WO2014120114A1

WO2014120114A1 - Microneedle-based natremia sensor and methods of use

Info

Publication number: WO2014120114A1
Application number: PCT/US2013/023562
Authority: WO
Inventors: Trevor John MOODY; Thomas Schulte
Original assignee: Empire Technology Development Llc
Priority date: 2013-01-29
Filing date: 2013-01-29
Publication date: 2014-08-07

Abstract

A device, system, and method for measuring an analyte concentration in an animal are disclosed. The device may include multiple microneedles with associated electrodes and conductors in electrical communication with the electrodes. The device may include a substrate on which the microneedles may be mounted, and the device may be placed in contact with an animal's skin so that the electrodes may contact interstitial fluid in the skin epidermis. A system may include the device and other electronic components to provide a current to some of the electrodes. The system may also sense the voltage across at least two electrodes. The system may include one or more electronic devices to calculate an impedance measurement based on the currents and voltages. The electronic device may use the impedance measurement to calculate the concentration of the analyte and provide it to an output device for observation by a user.

Description

MICRONEEDLE-BASED NATREMIA SENSOR AND METHODS OF USE BACKGROUND

[0001] Despite high incidence of serum sodium concentration disturbances (dysnatremia, hyponatremia, hypernatremia) in patients presenting at an emergency department, as well as hospitalized patients, there appear to be no technological tools that provide a real-time and continuous reading of this important electrolyte. As a result, it may be difficult to track patients at risk of dysnatremia (serum sodium concentration outside the normal ranges) and to administer therapies. Additionally, the inability to monitor serum sodium concentration may also be a serious problem for healthy individuals taking part in high exertion occupations and athletics such as marathons.

[0002] Frequently, tests of serum sodium concentration may be ordered to determine if a patient is within normal physiological values of about 135 mmol/L to about 145 mmol/L. A patient with serum sodium concentration greater than about 145mmol/L may be considered to have hypernatremia, which may be strongly associated with dehydration. Alternatively, a patient with serum sodium concentration less than about 135 mmol/L may be considered to have hyponatremia, which may be associated with edema or overhydration. It may be understood, however, that non-physiological levels of serum sodium may be indicative of other pathologies including kidney malfunction.

[0003] Both hyper- and hypo-natremia are clinically dangerous conditions that should be treated quickly. However, too rapid correction of serum sodium can result in either cerebral edema and cerebral de-myelination, either of which can lead to serious and permanent neurological damage. Hence, a real-time serum sodium concentration sensor may not just provide a current serum sodium reading, but also may be used to monitor the rate of change in sodium concentration, thereby allowing a physician to be certain that the serum sodium level is within safe limits. [0004] At present, most serum sodium tests in patients rely on analyzing the sodium concentration in blood samples pulled from a patient. It is clear that such a method, even if automated at bedside, may still provide delayed readings. Additionally, multiple needle sticks to obtain blood samples over time may be uncomfortable for the patient. It is therefore clear that a real-time, minimally invasive device and method for assessing serum blood sodium levels may be useful for patient and non-patient health care.

SUMMARY

[0005] In an embodiment, a device for measuring an analyte concentration in a bodily fluid may include a substrate assembly, multiple microneedles contacting the substrate assembly, at least one electrode associated with each of the microneedles, at least one conductor in electrical communication with at least one electrode, and at least one connector in electrical communication with at least one conductor. The substrate assembly may be configured to contact a portion of skin of an animal, and the microneedles may be configured to penetrate the portion of skin of the animal so that at least one of the electrodes contacts the bodily fluid.

[0006] In an embodiment, a system for measuring an analyte concentration in a bodily fluid may include a device for measuring an analyte concentration in a bodily fluid that may include a substrate assembly, multiple microneedles contacting the substrate assembly, at least one electrode associated with each of the microneedles, one or more conductors in electrical communication with the one or more electrodes, and at least one connector in electrical communication with the one or more conductors. In addition, the substrate assembly may be configured to contact at least a portion of skin of an animal, and the microneedles may be configured to penetrate the portion of skin of the animal so that at least one electrode is in contact with the bodily fluid. The system may also include one or more sources of electrical current and one or more electrical sensors each having a sensor input and a sensor output, in which the sensor output may be configured to provide one or more sensor output data. The system may also include one or more electronic switches configured to place at least one conductor in electrical communication with at least one source of electrical current and one of the sensor inputs, and at least one electronic device configured to receive the sensor output data and calculate an analyte concentration.

[0007] In an embodiment, a method of measuring an analyte concentration in a bodily fluid may include providing a system for measuring an analyte concentration in a bodily fluid. The system may include a device for measuring an analyte concentration in a bodily fluid which may be composed of a substrate assembly, multiple microneedles contacting the substrate assembly, one or more electrodes associated with each of the microneedles, one or more conductors in electrical communication with the electrodes, and at least one connector in electrical communication with the one or more conductors. The substrate assembly of the system may be configured to contact at least a portion of skin of an animal, and microneedles may be configured to penetrate the portion of skin of the animal so that at least one electrode may contact the bodily fluid. The system may also include at least one source of electrical current and at least one electrical sensor having a sensor input and a sensor output, in which the sensor output may be configured to provide one or more sensor output data. The system may also include at least one electronic switch configured to place at least one of the conductors in electrical communication with least one source of electrical current and at least one sensor input, and at least one electronic device configured to receive the sensor output data and calculate analyte concentration data. The method may further include contacting the device for measuring the analyte concentration in a bodily fluid to a portion of skin of an animal, providing electrical current from at least one source of electrical current to at least one of the conductors, measuring, by at least one electrical sensor, at least some sensor output data, providing the sensor output data to one or more electronic devices, calculating, by at least one electronic device, the analyte concentration based at least in part on the sensor output data, and providing the analyte concentration to an output device.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIGS. 1A-B illustrate embodiments of a device to measure an analyte concentration in bodily fluids of an animal in accordance with the present disclosure.

[0009] FIGS. 2A-F illustrate embodiments of microneedles with associated electrodes in a device to measure an analyte concentration in bodily fluids of an animal in accordance with the present disclosure.

[0010] FIG. 3 illustrates an embodiment of a disposable substrate assembly for a device to measure an analyte concentration in bodily fluids of an animal in accordance with the present disclosure.

[0011] FIG. 4 illustrates an embodiment of electronic components that may be included in a system to measure an analyte concentration in bodily fluids of an animal in accordance with the present disclosure.

[0012] FIG. 5 illustrates an example of an electronic device that may control electronic components and receive data from a device to measure an analyte concentration in bodily fluids of an animal in accordance with the present disclosure.

[0013] FIG. 6 is a flow chart illustrating an embodiment of a method to measure an analyte concentration in bodily fluids of an animal in accordance with the present disclosure.

DETAILED DESCRIPTION

[0014] Extracellular fluid comprises about 20% of total body weight, of which about 80% (or about 12 L total fluid volume) may be found in the interstitial fluid and the remaining about 20% (or about 3 L) may be found in blood plasma. Sodium is the primary cation found in both interstitial fluid and blood plasma, in concentrations of about 150 mEq/L in plasma and about 145 mEq/L in the interstitial fluid. Other common cations, including potassium, calcium, and magnesium, may be present in much smaller concentrations in either fluid (less than about 10 mEq/L). It is therefore apparent that a measurement of interstitial sodium concentration may serve as a reasonable substitute for direct plasma measurements of the same cation. The static resistance of pure water at 25 °C is about 182 kQ/m, while the static resistance of a 300 mEq/L solution of sodium cations in water may be about 0.21 Ω/m. It is therefore clear that a measurement of static resistance (or frequency dependent impedance) of interstitial fluid in an animal may be a highly sensitive way to determine the plasma sodium concentration, since the major cation in both the serum and interstitial fluid may be sodium.

[0015] One method to measure interstitial fluid impedance may be through the use of multiple conductive microneedles held together in an assembly. A microneedle assembly with several electrically conductive electrodes may be placed on the skin, the microneedles being long enough to penetrate the stratum corneum layer into the epidermis. In one embodiment, each microneedle may be about 200 μιη high and about 40 μιη wide at the base. In another embodiment, each microneedle may be about 500μιη high and about 40μιη wide at the base. In yet another embodiment, each microneedle may be about ΙΟΟΟμιη high and about 40μιη wide at the base. At this size, the microneedles may not penetrate into nerves in the deeper dermis layer, and hence may be essentially pain free.

[0016] The conductive microneedle electrodes may then contact interstitial fluid in the epidermis. An impedance sensor system may be attached to the conductive electrodes and an impedance measurement may be made between the electrodes. The impedance measurement may be an average impedance or a complex impedance. As noted above, the serum sodium concentration may be determined based on a measurement of the interstitial fluid impedance. The serum sodium concentration may be presented to a user on a monitor as a real-time numerical value, or as a 2-dimensional graph over time. The real-time reading and graphical display may be displayed on a dedicated serum sodium concentration monitor or on a multi -parameter patient monitor.

[0017] FIGS. 1A and IB illustrate non-limiting embodiments of a device for measuring an analyte concentration (such as sodium cation concentration) in a bodily fluid. The device may include a substrate assembly 110 which may contact one or more microneedles 120. In one non-limiting embodiment, FIG. 1A, a single electrode 130 may be associated with each microneedle 120. In another non-limiting embodiment, FIG. IB, each microneedle 120 may have two electrodes, 130 and 135, associated with it. As illustrated in FIG. IB, the two electrodes 130 and 135 may be electrically isolated from each other. At least one conductor 140 may be in electrical contact with each electrode 130. In the non- limiting embodiment illustrated in FIG. IB, a microneedle 120 may have two conductors 145 and 140 associated with it, each conductor associated with one of the two electrodes 130 and 135 of the microneedle, respectively. It may be appreciated that the pair of conductors 140 and 145 may similarly be electrically isolated from each other. For ease of forming electrical contacts between the electrodes 130 (and/or 135) and additional electronics (a non-limiting embodiment of which is illustrated in FIG. 4), the conductors 140 (and/or 145, in FIG. IB) may further form electrical contact with one or more electrical connectors 150.

[0018] As illustrated in FIG. 1A, the device may be placed in contact with a portion of the skin of an animal, such as a human. The contact may be made so that at least a portion of the electrodes 130 (and/or 135 in FIG. IB) may penetrate the stratum corneum 102 of the skin and penetrate into the epidermis 104. The microneedles 120, however, may not be long enough to penetrate into the dermal layer 106 beneath the epidermis. In this manner, the electrodes 130 (and/or 135, in FIG. IB) may be placed in contact with bodily fluid such as the interstitial fluid of the animal.

[0019] The substrate assembly 110 may be fabricated from any appropriate material including a flexible material. In one non-limiting example, the substrate assembly 110 may be fabricated at least in part of a biocompatible material. Non-limiting examples of materials from which the substrate assembly 110 may be manufactured may be one or more of a polyether ether ketone, a ceramic, a liquid crystal polymer, a polytetrafluoroethylene, a fluoropolymer, a polyester, a polycarbonate, a polypropylene, a high density polyethylene, a low density polyethylene, a polyurethane, a polyimide, and a silicone. The substrate assembly 110 may also include an adhesive material to assist contacting the substrate (along with its microneedles) to the animal skin. Alternatively, the substrate assembly 110 may be associated with a device, such as an armband or other holding device (including, without limitation, an elastic band, a hook-and-loop closed web, and a belt) to help hold the substrate assembly adjacent to or against the portion of skin of the animal. The substrate assembly 110 may be reusable or may be disposable after a single use.

[0020] The microneedles 120 may be fabricated as part of the substrate assembly 110, or they may be mounted on the substrate assembly. The microneedles 120 may have a height of about 100 μιη to about 1500 μιη. Non-limiting examples of microneedle 120 height may include about 100 μιη, about 200 μιη, about 400 μιη, about 600 μιη, about 800 μιη, about 1000 μιη, about 1200 μιη, about 1400 μιη, about 1500 μιη, and ranges between any two of these values. In one non-limiting example, the microneedles 120 may have a height of about 500 μιη. In some non-limiting embodiments, the microneedles 120 may have a conical shape. In other non-limiting embodiments, the microneedles 120 may have a pyramidal shape. The base of the microneedles 120 may have a width of about 50 μιη to about 500 μιη. Non-limiting examples of microneedle 120 base width may include about 50 μιη, about 60 μηι, about 80 μιη, about 100 μιη, about 200 μιη, about 300 μιη, about 400 μηι, about 500 μιη, and ranges between any two of these values. In one non-limiting example, the microneedles 120 may have a base width of about 160 μιη. The substrate assembly 110 may be associated with any number of microneedles 120 that may be arrayed on the substrate assembly in any manner. The microneedles 120 may be arrayed on the substrate assembly 110 according to a grid pattern, a line, concentric circles, other geometrical shapes, or randomly. The substrate assembly 110 may have about 2 microneedles to about 100 microneedles. Non-limiting examples of the number of microneedles 120 associated with a substrate assembly 110 may include about 2 microneedles, about 5 microneedles, about 10 microneedles, about 20 microneedles, about 40 microneedles, about 60 microneedles, about 80 microneedles, about 100 microneedles, and ranges between any two of these values. In one non-limiting example, the number of microneedles 120 may be about 25 microneedles.

[0021] The microneedles 120 may be fabricated from either an electrically nonconducting or conducting material. Non-limiting examples of electrically non-conducting material may include one or more of a hard plastic, a rubber, a ceramic, and/or a glass. Non- limiting examples of an electrically conducting material may include one or more of gold, stainless steel, platinum, a platinum/iridium alloy, gold-coated stainless steel, and titanium.

[0022] FIGS. 2A-F illustrate some non- limiting examples of microneedle constructions 200 showing possible arrangements of electrodes and conductors. FIG. 2A illustrates an essentially cone-shaped microneedle 210 constructed of an electrically nonconducting material. The interior of the microneedle 210 may include a conducting electrode 215. The conducting electrode 215 may be disposed against an interior wall of the microneedle 210 or may be constructed as a plug filling at least the interior tip end of the microneedle. The microneedle 210 may be constructed so that fluid contacting the microneedle outer surface may also contact the electrode 215 disposed in the interior of the microneedle, for example through a hole or port in the microneedle. A conductor 220 may be placed in electrical contact with the electrode 215 inside the microneedle 210.

[0023] FIG. 2B illustrates an example of an electrically non-conducting microneedle 210 having an outer surface on which a conducting electrode 215 has been affixed. In a non-limiting example, the microneedle 210 may have a proximal side associated with the substrate assembly, while a conducting electrode 215 may be plated on a distal side of the microneedle such as at a tip end. The microneedle 210 may be hollow or filled. In the non-limiting embodiment of FIG. 2B the conductor 220 may be placed within the interior of the microneedle 210 and may form an electrical contact with the electrode 215 plated on the distal exterior surface of the microneedle for example through a port in the microneedle tip.

[0024] FIG. 2C illustrates another non-limiting example of a microneedle construction 210. The microneedle 210 may be an electrically non-conducting material having an exterior surface on which the electrode 215 is placed. A conductor 222 may also be placed on the exterior surface of the microneedle 210 forming an electrical contact with the electrode 215. Additional non-conducting material 224 may be used to coat the conductor 222 so that only the electrode 215 may form an electrical contact with the interstitial fluid under the animal skin surface.

[0025] FIG. 2D illustrates yet another non-limiting example of a microneedle 212 composed at least in part of an electrically conducting material. In this example, the conducting microneedle 212 may be coated on at least a portion of its exterior surface with an insulating material 216. The non-conductive coating 216 may extend from a proximal side of the microneedle 212 that is in contact with the substrate assembly, along some portion of the exterior surface of the microneedle, thereby leaving a conductive tip portion at a distal side of the microneedle. [0026] FIG. 2E illustrates another non-limiting example of a microneedle. In FIG. 2E, the microneedle may be fabricated by co-extruding a non-conductive material 230 and a conductive material 235, in which the conductive material may be surrounded by the non- conductive material. In one non-limiting example, the conductive material may be composed of polyamide 6 mixed with carbon black. In another non-limiting example, the conductive material may be composed of polyamide 6 mixed with carbon fibers. In one non- limiting example, the non-conductive material may be composed of polycarbonate. An electrode tip, comprising exposed conductive material 235, may be fashioned by injection molding the two materials together. Alternatively, the conducting electrode tip may be fashioned by removing some of the surrounding non-conducting material 230 leaving a free tip end. A conductor may form an electrical contact with the electrically conducting material 235.

[0027] FIG. 2F illustrates a two-electrode version of a microneedle 210. For example, FIG. 2F may be one embodiment of a dual-electrode microneedle as illustrated in FIG. IB. In FIG. 2F, a microneedle 210 may include two electrically isolated electrodes, 215 and 240. Each electrode 215 and 240 may have an electrical contact to an individual conductor, 220 and 221, respectively. The conductors 220 and 221 may be electrically isolated, so that there is essentially no electrical communication between the two conductors. Although FIG. 2F appears to illustrate electrodes 215 and 240 associated with an outer surface portion of the microneedle 210, it may be appreciated that other fabrication methods may be used to create a microneedle having multiple electrodes. As one non-limiting example, a co-extruded microneedle as illustrated in FIG. 2E may include two electrically isolated conductive portions similar to 235 in FIG. 2E. A microneedle similar to that illustrated in FIG. 2D may include two electrically conducting halves of a single microneedle separated internally by a non-conducting portion. Thus, conducting microneedle body 212 in FIG. 2D may be split in half, the halves separated by a non-conducting material. Additionally, while the dual-electrode microneedle 210 illustrated in FIG. 2F may have conductors 220 and 221 affixed to the electrodes 215 and 240, respectively, within the body of the microneedle, it may be appreciated that one or more of the conductors may be directed on the outer surface of the microneedle in a manner suggested in FIG. 2C.

[0028] As indicated in FIGS. 2A-F, at least one electrode may be associated with each microneedle, and a conductor may be placed in electrical contact with each electrode. Both electrode and conductor may be fabricated from any suitable electrically conductive material, including, without limitation, gold, platinum, a platinum iridium alloy, and carbon. It may be understood that an electrode and its associated conductor may be fabricated from the same material or from different materials.

[0029] A system for measuring an analyte, such a sodium, found in the interstitial fluid and/or plasma of an animal, may include a device for measuring an analyte concentration as disclosed above including a substrate assembly, multiple microneedles in contact with the substrate, at least one electrode associated with each microneedle, a conductor in electrical connectivity with each electrode, and a connector in electrical communication with the conductors. As disclosed above, the measuring device may be placed in contact with the skin of a patient and/or animal in a manner to permit the electrodes of the microneedles to contact the interstitial fluid within the epidermal layer. FIG. 3 illustrates a plan view of a non-limiting example of such a device. Thus, the substrate assembly 310 is shown having microneedles 320 associated with it. At least one conductor 340 can be seen associated with each microneedle 320, specifically in electrical contact with the electrode (not shown) associated with the microneedle. It may be understood that FIG. 3 may be a non- limiting example of a device in which a single electrode may be associated with each microneedle 320. In an alternative embodiment, more than one conductor 340 may be associated with each microneedle 320 having more than one electrode associated with it. The sensing device may also include a connector 350 serving to provide a means to form an electrical contact between each of the conductors 340 and additional electronics downstream of the measuring device.

[0030] It may be understood that the non-limiting embodiment of a measuring device illustrated in FIG. 3 may be interpreted as a detachable device from additional electronics. The device may be a single -use device that may be discarded after being applied to a single animal or patient for a single measurement or set of measurements. Alternatively, the device may be used multiple times either with the same animal and/or patient or with other animals and/or patients. In another non-limiting embodiment, the measuring device may be effectively permanently associated with electronics to measure the analyte concentration and present them to a user.

[0031] FIG. 4 illustrates one non-limiting embodiment of a group of electronics that may be associated with the measuring device, disclosed above in one non-limiting embodiment in FIG. 3. Such electronics, in addition to the measuring device disclosed above may together form a system to measure an analyte concentration in an animal bodily fluid.

[0032] Signals to and from the microneedle electrodes may be carried over the conductors 340 of FIG. 3. The signals may be conveyed via connector 350 of FIG. 3. The electronics in FIG. 4 may transmit signals to, and receive signals from, the electrodes over signal lines 410a-n. Signal lines 410a-n may be associated with a companion connector (not shown) associated with the system electronics.

[0033] Each of the signal lines 410a-n may be placed in electrical communication with one or more electrical current sources 430 and/or one or more electrical voltage sensors 440 by means of at least one electronic switch 420. The electronic switch 420 may be configured to receive current from at least one source of electrical current 430 over a current transmission line 425. The electronic switch 420 may then direct the electrical current to one or more electrodes. The electronic switch 420 may also be configured to receive electrical signals from one or more electrodes and transmit the one or more signals to one or more electrical voltage sensors 440 over at least one voltage sensor input line 445. It may be understood that the one or more electronic switches 420 may be controlled over an electronic switch control line 465 by one or more electronic devices 460. Data transmitted over the electronic switch control line 465 may program or otherwise control the one or more electronic switches 420 to direct the signal flow from the one or more sources of electrical current 430 over their respective current transmission lines 425 to the electrodes, and the signal flow from the one or more electrodes to the one or more electrical voltage sensors 440 over their respective voltage sensor input lines 445.

[0034] The one or more sources of electrical current 430 may source a direct current or an alternating current. The one or more sources of electrical current 430 may be controlled by one or more electronic devices 460 over one or more current source control lines 437. In one non-limiting example, the source of electrical current 430 may be controlled to source a direct current of about 0.001 mA to about 10 mA. Examples of such direct currents may include, without limitation, about 0.001 mA, about 0.005 mA, about 0.01 mA, about 0.05 mA, about 0.1 mA, about 0.5 mA, about 1mA, about 5 mA, about 10 mA, or ranges between any two of these values. Alternatively, the source of electrical current 430 may be controlled to source an alternating current of about 0.001 mA RMS to about 10 mA RMS, and at frequencies of about 1 kHz to about 10 MHz. Examples of such alternating currents may include, without limitation, about 0.001 mA RMS, about 0.005 mA RMS, about 0.01 mA RMS, about 0.05 mA RMS, about 0.1 mA RMS, about 0.5 mA RMS, about 1mA RMS, about 5 mA RMS, about 10 mA RMS, or ranges between any two of these values. Examples of such alternating current frequencies may include, without limitation, about 1 kHz, about 5 kHz, about 10 kHz, about 50 kHz, about 100 kHz, about 500 kHz, about 1 MHz, about 5 MHz, about 10 MHz, or ranges between any two of these values.

[0035] The current sourced by the one or more sources of electrical current 430 may be measured by one or more current sensors 450. In one non-limiting embodiment, a current sensor 450 may measure the current directly from the current source 430 over a current sensor input line 435. In an alternative embodiment, the electronic switch 420 may also provide electrical communication between the current sensor 450 and the electrodes receiving the current from the source of electrical current 430. The current measurement may be provided as current sensor output data from the current sensor 450 to one or more electronic devices 460 over a current sensor output line 455. Non-limiting examples of current sensors may include devices using operational amplifiers, low noise amplifiers, and isolation transformers. The current sensor output data may be either in analog or digital format.

[0036] An impedance measurement may be considered a frequency-dependent resistance measurement, and may be calculated as a frequency dependent voltage divided by a frequency dependent current. As disclosed above, a current sensor 450 may provide current sensor output data to one or more electronic devices 460 for making such a calculation. A voltage may be measured across any two electrodes by means of an electrical voltage sensor 440 that may receive signals from one or more electrodes, as selected by the electronic switch 420, over one or more voltage sensor input lines 445. The voltage measurement may be supplied as voltage sensor output data over a voltage sensor output line 467 that may provide the voltage sensor output data to one or more electronic devices 460. Non-limiting examples of such electrical voltage sensors 440 may include devices using operational amplifiers, low noise amplifiers, and isolation transformers. The voltage sensor output data may also be supplied in either analog or digital format to the one or more electronic devices 460. [0037] The one or more electronic devices 460, as disclosed above, may act to receive one or more sensor output data, for example from the electrical current sensor 450 and electrical voltage sensor 440. The one or more electronic devices 460 may include a computing device capable of receiving the sensor output data and calculating an analyte concentration, such as the concentration of sodium cations in the interstitial fluid, based at least in part on such data. In one non-limiting example, the one or more electronic devices 460 may receive current sensor output data from current sensor 450 and voltage sensor output data from voltage sensor 440 and calculate an impedance value as disclosed above. The one or more electronic devices 460 may use the calculated impedance value or values along with other programming data and/or algorithms to calculate the analyte concentration. The one or more electronic devices 460 may then transmit the analyte concentration data over some electronic communication means 475 to one or more output devices 470. The communication means 475 may include any means for data transmission, including but not limited to a serial connection, a parallel connection, an Ethernet connection, an optical connection, a wireless connection, a telephonic connection, or combination thereof. While the one or more electronic devices 460 may provide concentration information to one or more output devices 470 to be accessed by one or more users, the one or more electronic devices may also directly provide user information by means of visual, audio, or other types of alarms. Thus, one or more electronic devices 460 may provide an alarm if the analyte concentration determined to exceed a maximum analyte concentration level. For example, if the analyte comprises sodium cations and the determined concentration level of a human patient is greater than about 145mmol/L, the one or more electronic devices 460 may issue an alarm to indicate possible hypernatremia. Alternatively, the one or more electronic devices 460 may provide an alarm if the analyte concentration is determined to be less than a minimum analyte concentration level. Thus, if the analyte comprises sodium cations and the determined concentration level of a human patient is less than about 135 mmol/L, the one or more electronic devices 460 may issue an alarm to indicate possible hyponatremia. The alarms indicating the two conditions (hypernatremia and hyponatremia) may be the same, or different alarms may be issued by one or more electronic devices 460 to indicate that the different conditions may exist.

[0038] Data from the one or more electronic devices 460 may be transmitted over a communication means 475 to one or more output devices 470. The one or more output devices 470 may be physically associated with the system for measuring the analyte. As one non-limiting example, the system may comprise a small portable device intended to be worn or carried by the animal or patient. An output device 470 in such an example may include a small display screen such as an LCD screen or an LED display. In another non-limiting example, the system may comprise a non-portable device, such as a device similar to a laptop or desktop computer. An output device 470 may then comprise a computer-type monitor physically associated with the system.

[0039] In other non-limiting embodiments, the one or more output devices 470 may be devices remote from or otherwise not physically associated with one or more electronic devices system. In one non-limiting embodiment, an output device 470 may be a monitor associated with a separate computer system capable of accessing the concentration data remotely from the system. The separate computer system may access this information from a website over an Ethernet connection, through a wireless connection (such as, without limitation, a local area network, a personal area network, or a wireless telephony network), or a combination of such remote access technologies. In other non-limiting embodiments, an output device 470 may be associated with a cellular phone, a tablet computer, or other smaller portable electronic device. It may be appreciated that an output device 470 may be configured to display the analyte concentration data from more than one system for measuring analyte concentrations. Such an output device 470 may find use in a hospital or other clinical setting in which a health care professional may be required to monitor the analyte concentration of a number of patients.

[0040] An output device 470 may include a display that may provide concentration data to a user in any of a number of formats. In one non-limiting example, the format may simply include numerical data (for example on a small portable device with a limited visual display area such as a small LCD screen or LED display). The numerical data may be updated automatically according to a time schedule or on demand by a user activating an input device of either an electronic devices 460 or an output device 470. Input devices may include, without limitation, a touch- sensitive display screen, a keyboard, a mouse, a dedicated physical input (such as a push-button), a voice activated input device, or a combination thereof. In an alternative embodiment, the format may include a graphical data representation such as a time-course display plot. In yet another embodiment, the output device may provide a hard copy of the concentration data, for example on a strip chart recorder or as other more permanent records. It may be understood that the output device 470 may display data in any one or more formats or combination of formats, and may include alarm data, and/or other patient specific data.

[0041] It may be appreciated that the order and types of connections among and between the electronic components depicted in FIG. 4 represent only one non-limiting embodiment of electronics that may be associated with a system to measure an analyte concentration. Alternative embodiments may include additional components such as analog/digital converters used to convert signals for processing by an electronic device 460. It may be understood that more than one electronic device 460 may receive sensor output data, more than one current source 430 may be used to supply current to the electrodes, and more than one electrical voltage sensor 440 may receive signals from the concentration measuring device electrodes. Alternative embodiments may include electronic components that may combine functions illustrated by the separate elements illustrated in FIG 4. In one non- limiting example, the voltage sensing function of 440 and current sensing function of 450 may be combined into a single electrical sensor having one or more sensor input lines and one or more sensor output lines that may provide sensor output data directly related to an impedance measurement. Control of components, such as the switch 420 and the electrical current supply 430, may be supplied an electronic device 460 as illustrated in FIG. 4 (lines 465 and 437, respectively) or may be supplied by one or more alternative independent devices, or by a combination of devices. In addition, more than one output device 470 may receive data from an electronic device 460 over one or more communication means 475.

[0042] FIG. 5 illustrates one embodiment of components that may comprise an electronic device 460. The components of the electronic device 460 may include those of electronic system 500 as illustrated in FIG. 5. The electronic system may comprise a number of inputs and outputs along with internal computational and processing elements. The various components of the electronic system may be in mutual communication by means of a communications bus 505. The computational components may include at least one processor 510 in data communication with some components of computer memory, such as dynamic memory 515 and static memory 520. While only a single processor unit 510 is illustrated in FIG. 5, it is understood that such an electronic system 500 may incorporate a number of processing units acting either sequentially or in parallel. Dynamic memory components 515 may include, without limitation, DRAMs and VRAMs. Static memory components 520 may include, as non-limiting examples, disk drives, thumb drives, flash drives, ROMs, PROMs, EPROMs, and CD-ROM drives. Static memory, dynamic memory, or both static and dynamic memory may be used to hold operating instructions and/or data for the electronic system for use in accomplishing the variety of its activities. [0043] The electronic system 500 may receive a variety of inputs through one or more device input interfaces 535. Inputs may be received from one or more electrical sensors and/or feedback data from devices under control by the system (such as the one or more sources of electrical current or electronic switch). Inputs from the electrical sensors through the device inputs interface 535 may include, without limitation, serial digital signals, parallel digital signals, or analog signals. Device input interface 535 may be one or more wired interfaces and/or a wireless interfaces including, without limitation, RF wireless interfaces, a LAN interface, a WAN interface, or an IR interface.

[0044] System user inputs may be provided through one or more user input interfaces 525. A user input interface 525 may receive data from one or more input devices including, but not limited to, a keyboard, a mouse, a voice recognition system, and a digital tablet interface.

[0045] The electronic system 500 may also provide a number of data outputs by means of one or more device output interfaces 540. In one non-limiting example, the electronic system 500 may provide outputs to control one or more electronic switches, one or more sources of electrical current, or other devices for control. Such controls may include without limitation, a current source amplitude, a current source frequency, a switch configuration to form electrical connections between one or more electrodes and one or more current source devices, and a switch configuration to form electrical connections between one or more electrodes and one or more electrical voltage sensors.

[0046] In addition, an electronic system 500 may include one or more user output interfaces 530. User output interfaces 530 may direct information to one or more devices used by a system user. Embodiments of such output devices may include visual monitors such as CRT monitors, LED monitors, and LCD monitors, video monitors, and auditory devices such as speakers, as non-limiting examples. [0047] It is understood that the electronic system may also be in data communication with any number of other devices not specifically disclosed above, such as other electronic systems that may hold additional instructions and/or data for accomplishing the activities required for the concentration measuring system. Connectivity to such additional devices may be accomplished by means of additional communication interfaces 545. In one embodiment, the electronic system may be in data communication with one or more additional computing devices to provide multi-processor computation capabilities. In another embodiment, the electronic system may communicate with a server that hosts one or more libraries of analyte concentration data. Communication interface 545 may use any one or more communication protocols including, without limitation, wired protocols, wireless protocols, internet protocols, personal network protocols and/or IR communication protocols.

[0048] FIG. 6 is a flow chart of one non-limiting embodiment of a method to measure the concentration of an analyte, such as sodium cations, in a bodily fluid of an animal and/or human. The method may include providing a system 610 for measuring an analyte concentration. Such a system may include any or all of the features disclosed above for a device to measure an analyte concentration (such as depicted in FIGS. 1A, IB, 2A-F, and 3), and associated electronic components such as those disclosed above and depicted in FIGS. 4 and 5. The device for measuring the analyte concentration may then be placed in contact 615 with the skin of the animal or human to be measured.

[0049] The system for measuring the analyte concentration may include at least one source of electrical current, and the system may then be configured to provide at least some electrical current 620 to one or more conductors in electrical communication with one or more respective electrodes. In one non- limiting embodiment, the source of electrical current may be supplied to the electrodes by means of at least one electronic switch placing the respective electrode conductors in electrical communication with the one or more current sources. In one non-limiting example, the electronic switch may be controlled by at least one electronic device. In another non-limiting example, the one or more sources of electrical current may also be controlled by one or more electronic devices. Control of the current source may include control of one or more electrical current parameters, including, without limitation, an amount of current, an output voltage of the current supply, and/or the frequency (direct or alternating) of the current.

[0050] The system may then be used to measure 625 data from at least one sensor output. The sensors may include, without limitation, a voltage sensor and a current sensor. In one non-limiting embodiment, at least one electrical voltage sensor may be placed in electrical communication with at least one electrode conductor by means of an electronic switch. In another non-limiting embodiment, at least one electrical current sensor may be place in electrical communication with at least one electrode conductor by means of an electronic switch. In one non-limiting example, the electronic switch may be controlled by at least one electronic device.

[0051] Output data from the at least one electrical sensor may be provided 630 to the at least one electronic device. In one non-limiting example, the output data may include a voltage measurement from a voltage sensor and a current measurement from a current sensor. These data may be used, at least in part, by one or more electronic devices to calculate 635 the analyte concentration. In one non-limiting embodiment of the method, one or more electronic devices may calculate the analyte concentration based at least in part on calculating an impedance measurement derived from a voltage measurement and a current measurement. In one non-limiting embodiment, the impedance measurement may be an average impedance measurement. In another non-limiting embodiment, the impedance measurement may be a complex impedance measurement. In some non-limiting examples, the analyte concentration may be calculated by comparing a measured impedance value or separate current and voltage sensor output data against values in a look-up table. The look-up table may give data values that correspond to solutions having known concentrations of the analyte. Non-limiting examples of such solutions may include samples of serum from an animal or laboratory designed soltutions. In an alternative example, the impedance values or separate current and voltage sensor output data may be used as inputs to a mathematical model that may calculate the analyte concentration. In one non-limiting example, the mathematical model may be based on a linear relationship between a measured analyte concentration of a solution and the measured average impedance of that solution. In another example, the mathematical model may be based on a predetermined relationship between the analyte concentration and the measured phase change in a complex impedance measurement.

[0052] Once the analyte concentration has been determined, one or more electronic devices may transmit 640 the concentration data to an output device. The output device may display the concentration data in any of a number of formats for a user to view. One or more electronic devices may also transmit the concentration data to a logging device to retain the concentration data in a database associated with the animal or human. The database may be located on one or more electronic devices or may be located on a remote electronic device such as a database server. The database may also include other data associated with the animal or human. The electronic system and/or the output device may activate an alarm if the concentration data are greater than a maximum concentration value or less than a minimum concentration value. The maximum concentration value and minimum concentration value may be stored in one or more electronic devices or in another device that may be accessed by one or more electronic devices. EXAMPLES

Example 1: A Device for Measuring an Analyte Concentration in a Bodily Fluid

[0053] Twenty-five (25) stainless steel, gold coated needles were mounted in a 5x5 array configuration with 1mm spacing in a polyphenylsulfone substrate. The substrate and the needles were coated with a paralene material. The distal 100 um of each needle was left uncoated. A flexible printed circuit board was attached to the back of the substrate, Conductors on the flexible printed circuit board were connected to each needle so that approximately half of the needles were connected to one connector and the remainder of the needles were connected to the other connector, immediately adjacent needles were connected to different connectors, The substrate was applied to skin on an animal's limb and was subsequently held in place with a strap that encircled the limb.

Example 2: A Method for Calculating an Analyte Concentration

[0054] The needle configuration described in Example 1, above, was used to determine an analyte concentration. An AC current of about lOOuA and about 100kHz was applied to the microneedle assembly connectors. The impedance was determined by measuring the voltage drop across the connectors. The impedance vector and phase change was also measured. By measuring the impedance vector and phase change, and comparing it with data in look up tables, it was possible to measure the concentration of sodium in the serum. The data in the look up tables was obtained from experimentation using simulated serum and animal serum samples. The impedance was displayed on an associated monitor and displayed both an actual numeric current Na concentration and a trend line of Na concentration over time.

[0055] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated in this disclosure, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can, of course, vary. It is also to be understood that the terminology used in this disclosure is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0056] With respect to the use of substantially any plural and/or singular terms in this disclosure, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth in this disclosure for sake of clarity. It will be understood by those within the art that, in general, terms used in this disclosure, and especially in the appended claims (e.g. , bodies of the appended claims) are generally intended as "open" terms (e.g. , the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.). While various compositions, methods, and devices are described in terms of "comprising" various components or steps (interpreted as meaning "including, but not limited to"), the compositions, methods, and devices can also "consist essentially of" or "consist of" the various components and steps, and such terminology should be interpreted as defining essentially closed- member groups.

[0057] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g. , "a" and/or "an" should be interpreted to mean "at least one" or "one or more"); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g. , the bare recitation of "two recitations," without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to "at least one of A, B, and C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g. , " a system having at least one of A, B, and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0058] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed in this disclosure also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed in this disclosure can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0059] From the foregoing, it will be appreciated that various embodiments of the present disclosure have been described for purposes of illustration, and that various modifications may be made without departing from the scope and spirit of the present disclosure. Accordingly, the various embodiments disclosed are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

CLAIMS What is claimed is:

1. A device for measuring an analyte concentration in a bodily fluid, the device comprising: a substrate assembly;

a plurality of microneedles contacting the substrate assembly; at least one electrode associated with each of the plurality of microneedles; at least one conductor in electrical communication with the at least one electrode; and

at least one connector in electrical communication with the at least one conductor,

wherein the substrate assembly is configured to contact a portion of skin of an animal, and

wherein the plurality of microneedles are configured to penetrate the portion of skin of the animal thereby contacting the at least one electrode with the bodily fluid.

2. The device of claim 1, wherein the substrate assembly is a flexible material.

3. The device of claim 1, wherein the substrate assembly is at least in part a biocompatible material.

4. The device of claim 1, wherein the substrate assembly comprises one or more of the following: a polyether ether ketone, a ceramic, a liquid crystal polymer, a polytetrafluoroethylene, a fluoropolymer, a polyester, a polycarbonate, a polypropylene, a high density polyethylene, a low density polyethylene, a polyurethane, a polyimide, and a silicone.

5. The device of claim 1, wherein the substrate assembly comprises an adhesive.

6. The device of claim 1, wherein the substrate assembly is disposable.

7. The device of claim 1, further comprising a device configured to affix the substrate assembly adjacent to the portion of skin of the animal.

8. The device of claim 1, wherein the plurality of microneedles are mounted on the substrate assembly.

9. The device of claim 1, wherein the plurality of microneedles are one or more of the following: gold, stainless steel, platinum, platinum/iridium alloy, gold-coated stainless steel, and titanium.

10. The device of claim 1, wherein the plurality of microneedles have a length of about 100 μιη to about 1500 μιη.

11. The device of claim 1, wherein the plurality of microneedles have a length of about 500 μιη.

12. The device of claim 1, wherein the plurality of microneedles have a base width of about 50 μιη to about 500 μιη.

13. The device of claim 1, wherein the plurality of microneedles have a base width of about 160 μιη.

14. The device of claim 1, wherein the plurality of microneedles comprises about 2 to about 100 microneedles.

15. The device of claim 1, wherein the plurality of microneedles comprises about 25 microneedles.

16. The device of claim 1, wherein at least one of the plurality of microneedles is associated with two electrodes.

17. The device of claim 16, wherein the two electrodes are electrically isolated from each other.

18. The device of claim 1, wherein each electrode is disposed within the microneedle associated with the electrode.

19. The device of claim 1, wherein each electrode is disposed on an outer surface of the microneedle associated with the electrode.

20. The device of claim 1, wherein the electrode comprises a conductive material contacting a tip of a non-conductive microneedle.

21. The device of claim 1, wherein: the microneedle comprises a conductive body having a proximal side in contact with the substrate assembly;

the electrode comprises a conductive tip in contact with a distal side of the conductive body; and

the conductive body is coated with a non-conductive material on an outer body surface.

22. The device of claim 1, wherein: the microneedle comprises a non-conductive body having a proximal side in contact with the substrate assembly; and

the electrode comprises a conductive tip in contact with a distal side of the non-conductive body.

23. The device of claim 1, wherein each electrode comprises one or more of the following: gold, platinum, a platinum iridium alloy, and carbon.

24. The device of claim 1, wherein the at least one conductor comprises one or more of the following: copper, steel, aluminum, gold, platinum, a platinum iridium alloy, and carbon.

25. The device of claim 1, wherein the animal is a human.

26. The device of claim 1, wherein the analyte comprises sodium cations.

27. A system for measuring an analyte concentration in a bodily fluid, the system comprising: a device for measuring an analyte concentration in a bodily fluid, the device comprising:

a substrate assembly,

a plurality of microneedles contacting the substrate assembly, at least one electrode associated with each of the plurality of microneedles,

one or more conductors in electrical communication with the at least one electrode, and

wherein the substrate assembly is configured to contact at least a portion of skin of an animal, and wherein the plurality of microneedles are configured to penetrate the portion of skin of the animal thereby contacting the at least one electrode with the bodily fluid;

at least one source of electrical current;

at least one electrical sensor having a sensor input and a sensor output, wherein the sensor output is configured to provide one or more sensor output data; at least one electronic switch configured to place at least one of the one or more conductors in electrical communication with one or more of the at least one source of electrical current and the at least one sensor input; and

at least one electronic device configured to receive the sensor output data and calculate an analyte concentration.

28. The system of claim 27, wherein the at least one source of electrical current comprises a source of alternating electrical current.

29. The system of claim 27, wherein the at least one source of electrical current is controllable by at least one electronic device.

30. The system of claim 27, wherein the one or more sensor output data comprise impedance data.

31. The system of claim 27, wherein the at least one electronic switch is controlled by the at least one electronic device.

32. The system of claim 27, further comprising an output device to which the at least one electronic device transmits the calculated analyte concentration.

33. The system of claim 27, wherein the at least one electronic device comprises an alarm configured to activate when the analyte concentration is greater than an analyte maximum concentration value.

34. The system of claim 27, wherein the at least one electronic device comprises an alarm configured to activate when the analyte concentration is less than an analyte minimum concentration value.

35. The system of claim 27, wherein the analyte concentration comprises a concentration of sodium cations within the bodily fluid.

36. A method of measuring an analyte concentration in a bodily fluid, the method comprising: providing a system for measuring an analyte concentration in a bodily fluid, the system comprising:

a device for measuring an analyte concentration in a bodily fluid, comprising: a substrate assembly,

wherein the substrate assembly is configured to contact at least a portion of skin of an animal, and wherein the plurality of microneedles are configured to penetrate the portion of skin of the animal thereby contacting the at least one electrode with the bodily fluid,

at least one source of electrical current,

at least one electrical sensor having a sensor input and a sensor output, wherein the sensor output is configured to provide one or more sensor output data, at least one electronic switch configured to place at least one of the one or more conductors in electrical communication with one or more of the at least one source of electrical current and the at least one sensor input, and

at least one electronic device configured to receive the sensor output data and calculate analyte concentration data;

contacting the device for measuring an analyte concentration in a bodily fluid to a portion of skin of an animal;

providing electrical current from the at least one source of electrical current to at least one of the one or more conductors;

measuring, by the at least one electrical sensor, at least one sensor output data; providing the at least one sensor output data to the one or more electronic devices;

calculating, by the at least one electronic device, the analyte concentration based at least in part on the at least one sensor output data; and

providing the analyte concentration to an output device.

37. The method of claim 36, wherein providing electrical current to at least one of the one or more conductors comprises controlling, by the electronic device, at least one electronic switch to place the at least one conductor in electrical communication with the electrical current.

38. The method of claim 36, wherein the source of electrical current is controllable by the at least one electronic device.

39. The method of claim 38, further comprising controlling at least one electrical current parameter by the at least one electronic device.

40. The method of claim 39, wherein the at least one electrical current parameter is one or more of a current, a voltage, and a frequency.

41. The method of claim 36, wherein providing the at least one sensor output data to the one or more electronic devices comprises controlling, by the electronic device, at least one electronic switch to place the at least one conductor in electrical communication with the at least one sensor input.

42. The method of claim 36, wherein calculating, by the at least one electronic device, an analyte concentration comprises calculating an analyte concentration based at least in part on an impedance measurement.

43. The method of claim 42, wherein the impedance measurement is an average impedance measurement.

44. The method of claim 42 wherein the impedance measurement is a complex impedance measurement.

45. The method of claim 36, wherein calculating, by the at least one electronic device, the analyte concentration comprises one or more of the following: comparing the at least one sensor output data to a value in a look-up table; and providing the at least one sensor output data to a mathematical model.

46. The method of claim 36, further comprising activating an alarm in response to the analyte concentration data being greater than an analyte maximum concentration value.

47. The method of claim 36, further comprising activating an alarm in response to the analyte concentration data being less than an analyte minimum concentration value.

48. The method of claim 36, wherein the analyte concentration comprises a concentration of sodium cations within the bodily fluid.