release assembly 100 includes a groove that allows the release assembly 100 to slide over the locking assembly while maintaining the surface of the release assembly 100 continuously flush with the upper surface of the skin contact portion 30 when the release assembly 100 is withdrawn from the device. In use, according to this preferred embodiment, the release assembly 100 is removed by the user before pressing the upper housing 25 to insert the microneedles into the subject's skin and while being held by the user. After removing the device from the subject after use, the user is instructed to adhere the release assembly 100 to an adhesive layer on the lower surface of the skin contact portion 30 to cover the protruding microneedles. In another example of this embodiment, the release assembly 100 is elastically engaged to the device such that the release assembly 100 can remain engaged to the device after it has been withdrawn by the user, and after the device has been removed from the subject after use, the release assembly 100 is then repositioned to cover the protruding microneedles. In yet another example of this embodiment, the release assembly 100 and the upper housing 25 are designed such that once the release assembly 100 is removed, the release assembly 100 can be slidably or otherwise engaged to the upper housing 25, where it is intended to be stored on the device during use and removed as a covering assembly after the device has been removed from the subject.

[0180] In some embodiments, the device is configured to assist the user in removing the device from the subject. It will be appreciated that the use of an adhesive layer may make it difficult to remove the device from the skin. Examples of such configurations include leaving a portion of the skin contact surface 35 uncoated with adhesive, creating a gap between the subject's skin and the surface 35, where the user uses the gap as a leverage point to assist in pulling the device away from the skin by breaking the adhesive bond. In another example, a lever mechanism that is not located on the skin contact surface is added to allow for a greater gap than that created by having no adhesive on a portion of the skin contact surface. In yet another example, a tab that extends beyond at least one edge of the skin contact portion 30 and engages the adhesive layer may be added, where the user pulls the tab with sufficient force to cause the adhesive layer to stretch and soften, further causing the adhesive to peel away from the skin contact surface 35 and the skin.

[0181] In some embodiments of the present invention, the device is designed such that the release assembly 100 is locked in position prior to use of the device, unless pressure is applied to the upper housing 25. This embodiment is intended to further reduce the risk of the release assembly 100 being prematurely withdrawn. In an example of this embodiment, features on the release assembly 100 and on at least one of the upper housing 25 and the skin contact portion 30 are configured to be locked in engagement when the upper housing 25 is not pressed down. When the upper housing 25 is pressed, features on at least one of the upper housing 25 and the skin contact portion 30 are deformed such that the release assembly 100 is disengaged and allowed to be withdrawn.

[0182] In still other embodiments, the release assembly 100 does not need to be removed from the device by the user. According to these embodiments, the release assembly 100 includes an elastic component with a high enough rigidity such that when subjected to closing forces that may occur during manufacturing, storage, and in the user's hand prior to application to the subject, the release assembly 100 does not substantially deflect, but has enough elasticity that it deflects when the user intends to apply a closing force to the device when the device is applied to the subject's skin. During this bending, the release assembly 100 is deflected, allowing the upper housing 25 to close towards the skin contact portion 30. In these embodiments, the release assembly 100 can also act as a locking assembly, or the release assembly 100 can be separated from the locking portion. In a portion of these embodiments, a feature labeled as latch 220 in FIGS. 5A, 5B, and 7 forms the release assembly 100.

[0183] The dimensions of each space 45 of the device are defined such that the microneedles can extend therethrough unobstructed, and at least one tapered portion of the microneedles does not impact the side of the opening during insertion. In some embodiments, the opening may have a sufficient cross-section such that no portion of the microneedles contacts the side of the space during insertion. In other embodiments, at least a portion of the opening along its length will have a cross-section such that a portion of the length of the microneedles contacts the side of the opening during insertion. According to this embodiment, the opening serves to support a portion of the length of the microneedles to help prevent the microneedles from bending during insertion.

[0184] In some embodiments of the device, the skin contact portion 30 includes a further space or recess for receiving a protrusion on the release assembly to help maintain the release assembly until it is removed by the user. Additionally or alternatively, the skin contact portion 30 includes a protrusion designed to be received in a groove in the release assembly to help maintain the release assembly in position until intentionally removed by the user.

[0185] The embodiments shown in FIGS. 4, 5A, 5B, 6, and 7 include a locking portion in the form of a latch 220 that will permanently lock the permanent locking arm 205 in the second position, preventing the arm 205 from moving in any hinged manner. In the shown embodiment, the latch 220 is a simple one-piece assembly that is capable of deflecting in response to movement of the arm 205 towards the closed position, but then returns to its original position when the arm 205 is in the second position 205b, thus locking the arm 205 in position.

[0186] Without actuating on the arm 205, the locking portion can actuate on other components of the device to lock the component arm in position. For example, the locking portion can actuate on the upper housing 25, and the upper housing 25 maintains the arm 205 in the second position. In a further alternative, the locking portion can actuate on the PCB 65, and the PCB 65 maintains the arm 205 in the second position.

[0187] In a number of other embodiments, the locking portion includes a groove on the upper housing 25 into which a protrusion is inserted to lock the upper housing 25 in the closed position (e.g., the arm 205 in the second position). In one embodiment, the locking portion includes an elastic component designed to allow the locking portion to move when struck by the upper housing 25 to allow the upper housing 25 to close relative to the skin contact portion 30, so that once the upper housing 25 is closed, the locking portion is allowed to move to lock the upper housing 25 in position in the closed position. In one embodiment, the device includes a protrusion on the upper housing 25 designed to be inserted into the groove in the closed position, the protrusion including an elastic component allowing the protrusion to move to allow the upper housing 25 to close relative to the skin contact portion 30, and after the upper housing 25 is closed relative to the skin contact portion 30, the protrusion moves and is inserted into the groove in the locking portion to lock the upper housing 25 in the closed position. The elastic component may include a shaft that is sufficiently deformable to allow the upper housing 25 to close without the shaft softening, such that the elastic component will attempt to return to its original position after the upper housing 25 is closed. In a non-preferred but still functional embodiment, the elastic component includes a coil spring.

[0188] The elastic component of the locking portion can be made of any suitable material having the necessary rigidity and softening point. Examples of suitable materials include amorphous plastics, crystalline plastics, elastic steels, inelastic steels, stainless steels, or other materials known in the art having suitable mechanical properties.

[0189] In a preferred embodiment of the present invention, the locking portion is made of the same material as the skin contact portion 30 to facilitate the skin contact portion being made with the integrated locking portion.

[0190] In a particularly preferred embodiment of the present invention, the force required to deflect or otherwise move the elastic component is designed to be large enough that the pressure the user needs to provide to deform the elastic component, thereby causing the upper housing 25 to close towards the skin contact portion, is sufficient to insert the microneedles into the skin. According to this embodiment, the elastic component of the locking portion is used to set the force required to close the device (and thus position the arm in the second position), and to ensure that this force is sufficient to insert the microneedles into the skin at the position where they are to be embedded.

[0191] In a number of other embodiments, the locking portion includes at least one adhesive area located on at least one of the lower surface of the upper housing 25 and the upper surface of the skin contact surface 35. When the device is closed, one or more adhesive areas adhere the upper housing 25 to the skin contact portion 30, locking the device in the closed position.

[0192] In another embodiment of the present invention, the locking portion can assume three different stable states. In the first state, before the upper housing 25 is pushed downward towards the skin contact portion 30 to close the device, the locking portion is in a disengaged configuration. In the second state, the locking portion is in a first engaged position. When the locking portion is in the first engaged position, it locks the microneedles 15 in the embedded position in the skin (e.g., the arm 205 is in the second position). In the third state, the locking portion is in a second engaged position. In this state, the locking portion locks the device in the open position (e.g., the arm 205 is in the first position), while the microneedles are retracted into the device to improve the likelihood of a needlestick injury caused by the protrusion of the microneedles after device use. In one example of this embodiment, the locking portion includes a user engagement portion that can be grasped or otherwise engaged by the user, such as by engaging a fingernail under the suspension flange, enabling the user to deflect the elastic portion of the locking portion. According to this example, the user presses the upper housing 25 to close the device and locks it in place, as in other embodiments disclosed herein. When it is necessary to remove the device from the subject, the user engages the locking portion and deflects the locking portion in a first direction to unlock the upper housing 25 from the skin contact portion 30, and then deflects the locking portion in a second direction to lock the device in the open position (e.g., the arm 205 is in the first position), while the microneedles are in the retracted position. In a preferred embodiment of this example, in the first direction, the locking portion moves away from the body of the device, and in the second direction, it moves towards the body of the device. When sufficiently deflected in the second direction, the locking portion is designed to, for example, stably engage in a groove to prevent unintentional closure of the device.

[0193] In some embodiments of the present invention, when inserted into the skin, a downward force on the microneedles is provided through the elastic components of the locking portion, which is applied when the device is locked in the closed position (e.g., the movable arm is in the second position). In some embodiments, the effective locking of the movable arm in the second position is provided through a dedicated spring or other suitable biasing means. In many other embodiments, the spring or other biasing means is not dedicated to the locking function and can, for example, also act as the motive force to move the arm from the first position to the second position. For example, a torsion spring can apply a closing torque to a pivot point (if present). In yet another example, a flat, disk-shaped, or coil spring is positioned at the rear end of the microneedles such that when the device is closed, the spring is twisted or compressed, causing a downward force to be applied to the microneedles when the device is in the closed position.

[0194] Although not an essential feature of the present invention, for many applications where the microneedles are used to conduct current to the skin, conduct current from the skin, or conduct current through the skin, a PCB 65 is required. With this in mind, the PCB can carry a microprocessor and / or volatile electronic memory (e.g., RAM) and / or non-volatile electronic memory (e.g., ROM) and / or a wireless network module (e.g., Bluetooth TMmodule). The device will of course include a power source, typically in the form of a button battery.

[0195] In the embodiment shown in Figure 3A, it further includes a user-visible light-emitting diode LED 120. The function of the LED 120 can be to confirm to the user and / or the subject that the microneedles are properly embedded in the skin during application and are maintained for a long time.

[0196] The LED is electrically connected to the PCB 65, and the PCB 65 is electrically connected to the microneedles 15. The proper embedding of the microneedles can be judged by referring to any one or more of the current, resistance to current, or impedance between two microneedles.

[0197] Alternatively, the proper embedding of a single microneedle can be judged by referring to any one or more of the current, resistance to current, or impedance between a single microneedle and some other electrical contact of the device with the skin. As an example, a conductive pad can be placed on the surface of the skin, where in some examples, the conductive pad is placed on the surface of the housing that contacts the skin. When the microneedle is inserted into the skin, this conductive pad contacts at least one microneedle to complete the circuit. The completion of this circuit is used to indicate the correct insertion of the microneedle.

[0198] The electronic device involved can be simple, and any example of biological fluid on the skin, such as interstitial fluid (which is naturally conductive), acts to complete the circuit including the LED. Assume that proper insertion is indicated by the simple contact of the microneedle with the biological fluid. The LED emits light when the microneedle contacts the biological fluid (and vice versa), thus providing a visual indication of correct embedding.

[0199] More complex electronic device configurations may be required to provide a higher degree of assurance of proper microneedle embedding. For example, consider whether the minimum length of the microneedle is embedded, thus providing assurance of insertion of the microneedle to a specific minimum depth. The device can include electronic device means for measuring parameters such as current, and a higher current is indicated or the microneedle is more fully embedded. Program instructions executed by an on-board processor or otherwise associated with the device can use parameters such as current (possibly combined with other physiological or environmental parameters) as input to provide an indication of the degree of embedding of the microneedle.

[0200] Another function of the LED can be to provide other information, such as the battery charge level. For example, the LED can be connected to a microprocessor capable of monitoring the battery voltage, and when the voltage drops below a predetermined threshold, the microprocessor causes the LED to flash red. This value can be a voltage slightly higher than the minimum operating voltage to allow the subject to have time to obtain a replacement battery (or replace the device when the battery is not user-serviceable) before the device becomes inoperable.

[0201] In other embodiments, the LED can produce an output indication of the data connection status. For example, the LED can alternately flash red and green lights to warn of an interruption in the wireless data connection to a remote device such as a smartphone. The smartphone may be responsible for processing the sensor output and, when a threshold (such as glucose concentration) is exceeded, warns the subject through a sound output. In this embodiment, the LED and the device network module can be connected to a microprocessor that monitors the connection status of the module, and when the connection is established and / or lost, it causes the LED to produce an output. While an application software on the smartphone can be used to warn the subject of the loss of the information connection, the smartphone may run out of power (e.g., the battery is depleted), in which case the only means for the subject to be warned is through the device itself.

[0202] Through a buzzer or a micro speaker, a similar output function to that of the LED can be provided to provide an audible output that can be understood by the subject. For example, the output can be a tone, a series of tones, or a synthesized voice.

[0203] Now referring to an alternative embodiment of the device shown in FIG. 9, which is a modified version of the embodiments shown in FIGS. 4 to 8. The embodiment of FIG. 9 includes a temperature sensor 300 that, in operation, extends through a space 305 in the skin contact portion 30 to contact the surface of the subject's skin. The temperature sensor 300 can be a thermocouple or a thermistor, for example, and is operatively connected to a microprocessor on the PCB 65. The temperature sensor can directly contact the skin or can be separated from the skin by means of a thermally conductive material.

[0204] The temperature sensor can be disposed in a recess or other form sized to receive the temperature sensor. The recess can be made of a thin sheet of plastic material, such as a thermally conductive plastic having a metal or other filler, to facilitate the transfer of thermal energy from the underlying skin to the temperature sensor. The temperature sensor can be surrounded by a thermally conductive paste to facilitate the transfer of thermal energy from the recess walls to the temperature sensor.

[0205] The bottom plate of the recess can extend outward from the device such that when the device is applied to the skin surface, the bottom plate of the recess is nudged onto the skin surface, thereby facilitating the transfer of thermal energy from the skin to the temperature sensor. It will be understood that pushing the bottom plate of the recess too hard onto the skin surface may force blood out of the skin capillaries, thereby artificially cooling the skin surface.

[0206] Preferably, only the bottom plate of the recess is made of a thermally conductive material, and the remaining portion is made of a low thermal conductivity material. Through this configuration, the thermal energy from the skin will not be diverted away from the temperature sensor.

[0207] An insulating material can form the top of the recess to ensure that the thermal energy is retained near the temperature sensor and is not lost to the interior cavity of the housing.

[0208] The recess may include a space extending through the bottom plate, enabling the temperature sensor to directly contact the skin surface. Given that heat energy does not need to pass through any intervening material, it is expected that the temperature will be closer to the actual skin temperature.

[0209] In a further modification, the temperature sensor can be an infrared sensing module, and in this case, at least the material of the recess bottom plate should not substantially interfere with its operation. It is expected that a space can be formed in the bottom plate to allow the infrared sensing module to be directly exposed to the skin surface for effective and accurate reading of the skin temperature.

[0210] The signal output from the temperature sensor 300 can be used for calculations performed by a microprocessor (or a remote microprocessor) to more accurately determine the concentration of the target analyte. For example, the microprocessor may have access to a range of stored calibration curves, each curve being applicable at a given temperature. Based on the output of the temperature sensor 300, an appropriate calibration curve can be selected, and a more accurate analyte concentration can thus be determined.

[0211] The embodiment of FIG. 9 includes a release assembly 100 having a pair of protrusions (a first protrusion 310 is marked, and the second protrusion in the pair of protrusions is shielded by the first protrusion). The protrusion 310 extends downward and passes through the space 315 in the skin contact portion 30. The function of the protrusion 310 is to prevent the release assembly 100 from moving laterally until the lower surface of the skin contact portion 30 presses against the skin. The action of pressing against the skin causes the protrusion 310 to vertically withdraw from the space 315, allowing the release assembly 100 to be pulled laterally by the subject. This mechanism prevents the release assembly 100 from being inadvertently removed before the device is properly applied to the skin surface. Without this mechanism, the microneedles 15 may be caused to prematurely extend through the space 45 and may become contaminated by contact with air or objects, or may be physically damaged, for example, by snagging on clothing.

[0212] Some embodiments of the device may require the area above the microneedles to be electrically insulated to prevent the moist surface of the skin (as distinct from the biological fluid beneath it) from forming a conductive path between the microneedles.

[0213] As another means of controlling humidity, an absorbent material can be positioned on the microneedle fixation portion and near the microneedle tip. In multiple embodiments of the device for sensing applications, the material is used to absorb any excess liquid that may be generated by the insertion of the microneedles into the skin, to improve the subject experience, and to ameliorate any problems that may be caused by liquid contacting other parts of the device, such as electronic circuitry or electrical contacts. In embodiments of the device such as liquid extraction applications, the material acts as a wicking medium to transport liquid from the microneedles to the desired final location on or outside the device. In some embodiments, the absorbent material is in the form of a sheet. In embodiments where it is desirable to prevent contamination or damage to the microneedles prior to insertion, the sheet includes an opening through which the microneedles pass, where the size of the opening is sized large enough to prevent the absorbent material from contacting the microneedles during microneedle insertion, but also small enough to allow excess liquid exuding from the entry penetration point generated by the microneedles to contact the material and be absorbed by the material. In other multiple embodiments, such as when the device is intended to be used for liquid extraction, there are no openings in the sheet of absorbent material, or the size of the openings is sized such that the absorbent material contacts the microneedles during and after insertion to assist in its wicking action. In embodiments where there are no openings in the sheet, as part of the insertion process, openings are created when the microneedles pass through the sheet material.

[0214] The device can be used for and / or be used in any suitable application where microneedles are required to be embedded in the subject's skin for an extended period of time.

[0215] This application includes sensing based on electrochemical aptamers, whereby a target analyte in a biological fluid or tissue is detected by binding to a capture entity such as an aptamer that includes a redox indicator. The captured entity can be covalently or non-covalently bound to the microneedle, and the redox indicator causes an electronic signal to be transmitted by the microneedle when binding to the target analyte. The target analyte can be a drug or other exogenous species, or an endogenous species such as a hormone or metabolite.

[0216] When the microneedles act as electrodes to detect analytes present in the skin layer, the device can include circuitry and components to electrically excite the electrodes and receive, measure, and process the electronic signals generated by the electrical excitation. According to this embodiment, the microneedles can include a tip, a shaft, and a base, where the electronic signal is generated at an electrode that is plated on the surface of the microneedle or integrated within the microneedle, transmitted along the shaft of the microneedle to the base of the microneedle, where an electrical connection is established at the base or shaft of the microneedle to transmit the electronic signal from the electronic circuitry to the electrode or from the electrode to the electronic circuitry. The electrode can be formed near the tip of the microneedle, on at least a portion of the shaft of the microneedle and not near the tip of the microneedle, or near the tip of the microneedle and simultaneously on at least a portion of the shaft of the microneedle.

[0217] Microneedles can be connected to an electronic circuit by a variety of methods known in the art, such as soldering, wire winding, or spring-loaded pins. In one embodiment, the microneedles are fixed to pass through a plate or block of dielectric material, and the connection portion of the microneedles is positioned on or above the surface of the plate or block remote from the tips of the microneedles. A ZEBRA connector can be used to connect the microneedles to the electronic circuit to enhance connection reliability, and in at least one direction, there is no need to precisely align the ZEBRA connector to the microneedle terminals.

[0218] Further potential applications include delivering current to the skin for the purpose of muscle stimulation, or in stimulating or restricting the biological processes of a subject. Similarly, the device can be used to detect current in the skin of a subject, such as detecting nerve conductance.

[0219] In any of the above applications, the microneedles can be solid or hollow as needed or desired.

[0220] The length of the microneedles can be selected according to the particular application. Generally, the microneedles are required to extend at least into the stratum corneum. The depth of the stratum corneum varies according to location. For example, the stratum corneum on the soles of the feet is relatively thick, and the stratum corneum on the back of the hand is relatively thin. Therefore, the length of the microneedles extending beyond the housing can be adjusted according to the location of the application.

[0221] In some cases, the microneedles may need to extend deeper into the stratum corneum and into the epidermis, dermis, and even the lower layers of the hypodermis, including subcutaneous tissue. Similarly, the length of the microneedles can be set to extend beyond the device.

[0222] One of ordinary skill in the art can also understand that it may be necessary to set the microneedle length according to the intended subject. For example, relatively short microneedles are generally required to contact the subcutaneous tissue of a neonatal subject, while at the same location, an adult subject will require longer microneedles.

[0223] In some applications, it may be desirable for one microneedle to penetrate deeper into the skin than another microneedle. Thus, the two microneedles can terminate at different distances from the skin surface, or terminate at different distances from the microneedle fixation portion. In some embodiments, the two microneedles have different lengths. In other embodiments, the microneedles have the same length, and the fixation portion is used to axially misalign one microneedle relative to the other. For example, the fixation portion can be multi-layered, having a first electrode extending from a first layer and a second electrode extending from a second layer.

[0224] In general applications, the microneedles can extend outward from the device at a distance between about 10 μm and about 5000 μm. In many applications, a useful distance is between about 500 μm and about 4000 μm.

[0225] One of ordinary skill in the art will understand that the invention described herein allows for further variations and modifications in addition to those specifically described.

[0226] For example, the movable arm can be moved by the user squeezing or pressing on the elastic part of the device housing, by actuation of the rotating rod, or by moving the arm downward along the inclined sliding assembly.

[0227] The skin contact portion of the device has been drawn with its lower (skin contact surface) being the correct plane. However, in some embodiments, it can be curved to conform to the surface of a body part, such as a finger, wrist, heel, or ear. The skin contact portion can have a certain degree of elasticity (in at least one direction) to conform to the surface of the body part.

[0228] The space through which the microneedles extend is typically shown as an opening. However, other types of spaces can be considered. In some embodiments, the space is not an opening, and in this embodiment, the microneedles extend through the periphery of the space to the skin contact portion.

[0229] The device can include a thermal energy sensor maintained on the subject in the same way as the protrusion (e.g., a needle) of an electrochemical sensor device. Thus, the thermal energy sensor can monitor the temperature for a long time of the target analyte being detected. Therefore, the ability to determine the temperature over a long time results in a more accurate determination of the analyte concentration at any point in time and also over a potentially long period.

[0230] The inventors propose that the protrusion (e.g., a needle) of an electrochemical sensor device needle can perform three functions, and each function acts together to provide an accurate determination of the concentration of the target analyte in the subject. First, the needle pierces the skin and extends into the subcutaneous tissue of the subject so that the terminal portion contacts the biological fluid or tissue of the subject. Second, the needle terminal portion can be loaded with a detection component (e.g., an aptamer) that can selectively interact with the target analyte, making the needle act as a whole as a working electrode. Third, the needle can act to sense the temperature of the biological fluid or tissue of the subject. An accurate determination of the biological fluid or tissue temperature allows a temperature correction factor to be applied to the concentration of the target analyte determined by the electrochemical sensor.

[0231] The needle can be made of metal, silicon, polymer, glass, or ceramic. The base of the needle is usually bonded to a base substrate to form an array. The needle base substrate can include an adhesive to improve bonding to the skin.

[0232] Of course, the needle can have a larger size. There is usually no upper limit on the size, unless it must be acceptable to the subject.

[0233] When the needle is in the form of a wire, it can be used in the context of the present invention. However, the wire is usually elastic and may not be stable enough to penetrate the skin surface. If needed, a guide can be used to assist in inserting it into the subcutaneous tissue.

[0234] The electrochemical sensor of the present invention can be implemented as an electrochemical aptamer (EAB) sensor. The EAB sensor can be provided in the form of a wearable patch or the like, which has a needle extending through the skin surface and into the analyte-detectable biological fluid or tissue of the subject.

[0235] The EAB sensor can be of potentiometric, amperometric or conductometric type. In a potentiometric sensor, the equilibrium of the region where the analyte can be detected is set at the sensor interface, the electrode or membrane potential is measured at the sensor interface, and the information of the sample is derived from the potential difference between two electrodes. An amperometric sensor is based on the potential difference applied between the reference and working electrodes, which causes the oxidation or reduction of a redox-active substance; the resulting current is measured. A conductometric sensor is based on the measurement of conductivity at a series of frequencies.

[0236] The EAB sensor is usually an amperometric sensor, and an aptamer (such as DNA, RNA or XNA) is bound to the working electrode. Gold is usually used as the probe surface of the working electrode. The aptamer has an associated redox-active substance, acting as an indicator. The redox indicator is usually methylene blue solution. After binding to the target analyte, the aptamer undergoes a conformational change, bringing the redox indicator closer to the working electrode surface. This increase in proximity increases the transfer of electrons from the redox indicator to the electrode. The increased rate of electron transfer causes a change in the Faraday current detected by the potentiostat.

[0237] An aptamer is a small (usually 20 to 60 nucleic acids) single-stranded RNA, DNA or XNA oligonucleotide that can bind to a target drug with high affinity and specificity. Aptamers can be regarded as nucleic acid analogs of antibodies, but aptamers are produced by an in vitro cell-free process, which is simpler and cheaper than producing antibodies by cell culture or in vivo methods.

[0238] Aptamers are usually selected from a combinatorial library having a large number (about 10 18 pieces) of different oligonucleotides. Compared with DNA aptamers, RNA aptamers provide significantly greater structural diversity, and their applications are complicated by stability problems due to RNase, high temperature and adverse pH.

[0239] The selection of aptamers selective for a given drug is facilitated by a process called SELEX (Systematic Evolution of Ligands by Exponential Enrichment). This process can be regarded as two alternating stages. In the first stage, the library oligonucleotides are amplified to the desired concentration by polymerase chain reaction (PCR). For the selection of RNA aptamers, single-stranded oligodeoxyribonucleotides are generated by in vitro transcription of double-stranded DNA with T7 RNA polymerase. For DNA aptamers, a pool of single-stranded oligodeoxyribonucleotides is generated by strand separation of double-stranded PCR products. In the second stage, the amplified products are incubated with the target drug, and the oligonucleotides that bind the drug are used in the next round of SELEX.

[0240] Separation of oligonucleotides with higher affinity for the target drug and removal of unbound oligonucleotides are achieved through strong competition at the binding site. The selection pressure increases in each round of SELEX. Maximum enrichment of the oligonucleotides with the strongest affinity for the target molecule is typically achieved after 5 to 15 rounds.

[0241] EAB sensors are typically incorporated into a circuit with a reference electrode. The reference electrode is the site of a known chemical reaction with a known redox potential. For example, a reference electrode based on the silver-silver chloride (Ag|AgCl) redox couple has a fixed and known potential, forming the point at which the redox potential of the working electrode is measured. Also typically included in the circuit is a counter electrode, which serves as the cathode or anode to the working electrode. Since the applied voltage bias does not pass through the reference electrode (due to the impedance of the potentiometer), any potential generated is attributed to the working electrode. The current is measured as the potential of the interrogation electrode compared to the stable potential of the reference electrode. The potential difference generates a current in the circuit, thus producing an output signal. The signal quantifies target binding according to electron transfer, which ideally binds to the target in a stoichiometric ratio.

[0242] As described above, EAB sensors can be implemented in various forms, one of which is a needle-based patch. When the patch is applied to a subject, the needles penetrate the subject's skin and contact the patient's body fluid. The needle tip serves as the working electrode, and the redox indicator label is associated with the aptamer at the tip. This configuration provides a minimally invasive platform for real-time, continuous in vivo drug detection, which has sufficient sensitivity and selectivity for monitoring the amount of drug in the patient's body over time. EAB sensors can also perform single-point measurements.

[0243] The aptamer and the needle can be used together in the form of an EAB biosensor, so that the aptamer-loaded needle is inserted through the skin to contact the biological fluid. The needle essentially serves as the working electrode for detecting the analyte in the biological fluid. Typically, a second needle is used as the counter electrode, and a third needle serves as the reference electrode.

[0244] Each aptamer molecule has an associated redox indicator, such as methylene blue solution. Binding of the target analyte causes a conformational change in the aptamer, which adjusts the proximity of the redox indicator to the surface of the needle, resulting in an increase or decrease in electron exchange at the needle surface. The resulting change in current through the needle can be used to determine the concentration of the target analyte in the biological fluid.

[0245] EAB sensors have been shown to successfully detect endogenous analytes in biological fluids, such as metabolites, hormones, antibodies, and cancer markers. Exogenous analytes such as drugs, toxins, and infectious agents have also been detected.

[0246] When EAB sensors show significant promise, problems arise in the art regarding the accuracy of the provided target analyte concentration. Analyte concentration is typically determined by comparing the sensor output current to a calibration curve. Almost always, the calibration curve is prepared at a temperature different from that of the subject's subcutaneous tissue. To overcome this difference, a temperature correction factor is applied to the biosensor output. Of course, any temperature correction factor is based on an accurate determination of the subject's temperature.

[0247] Referring to FIG. 10, an analyte and temperature sensing needle 410 is shown. The terminal portion 410a is coated with an aptamer specific to the target analyte, and the aptamer has an associated redox indicator. Thus, the needle 410 acts as a working electrode. The needle 410 is fixed to a support 412 and typically has a second needle (not shown, acting as a counter electrode) and a third needle (not shown, acting as a reference electrode).

[0248] The needle 410 is in contact with a temperature sensor 415, which is, for example, a micro-thermistor or a thermocouple. A useful high-precision small glass bead thermistor is model S14A10310 (Sensor Scientific Corporation, New Jersey, USA). The size of the bead is 0.36x0.5 mm, allowing it to be combined with a needle having a cavity and providing a very low thermal mass. The low thermal mass provides a rapid response to temperature changes and minimizes the active extraction of thermal energy from the subject's tissue. A lower accuracy (if acceptable in the context of the application) is provided by the less expensive model S14A10310. When the thermistor contacts the subject's tissue, it may be necessary to ensure the biocompatibility of the material.

[0249] A thermal conductive material 420, such as thermal paste, thermal putty, ointment or gel, is applied around the needle 410 and the temperature sensor 415 to ensure the effective transfer of thermal energy from the needle 410 to the temperature sensor 415. A suitable thermal paste is DP-200-30 (Taica Corporation, Japan), which is thermally conductive and electrically insulating. A useful thermal putty is TG-NSP35-1LB (T-Global Technology Limited, UK).

[0250] The needle 410 includes an extension portion 410b, the upper surface of which can form an auxiliary surface that can contact the temperature sensor 415 to improve the transfer of thermal energy. It will be understood that it is generally desirable for as much thermal energy as possible to be transferred from the subject's subcutaneous tissue through the needle 410 to the temperature sensor 415 so that the temperature sensor 415 can be used to accurately detect the temperature of the tissue.

[0251] The temperature sensor 415 has a pair of wires 425 to generally carry the output signal to a processor (not shown), and the signal is used as an input value and analyzed according to program instructions.

[0252] Preferably, the dimensions of the temperature sensor 415, the pair of wires 425, the extension portion 410b, and the thermal conductive material 420 shown in FIG. 10 are sized to be as small as possible to avoid acting as heat dissipation fins, thereby limiting the amount of heat energy that the temperature sensor 415 can absorb and report from the processor. In view of this, the support 412 is preferably made of a material having low thermal conductivity, such as plastic, so that heat energy is not diverted away from the temperature sensor 415.

[0253] Now referring to the embodiment of FIG. 11, which uses non-contact means to measure the temperature of the needle 410. In particular, the temperature sensor 415 is an infrared sensing module for receiving heat energy (such as energy in the infrared spectrum). The infrared sensing module (i.e., the temperature sensor 415) can be of the active type (where the module simultaneously directs infrared radiation onto the target and detects the infrared radiation emitted by the target) or the passive type (where the module only detects the infrared radiation emitted by the target).

[0254] The infrared sensing module (i.e., the temperature sensor 415) may require a relatively large target area to operate, and the size of the extension portion 410b of the needle is sized to be sufficient to act as the target surface. In some embodiments, the extension portion 410b can be extended to a greater extent than shown in the figure, as long as it acts as the target area for the infrared sensing module (i.e., the temperature sensor 415).

[0255] Considering heat dissipation due to the thermal mass of the thermistor, thermocouple, thermal paste, and output wires, the non-contact method of temperature sensing may be preferred.

[0256] Now referring to FIG. 12, a modification of the embodiment of FIG. 11 is shown, including a thermal isolation cover 430 covering the upper portion of the needle 410, the temperature sensor 415, and the thermal conductive material 420. The thermal isolation cover can be made of foamed or similar material and acts to limit the loss of heat energy to the atmosphere. In the embodiment of FIG. 12, the thermal conductive material 420 and the thermal isolation cover 430 act together to guide the heat energy as far as possible to the temperature sensor 415 to accurately represent the temperature in the subcutaneous tissue of the subject.

[0257] As shown in FIG. 13, the thermal isolation cover 430 has been added to the embodiment of FIG. 11 for the same reason as in FIG. 12. The thermal isolation cover 430 in the example of FIG. 13 is modified to include a window 435 to expose the surface infrared sensor (i.e., the temperature sensor 415) of the needle extension portion 410b.

[0258] In the embodiment of FIG. 14, the needle 410 has a cavity 440 that receives the temperature sensor 415 and carries the output wire 425 from the temperature sensor 415 out of the needle. In this embodiment, the temperature sensor 41 can be in direct contact with the biological fluid of the subject's subcutaneous tissue at the same tissue depth as the aptamer, thus providing a very accurate reading and being little affected by the thermal mass of other components of the electrochemical sensor. In addition, heat energy is transmitted through the needle 410 wall to the side of the temperature sensing 415, further improving the accuracy of the reading.

[0259] It may be necessary to increase the cross-sectional area of the needle 410 to accommodate the temperature sensor 415.

[0260] The expected needle 410 can form part of a thermocouple, as shown in the embodiment of FIG. 15. As is known, a thermocouple is formed by the generation of a junction typically welded between two different metals. The needle 410 can provide one of the two metals, and the second of the two metals can be the thermocouple stage wire 445 that extends through the cavity 440 all the way to the tip of the needle 410. The terminal of the thermocouple stage wire 445 is welded to the tip of the needle 410. The second wire 450 is welded to the needle 410, and the thermocouple stage wire 445 and the second wire 450 will carry the signal to the processor.

[0261] In other embodiments, the temperature sensor is disposed adjacent to the needle to determine the tissue temperature of the tissue very close to where the needle is inserted. Referring to FIG. 16, an integrated, stand-alone, wearable device 500 including three needles 410 configured as a working electrode, a counter electrode, and a reference electrode respectively is shown. The needles 410 extend through the skin contact plate 505, which presents a downward-facing surface to contact the skin surface 600 of the subject during use. The skin contact plate 505 additionally provides a lower housing portion that engages with the upper housing portion 510 to completely enclose all electronic devices and other components.

[0262] The device 500 includes a cavity 515 sized to receive a temperature sensor 415 such as a thermistor or a thermocouple. The cavity 515 can be made of a thin sheet material of thermally conductive plastic, such as plastic with a metal or other filler, to facilitate the transfer of heat energy from the underlying skin surface 600 to the temperature sensor 415. The temperature sensor 415 is surrounded by a thermally conductive paste to facilitate the transfer of heat energy from the cavity 515 wall to the temperature sensor 415.

[0263] It will be noted that the bottom plate of the recess 515 slightly extends beyond the lower surface of the skin contact plate 505. The effect of this configuration is that when the skin contact plate 505 is applied to the skin surface 600, the bottom plate of the recess 515 is nudged onto the skin surface 600, thus facilitating the transfer of thermal energy from the skin surface 600 to the temperature sensor 415. It will be understood that pushing the bottom plate of the recess 515 too forcefully onto the skin surface may force blood to flow out of the skin capillaries, thus artificially cooling the skin surface 600.

[0264] Preferably, only the bottom plate of the recess 515 is made of a thermally conductive material, and the remaining part is made of a low thermal conductivity material. Through this configuration, the thermal energy from the skin will not be diverted away from the temperature sensor.

[0265] An insulating material (not shown) may be included to form the top of the recess 515 to ensure that the thermal energy is retained near the temperature sensor 415 and is not lost to the interior of the housing (such as the skin contact plate 505 and the upper housing portion 510).

[0266] The embodiment of FIG. 16 can be modified such that the temperature sensor 415 extends through an opening in the bottom plate of the recess 515 to directly contact the skin surface 600. Considering that the thermal energy does not need to pass through any intermediate material, it is expected that the temperature will be closer to the actual skin temperature.

[0267] In a further modification, the temperature sensor 415 is an infrared sensing module, and in this case, at least the material of the bottom plate 515 of the recess should not substantially interfere with its operation. It is expected that an opening can be formed in the bottom plate to allow the infrared sensing module (i.e., the temperature sensor 415) to be directly exposed to the skin surface 600 for effective and accurate reading of the skin temperature.

[0268] Referring to FIG. 17, a basic circuit for the operation of the present invention is shown. Although it will be understood that a thermistor temperature sensor can alternatively be applied to the reference electrode or the counter electrode, the thermistor temperature sensor is shown applied to the working electrode. In some embodiments, a dedicated needle is only provided for the purpose of temperature measurement.

[0269] Only the needle is described herein as the preferred embodiment, and the needle can be interchangeably a microneedle or others similar. However, a wire can be used instead of the needle, and in this case, the wire can be wound around the temperature sensor to enhance the transfer of thermal energy to the temperature sensor. Considering that copper has excellent thermal conductivity and is easily available, a copper wire can be preferred. It may be necessary to use a guide (such as a small cannula) to embed the wire in the subcutaneous tissue or biological fluid.

[0270] Those with ordinary knowledge in this technical field will understand that, in addition to the specific embodiments described, the present invention described herein is susceptible to other variations and adjustments. It will be understood that the present invention includes all such variations and adjustments. All such variations and adjustments fall within the spirit and scope of the present invention.

[0271] Therefore, the spirit and scope of the present invention are not limited by the foregoing examples, but will be understood in the broadest concept permitted by law. In summary, although the present invention has been disclosed as above by way of examples, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention pertains, without departing from the spirit and scope of the present invention, may make various changes and modifications. Therefore, the scope of protection of the present invention shall be subject to what is defined by the appended claims for patent.

Claims

1. An electrochemical sensor device for contacting one or more protrusions with biological fluid or tissue under the skin of a subject for a long time, the device comprising: One or more protrusions, each configured to penetrate the skin; A skin contact portion defining a skin contact surface and one or more spaces allowing the one or more protrusions to extend therethrough; A movable portion configured to move the one or more protrusions from a first position behind the skin contact surface to a second position protruding from the skin contact surface; Optionally, a maintaining portion configured to maintain the skin contact surface in contact with the skin during use; And a thermal energy sensor configured to determine the temperature of the biological fluid or tissue around the one or more protrusions when the one or more protrusions contact the biological fluid or tissue, Wherein the movable portion is configured to move from the first position to the second position.

2. The device according to claim 1, wherein the movable portion moves along a generally arcuate path or other type of non-linear path.

3. The device according to claim 1 or 2, wherein the movable portion has a connecting end and a free end.

4. The device according to claim 3, Wherein the free end moves a longer distance than the connecting end.

5. The device according to any one of claims 1 to 4, wherein the non-linear path is described with reference to the free end.

6. The device according to any one of claims 1 to 5, wherein the non-linear path is less than about 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm or 3 mm.

7. The device according to any one of claims 2 to 6, wherein the angular measure of the arc is less than about 45 degrees, 40 degrees, 35 degrees, 30 degrees, 25 degrees, 20 degrees, 15 degrees, 14 degrees, 13 degrees, 12 degrees, 11 degrees, 10 degrees, 9 degrees, 8 degrees, 7 degrees, 6 degrees or 5 degrees.

8. The device according to any one of claims 1 to 7, wherein the movable portion has a pivot portion, a hinge portion, a bend portion or a joint portion.

9. The device according to any one of claims 1 to 8, wherein the movable portion is associated with a fixed portion.

10. The device according to claim 9, wherein, During use, the fixed portion is fixed, and the movable portion is movable relative to the fixed portion.

11. The device according to claim 9 or claim 10, wherein the fixed portion includes a part allowing the movable portion to pivot, articulate, bend or join.

12. The device according to any one of claims 9 to 11, wherein the fixed portion is in a fixed spaced relationship with the skin contact surface.

13. The device according to any one of claims 9 to 12, wherein the spacing between the fixed portion and the skin contact surface is less than about 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm or 2 mm.

14. The device according to any one of claims 9 to 13, wherein the fixed portion is generally lateral to the movable portion.

15. The device according to any one of claims 1 to 14, further comprising a user-actuable release portion configured to maintain the movable portion in the first position until the user actuates the release portion, while the movable portion is released and allowed to move to the second position.

16. The device according to any one of claims 1 to 15, further comprising a locking portion configured to lock the movable portion when in the second position.

17. The device according to any one of claims 1 to 16, which is configured such that movement of the movable portion from the first position to the second position requires motive power from within and / or outside of the device.

18. The device according to claim 17, wherein the motive power within the device is derived from a spring, an elastically deformable member, a shape memory member, or other biasing means; and the motive power outside of the device is derived from a user.

19. The device according to any one of claims 1 - 18, wherein the device does not have an internal motive power generator for moving the movable portion from the first position to the second position.

20. The device according to any one of claims 1 - 19, wherein the maintaining portion is a dermatologically acceptable composition located on or around the skin contact surface or comprises a dermatologically acceptable composition located on or around the skin contact surface.

21. The device according to claim 20, wherein the dermatologically acceptable composition is an adhesive or an equivalent thereof having the same functionality.

22. The device according to any one of claims 1 - 21, wherein the maintaining portion is configured to mechanically hold the skin contact surface in contact with the skin.

23. The device according to claim 22, wherein the maintaining portion is selected from any one or more of the following: straps, bands, belts, clips, handles, plugs, buckles, sleeves, housings, socks, gloves, covers, caps, underwear, undershirts, shirts, bras, tops, trousers, scarves, rings, glasses, or collars.

24. The device according to any one of claims 1 - 23, wherein the one or more protrusions are mechanically directly or indirectly connected to the movable portion.

25. The device according to any one of claims 1 - 24, wherein the one or more protrusions are wires, needles, and / or microneedles.

26. The device according to claim 25, wherein the one or more protrusions form an array.

27. The device according to any one of claims 1 - 26, wherein the one or more protrusions have a sufficient length to contact the epidermal layer, dermal layer, or hypodermal layer of a subject.

28. The device according to any one of claims 1-27, wherein the one or more protrusions are configured to function in use so as to: introduce current into the skin or extract current from the skin or through the skin, introduce sound waves into the skin or extract sound waves from the skin or through the skin, introduce light into the skin or extract light from the skin or through the skin, introduce heat into the skin or extract heat from the skin or through the skin, sample liquid or tissue from the skin, or deliver a bioactive substance to the skin, or introduce an analyte sensing substance into the skin.

29. The device according to any one of claims 1-28, wherein each of the one or more protrusions is a conductor, and the device further comprises a circuit having an audible, visual or tactile indicator, the circuit being configured to actuate the indicator when the one or more protrusions contact a conductive liquid naturally present in the skin.

30. The device according to claim 29, wherein the circuit comprises at least two protrusions and the circuit is configured to be completed by the at least two protrusions contacting the conductive liquid naturally present in the skin so as to actuate the indicator.

31. The device according to claim 29, wherein the circuit comprises one protrusion and at least one conductive pad placed against the skin, and the circuit is configured to be completed by electrical communication between the protrusion and the pad with the conductive liquid naturally present in the skin so as to actuate the indicator.

32. The device according to any one of claims 1-31, the device comprising a housing sized such that when the device is applied to the skin, and the movable part is in the second position, and any part of each of the one or more protrusions protruding from the skin contact surface is embedded in the skin, most or substantially all of the housing extends no more than about 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm above the skin.

33. The device according to any one of claims 1-32, wherein the long time is greater than about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours or 96 hours.

34. The device according to any one of claims 1-33, the device being configured such that the one or more protrusions are inseparable from the device, or inseparable from the device without the aid of tools.

35. The device according to any one of claims 1-34, wherein the movable part and the fixed part are integral.

36. The device according to claim 35, wherein the integral moving part and fixed part are made of an elastically deformable material.

37. The device according to claim 35 or 36, wherein the integral moving part and fixed part are part of the circuit board of the device.

38. The device according to any one of claims 15 - 37, wherein the movable part is biased towards the second position and maintained in the first position, and is resisted by a user-actuable release part until the release part is actuated, at which time the movable part is released and allowed to move to the second position.

39. The device according to any one of claims 15 - 37, wherein the user-actuable release part is a flange, the flange being configured to hold the movable part in the first position, and the flange and / or the movable part being deformed by a driving force provided by the user to allow the movable part to be released from the flange and move to the second position.

40. The device according to any one of claims 1 - 39, wherein the movable part is hinge-associated with the skin contact part.

41. The device according to claim 40, wherein the hinge is located at or towards the peripheral region of the movable part and the skin contact part.

42. The device according to any one of claims 15 - 41, wherein the release part includes a member configured to maintain the movable part in the first position, but which is removable or deformable by the user to allow the movable part to move to the second position.

43. The device according to claim 42, wherein the member is removable by sliding generally over the skin contact part.

44. The device according to claim 42 or 43, wherein the member is generally wedge-shaped, and the device includes a hinge associating the movable part with the skin contact part, and the thin part of the wedge is disposed proximal to the hinge and the thick part of the wedge is disposed distal to the hinge.

45. The device according to any one of claims 42 - 44, wherein the release part is removable from the device and includes a handle to assist in manual removal.

46. The device according to any one of claims 1 - 45, wherein the one or more protrusions have an analyte detection element associated therewith.

47. The device according to claim 46, wherein the one or more protrusions are configured to serve as working electrodes.

48. The device according to claim 46, wherein the one or more protrusions have a reference solution in electrical communication therewith and are configured to serve as reference electrodes.

49. The device according to claim 46, wherein the one or more protrusions are configured to serve as counter electrodes for the working electrodes.

50. The device according to claim 46, wherein the one or more protrusions are dedicated to determining the temperature of the biological fluid or tissue around the one or more protrusions when inserted into the skin of the subject.

51. The device according to any one of claims 46 - 50, the device comprising a thermal insulation material for retaining thermal energy within the one or more protrusions.

52. The device according to claim 51, wherein the thermal insulation material surrounds a terminal portion of the one or more protrusions, the terminal portion being distal to a portion of one of the one or more protrusions inserted into the skin.

53. The device according to claim 51 or 52, wherein the thermal insulation material forms a cap on the terminal portion of the one or more protrusions, the cap being distal to a portion of one of the one or more protrusions inserted into the skin.

54. The device according to any one of claims 51 - 53, wherein the thermal insulation material surrounds the thermal energy sensor and the one or more protrusions.

55. The device according to any one of claims 46 - 54, wherein at least a portion of the one or more protrusions is made of metal, metal alloy, metal composition, or ceramic.

56. The device according to claim 55, wherein the metal, the metal alloy, the metal in the metal composition, or the ceramic, has a thermal conductivity k of at least about 200, 300, or 400 W / mK.

57. The device according to claim 55 or 56, wherein the metal, the metal alloy, or the metal in the metal composition is any one or more of copper, steel, silver, nickel, tin, zinc, lead, aluminum, and silicon, or comprises any one or more of copper, steel, silver, nickel, tin, zinc, lead, aluminum, and silicon.

58. The device according to any one of claims 46 - 57, wherein the thermal energy sensor is configured to detect thermal energy in one of the one or more protrusions.

59. The device according to any one of claims 46 - 58, wherein the thermal energy sensor is applied to or directly oriented towards the one or more protrusions.

60. The device according to any one of claims 46 - 59, wherein the thermal energy sensor contacts the one or more protrusions, or otherwise is in thermal communication with the one or more protrusions.

61. The device according to claim 60, wherein the thermal communication is through a thermally conductive flowable substance located between the thermal energy sensor and one of the one or more protrusions.

62. The device according to any one of claims 46 - 61, wherein the thermal energy sensor is a thermocouple, a thermistor, or an infrared sensor.

63. The device according to claim 62, wherein one of the one or more protrusions forms part of the thermocouple or the thermistor.

64. The device according to any one of claims 46 - 63, wherein one of the one or more protrusions includes a cavity.

65. The device according to claim 64, wherein the thermal energy sensor is at least partially located within the cavity, or at least partially functions through the cavity.

66. The device according to claim 65, wherein the cavity holds a thermally conductive flowable substance to form a thermal communication between the thermal energy sensor and the surface of the cavity.

67. The device according to any one of claims 46 - 66, wherein the thermal energy sensor is configured to detect the thermal energy of tissue adjacent to one of the one or more protrusions.

68. The device according to claim 67, wherein the thermal energy sensor is applied to the skin surface or directly towards the skin surface.

69. The device according to claim 67 or 68, wherein the thermal energy sensor contacts the skin or otherwise has a thermal communication with the skin.

70. The device according to claim 69, wherein the thermal communication is through a thermally conductive solid material that has a thermal communication with the thermal energy sensor on a first side and a thermal communication with the skin on a second side.

71. The device according to claim 70, wherein the thermally conductive solid material is a metal or plastic, or plastic with a filler.

72. The device according to claim 71, wherein the filler is graphite, graphene, carbon fiber or other carbon - based material.

73. The device according to any one of claims 70 - 72, wherein the thermally conductive solid material has a thickness of less than about 5mm, 4mm, 3mm, 2mm, 1mm, 0.9mm, 0.8mm, 0.7mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm or 0.1mm.

74. The device according to any one of claims 46 - 73, wherein the thermal energy sensor is a thermocouple, a thermistor or an infrared sensor.

75. The device according to any one of claims 46 - 74, wherein the one or more protrusions and the thermal energy sensor are included in a housing or otherwise associated with the housing.

76. The device according to any one of claims 47 - 75, wherein the analyte detection element is an aptamer.

77. The device according to claim 76, the device includes a redox - active moiety associated with the aptamer and is configured to act as a reporter of the interaction of the target analyte with the aptamer.

78. A method for bringing one or more protrusions of an electrochemical sensor device into contact with a biological fluid or tissue under the skin of a subject, the method comprising the steps of: providing the device according to any one of claims 1 to 77; bringing the skin - contact surface of the device into contact with the subject; and causing or allowing the movable part to move from the first position to the second position, and causing or allowing the thermal energy sensor to determine the temperature of the biological fluid or tissue.

79. The device according to claim 78, wherein the device maintains the application to the skin for a period greater than about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, or 96 hours.

80. An electrochemical sensor device for bringing one or more protrusions into contact with biological fluid or tissue beneath the skin of a subject, the device comprising: one or more protrusions, each configured to penetrate the skin; a skin contact portion defining a skin contact surface and one or more spaces allowing the one or more protrusions to extend therethrough; a movable portion configured to move the one or more protrusions from a first position behind the skin contact surface to a second position protruding from the skin contact surface; a user-actuatable release portion configured to maintain the movable portion in the first position until the user actuates the release portion, whereupon the movable portion is released and caused or allowed to move to the second position; and a thermal energy sensor configured to determine the temperature of the biological fluid or tissue around the one or more protrusions when the one or more protrusions contact the biological fluid or tissue.

81. The device according to claim 80, wherein the release portion includes a member configured to maintain the movable portion in the first position, but the member is removable or deformable by the user to allow the movable portion to move to the second position.

82. The device according to claim 81, wherein the member is removable by sliding substantially over the skin contact portion.

83. The device according to claim 81 or 82, wherein the member is generally wedge-shaped, and the device includes a hinge associating the movable portion with the skin contact portion, and the thin portion of the wedge is disposed proximal to the hinge and the thick portion of the wedge is disposed distal to the hinge.

84. The device according to any one of claims 80 - 84, wherein the release portion is removable from the device and includes a handle to assist in manual removal.

85. A method for bringing one or more protrusions into contact with biological fluid or tissue beneath the skin of a subject, the method comprising the steps of: providing the device according to any one of claims 80 to 84; bringing the skin contact surface of the device into contact with the subject; and actuating the user-actuatable release portion to cause or allow the movable portion to move from the first position to the second position, and to cause or allow the thermal energy sensor to determine the temperature of the biological fluid or tissue.

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