Needle-based device with temperature sensing function

Abstract

The electrochemical sensor device is for introducing a needle electrode into the skin of a subject to contact the biological fluid or tissue of the subject and detecting a target analyte. The device has a movable part for inserting the needle electrode into the skin of the subject and a thermal energy sensor for specifying the temperature of the biological fluid or tissue.

Description

Technical Field

[0001] The present invention generally relates to an apparatus for introducing a needle into the skin of a subject and holding the needle in place. The needle contacts the subject's body fluid and detects a target analyte therein. The apparatus is configured to be simple, lightweight and have a low profile so as not to be relatively obstructive to the subject. Further, the apparatus has a temperature sensing function for improving the accuracy of target analyte detection.

Background Art

[0002] Advances in microfabrication technology in the 1990s enabled the large-scale production of microneedle devices for medical use.

[0003] The length of a single microneedle is usually 150 - 1500 μm, the width is 50 - 250 μm, and the tapered tip has a thickness of 1 - 25 μm. In the context of biosensor devices, microneedles can be conductive and function as working electrodes, counter electrodes or reference electrodes.

[0004] As a working electrode in an electrochemical biosensor, a microneedle can be coated with a detection element such as a redox-modified aptamer or an enzyme configured to sense a specific target analyte in a biological fluid such as interstitial fluid or blood. Usually, the biosensor is interrogated by the application of a potential (e.g., square wave voltammetry). The peak current passing through the working electrode is measured and the value is used to identify the amount of analyte present around the working electrode.

[0005] The prior art discloses a number of devices for inserting microneedles into the skin of a subject. Such devices are generally configured to facilitate the application of microneedles by the subject in a non-clinical environment such as at home. Ease of use and reproducibility are the main objectives of these devices.

[0006] Some devices are specialized only for the application of microneedles, and once their task is completed, the devices are removed along with the microneedles. Other prior art devices are configured to be separated from the microneedles, such that the microneedles can remain in place within the skin for a certain period of time after introduction. Within the skin, the microneedles can sense increases and decreases in the concentration of analytes in the interstitial fluid.

[0007] Yet another type of prior art device is configured to introduce the microneedles with the device, and the device and microneedles remain in place on the subject for a certain period of time. Although these devices provide simplicity to the subject using the device, they present many problems.

[0008] One problem is that such devices are generally obtrusive and easily noticed by the subject. The device may catch on clothing or other nearby objects and become completely or partially detached. These devices need to be worn overnight, and significant discomfort can occur if the subject rolls over on the device.

[0009] A further problem is that prior art devices are composed of a large number of individual components and are complex. This increases the cost of the device and also the tendency to malfunction. The large number of components also increases the weight of the device, thereby increasing the annoyance for the subject. It has been found that the discomfort related to the weight increases proportionally to the period during which the device is worn. In some applications (such as hormone monitoring), continuous real-time data may be required over a period of several weeks. Although the device is likely to be replaced several times during that period, the problem of the subject wearing a heavy device over a long period remains.

[0010] A further problem arises in that it may be uncertain for the subject whether the microneedle has properly penetrated the skin in the first instance, and further whether the microneedle remains properly embedded in the skin over time. Conventional art devices typically include a housing, the lower surface of which is at the same height as the surface of the skin. Due to the presence of the housing, it is difficult, if not impossible, for the subject to view the surface of the skin and confirm whether the microneedle is properly embedded. If in doubt, the device can be removed and a new one applied to the skin. If the microneedle was actually properly inserted, the replacement of the device is wasted.

[0011] In a biosensor device based on a microneedle such as those described above, problems occur when the interaction between the target and the working electrode is temperature-dependent. For example, the conformation or structure of the detection element can change with temperature, especially when the detection element is a biomolecule such as a protein or nucleic acid. Such conformational or structural changes can alter the binding rate of the target analyte. When the detection element is an enzyme, the catalytic rate can increase or decrease in response to temperature.

[0012] In any case, a calibration curve or other standard against which the sensor output is evaluated will not provide an accurate baseline if the standard was established at a temperature different from the temperature of the test sample at the time of reading. Of course, an inaccurate baseline results in an inaccurate analyte concentration value.

[0013] The problem of temperature dependence may not occur in laboratory-based analysis where the temperature of the sample is tightly controlled to be the same as or similar to the temperature of the relevant reference substance.

[0014] However, in many applications, the temperature of the sample cannot be controlled, and there is a very high likelihood of a temperature mismatch between the reference material and the test sample. An important example is when the test sample is an in situ biological fluid. Normal body temperature is generally considered to be 37.5 °C, but an individual's body temperature can vary significantly throughout the day, and even more so during an episode of infection or in response to environmental temperature. Furthermore, significant variations are seen among individuals tested under the same conditions. These variations have been found to be sufficient to provide an inaccurate output for standards carried out at 37.5 °C when the test sample is within the expected range of body temperature variation.

[0015] The prior art provides for the use of mathematical correction factors to account for the temperature difference between the reference sample and the test sample. While these approaches are generally effective in improving the accuracy of sensor output, they rely on the accurate determination of the test sample temperature. This presents a particular challenge when the test sample is an in situ biological fluid and accurate temperature readings are not readily obtainable because the fluid is inaccessible to a temperature probe.

[0016] One aspect of the present invention is to provide an improvement over prior art micro-needle-based biosensors. The improvement can be one or more of protrusion, size, weight, complexity, cost, the ability to monitor improper implantation, or accuracy. The improvement may be provided by only one embodiment of the present invention. In some situations, the present invention may not provide any improvement at all, but instead may only provide a useful alternative to prior art devices.

[0017] The discussion of documents, acts, materials, devices, articles, etc. is included in this specification only for the purpose of providing context for the present invention. None of these matters, either singly or in combination, is intended to suggest or indicate that they formed part of the prior art base or were common general knowledge in the field related to the present invention prior to the priority date of each claim of this application. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0018] Although not necessarily in the broadest aspect, in a first aspect, the present invention provides an electrochemical sensor device for bringing one or more protrusions into long-term contact with a biological fluid or tissue under the skin of a subject, the device comprising: one or more protrusions configured to penetrate the skin; a skin contact portion defining a skin contact surface and one or more spaces through which the one or more protrusions can extend; a movable portion configured to move the one or more protrusions from a first position behind the skin contact surface to a second position; optionally, a holding portion configured to hold the skin contact surface in contact with the skin during use; a thermal energy sensor configured to determine the temperature of the biological fluid or tissue around the one or more protrusions when in contact with the biological fluid or the tissue; and the movable portion is configured to move from the first position to the second position.

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

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

[0021] In one embodiment of the first aspect, the free end moves a longer distance than the connection end.

[0022] In one embodiment of the first aspect, the non-linear path is described by 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 angle of the arc is less than about 45°, 40°, 35°, 30°, 25°, 20°, 15°, 14°, 13°, 12°, 11°, 10°, 9°, 8°, 7°, 6° or 5°.

[0025] In one embodiment of the first aspect, the movable part has a pivoting part, a hinge part, a bending part or an attachment part.

[0026] In one embodiment of the first aspect, the movable part is related to the attachment part.

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

[0028] In one embodiment of the first aspect, the attachment part includes a portion that allows the movable part to pivot, hinge, bend or attach.

[0029] In one embodiment of the first aspect, the attachment part has a fixed spacing relative to the skin contact surface.

[0030] In one embodiment of the first aspect, the attachment part has a spacing of less than about 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm or 2 mm from the skin contact surface.

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

[0032] In one embodiment of the first aspect, the device further includes a user - operable release part, which is configured to hold the movable part in the first position until the release part is actuated by the user, and when the release part is actuated by the user, the movable part is released and can move to the second position.

[0033] In one embodiment of the first aspect, the apparatus further includes a locking unit configured to lock the movable part when the movable part is in the second position.

[0034] In one embodiment of the first aspect, the apparatus is configured such that moving the movable part from the first position to the second position requires power generated inside and / or outside the apparatus.

[0035] In one embodiment of the first aspect, the power generated inside the apparatus is derived from a spring, an elastically deformable member, a shape memory member, or other biasing means, and the power generated outside the apparatus is derived from a user.

[0036] In one embodiment of the first aspect, the apparatus does not have an internal power generator configured to move the movable part from the first position to the second position.

[0037] In one embodiment of the first aspect, the holding part is a dermatologically acceptable composition disposed on or around the skin contact surface or includes a dermatologically acceptable composition.

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

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

[0040] In one embodiment of the first aspect, the holding part is selected from one or more of a strap, a band, a belt, a clamp, a grip, a cord, a fastener, a sleeve, a stocking, a sock, a glove, a cap, a hat, pants, a singlet, a shirt, a bra, a top, trousers, a scarf, a ring, glasses, and a choker.

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

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

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

[0044] In one embodiment of the first aspect, the one or more protrusions have a sufficient length to be able to contact the epidermis, dermis or subcutaneous layer of the subject.

[0045] In one embodiment of the first aspect, the one or more protrusions are configured to conduct an electric current to, from or through the skin, conduct a sound wave to, from or through the skin, conduct light to, from or through the skin, conduct heat to, from or through the skin, sample fluid or tissue from the skin, deliver a biologically active substance to the skin or introduce an analyte sensing substance into the skin during use.

[0046] In one embodiment of the first aspect, each of the one or more protrusions is conductive, and the device further includes a circuit having an audio, visual or tactile indicator, the circuit being configured to activate the indicator when the one or more protrusions are in contact with a conductive fluid naturally present within the skin.

[0047] In one embodiment of the first aspect, the circuit includes at least two protrusions, the circuit being configured to be completed by the at least two protrusions in contact with the conductive fluid naturally present within the skin in order to activate the indicator.

[0048] In one embodiment of the first aspect, the circuit includes one protrusion and at least one conductive pad placed against the skin, and the circuit is configured such that, in order to activate the indicator, the one protrusion and the conductive pad are completed by being in electrical communication with the conductive fluid naturally present within the skin.

[0049] In one embodiment of the first aspect, the device includes a housing, and when the device is applied to the skin, the movable part is in the second position, and any part of each of the one or more protrusions on the skin contact surface is embedded in the skin, the housing has dimensions such that most or substantially all of it extends over the skin within a range not exceeding about 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm, 19mm or 20mm.

[0050] In one embodiment of the first aspect, the long time is longer 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 one embodiment of the first aspect, the one or more protrusions cannot be separated from the device or are inseparable without the assistance of an instrument.

[0052] In one embodiment of the first aspect, the movable part and the attachment part are integrally formed.

[0053] In one embodiment of the first aspect, the integrally formed movable part and attachment part are made of an elastically deformable material.

[0054] In one embodiment of the first aspect, the integrally formed movable part and attachment part are part of the circuit board of the device.

[0055] In one embodiment of the first aspect, the movable part is biased towards the second position and is held at the first position against the biasing force by the releasable part operable by the user until the releasable part is actuated. When the releasable part is actuated, the movable part is released and can move to the second position.

[0056] In one embodiment of the first aspect, the releasable part operable by the user is a ledge configured to hold the movable part at the first position, and the motive force provided by the user deforms the ledge and / or the movable part so that the movable part is released from the ledge and can move to the second position.

[0057] In one embodiment of the first aspect, the movable part is hinge - connected to the skin - contacting part.

[0058] In one embodiment of the first aspect, the hinge is disposed in or towards the peripheral region of the movable part and the skin - contacting part.

[0059] In one embodiment of the first aspect, the releasable part includes a member configured to hold the movable part at the first position, and the member is removable or deformable by the user so that the movable part can be moved to the second position.

[0060] In one embodiment of the first aspect, the member is removable by sliding it generally across the skin - contacting part.

[0061] In one embodiment of the first aspect, the member is generally wedge - shaped, and the device includes a hinge associating the movable part with the skin - contacting part, with the narrow part of the wedge disposed proximal to the hinge and the wide part of the wedge disposed distal to the hinge.

[0062] In one embodiment of the first aspect, in one embodiment of the first aspect, the release portion is removable from the device and includes a gripping portion to facilitate manual removal.

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

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

[0065] In one embodiment of the first aspect or the third aspect, the one or more protrusions have a reference solution that is in electrical communication with the one or more protrusions and is configured to function as a reference electrode.

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

[0067] In one embodiment of the first aspect or the third aspect, when the one or more protrusions are inserted into the skin of the subject, the one or more protrusions are specialized to function to identify the temperature of the biological fluid or tissue around the one or more protrusions.

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

[0069] In one embodiment of the first aspect or the third aspect, the thermal insulation material surrounds the distal ends of the one or more protrusions that are distal from a portion of one of the one or more protrusions inserted into the skin.

[0070] In one embodiment of the first aspect or the third aspect, the thermal insulation material forms a cap on the distal ends of the one or more protrusions that are distal from a portion of one of the one or more protrusions inserted into the skin.

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

[0072] In one embodiment of the first or third aspect, the one or more protrusions are at least partially made of metal, metal alloy, combination of metals, or ceramic.

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

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

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

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

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

[0078] In one embodiment of the first or third aspect, the being in thermal communication is via a thermally conductive and fluidic substance disposed between the thermal energy sensor and one of the one or more protrusions.

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

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

[0081] In one embodiment of the first aspect or the third aspect, one of the one or more protrusions includes a lumen.

[0082] In one embodiment of the first aspect or the third aspect, the thermal energy sensor is at least partially disposed within the lumen or functions at least partially through the lumen.

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

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

[0085] In one embodiment of the first aspect or the third aspect, the thermal energy sensor is applied to the surface of the skin or is directed towards the surface of the skin.

[0086] In one embodiment of the first aspect or the third aspect, the thermal energy sensor is in contact with the skin or is in thermal communication with the skin.

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

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

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

[0090] In one embodiment of the first aspect or the third aspect, the thermally conductive solid material has a thickness of 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 one embodiment of the first aspect or the third aspect, the thermal energy sensor is a thermocouple, a thermistor, or an infrared sensor.

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

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

[0094] In one embodiment of the first aspect or the third aspect, it includes a redox-active species associated with the aptamer and configured to function to report the interaction between the target analyte and the aptamer.

[0095] In the second aspect, the present invention provides 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 providing a device according to any embodiment of the first aspect, bringing the skin contact surface of the device into contact with the subject, causing or enabling the movable part to move from the first position to the second position, and causing or enabling the thermal energy sensor to determine the temperature of the biological fluid or the tissue.

[0096] In one embodiment of the second aspect, the device remains applied to the skin for a period exceeding 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 tissue under 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 of the skin contact surface; a user-activatable release portion configured to hold the movable portion in the first position until the user activates the release portion, and when the release portion is activated by the user, the movable portion is released and is movable or can be moved to the second position; a thermal energy sensor configured to identify the temperature of the biological fluid or the tissue around the one or more protrusions when in contact with the biological fluid or the tissue; and.

[0098] In one embodiment of the third aspect, the release portion is configured to hold the movable portion in the first position, but includes a member that is removable or deformable by the user such that the movable portion can be moved to the second position.

[0099] In one embodiment of the third aspect, the member is removable by sliding generally across the skin contact portion.

[0100] In one embodiment of the third aspect, the member is generally wedge-shaped, and the device includes a hinge that associates the movable part with the skin contact part, with the narrow part of the wedge disposed proximal to the hinge and the wide part of the wedge disposed distal to the hinge.

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

[0102] In the fourth aspect, the present invention provides a method for 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, contacting the skin contact surface of the device with the subject, actuating an operable release member by the user to move or enable movement of the movable part from the first position to the second position, and causing or enabling the thermal energy sensor to identify the temperature of the biological fluid or the tissue.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0104] Unless otherwise indicated in this specification, features in the drawings that are given the same reference signs are considered to be the same features or at least functionally similar features when used across different drawings.

[0105] The drawings are not drawn to a particular scale or dimension and are not presented as showing all embodiments perfectly accurately.

[0106] After considering this description, it will be apparent to those skilled in the art how the invention may be implemented in various alternative embodiments and alternative uses. However, while various embodiments of the invention are described herein, these embodiments are presented by way of example only and are not limiting. Accordingly, the description of these various alternative embodiments should not be construed as limiting the scope or breadth of the invention. Further, the description of advantages or other aspects applies to specific exemplary embodiments and not necessarily to all embodiments or any embodiments actually covered by the claims.

[0107] Throughout the description and claims of this specification, the terms "comprising", "including" and variations of such terms are not intended to exclude other additives, components, integers or steps.

[0108] Throughout this specification, references to "one embodiment" or "an embodiment" mean that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, although they may be.

[0109] As used herein, terms related to position such as "horizontal", "across", "above", "overlying", "below", "higher", "lower", "upper", "lower", "plan view", etc. should be considered with reference to the present invention when applied to the upward-facing area of the skin of a subject such as the upper surface of a person's thigh when the person is sitting on a chair. The present device may be applied to an area of the skin having an orientation different from the upright orientation described above, and in this case, those skilled in the art can adequately reformulate the terms related to the above positions.

[0110] The term "subject" is used to refer to an animal (including humans and non-human animals) to which the present device can be applied. The term "user" is used to refer to a human who applies the present device to a human or non-human animal. The subject and the user may be the same human subject, but they do not necessarily have to be.

[0111] The term "biological fluid" includes, but is not limited to, interstitial fluid, blood, saliva, lacrimal gland 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, liver secretions, bile, or exudate, and can be any biological fluid of the subject that comes into contact with the needle electrode of the electrochemical sensor in vivo during use. "Tissue" includes a volume containing one or more cells.

[0112] Unless the context of use clearly indicates the contrary intention, the terms "needle", "microneedle", and "wire" are used synonymously. Each is functionally identical or similar and can be inserted into the skin of a subject to contact a biological fluid or tissue.

[0113] Various different embodiments of the present invention are disclosed herein (by the drawings or the description), and the embodiments have one or more features disclosed in their context. It will be understood that there is no intention to limit the use of a particular feature or combination of features in the embodiments in which they are disclosed. For example, a first embodiment may be disclosed as including features A and B, and a second embodiment may be disclosed as including features C and D. The present invention is intended to include within the scope of the invention embodiments having any one, two, three, or four of features A, B, C, and D in any available combination.

[0114] However, those skilled in the art will appreciate that certain combinations may be less preferable or actually taboo. For example, if feature B requires feature A to operate, an embodiment including the combination of features B, C, and D may not be feasible.

[0115] The present invention is based at least in part on the discovery that an improved or alternative sensor device is provided with a temperature sensing function to improve the accuracy of the output of the device. Further details of the temperature sensing function are provided below.

[0116] The device includes a movable part that biases the microneedles against the skin of the subject and moves in a non-linear path. Further, the non-linear path may be of limited length and may be arcuate to a limited extent. With this configuration, the main movable part of the device only requires a limited range of movement in the vertical direction to place and insert the microneedles against the skin of the subject. The limited range of movement allows the housing of the device to have a relatively low profile when viewed laterally. Therefore, the device rises to a relatively small height on the skin and is thus unobtrusive to the subject.

[0117] Furthermore, the nonlinear path of the movable part enables the use of a simplified mechanism. For example, the movable part can move by means of a simple bending or hinge mechanism. These mechanisms require a relatively small number of components and, overall, enable the development of a smaller, lighter, simpler, more reliable, and less expensive device.

[0118] Certain embodiments of the present invention have further features which, alone or in combination with other features, provide further advantages over the prior art or more useful alternatives. Such embodiments will be more fully described by reference to the non-limiting preferred embodiments described below.

[0119] Refer to FIG. 1 showing a basic form of the device (10) having a microneedle array (one microneedle denoted as 15) attached to a movable part which is an elastically deformable arm (20) in this embodiment. The arm (20) is biased to take a straight configuration (20b), but first presents to the user an arm bent to curve upward as shown by the dashed line indication (20a).

[0120] The device (10) includes a rigid housing (25) having a skin contact portion (30) defining a downward-facing skin contact surface (35) on its lower side. The skin contact surface (35) is placed on the skin of the subject and is held there by areas of dermatologically acceptable adhesives (40a, 40b). Suitable adhesives typically have water resistance so that the subject can take a bath normally. The adhesives typically have sufficient adhesiveness to prevent peeling that may occur during daily activities such as dressing, undressing, sleeping, performing housework, mild to moderate sports activities, rubbing against objects while walking, etc. The level of the adhesive is usually not large so as not to cause difficulty, discomfort, pain, irritation or skin damage when removing the device.

[0121] The exemplary adhesive is a type of synthetic rubber adhesive or a tackifying acrylic adhesive used in medical tapes. A double-sided medical tape such as 3M (trademark) 1577 tape can be used, where one side adheres to the device and the other side adheres to the skin of the subject.

[0122] The skin contact portion (30) includes a space (45), and the margins of the space are marked as (45a) and (45b). The space (45) provides respective passages through which the microneedles (15) pass, and when the arm (20) is in the straight position (20b), it enables the tip region of the microneedles to penetrate and be embedded in the underlying skin (50).

[0123] The arm (20) is held in a bent state by a ledge (55) that functions as a release means. When the user wants to insert the microneedles (15) into the skin (50), the button (60) is depressed as indicated by the arrow. The lower surface of the button (60) bears against the ledge (50), and since the ledge (55) has the ability to deform (e.g., is made of a material such as rubber or is formed from flexible protrusions on the inner surface of the housing (25)), it bends downward under the force so that the edge of the arm (20a) is released. The elastic nature of the arm (20a) causes it to quickly return to its biased straight position (20b), thereby pushing the microneedles (15) into the underlying skin (50). The ledge (55) is configured to exhibit sufficient elasticity to resist the biasing force in the arm (20a), but its elasticity is not sufficient to resist the downward force applied when the button (55) is depressed.

[0124] In the embodiment of FIG. 1, one end of the arm (20) is fixed to the housing (25) by a fastener (65). The arm (20) is flexible, but its flexibility is not so high that it can easily move away from the position (20b) when it is in place on the skin (50) of the subject. By moving the arm (20) away from the position (20b), the microneedle (15) can be withdrawn from the skin (50). Considering the bias of the arm (20) towards the position (20b), a locking mechanism may not be necessary to hold the arm in the position (20b). However, if necessary, a suitable locking mechanism for the embodiment of FIG. 2A will be described below.

[0125] FIG. 2A shows an alternative basic form of the device (200) in which the arm (205) is rigid and hinge-connected to the housing (25) via a hinge pin (210). The embodiment of FIG. 2A operates in the same manner as the embodiment of FIG. 1 as long as the ledge (55) acts 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 ledge (55), causing the ledge (55) to bend and releasing the free end of the arm (205a). The button (215) is continuously pressed by the user until the arm takes the position (205b), at which position the microneedle (215) is embedded in the skin (50). Again, the point on the free end of the arm (205a) moves along a non-linear path, which in this embodiment is an arc that is a segment of a circle, and the origin of the circle is at the hinge pin (210).

[0126] It will be appreciated that the hinge structure of the embodiment of FIG. 2A does not provide resistance to the arm (205) attempting to move away from the position (205b) by hinge movement while the device is attached. Thus, there is a risk of the microneedle (15) being pulled out of the skin when it is within the skin (50). Accordingly, a locking mechanism is provided to hold the arm in position (205b). This mechanism includes, for example, a deformable latch (220) formed from an internal protrusion formed from a material having a certain degree of flexibility or 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 bent to the left (as in the figure) under the force applied by the user via the button (215) and the inclined upper surface. When the end of the arm (205) clears the lower corner of the inclined upper surface, the latch (220) returns to its normal upright position (as in the figure) and the free end of the arm (205b) seats firmly in the recess in the base of the latch (220).

[0127] 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 held in a predetermined position by release means (55). In this embodiment, the release means is removable by the user when the device (200) is applied to the subject. After the release means (55) is removed, the arm (205a) is pushed downward by the user to assume a second position (205b).

[0128] In the embodiments of FIGS. 1, 2A and 2B, when the free end of the arm (20 or 205) is released from the ledge (55), it moves non-linearly as it returns to its biased position (20b). Considering a single point on the free end of the arm (20 or 205), that point moves along a non-linear path that describes an arc. In the context of the present invention, the terms "arc", "arcuate" and similar terms mean a curve joining any two points. The term "arc" is, in some embodiments, a segment of a circle (see, for example, the embodiment of FIG. 2A), but should not be construed as being limited to meaning only a segment of a circle.

[0129] As is apparent from both the basic embodiments of FIGS. 1 and 2A and 2B, in each case, the arm (20 or 205) moves a relatively short distance when transitioning from the first position to the second position. In fact, in these embodiments (and certain other embodiments), the device is intentionally configured such that the arm cannot move along a path outside of the path between the first and second positions. In other words, the device can be configured such that the arm cannot move along a path outside of the shortest distance between the first and second positions.

[0130] By providing a limitation on the path along which the arm can move, advantages are provided insofar as the height of the device (in the vertical direction as shown) is also limited. Thus, the device can take a low profile that extends only a relatively short distance over the skin of the subject (in a dimensional sense).

[0131] Next, referring to FIGS. 3A and 3B, there is shown a preferred device that is generally configured in accordance with the embodiment of FIG. 1 and is operable in general agreement with the embodiment of FIG. 1. The arm (20) is integrally formed with a PCB (65) that carries various electronic components necessary for the operation of the device. The PCB material is elastically deformable, and when the arm (with micro-needles attached to the terminals) is bent upward as shown to place the arm in the first position and then released, the arm takes the second position due to the natural bias of the arm to the second position.

[0132] The arm (20) is held in the first position by the end of the arm (20) located on the ledge (55), as most clearly shown in FIG. 1A. In this position, the micro-needles (15) are held within the device without extending through the space (45). This is the configuration in which the device is provided for use and applied to the skin of the subject.

[0133] The arm (20) is connected to a micro-needle mounting block (70) that supports the micro-needles. The mounting block (70) also includes a conduit (not shown) for carrying current from each micro-needle (015) to one of a number of connection points (75) on the PCB (65). With this configuration, electrical signals can be transmitted to and / or from the micro-needles embedded in the subject's skin. For example, the device can be configured as a sensor having micro-needles configured to contact a biological fluid or tissue within the subject's body to detect an analyte therein. The biological fluid can be, but is not limited to, interstitial fluid, blood, or a mixture thereof. Electrical signals from the micro-needles are transmitted to the PCB for amplification, filtering, encoding, analysis, transmission, or other electrical or electronic processes.

[0134] In this embodiment, the PCB serves a dual role of holding the electronic components of the device and functioning as a driving means for moving the micro-needles from an internal position to an external position within the device. The PCB material has been found to be well-suited for providing a preferred limited operating range for the arms of the device. This configuration reduces the number of components within the device.

[0135] The upper surface of the housing (25) shows the operating surface of a button (215) that can be depressed by the user's finger. The button (215) is biased upwardly either by a spring or by being integrally formed with the material of the housing (25). In the latter form of biasing, the button (215) can be attached to an arm that is integral with the housing material and biased such that the upper surface of the button (215) is in the same plane as the housing (25).

[0136] The lower part (not shown) of the button (215) is placed on the upper surface of the arm (20), the upper surface being the back of the PCB (65). When the button (215) is depressed, the arm (20) is biased downward and released from the ledge (55), assuming a second position. In the second position, it can be seen that the microneedles extend through their respective spaces (45) and embed into the underlying skin (e.g., the epidermis, dermis, or subcutaneous layer of a subject).

[0137] The natural biasing of the PCB (65) material towards the second position is strong enough for the arm (20) to remain in the second position without the need for means to lock the arm in the second position. Thus, the microneedles (15) can remain embedded in the subject's skin for an extended period.

[0138] In an alternative embodiment, the arm (20) has a curved configuration when in the second position and is naturally biased to move away from the second position. In another embodiment, the biasing of the arm (20) towards the second position is strong enough to prevent movement away from the second position. In such embodiments (and other embodiments), a locking mechanism may be provided to prevent movement of the arm away from the second position so that the microneedles (15) do not retract into the device and remain embedded in the skin. A suitable locking mechanism is the latch mechanism disclosed in connection with other embodiments in this application. Other locking mechanisms will be apparent to those skilled in the art having the benefits of this specification.

[0139] The housing (25) includes opposing recesses (80) to facilitate gripping between the user's thumb and index finger and to hold the device against the surface of the skin. The user's first finger can freely actuate the button (215) to embed the microneedles (15) into the underlying skin.

[0140] To enable the device to be held in place on the subject's skin for an extended period, a dermatologically acceptable adhesive layer (not shown) may be applied to the skin contact surface (35). The adhesive layer can cover part or substantially all of the skin contact surface (35). As described for other embodiments of the device described herein, a manually releasable flexible layer may cover the adhesive until the device is applied to the skin.

[0141] Referring now to FIGS. 4, 5A, 5B, 6, and 7, there is shown a preferred device that is generally configured in accordance with the embodiment of FIG. 2B and is operable in a manner generally similar to the embodiment of FIG. 2B.

[0142] This embodiment includes an upper housing portion (25) and a skin contact portion (30). A removable flexible layer (90) that can be grasped via a tab (95) is also provided. Removal of this flexible layer exposes the dermatologically acceptable adhesive on the skin contact surface (35). As described above, the adhesive is intended to hold the device on the subject's skin for an extended period. The flexible layer (90) functions to prevent curing or drying of the adhesive and to prevent contamination of the adhesive layer prior to use and / or premature adhesion of the adhesive to the package or other surfaces. In a particularly preferred embodiment, in addition to covering the adhesive layer, the flexible layer (90) extends over the space (45) to prevent contamination of the microneedles (15) and to help prevent unintentional needle sticks to the user.

[0143] The device may have a holding portion that functions to hold the device on the skin such that the protrusions remain in contact with the subject's body fluid or tissue. The holding portion may be dedicated to that function or may serve another function.

[0144] In many situations, a retaining portion that is a dermatologically acceptable adhesive or includes such an adhesive is useful. The adhesive makes it possible to simplify the application of the device by the user, and often requires removing a protective backsheet to expose the adhesive and then contacting the exposed adhesive with the skin. Since this application method is similar to that of an adhesive plaster, it is a process already familiar to the user.

[0145] As an alternative to the use of an adhesive, the retaining portion can be some mechanical means for holding the device in the required position on the skin. For example, the device can include a dedicated strap that engages with an adjustable limb to hold the device firmly attached to the subject. Alternatively, the device can be incorporated into an item of jewelry such as a ring that functions to hold a wearable item such as a glove or a shirt in place. The device can be configured to engage with a separate wearable item (e.g., by complementary hook and loop means) or the wearable item can be integrated with it.

[0146] In some embodiments, the device is simply held by a wearable item that is wearable with respect to the housing. For example, the retaining portion can be a snug-fitting elastic glove worn over the device.

[0147] In some embodiments, the retaining portion is any surface or part of the device that contacts the subject's skin, and the characteristics of the subject are at least partially responsible for holding the device in place on the subject. For example, the device can be configured to be held between two parts of the body that are normally in proximity or within an existing anatomical structure. The device can be formed to have a shape and / or dimensions such that it is held between the toes, between the buttocks, within the groin, within the buccal cavity, within the nostrils, within the ear canal, or within the umbilicus.

[0148] In other embodiments, the device housing may be formed to have a shape and / or dimensions that fit snugly, for example, over a finger, toe, or ear. The device housing may be elastically deformable, for example, composed of a rubberized material, and configured to be stretched over any anatomical part (such as a finger).

[0149] Each of the foregoing embodiments is considered to be a holding part in the context of the present invention.

[0150] The device further includes a release member (100) having a gripping portion (105) and a wedge portion (110), the function of which will be described in more detail below.

[0151] Here, referring to the exploded views of FIGS. 5A and 5B, components similar to those in the previous figures will become immediately apparent.

[0152] In this embodiment, the motive force for moving the arm (205) and thereby pushing the microneedle (15) into the underlying skin is provided by the user. In use, the user places a finger on the upper housing (25) and presses downward. Further, the arm (205) is movable by a hinge configuration.

[0153] The hinge configuration is provided via opposing lugs (115) extending from the skin contact portion (30), each lug including an opening. The arm (205) includes opposing disks (120) extending laterally, each disk seating in the opening of the lug (115). It is clear that the arm (205) is hinge-operable relative to the skin contact portion (30), enabling movement from a first position to a second position.

[0154] The arm (205) is presented to the user with the arm in the first position. The arm (205) is held in the first position by the wedge portion (110) of the release member (100). Before removing the release member (100), the wedge is inserted between the skin contact portion (30) and the arm (205), thereby holding the microneedle within the device.

[0155] When attempting to apply the device to the skin of a subject, the user removes the flexible layer (90) by pulling on the tab (95) to expose the adhesive layer on the skin contact surface (35). The device is then applied to the skin and the adhesive holds the device in place for an extended period of time.

[0156] Once the device is applied to the skin, the user grasps the grip portion (105) and pulls to the left (as shown) to completely remove the release member (100). The release member (100) no longer has a function and is discarded at this point. By removing the release member (100), the arm (205) is released from the first position and can be moved to the second position (under the downward force applied by the user), whereby 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 downward through the space (45) into the skin below.

[0157] As will be appreciated, the release member (100) can be configured to prevent the upper housing (25) of the device from closing against the skin contact portion (30) when not intended by the user. The release member (100) is inserted or juxtaposed 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) such that the tip of the microneedle (i.e., the protrusion) can protrude sufficiently from the base of the hole in the skin contact portion (30). By preventing closure, movement of the arm (205) from the first position to the second position is also prevented. Therefore, when the release member (100) is in a predetermined position, the tip of the microneedle is not inadvertently accessed, preventing contamination or damage to the microneedle. When using the device, the user removes the release member (100) as a step in the usage process. In a preferred embodiment of the use of the device, the user first adheres the device to the skin of the subject and then removes the release member (100) before pressing the upper housing (25) to insert the microneedles into the skin.

[0158] Before removal by the user, the release member (100) can be held in place by any one of a variety of features. In one example, the release member (100) includes protrusions that fit into recesses in the upper housing (25), the skin contact portion (30), or both the upper housing (25) and the skin contact portion (30), assisting in holding the release member in place until it is intentionally removed. In another example, the skin contact portion (30) or the upper housing (25) is designed to be slidably assembled so as to assist in holding the release member in place by the friction between the release member (100) and either the upper housing (25) or the skin contact portion (30) until the release member (100) is intentionally removed. In yet another example, magnetic force can be used to assist in holding the release member (100) in place. In one embodiment of the present invention, a magnet mounted within the release member (100) is arranged to be close to a Hall effect sensor disposed in either the upper housing (25) or the skin contact portion (30) when the release member (100) is in a predetermined position. According to this embodiment, when the release member (100) is removed by the user, the Hall effect sensor detects the removal of the magnet and causes the device to perform some operation, such as powering on an available electronic circuit and converting from sleep mode to active mode. The above are examples of possible ways to assist in holding the release member (100) in place before intentional removal, which can be used alone or in combination, and it should be understood that other methods known in the art can also be used alone or in combination with a given example.

[0159] In some embodiments of the present invention, the release member (100) can also function as a cover element used to cover the microneedles after the device is removed from the subject. In a preferred example of this embodiment, the locking element is located on the upper housing (25) and extends downwardly towards the skin contact portion (30). The release member (100) includes a groove for continuously maintaining the surface of the release member (100) facing the upper surface of the skin contact portion (30) while allowing the release member (100) to slide through the locking element when the release member (100) is pulled out of the device. In use, the release member (100) according to this preferred embodiment is removed and held by the user before pressing the upper housing (25) to insert the microneedles into the subject's skin. After the device is removed from the subject after use, the user is instructed to adhere the release member (100) to the adhesive layer on the lower surface of the skin contact portion (30) so as to cover the protruding microneedles. In another example of this embodiment, the release member (100) remains attached to the device even after being pulled out by the user, and then is repositioned to cover the protruding microneedles after the device is removed from the subject after use, and is flexibly attached to the device. In yet another example of this embodiment, the release member (100) and the upper housing (25) can be designed to be slidably engaged or otherwise engaged with the upper housing (25) after it is removed, in which case the release member (100) is stored during use of the device and is intended to be removed for use as a cover element after the device is removed from the subject.

[0160] In some embodiments, the device is configured to facilitate removal of the device from the subject by the user. As will be appreciated, the use of an adhesive layer may make it difficult to remove the device from the skin. Examples of such configurations include not coating a portion of the skin contact surface (35) with an adhesive such that there is a gap between the subject's skin and the surface (35). The user uses this gap as a lever point to assist in pulling the device away from the skin by breaking the bond of the adhesive. In another example, a lever mechanism that is not located on the skin contact surface is incorporated to allow for a higher gap than would be formed by the absence of an adhesive on a portion of the skin contact surface. In yet another example, a tab can be incorporated that extends beyond at least one end of the skin contact portion (30) and is attached to the adhesive layer. In this case, the user pulls on the tab with sufficient force to stretch and yield the adhesive layer, separating the adhesive from the skin contact surface (35) and the skin.

[0161] In some embodiments of the present invention, the device is designed such that the release member (100) is locked in its position prior to use of the device unless pressure is applied to the upper housing (25). This embodiment is intended to further improve the risk of the release member (100) being prematurely withdrawn. In one example of this embodiment, there are portions on the release member (100) and on at least one of the upper housing (25) and the skin contact portion (30) that engage lockably when the upper housing (25) is not being pushed. When the upper housing (25) is pushed down, the portion on at least one of the upper housing (25) and the skin contact portion (30) is distorted, releasing the engagement of the release member (100) such that it can be withdrawn.

[0162] In yet other embodiments, it is not necessary for the user to remove the release member (100) from the device. According to these embodiments, the release member (100) has a sufficiently high rigidity so as not to substantially bend when receiving a closing force that may be present in the device while in the user's hand prior to manufacture, storage, and application to the subject, but includes a sufficiently flexible flexible element that bends when the user intentionally applies a closing force to the device when applied to the subject's skin. By bending in this way, the release member (100) bends and the upper housing (25) can close towards the skin contact portion (30). In these embodiments, the release member (100) may also function as a locking element or the release member (100) may be separate from the locking portion. In some of these embodiments, features such as those labeled (220) in FIGS. 5A, 5B, and 7 form the release member (100).

[0163] Each space (45) of the device is formed to have dimensions such that the microneedle can clearly extend therethrough and at least the tapered portion of the microneedle does not affect the side surface of the hole during insertion. In some embodiments, the hole may have a sufficient cross-section such that no portion of the microneedle contacts the side surface of the space during insertion. In other embodiments, at least a portion of the hole along its length has a cross-section such that a portion of the length of the microneedle contacts the side surface of the hole during insertion. According to this embodiment, the hole functions to help support a portion of the length of the microneedle to assist in preventing the microneedle from bending when the microneedle is inserted.

[0164] In some embodiments of the present device, the skin contact portion (30) includes an additional space or recess configured to receive a protrusion on the release member to assist in holding the release member until it is removed by the user. Additionally or alternatively, the skin contact portion (30) includes a protrusion designed to be received in a recess of the release member to assist in holding the release member in place until it is intentionally removed by the user.

[0165] The embodiments shown in FIGS. 4, 5A, 5B, 6, and 7 include a locking portion in the form of a latch (220) that permanently locks the arm (205) in the second position, preventing the arm (205) from performing any hinge movement. In the illustrated embodiment, the latch (220) can flex in response to movement of the arm (205) towards the closed position, but returns to its original position when the arm (205) is in the second position (205b), thereby locking the arm (205) in place with a simple single member.

[0166] The locking portion acts not on the arm (205), but on another component of the device, and that component can lock the arm in place. For example, the locking portion acts on the upper housing (25), and the upper housing (25) can hold the arm (205) in the second position. As a further alternative, the locking portion acts on the PCB (65), and the PCB (65) can hold the arm (205) in the second position.

[0167] In other embodiments, the locking portion includes a recess into which a protrusion on the upper housing (25) is inserted to lock the upper housing (25) in the closed position (i.e., the state where the arm (205) is in the second position). In one embodiment, the locking portion includes a flexible element designed such that when the locking portion is struck against the upper housing (25), the locking portion can move, enabling the housing (25) to close relative to the skin contact portion (30). Thus, when the upper housing (25) closes, the locking portion moves to lock the upper housing (25) in the closed position. In one embodiment, the device includes a protrusion on the upper housing (25) designed to be inserted into the recess of the locking portion. The protrusion includes a flexible element such that the protrusion can move, enabling the upper housing (25) to close relative to the skin contact portion (30). After the housing (25) closes relative to the skin contact portion (30), the protrusion is moved and inserted into the recess of the locking portion to lock the upper housing (25) in the closed position. The flexible element may include a shaft that is sufficiently deformable so that the upper housing (25) can close without yielding of the shaft. Therefore, the flexible element attempts to return to its original position after the upper housing (25) closes. In a less preferred but functional embodiment, the flexible element includes a coil spring.

[0168] The flexible element of the locking portion can be manufactured from any suitable material having the required rigidity and yield point. Examples of suitable materials include amorphous plastics, crystalline plastics, spring steel, springless steel, stainless steel, or other materials known in the art as having suitable mechanical properties.

[0169] 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 manufacture of the skin contact portion having an integral locking portion.

[0170] In a particularly preferred embodiment of the present invention, the force required to deflect or move the flexible element is designed such that the pressure that the user needs to supply to deform the flexible element and thereby close the upper housing (25) towards the skin contact portion is sufficient to insert the microneedles into the skin. According to this embodiment, the flexible element of the locking portion sets the force required to close the device (thereby moving the arm to the second position), and the force is used to ensure that it is sufficient to insert the microneedles into the intended position embedded in the skin.

[0171] In other embodiments, the locking portion includes at least one adhesive region 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, the one or more adhesive regions adhere the upper housing (25) to the skin contact portion (30) and lock the device in the closed position.

[0172] In another embodiment of the present invention, the locking part can take three different stable states. In the first state, the locking part is in a disengaged configuration before the upper housing (25) is pushed downward towards the skin contact part (30) to close the device. In the second state, the locking part is in the first engagement position. When the locking part is in the first engagement position, the locking part serves to lock the microneedles (15) in the implanted position within the skin (i.e., the arm (205) is in the second position). In the third state, the locking part is in the second engagement position. In this state, the locking part locks the device in the open position with the microneedles retracted into the device (i.e., the arm (205) is in the first position) in order to improve the likelihood of needle stick injuries due to the microneedles protruding after use of the device. In an example of this embodiment, the locking part includes a user engagement part that can be gripped or otherwise engaged by the user, for example, by engaging a claw under a protruding ledge so that the user can flex the flexible part of the locking part. According to this example, to close the device, the user presses the upper housing (25) and locks it in place, as in the other embodiments disclosed in this application. If it is desired to remove the device from the subject, the user engages the locking part, flexes it in a first direction to unlock the upper housing (25) from the skin contact part (25), and then flexes the locking part in a second direction to lock the device in the open position with the microneedles in the withdrawn position (i.e., the arm is in the first position). In a preferred embodiment of this example, the locking part is moved in a first direction away from the body of the device and in a second direction towards the body of the device. When sufficiently deflected in the second direction, the locking part is designed to stably engage a recess, for example, to prevent the device from closing unintentionally.

[0173] In some embodiments of the present invention, the downward force on the microneedle when inserted into the skin is provided via a flexible element of a locking portion that applies a downward force when the device is locked in the closed position (i.e., when the movable arm is in the second position). In some embodiments, effective locking of the movable arm in the second position is provided by a dedicated spring or other suitable biasing means. In other embodiments, the spring or other biasing means is not dedicated to the locking function and can also act, for example, as the motive force for moving the arm from the first position to the second position. For example, a torsion spring can apply a closing torque at the pivot point (if present). In yet another example, a leaf spring, a disc spring, or a coil spring is attached to the rear of the microneedle, and when the device is closed, the spring is distorted or compressed to apply a downward force to the microneedle when the device is in the closed position.

[0174] Although not an essential feature of the present invention, a PCB (65) is required in many applications where the microneedle is intended to conduct current to, from, or through the skin. In this regard, the PCB can hold a microprocessor and / or volatile electronic memory (such as RAM), and / or non-volatile electronic memory (such as ROM), and / or a wireless networking module (such as a Bluetooth (trademark) module). Of course, the device includes a power source, typically a button battery.

[0175] The embodiment shown in FIG. 3A includes a light-emitting diode (LED) (120) that can be seen by the user. One function of the LED (120) is to allow the user and / or the subject to confirm that the microneedle is properly embedded in the skin during application and maintains its state during prolonged wear.

[0176] The LED is electrically connected to the PCB (65), and the PCB is electrically connected to the microneedle (15). Proper embedding of the microneedle can be determined by referring to either the flow of current between the two microneedles, the resistance to current, or the impedance.

[0177] Alternatively, proper implantation of a single microneedle can be determined by referring to any one of the current flow, resistance to current, or impedance between the single microneedle and other electrical contacts of the device with the skin. As an example, a conductive pad can be disposed against the surface of the skin, and in some examples, the conductive pad is disposed on the surface of the housing that contacts the skin. This conductive pad cooperates with at least one of the microneedles to complete an electrical circuit when the microneedle is inserted into the skin. Completion of this circuit is used to indicate correct insertion of the microneedle.

[0178] The electronic circuit involved may be simple, and any example thereof is a biological fluid of the skin, such as interstitial fluid (which is naturally conductive), and acts to complete a circuit including an LED. Proper implantation is assumed to be indicated by simple contact between the microneedle and the biological fluid. The LED is lit when the microneedle contacts the biological fluid (or vice versa), thereby providing a visual indication of correct implantation.

[0179] To provide a higher level of assurance of accurate microneedle implantation, a more sophisticated electronic configuration may be required. For example, it is considered whether a microneedle of minimum length has been implanted, thereby providing assurance of insertion of the microneedle to a specific minimum depth. The device may include electronic means for measuring a quantity of a parameter such as current flow, in which case a higher current flow indicates more complete implantation of the microneedle. Program instructions executed by a processor mounted on the device or a processor associated with the device may use a parameter such as current flow (optionally along with other physiological or environmental parameters) as an input to provide an indication of the degree of microneedle implantation.

[0180] Additional functions of the LED can provide other information such as the charging level of the battery. For example, the LED may be connected to a microprocessor capable of monitoring the battery voltage, and the microprocessor may cause the LED to blink red when the voltage drops below a predetermined threshold. This value may be a voltage slightly above the minimum operating voltage to allow the subject to access a replacement battery (or a replacement device if the user is not able to service the battery) before the device becomes inoperable.

[0181] In other embodiments, the LED may generate an output indication of the data connection status. For example, the LED may alternately blink red and green light to warn of an interruption in the wireless data connection with a remote device such as a smartphone. The smartphone may process sensor outputs and be responsible for warning the subject by audible output when a threshold (such as glucose concentration) is exceeded. In such embodiments, the LED and the device network module may be connected to a microprocessor, which monitors the connection status of the module and causes an output to be generated to the LED when the connection is established and / or lost. The application software on the smartphone may be configured to warn the subject that the data connection has been lost, but the smartphone may lose power (e.g., run out of charge), and in that case, the only means of warning the subject may be by the device itself.

[0182] An output function similar to that of the LED can be provided by a buzzer or a small speaker to provide audible output that can be understood by the subject. The output can be, for example, a tone, a series of tones, or a synthesized voice.

[0183] Next, refer to an alternative embodiment of the apparatus shown in FIG. 9, which is a modified version of the embodiment shown in FIGS. 4 to 8. The embodiment of FIG. 9 includes a temperature sensor (300) that extends through the space (305) of the skin contact portion (30) to contact the surface of the subject's skin during operation. The temperature sensor (300) can be, for example, a thermocouple or a thermistor operably connected to a microprocessor on a PCB (65). The temperature sensor can be in direct contact with the skin or may be separated from the skin via a thermally conductive material.

[0184] The temperature sensor can be disposed within a pocket or other formation sized to receive the temperature sensor. The pocket can be made of a thin sheet-like material of plastic such as 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 pocket wall to the temperature sensor.

[0185] The floor of the pocket may extend outward from the device such that when the device is applied to the skin, the floor of the pocket is gently pressed onto the skin surface, thereby facilitating the transfer of thermal energy from the skin to the temperature sensor. It will be appreciated that pressing the floor of the pocket too hard onto the skin surface can push blood out of the skin capillaries, thereby artificially cooling the skin surface.

[0186] Preferably, only the floor of the pocket is made of a thermally conductive material and the remainder is made of a low thermal conductivity material. With such a configuration, thermal energy from the skin is not sent away from the temperature sensor.

[0187] To ensure that thermal energy is retained around the temperature sensor and not lost in the internal cavity of the housing, the ceiling of the pocket can be formed of an insulating material.

[0188] The pocket may include a space extending through the floor such that the temperature sensor can directly contact the skin surface. Considering that it is not necessary for thermal energy to cross the intervening material, a temperature closer to the actual skin temperature is expected.

[0189] In a further variant, the temperature sensor may be an infrared sensor module, in which case at least the material of the pocket floor must not substantially interfere with its operation. It is conceivable to form a space in the floor so that the infrared sensor module is directly exposed to the skin surface and can accurately read the skin temperature.

[0190] The signal output from the temperature sensor (300) can be used in calculations performed by a microprocessor (or a remote microprocessor) to more accurately identify the concentration of the target analyte. For example, the microprocessor can access the range of stored calibration curves, each curve being executed at a predetermined temperature. Based on the output of the temperature sensor (300), an appropriate calibration curve can be selected, thus more accurately identifying the analyte concentration.

[0191] The embodiment of FIG. 9 includes a release member (100) having a pair of protrusions (the first protrusion is designated as (310) and the second protrusion of the pair is hidden by the first protrusion). The protrusion (310) extends downward through the space (315) within the skin contact portion (30). The function of the protrusion (310) is to prevent the release member (100) from moving laterally until the lower surface of the skin contact portion (30) is pressed against the skin. By the act of pressing the skin, the protrusion (310) projects vertically out of the space (315), enabling the release member (100) to be pulled laterally by the subject. This mechanism prevents the release member (30) from being accidentally removed before the device is properly applied to the skin surface. Without such a mechanism, the microneedles (15) may extend prematurely through the space (45) and be contaminated by contact with air or objects or physically damaged, for example, by catching on clothing.

[0192] In some embodiments of the device, the upper region of the microneedles may need to be electrically insulated to avoid the wet surface of the skin (which is different from the underlying biological fluid) that forms the conduction path between the microneedles.

[0193] As another means of controlling moisture, absorbent material may be disposed on the microneedle attachment portion and proximal to the microneedle tip. In embodiments of the device for sensing applications, the absorbent material is configured to absorb any excess fluid that may be generated by the insertion of the microneedles into the skin to improve the experience of the subject and to improve problems that fluid contact with other parts of the device, such as electronic circuits or electrical contacts, may cause. In embodiments of the device for fluid extraction applications, the absorbent material acts as a wicking agent to transport the fluid from the microneedle site to the required final site 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 holes through which the microneedles pass, the holes being large enough to prevent the absorbent material from contacting the microneedles during the insertion process of the microneedles, but small enough to allow excess fluid exuding from the access penetration points created by the microneedles to contact and be absorbed by the material. In other embodiments, such as when the device is intended for use in fluid extraction, the sheet of absorbent material either has no holes or the holes are sized such that the absorbent material contacts the microneedles during and after the insertion of the microneedles to assist in its wicking action. In embodiments where the sheet has no holes, the microneedles form holes as they pass through the sheet as part of the insertion process.

[0194] The device may be configured for use and / or used in any suitable application where the microneedles need to be embedded in the subject's skin for an extended period of time.

[0195] Such uses include electrochemical aptamer-based sensing in which a target analyte in a body fluid or tissue is detected by binding to a capture agent such as an aptamer that includes a redox reporter. The capture agent may be bound to the micro-needle by a covalent or non-covalent bond, and the redox reporter causes an electrical signal to be transmitted by the micro-needle upon binding of the target analyte. The target analyte can be a drug or other exogenous species or an endogenous species such as a hormone or metabolite.

[0196] When the micro-needle functions as an electrode for detecting an analyte present in a layer of skin, the device may include circuitry and components for electrically exciting the electrode and receiving, measuring, and processing the electrical signal resulting from the electrical excitation. According to this embodiment, the micro-needle may include a tip, a shaft, and a base, and the electrical signal is generated by an electrode that is coated on the surface of the micro-needle or integrated into the micro-needle and is transmitted along the shaft of the micro-needle to the base of the micro-needle, and an electrical connection is made to the base or shaft of the micro-needle to transmit the electrical signal to and from the electrode to an electronic circuit. The electrode can be formed proximal to the tip of the micro-needle, on at least a portion of the shaft of the micro-needle, and on a portion that is not proximal to the tip of the micro-needle, or on both proximal to the tip of the micro-needle and on at least a portion of the shaft of the micro-needle.

[0197] The micro-needle can be connected to an electronic circuit by various methods known in the art, such as soldering, wire wrapping, or spring-loaded pins. In one embodiment, the micro-needle is attached to pass through a plate or a block of dielectric material, and the connection portion of the micro-needle is disposed distal to the tip of the micro-needle. Using a zebra strip connection, the micro-needle can be connected to an electronic circuit, facilitating a robust connection without the need to accurately align the zebra connector with the micro-needle end in at least one dimension.

[0198] Further potential uses are for the delivery of an electric current to the skin for the purpose of muscle stimulation or for the stimulation or inhibition of biological processes of a subject. Similarly, the device can be used to detect an electric current in the skin of a subject, for example, to detect nerve conductance.

[0199] In any of the above uses, the microneedles may be solid or hollow, as required or desired.

[0200] The length of the microneedles can be selected according to a particular use. Typically, the microneedles are required to extend at least beneath the stratum corneum. The depth of the stratum corneum varies depending on the location; for example, the layer is relatively thick on the soles of the feet and relatively thin on the backs of the hands. Accordingly, the length of the microneedles extending beyond the housing can be adjusted according to the intended site of application.

[0201] In some cases, the microneedles may need to extend well beneath the stratum corneum and into the underlying subcutaneous tissue, including the epidermis, dermis, and even deeper subcutaneous layers. Again, the length of the microneedles extending beyond the device can be set accordingly.

[0202] One skilled in the art will also understand that it may be necessary to set the length of the microneedles according to the intended subject. For example, relatively short microneedles are generally required to achieve contact with the subcutaneous tissue of neonatal subjects, while longer microneedles will be required for adult subjects at the same site.

[0203] In some applications, it may be desirable for one microneedle to penetrate the skin deeper compared to another microneedle. Thus, the two microneedles can terminate at different distances from the skin surface or at different distances from the microneedle attachment portion. In some embodiments, the two microneedles have different lengths. In other embodiments, the microneedles are of the same length and the attachment portion is configured to axially displace one microneedle relative to the other. For example, the attachment portion may be a multilayer having a first electrode extending from a first level and a second electrode extending from a second level.

[0204] In a typical application, the microneedle can extend outwardly from the distance device by about 10 μm to about 5000 μm. In many applications, a distance of about 500 μm to about 4000 μm is useful.

[0205] Those skilled in the art will understand that the invention described in this application may be subject to further variations and modifications other than those specifically described.

[0206] For example, the movable arm can be moved by the user pushing or pressing on the flexible portion of the device housing, by actuating a rotary lever, or by sliding an element along an incline to bias the arm downward.

[0207] The skin contact portion of the device is depicted as being strictly planar on its lower surface (skin contact surface), but in some embodiments, it may 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 flexibility (in at least one direction) to conform to the surface of the body part.

[0208] The space through which the microneedle extends is generally shown as an opening, but other types of spaces are also conceivable. In some embodiments, the space is not an opening, and one such embodiment has microneedles extending through the space around the skin contact portion.

[0209] The device can include a thermal energy sensor that is maintained on a subject in the same manner as the protrusion (such as a needle) of an electrochemical sensor device. Thus, the thermal energy sensor can monitor temperature over a long period during which a target analyte is detected. Therefore, the ability to measure temperature over a long period results in a more accurate determination of analyte concentration at any given time and potentially over a long period.

[0210] The inventors propose that the needle protrusion (such as a needle) of an electrochemical sensor device can perform three functions. Each of the functions cooperates to provide an accurate determination of the concentration of a target analyte in a subject. First, the needle pierces the skin and extends into the subcutaneous tissue of the subject such that the distal end contacts the subject's body fluid or tissue. Second, the needle distal end can carry a detection element (such as an aptamer) that can selectively interact with the target analyte such that the needle functions as a working electrode as a whole. Third, the needle can function to sense the temperature of the subject's body fluid or tissue. An accurate determination of the temperature of the body fluid or tissue allows for the application of a temperature-based correction factor to the concentration of the target analyte determined by the electrochemical sensor.

[0211] The needle is made of metal, silicon, polymer, glass, or ceramic, and the base of the needle is typically attached to a base substrate to form an array. The needle base substrate can include an adhesive to improve engagement with the skin.

[0212] Of course, the needle can be larger in size. The size generally has no upper limit except for the range that must be acceptable to the subject.

[0213] The needle can be useful in the context of the present invention when in the form of a wire. However, a wire is generally flexible and thus may not be robust enough to pierce the skin surface. If necessary, an introducer can be used to facilitate insertion into the subcutaneous tissue.

[0214] The electrochemical sensor of the present invention can be implemented as an Electrochemical Aptamer-based (EAB) sensor. The EAB sensor can be provided in the form of a wearable patch or the like having a needle that extends into the body fluid or tissue of a subject where the analyte is detectable through the skin surface.

[0215] The EAB sensor can be of the potentiometric, amperometric, or conductivity measurement type. In a potentiometric sensor, either the electrode or the membrane potential is measured, and local equilibrium is established at the sensor interface where information about the sample is derived from the potential difference between two electrodes. An amperometric sensor depends on the potential applied between a reference electrode and a working electrode to cause oxidation or reduction of redox-active species, and the resulting current is measured. A conductivity measurement sensor depends on the measurement of conductivity at a series of frequencies.

[0216] The EAB sensor is usually of the amperometric type, and an aptamer (DNA, RNA, XNA, etc.) is bound to the working electrode. Gold is often used as the probe surface of the working electrode. The aptamer has a related redox-active species that acts as a reporter. The redox reporter is often methylene blue. When the target analyte binds, the aptamer undergoes a conformational change, bringing the redox reporter closer to the working electrode surface. This increased proximity increases the electron transfer from the redox reporter to the electrode. The increase in the electron transfer rate contributes to the change in the Faradaic current detected by a potentiostat.

[0217] An aptamer is a small (usually 20 - 60 nucleotides), single-stranded RNA, DNA, or XNA oligonucleotide that can bind to a target drug with high affinity and specificity. Aptamers are considered nucleotide analogs of antibodies, but the production of aptamers is a much simpler and cheaper in vitro cell-free process than the production of antibodies by cell culture or in vivo methods.

[0218] An aptamer usually has a huge number (up to 10 18) is selected from a combinatorial library containing different oligonucleotides. RNA aptamers have much higher structural diversity compared to DNA aptamers, but their application is complicated due to stability issues in the presence of RNases, high temperatures, and unfavorable pH values.

[0219] The selection of aptamers selective for a given drug can be facilitated by a process known as SELEX (Systematic evolution of ligands by exponential enrichment). This process can be considered in two alternating stages. In the first stage, library oligonucleotides are amplified to the desired concentration by polymerase chain reaction (PCR). In the selection of RNA aptamers, double-stranded DNA is transcribed in vitro with T7 RNA polymerase to generate single-stranded oligoribonucleotides. In the case of DNA aptamers, a pool of single-stranded oligodeoxyribonucleotides is generated by strand separation of the double-stranded PCR product. In the second stage, the amplification product is incubated with the target drug, and the oligonucleotides that bind to the drug are used in the next SELEX round.

[0220] The separation of oligonucleotides with high affinity for the target drug and the removal of unbound oligonucleotides are achieved by intense competition for the binding site. The selection pressure increases with each SELEX round. The maximum enrichment of the oligonucleotide pool by the aptamer with the highest affinity for the target molecule is usually achieved after 5 - 15 rounds.

[0221] EAB sensors are typically incorporated into a circuit that has a reference electrode. The reference electrode is a site of a known chemical reaction that has a known redox potential. For example, a reference electrode based on the silver-silver chloride (Ag|AgCl) redox couple has a fixed known potential that forms the point at which the redox potential of the working electrode is measured. Also, typically, the circuit also includes a counter electrode that functions as a cathode or anode with respect to the working electrode. Since the applied voltage bias does not pass through the reference electrode (due to the impedance of the potentiostat), any potential generated is due to the working electrode. The current is measured as the potential of the interrogation electrode versus the stable potential of the reference electrode. The difference in potential generates a current within the circuit, thereby generating an output signal. The signal ideally quantifies the target binding depending on the electron transfer that is stoichiometrically proportional to the target binding.

[0222] As described above, EAB sensors are embodied in many forms, one of which is a needle-based patch. When the patch is applied to a subject, the needle penetrates the subject's skin and contacts the patient's body fluid. The tip of the needle functions as a working electrode, and an aptamer labeled with a redox reporter binds to the tip. This configuration provides a minimally invasive platform for real-time continuous in vivo drug detection, which has sufficient sensitivity and selectivity to monitor the amount of drug in a patient's body over time. The EAB sensor is also capable of single-point measurement.

[0223] The aptamer and the needle can be used together in the form of an EAB biosensor, whereby the aptamer-bearing needle is inserted through the skin and contacts the body fluid. The needle essentially functions as a working electrode for detecting an analyte in the biological fluid. Typically, a second needle is used as the counter electrode and a third needle functions as the reference electrode.

[0224] Each aptamer molecule has an associated redox reporter such as methylene blue. Binding of the target analyte causes a conformational change in the aptamer, which in turn modulates the proximity of the redox reporter to the needle surface, causing an increase or decrease in electron exchange with the needle surface. The resulting current change through the needle can be used to identify the concentration of the target analyte in the biological fluid.

[0225] The EAB sensor has been reported to successfully detect endogenous analytes such as metabolites, hormones, antibodies, and cancer markers in biological fluids. Exogenous analytes such as drugs, toxins, and infectious agents have also been detected.

[0226] Although the EAB sensor shows great promise, it is recognized in the art that problems arise with respect to the accuracy of the target analyte concentration provided. Analyte concentration is typically determined by comparing the sensor output current to a calibration curve. In most cases, the calibration curve is created at a temperature different from that of the subject's subcutaneous tissue. To overcome this discrepancy, a temperature correction factor is applied to the biosensor output. Of course, any temperature correction factor depends on an accurate determination of the subject's temperature.

[0227] Refer to FIG. 10 showing the specimen and the temperature sensing needle (410). The distal end (410a) is coated with an aptamer specific for the target analyte, and the aptamer has an associated redox reporter. Thus, the needle (410) functions as a working electrode. The needle (410) is typically attached to a support (412) having a second needle (not shown, functioning as a counter electrode) and a third needle (not shown, functioning as a reference electrode).

[0228] The needle (410) is in contact with a temperature sensor (415), such as a small thermistor or a thermocouple. A useful high-precision small glass bead thermistor is the S14A10310 model (Sensor Scientific, New Jersey, USA). The dimensions of the bead are 0.36×0.5 mm, which enables incorporation with a needle having a lumen and provides 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. In the less expensive S14A10310 model, a lower accuracy (acceptable in the context of the application) is provided. When the thermistor contacts the subject's tissue, it is necessary to ensure the biocompatibility of the material.

[0229] A thermally conductive material (420), such as paste, pate, grease or gel, is applied around the needle (410) and the temperature sensor (415) to ensure efficient transfer of thermal energy from the needle (410) to the temperature sensor (415). A suitable paste is DP-200-30 (TaiKa Co., Ltd., Japan), which is thermally conductive and electrically insulating. A useful pate is TG-NSP35-1LB (T Global Technology, UK).

[0230] The needle (410) includes an extension (410b), the upper surface of which can form an auxiliary surface that can be contacted by the temperature sensor (415) to improve the transfer of thermal energy. As will be understood, generally, as much thermal energy as possible is desirably transmitted from the subject's subcutaneous tissue through the needle (410) to the temperature sensor (415) so that the temperature of the tissue can be accurately detected using the sensor (410).

[0231] The temperature sensor (415) typically has a pair of wires (425) for transmitting an output signal to a processor (not shown), and the signal is used as an input value and analyzed according to program instructions.

[0232] The sensor (415), pair of wires (425), extension (410b), and thermally conductive material (420) shown in FIG. 10 act as a heat sink, and thus it is preferable that they be as small as possible in order to avoid limiting the amount of thermal energy that the sensor (415) can absorb and report to the processor. In this regard, the support (412) is preferably made of a material having low thermal conductivity, such as plastic, so that thermal energy does not leave the temperature sensor (415).

[0233] Next, reference is made to the embodiment of FIG. 11 that uses non-contact means to measure the temperature of the needle (410). In particular, the temperature sensor (415) is an infrared sensor module configured to receive thermal energy (i.e., energy in the infrared spectrum). The infrared sensor module (415) can be active (the module directs infrared radiation at a target and detects the infrared radiation emitted from the target) or passive (the module only detects infrared radiation emitted from the target).

[0234] The infrared sensor module (415) may require a relatively large target area for operation, and the extension (410b) of the needle may have dimensions sufficient to function as the target surface. In some embodiments, the extension (410b) may be extended larger than shown, as long as necessary to function as the target area of the infrared sensor module (415).

[0235] Considering that heat sinking due to the thermal mass of the thermistor, thermocouple, paste, and output wires is removed, a non-contact method of temperature sensing is preferred.

[0236] Next, refer to FIG. 12, which shows a variation of the embodiment of FIG. 11, including a heat insulation cap (430) that covers the upper part of the needle (410), the temperature sensor (415), and the thermally conductive material (420). The heat insulation cap may be made of a foam or similar material and functions to suppress the loss of thermal energy to the atmosphere. In the embodiment of FIG. 12, the thermally conductive material (420) and the heat insulation cap (430) cooperate to transfer thermal energy to the temperature sensor (415) as much as possible so as to appropriately represent the temperature within the subcutaneous tissue of the subject.

[0237] As shown in FIG. 13, for the same reason as described in FIG. 12, a heat insulation cap (430) is added to the embodiment of FIG. 11. The heat insulation cap (430) in the embodiment of FIG. 13 is modified to include a window (435) such that the surface of the needle expansion portion (410b) is exposed to the infrared sensor (415).

[0238] In the embodiment of FIG. 14, the needle (410) has a lumen (440) that receives the temperature sensor (415) and carries the output wire (425) from the sensor (415) to the outside of the needle. In this embodiment, the temperature sensor (415) is in direct contact with the body fluid of the subcutaneous tissue of the subject at the same tissue depth as the aptamer, thereby providing a very accurate reading that is hardly affected by the thermal mass of the other components of the electrochemical sensor. Further, thermal energy is transferred to the side surface of the temperature sensor (415) through the wall of the needle (410), further improving the accuracy of the reading.

[0239] It may be necessary to increase the cross-sectional area of the needle (410) to accommodate the temperature sensor (415).

[0240] The needle (410) may be considered to form part of a thermocouple, as shown in the embodiment of FIG. 15. As is well known, a thermocouple is often formed by creating a junction between two dissimilar metals by welding. The needle (410) provides one of the two metals, and the second of the two metals may be a thermocouple grade wire (445) that extends through the lumen (440) to the tip of the needle (410). The end of the thermocouple grade wire (445) is welded to the tip of the needle (410). A second wire (450) is soldered to the needle (410), and the thermocouple grade wire (445) and the second wire (450) transmit signals to a processor.

[0241] In other embodiments, the temperature sensor is disposed adjacent to the needle to measure the temperature of tissue that is very proximal to the tissue into which the needle is inserted. Refer to FIG. 16, which shows an integrated self - contained wearable device (500) that includes three needles (410a, 410b, 410c) configured as a working electrode, a counter electrode, and a reference electrode, respectively. The needles (410a, 410b, 410c) extend through a skin contact plate (505) that presents a downward - facing surface for contacting the skin surface (600) of the subject during use. The skin contact plate (505) further provides a lower housing portion that engages with an upper housing portion (510) to completely enclose all the electronic components and other components.

[0242] The device (500) includes a pocket (515) sized to receive a temperature sensor (415), such as a thermistor or a thermocouple. The pocket (515) is made of a thin sheet - like material of thermally conductive plastic, such as plastic with a metal or other filler, to facilitate the transfer of thermal energy from the underlying skin (600) to the temperature sensor (415). The temperature sensor (415) is surrounded by a thermally conductive paste to facilitate the transfer of thermal energy from the wall of the pocket (515) to the temperature sensor (415).

[0243] Note that the floor of the pocket (515) extends slightly beyond the lower surface of the skin contact plate (505). The effect of this configuration is that when the plate (505) is applied, the floor of the pocket (515) is gently pressed onto the skin surface (600), thereby facilitating the transfer of thermal energy from the skin (600) to the temperature sensor (415). It should be understood that by pressing the floor of the pocket (515) more strongly onto the skin surface, blood can be pushed out of the skin capillaries, thereby artificially cooling the skin surface (600).

[0244] Preferably, only the floor of the pocket (515) is made of a thermally conductive material, and the rest is made of a low thermal conductivity material. With this configuration, thermal energy from the skin does not move in a direction away from the temperature sensor.

[0245] To ensure that thermal energy is retained around the temperature sensor (415) and not lost in the internal cavities of the housings (505, 510), an insulating material (not shown) may be included to form the ceiling of the pocket (515).

[0246] The embodiment of FIG. 16 may be modified so that the temperature sensor (415) extends through the opening in the floor of the pocket (515) so as to be in direct contact with the skin surface (600). Considering that thermal energy does not require the passage of an intervening material, a temperature closer to the actual skin temperature is expected.

[0247] In a further modification, the temperature sensor (415) is an infrared sensor module, in which case at least the material of the floor of the pocket (515) should not substantially interfere with its operation. It is conceivable to provide an opening in the floor so that the infrared sensor module (415) is directly exposed to the skin surface (200) to accurately read the skin temperature.

[0248] Refer to FIG. 17 showing the basic circuit for the operation of the present invention. Although the thermistor temperature sensor is shown applied to the working electrode, it will be understood that it may alternatively be applied to the reference electrode or the counter electrode. In some embodiments, a dedicated needle is provided solely for the purpose of temperature measurement.

[0249] In the present application, the preferred embodiments have been described with reference only to needles, but the needles can be synonymous with micro needles and the like. However, a wire may be used instead of the needle, in which case the wire may be coiled around the temperature sensor to facilitate the transfer of thermal energy to the temperature sensor. Considering the excellent thermal conductivity of metals and their easy availability, copper wire is preferred. An introducer (such as a small cannula) may be required to embed the wire in subcutaneous tissue or body fluid.

[0250] It is understood that the present invention includes all the foregoing modifications and variations within the spirit and scope of the present invention, and actually further modifications and variations.

[0251] Therefore, the spirit and scope of the present invention should not be limited by the foregoing examples, but should be understood in the broadest sense permitted by law.

Claims

1. An electrochemical sensor device for making one or more protrusions contact a biological fluid or tissue under the skin of a subject for a long time, 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 through which the one or more protrusions can extend; a movable portion configured to move the one or more protrusions from a first position behind the skin contact surface to a second position of the skin contact surface; optionally, a holding portion configured to hold the skin contact surface in contact with the skin during use; a thermal energy sensor configured to identify the temperature of the biological fluid or the tissue around the one or more protrusions when in contact with the biological fluid or the 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 another type of non-linear path.

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

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

5. The device according to any one of claims 1 to 4, wherein the non-linear path is described by referring 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 angle of the arc is less than about 45°, 40°, 35°, 30°, 25°, 20°, 15°, 14°, 13°, 12°, 11°, 10°, 9°, 8°, 7°, 6° or 5°.

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

9. The device according to any one of claims 1 to 8, wherein the movable portion is related to a mounting portion.

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

11. The device according to claim 9 or 10, wherein the mounting portion includes a portion that enables the movable portion to pivot, hinge, bend or mount.

12. The attachment part has a fixed interval with respect to the skin contact surface, and the device according to any one of claims 9 to 11.

13. The attachment part has an interval of less than about 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm or 2 mm from the skin contact surface, and the device according to any one of claims 9 to 12.

14. The attachment part is generally lateral with respect to the movable part, and the device according to any one of claims 9 to 13.

15. Further includes a release part operable by the user, and the release part is configured to hold the movable part in the first position until the release part is actuated by the user. When the release part is actuated by the user, the movable part is released and can move to the second position, and the device according to any one of claims 1 to 14.

16. Further includes a locking part configured to lock the movable part when the movable part is in the second position, and the device according to any one of claims 1 to 15.

17. Moving the movable part from the first position to the second position is configured to require power generated inside and / or outside the device, and the device according to any one of claims 1 to 16.

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

19. Does not have an internal power generator configured to move the movable part from the first position to the second position, and the device according to any one of claims 1 to 18.

20. The holding part is a dermatologically acceptable composition disposed on or around the skin contact surface or includes a dermatologically acceptable composition, and the device according to any one of claims 1 to 19.

21. The dermatologically acceptable composition is an adhesive or a functional equivalent thereof, and the device according to claim 20.

22. The holding part is configured to mechanically hold the skin contact surface in contact with the skin, and the device according to any one of claims 1 to 21.

23. The holding part is the device according to claim 22, which is selected from one or more of a strap, a band, a belt, a clamp, a grip, a cord, a fastener, a sleeve, a stocking, a sock, a glove, a cap, a hat, pants, a singlet, a shirt, a bra, a top, trousers, a scarf, a ring, glasses and a choker.

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

25. The device according to any one of claims 1 to 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 to 26, wherein the one or more protrusions have a sufficient length to be capable of contacting the epidermis, dermis or subcutaneous layer of the subject.

28. The device according to any one of claims 1 to 27, wherein the one or more protrusions are configured to conduct an electric current to, from or through the skin, conduct a sound wave to, from or through the skin, conduct light to, from or through the skin, conduct heat to, from or through the skin, sample a fluid or tissue from the skin, deliver a biologically active substance to the skin or introduce an analyte sensing substance into the skin during use.

29. The one or more protrusions are each conductive, and the device further includes a circuit having an audio, visual or tactile indicator, and the circuit is configured to activate the indicator when the one or more protrusions are in contact with a conductive fluid naturally present in the skin. The device according to any one of claims 1 to 28.

30. The circuit includes at least two protrusions, and the circuit is configured to be completed by the at least two protrusions in contact with the conductive fluid naturally present in the skin to activate the indicator. The device according to claim 29.

31. The circuit of claim 29 includes one protrusion and at least one conductive pad disposed against the skin, and the circuit is configured such that, in order to activate the indicator, the one protrusion and the conductive pad are electrically communicated with the conductive fluid naturally present within the skin to be completed.

32. The device according to any one of claims 1 to 31, comprising a housing, wherein when the device is applied to the skin, the movable part is in the second position, and any part of each of the one or more protrusions on the skin contact surface is embedded in the skin, the housing has dimensions such that most or substantially all of it extends over the skin within a range not exceeding 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.

33. The device according to any one of claims 1 to 32, wherein the long time is longer 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 to 33, wherein the one or more protrusions cannot be separated from the device or are inseparable without the assistance of an instrument.

35. The device according to any one of claims 1 to 34, wherein the movable part and the attachment part are integrally formed.

36. The device according to claim 35, wherein the integrally formed movable part and attachment part are made of an elastically deformable material.

37. The device according to claim 35 or 36, wherein the integrally formed movable part and attachment part are part of the circuit board of the device.

38. The device according to any one of claims 15 to 37, wherein the movable part is biased towards the second position and is maintained at the first position against the bias by the release part operable by the user until the release part is actuated, and when the release part is actuated, the movable part is released and can move to the second position.

39. The release part operable by the user is a ledge configured to hold the movable part in the first position, and the motive power provided by the user deforms the ledge and / or the movable part so that the movable part can be released from the ledge and move to the second position. The device according to any one of claims 15 to 37.

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

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

42. The release part includes a member configured to hold the movable part in the first position, and the member is removable or deformable by the user so that the movable part can be moved to the second position. The device according to any one of claims 15 to 41.

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

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

45. The release part is removable from the device and includes a gripping part to facilitate manual removal. The device according to any one of claims 42 to 44.

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

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

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

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

50. The device according to claim 46, wherein the one or more protrusions are specialized to function to identify 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 to 50, comprising a heat insulating material configured to retain thermal energy within the one or more protrusions.

52. The device according to claim 51, wherein the heat insulating material surrounds the distal ends of the one or more protrusions that are distal from a part of one of the one or more protrusions inserted into the skin.

53. The device according to claim 51 or 52, wherein the heat insulating material forms a cap on the distal ends of the one or more protrusions that are distal from a part of one of the one or more protrusions inserted into the skin.

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

55. The device according to any one of claims 46 to 54, wherein the one or more protrusions are at least partially made of metal, metal alloy, combination of metals or ceramic.

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

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

58. The device according to any one of claims 46 to 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 to 58, wherein the thermal energy sensor is applied to or directed at the one or more protrusions.

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

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

62. The device according to any one of claims 46 to 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 to 63, wherein one of the one or more protrusions includes a lumen.

65. The electrochemical sensor according to claim 64, wherein the thermal energy sensor is at least partially disposed within the lumen or functions at least partially through the lumen.

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

67. The device according to any one of claims 46 to 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 or directed towards the surface of the skin.

69. The device according to claim 67 or 68, wherein the thermal energy sensor is in contact with or in thermal communication with the skin.

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

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

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

73. The device according to any one of claims 70 to 72, wherein the thermally conductive solid material has a thickness of 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.

74. The device according to any one of claims 46 to 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 to 74, wherein the one or more protrusions and the thermal energy sensor are housed within or are associated with a housing.

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

77. The device according to claim 76, comprising a redox active species associated with the aptamer and configured to function to report an interaction between a target analyte and the aptamer.

78. A method for contacting one or more protrusions of an electrochemical sensor device with a biological fluid or tissue under the skin of a subject, the method comprising providing a device according to any one of claims 1 to 77; contacting a skin contact surface of the device with the subject; moving or being able to move the movable part from the first position to the second position; and causing or being able to cause the thermal energy sensor to identify the temperature of the biological fluid or the tissue.

79. The method according to claim 78, wherein the device remains applied to the skin for a period exceeding 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 contacting one or more protrusions with a biological fluid or tissue under 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 through which the one or more protrusions extend; a movable part configured to move the one or more protrusions from a first position behind the skin contact surface to a second position of the skin contact surface; a user-actuable release part configured to hold the movable part in the first position until the user actuates the release part, and when the release part is actuated by the user, the movable part is released and moved or able to move to the second position. A thermal energy sensor configured to determine the temperature of the biological fluid or tissue around the one or more protrusions when in contact with the biological fluid or the tissue. An apparatus comprising the same. **Claim 81** The release portion is configured to hold the movable portion in the first position, but includes a member that can be removed or deformed by the user so that the movable portion can be moved to the second position. The apparatus according to claim 80. **Claim 82** The apparatus according to claim 81, wherein the member is removable by sliding it generally across the skin contact portion. **Claim 83** The member is generally wedge-shaped, and the apparatus includes a hinge that associates the movable portion with the skin contact portion. The narrow portion of the wedge is disposed proximal to the hinge, and the wide portion of the wedge is disposed distal to the hinge. The apparatus according to claim 81 or 82. **Claim 84** The release portion is removable from the apparatus and includes a gripping portion to facilitate manual removal. The apparatus according to any one of claims 80 to 84. **Claim 85** A method for bringing one or more protrusions into contact with biological fluid or tissue under the skin of a subject. The method includes providing an apparatus according to any one of claims 80 to 84, contacting the skin contact surface of the apparatus with the subject, actuating a release member operable by the user to move or enable movement of the movable portion from the first position to the second position, and causing or enabling the thermal energy sensor to determine the temperature of the biological fluid or the tissue.

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