Patent Application
20150250421
This invention relates to sensors for the detection of neurotransmitters and neuroactive substances. More specifically, this disclosure relates to in vivo chemical micro-sensors for selective neurotransmitter sensing with real-time, continuous monitoring.
Neurosensing has been in development for many years to monitor and detect changes and functions of the nervous system, including the brain. As the understanding of the nervous system has grown, so has the research and development of methods to detect and process chemicals related to how the nervous systems works and responds to different stimuli such as assorted biological materials and chemicals.
Sensors can be implanted to detect chemicals on the surface of the brain and monitor these levels to determine if intervention is indicated for the wellness of the patient. Sensors have also been used to detect environmental stimulation and then to stimulate other organs to produce a reaction. For example, these technologies have been used to detect light and then stimulate specific nerves or areas of the brain to provide a response analogous to natural visual processing.
Neurotransmitters can be monitored to determine the state of the systems and through this, preventative action can be taken. Detection of neurotransmitters in the brain and how the brain responds to them is being used as a research tool, for example to monitor assorted chronic diseases, disorders, and injuries. Furthermore, detection of neurotransmitters can potentially help to predict impending disorders so that some form of remedial action can take place to enhance the wellbeing of the patient.
Preferably, sensors need to be placed in the areas that the activity is most likely to be initiated. These locations could be deep within an organ, such as the brain.
To sense the neurotransmitter chemicals in these locations, microelectrodes have been developed. Some are provided as an array to be able to sense over a larger area while keeping the total contact area to a minimum. Some of these electrode devices are relatively long compared to the diameter so that they may reach deeper into the organ.
There are many different chemical neurotransmitters/neurochemicals used in brain function and throughout the body. One of the most common is dopamine which is used in many systems including the nervous, cardiovascular, hormonal and renal systems.
Another neurotransmitter that has been studied often is adenosine which is also important in cardiovascular and nervous systems. There are many other neurotransmitters that come in the form of amino acids, mono-amines, and peptides, for example.
Various electro-analytical techniques may be used to determine neurotransmitter activity at a micro-electrode probe tip. A recent key advance has been the development of fast-scan cyclic voltammetry (FSCV), which affords a superior combination of temporal and chemical resolution compared to other electro-analytical techniques. Sufficiently rapid rates of detection have been achieved for measurements of single cells to capture ultrafast single exo-cytotic release events.
Chemical resolution for FSCV is provided by a voltammogram, which is collected at each time point and functions as a chemical signature to identify the measured chemical species. FSCV has more recently been improved by the use of principal component regression, which is a chemometrics approach that permits statistical resolution of individual analytes from a mixed-analyte signal. FSCV has the capability of measuring major neuroactive substances in the brain, including dopamine, serotonin, norepinephrine, epinephrine, adenosine, histamine, nitric oxide, oxygen, and hydrogen peroxide. As an example, the utility of FSCV for investigating brain-behavior relationships has been demonstrated by studies monitoring dopamine in real time in ambulatory animals during goal-directed behavior and administration of abused drugs. The particular combination of temporal and chemical resolution makes FSCV a logical choice for real time monitoring of neuroactive substances.
Carbon-fiber microelectrodes (CFM) are currently considered to be the state-of-the-art microsensor for FSCV. These microelectrodes comprise a small diameter carbon-fiber, which is protected within an insulating layer, such as glass. The probe tip of carbon fiber is exposed and may be sharpened. A connection for support and electrical connection is provided at the other end. The small size (˜5- to 10 μm diameter) of the CFM reduces tissue damage, especially compared to a conventional microdialysis probe (˜300 μm diameter). The latter tends to compromise capillary blood flow in the sample region, disrupt neurotransmission, and induce neuronal trauma. A CFM affords a spatial resolution in the micron range and, when combined with extended-scan FSCV, provides a detection limit of ˜15 nM in the brain. However, the increased sensitivity of extended-scan FSCV is a trade-off against reduced response time of the CFM.
In the process of using a microelectrode, because of its small size, it can quickly lose its electro-activity induced by chemical reactions on the electrode such as oxidation. A microelectrode or probe can become “fouled” through damaged organic material blocking the sensing of the analyte neurotransmitter materials.
For FSCV measurements in freely behaving animals, the typical approach is to lower a fresh CFM acutely via a detachable microdrive. Use of a fresh CFM overcomes the diminution of response characteristics observed with long term implantation. Replacing the insulating layer of borosilicate glass with polyimide-coated fused silica extends the lifetime the CFM for longer term measurements. However, the ability to perform repeated measurements over weeks to months remains a highly prized, but as yet unrealized, goal of neurotransmitter monitoring. It is technically challenging and not commonplace with this configuration of CFM.
An additional limitation is that available CFMs are currently offered only as a single-probe microsensor. Microelectrode Arrays (MEAs) for electroanalytical techniques for sensing of neuroactive substances are known, and these have been fabricated using platinum on ceramic or silicon substrates or using pyrolyzed photoresist film on a silicon substrate. The latter provides a surface similar to carbon fiber. Use of MEAs provides concurrent, multi-site recording of brain activity. However, the size of the neurotransmitter probes developed to date limits their utility. Also, the necessary hardware and software supporting simultaneous measurements using greater than 4 channels has not yet been realized.
Emerging carbon nanomaterials such as nanotubes, nanofibers and micro-nanocrystalline diamond, have spurred renewed interest in investigating electrode material technology that is highly biocompatible, highly resistive to surface fouling and functional for extended time periods in chronic implants. Carbon nanotubes have been used on the electrode surface to provide a relevantly inert surface area in contact with biomaterials. Carbon is a good conductor and relevantly strong. Among carbon nanomaterials, conductive boron-doped diamond (BDD), in particular, offers excellent chemical, electrochemical and bio stability. BDD is an excellent electrode material for in vivo neurotransmitter analysis due to its intrinsic properties such as a wide electrochemical potential window, very small background “charging” current, chemical inertness and dimensional stability, increased working lifetime due to excellent biocompatibility, improved specificity, mechanical durability, pH-independent low background current, and high sensitivity due to weak adsorption of biomolecules such as proteins and oxidized products.
BDD is broadly classified into three categories based on its crystallite size: microcrystalline (MCD), nanocrystalline (NCD) and ultrananocrystalline (UNCD). NCD and MCD surfaces are sufficiently rough (Ra of ˜10-100 nm and 500-1000 nm RMS, respectively) to increase the risk of tissue damage. For implantable electrodes, UNCD with its as-deposited near atomic-scale smoothness (e.g., Ra of ˜5-8 nm RMS) offers an excellent choice.
Currently, diamond microelectrodes are custom-fabricated in several academic laboratories. In spite of many advantages, the diamond deposition on metal microwires requires careful surface preparation to seed the surface selectively with diamond nanoparticles, and achieving films that are continuous and pin-hole free is challenging due to the low re-nucleation rate associated with diamond growth chemistries. The commercial fabrication of diamond-based MEA's is also greatly hindered by the general incompatibility of diamond with wafer-scale microfabrication technologies for various reasons, including the large mismatch between the thermal expansion coefficient of diamond and typical semiconductor substrates and difficulties in planarization of hard and rough MCD layers. For NCD there can be challenges in controlling crystal size and high sp2 content in grain boundaries results in heterogeneous film properties. Currently, it is impractical for laboratories to fabricate high-quality diamond microsensors at a reasonable cost.
The following references provide some examples of the fabrication and use of microelectrode sensors in-vivo chemical sensing of neurotransmitters and neuroactive substances:
In summary, significant progress has been made in developing systems and methods for in-vivo chemical sensing of neurotransmitters and neuroactive substances. However, there remains a need for improved or alternative micro-electrode sensors and methods of fabrication of microelectrode sensors and sensor arrays for in vivo chemical sensing which address one or more of the above mentioned problems or disadvantages.
The present invention seeks to provide a micro-electrode sensor and sensor arrays for chemical sensing that address one of more limitations or disadvantages of known microelectrode sensors for in vivo sensing, e.g. for monitoring of neurotransmitters and neuroactive substances.
Thus aspects of the invention provide conductive nanocrystalline diamond microelectrode sensors, micro-electrode sensor arrays and methods of fabrication thereof.
One aspect of the invention provides a micro-electrode sensor for in-vivo chemical sensing, comprising:
a conductive microwire having a distal end portion comprising a tip,
a layer of nanocrystalline conductive diamond deposited on at least the distal end portion of the conductive microwire,
an overlying layer of a biocompatible insulating material extending over the conductive microwire and part of the layer of conductive diamond, and one or more sensor areas of the conductive layer of diamond, each sensor area defined by a respective opening in the insulating material exposing a surface of the conductive diamond layer.
For example, the conductive microwire comprises a metallic microwire, e.g. of diameter of 150 μm or less, such as a tungsten, tantalum, molybdenum, or niobium microwire. The layer of conductive diamond preferably comprises boron-doped diamond. The diamond surface preferably has a surface roughness substantially less than 500 nm rms. Advantageously, the conductive diamond layer comprises nanocrystalline diamond or ultrananocrystalline diamond. For example the diamond layer may have a rms surface roughness and average grain size of ˜20 nm, and preferably ˜10 nm, or less. The layer of insulating material is preferably a good insulator that may be 5 μm or less thick, and comprises a biocompatible material, such as aluminum oxide, glass, or a biocompatible polymer such as parylene, or alternatively, a layer of non-conductive diamond, preferably non-conductive nanocrystalline diamond or ultrananocrystalline diamond (UNCD).
The one or more sensor areas of the conductive diamond layer may be surface treated to chemically modify the conductive diamond surface, or the sensor areas may further comprise a coating, e.g. of a neuroactive substance, to improve chemical and electrical sensitivity and selectivity.
Since a sensor area or a plurality of sensor areas are defined by openings in the insulating layer, the one or more sensor areas may be arranged on the distal portion of the micro-electrode sensor to sense only particular areas of interest in vivo. That is the sensor area or areas may be limited to reduce interference from surrounding areas, thus increasing the signal to noise ratio, and improving sensitivity and selectivity.
For example, in one embodiment the distal end portion of the microwire may have a blunt or cylindrical tip and an exposed cylindrical surface of the layer of conductive diamond forms a sensor area around the circumference of the microwire, while an end surface the microwire is uncoated by conductive diamond, i.e. the end of the metal microwire may be exposed or coated with another material, such as an insulating material.
In another embodiment, the distal end portion of the microwire has a blunt or cylindrical tip and both the cylindrical surface and the end surface of the microwire are coated with the layer of conductive diamond to form the sensor area.
In another embodiment the distal end portion of the microwire comprises a tapered portion, tapering to a narrow or sharp tip and the one or more sensor areas are provided along a length of the tapered portion including the sharp tip.
In another embodiment the distal end portion of the microwire comprises a tapered portion tapering to a narrow or sharp tip and the one or more sensor areas are provided along a length of the tapered portion spaced from the tip. The sharp tip is coated with insulating material.
One or more sensor areas may be defined by a plurality of openings in the insulating layer spaced apart along a length of the distal end portion, spaced from the tip.
When distal end portion comprises a tapered portion tapering to a narrow tip, the one or more sensor areas may be defined by a plurality of openings in the insulating layer spaced apart along a length of tapered portion spaced from the tip.
When the distal end portion comprises a tapered portion tapering to a narrow tip, the one or more sensor areas may be defined by an opening in the insulating layer exposing the narrow tip.
A plurality of sensor areas can be defined by openings in the insulating material defining a two dimensional pattern of sensor areas along the distal end portion. Alternatively, a plurality of sensor areas can defined by openings in the insulating material defining a three dimensional pattern of sensor areas over the surface of the distal end portion.
One or more sensor areas may be defined along a length of 500 μm or less of the distal end portion near the tip and distal end portion may comprise a tapered portion which tapers to a sharpened tip of about 1 μm in diameter. The one or more sensor areas may include a sensor area at the tip or be spaced from the tip, e.g. at least 10 μm from the tip.
Another aspect of the invention provides a micro-electrode array sensor comprising an assembly of an array of plurality of micro-electrode sensors, for example an array of a two dimensional pattern or three dimensional pattern of micro-electrodes. The array may comprise multiple discrete sensors or it may be an array of a plurality of sensors micro-patterned on a planar substrate. For example a plurality of microwires may be patterned on a common substrate, and then coated with a conductive diamond layer.
As an example, an array of a plurality of microelectrodes sensors may be configured as neurostimulation electrode sensors, i.e. having a “stimulation-recording-detection” capability.
Yet another aspect of the invention provides a method of fabricating a micro-electrode sensor for in-vivo chemical sensing comprising:
a) providing a conductive microwire comprising a distal end portion having a tip;
b) depositing a conductive diamond layer on at least the distal end portion of the conductive microwire;
c) depositing a biocompatible insulating layer over the conductive microwire and the conductive diamond layer;
d) selectively removing part of the insulating layer overlying the conductive diamond layer to expose one or more sensor areas of the conductive diamond layer.
The method may further comprise surface treating the exposed sensor area of the conductive diamond layer to chemically modify the surface of the exposed sensor areas, e.g. plasma cleaning or electrochemical cleaning of the exposed sensor area.
The step of selectively removing part of the insulating layer comprises etching using a chemical, electrochemical, and/or laser process to pattern and expose said one or more sensor areas. For example, the insulating layer may be selectively removed from a sensor area at the tip of the microwire and/or selectively removed from one or more sensor areas of the distal end portion spaced from the tip.
Alternatively the insulating layer may be selectively deposited to leave sensor areas of the conductive diamond layer exposed.
Optionally, the method further comprises modifying the one or more sensor areas of the exposed conductive diamond with oxygen-containing functional groups, enzymes and other bio layers for selective detection of neuro-active substances, non-electroactive chemicals and other electroactive chemicals. Examples include a neuro-active substance comprising hydrogen peroxide or oxygen or an electroactive chemical comprising adenosine.
For example, the method may further comprise modifying the one or more sensor areas of the exposed conductive diamond with oxygen-containing functional groups comprising at least one of hydroxyl, carbonyl, and carboxylic groups. Modification of the exposed conductive diamond may be made to enhance detection and focus the detection on more specific neuro-active substances, non-electroactive chemicals and other electroactive chemicals.
The diamond micro-electrode sensors and sensor arrays may be configured for fast-scan cyclic voltammetry (FSCV) for chemical monitoring.
The use of nanocrystalline diamond (NCD) or ultrananocrystalline diamond (UNCD) microsensors can provide higher sensitivity, faster response time and reduced fouling and tissue interaction. For FSCV, they offer improved temporal and chemical resolution and help to realize the full potential of FSCV. UNCD microelectrodes can match or exceed the key characteristics of carbon fiber microelectrodes in response time, spatial resolution, sensitivity, and the minimization of tissue disruption.
The sensors have high surface stability due to the extreme chemical inertness of UNCD/NCD, high reproducibility from the extremely low background charging current arising from an ultra-smooth surface and sp3 carbon microstructure, and high sensitivity associated with individually electrically addressable ultra-small electrode sizes.
A highly reliable electrode-electrolyte interface can be achieved by using a patterned, ultra-smooth conductive UNCD/NCD micro-electrode array. The chemical inertness of BDD electrodes enables them to be used as long term implantable microsensors.
Thus improved or alternative microelectrode sensors, micro-electrode sensor arrays and methods of fabrication of micro-electrode sensors. The conductive diamond micro-electrode sensors are preferably fabricated with UNCD sensor areas.
The foregoing and other objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description, taken in conjunction with the accompanying drawings, of preferred embodiments of the invention, which description is by way of example only.
In the drawings, identical or corresponding elements in the different Figures have the same reference numeral.
The tip microwire is shaped or tapered, by conventional prior art etching or lapping, and then coated with the conductive diamond layer 611. For a simple structure where the entire tip forms a sensor area, the insulating material 110 may be selectively deposited on the microwire to leave the diamond tip exposed.
The sensing area of tip at the distal end may comprise one or more diamond sensing areas over a length of e.g. approximately 500 μm or less, or a length of 250 μm or less, and may include the tip or be spaced from the tip.
Thus,
In the embodiments described above, the microwire runs through the center of at least the distal portion of the microelectrode sensor. In some embodiments, this microwire may run the full length of the microelectrode sensor. In other embodiments the microwire runs only through the distal portion and the microwire is electrically connected to a conventional larger diameter (non-microwire) conductor for electrical connection at the proximal end.
Suitable materials for the microwire include tungsten (W), tantalum (Ta), niobium (Nb), or molybdenum (Mo) which provide an appropriate substrate on which nanocrystalline or ultrananocrystalline diamond may be deposited. Other conductive materials such as titanium (Ti), silicon (Si) or even possibly carbon fibers, may be used as the substrate material for the microwire on which the conductive NCD or UNCD layer is deposited. In some embodiments, a conductive adhesion layer, e.g. comprising titanium nitride, or the metals and materials listed above may be deposited on the microwire prior to the deposition of the conductive diamond to enhance the adhesion of the diamond to the microwire.
The microwire is sized for strength and flexibility while maintaining a small enough diameter that will minimize damage to the organ in which it is inserted. For example, the diameter of the microwire may be in a range of 25 μm to 300 μm. For some applications, diameter may preferably be 150 μm or less. Typically the length of the microwire may be about one to three millimeters in length.
Beneficially, the conductive diamond layer comprises nanocrystalline diamond (NCD) or more preferably ultrananocrystalline diamond (UNCD). The small grain size of the deposited diamond results in a significant reduction in interaction with the surrounding tissue compared to other diamond deposition grain sizes and carbon fiber microelectrodes (CFM). Not only does the smaller grain size reduce the occurrence of pin holes but causes less tissue damage, and reduced surface fouling and surface adsorption of biomaterials. For example, UNCD has a near atomic scale roughness of ˜5 to 8 nm rms. This is significantly less that the surface roughness of 500-1000 nm rms of conventional microcrystalline diamond (MCD) based electrodes which are currently standard for in vivo measurements.
UNCD further provides other excellent performance characteristics under much more extreme conditions than those typically encountered for in vivo applications. These characteristics include low background currents, dimensional stability at high current densities and potentials (e.g., 1 A/cm2 or greater for 100 hours at ˜7V wide electrochemical over-potentials for monitoring O2 and H2 evolution, and long electrode working lifetimes with a high level of physical and chemical inertness. For in vivo applications, it is advantageous to have low background current, i.e. to increase signal to noise ratios. Long lifetime with resistance to chemical or physical degradation or fouling is also beneficial for implantable micro-electrodes to be used for longer term in vivo sensing.
Using UNCD micro-electrode sensors as described above for in vivo sensing by electroanalytical methods known by those skilled in the art, detection limits beyond those used by other current state of the art in vivo sensors, such as CFM, can be realized. For sensors according to some embodiments, for example, it has been demonstrated that dopamine can be detected at levels less than 100 nM. In exemplary experiments, the detected level of dopamine is less than 10 nM. It was observed that the UNCD conductive diamond sensing area provided faster response times, e.g. less than 200 ms, relative to CFM.
Furthermore, microelectrode sensors according to embodiments of the invention are not limited to neurotransmitter sensing. Other analytes and conditions may be sensed, such as changes in pH or ferrocyanide/ferricyanide concentrations. If required, the diamond surface of the sensor areas may be modified to improve sensitivity and selectivity, e.g. by hydrogen or oxygen treatment or by functionalization of the surface with active species for the detection of certain chemicals or even for biosensing
Fabrication.
Micro-electrode sensors as described above may be fabricated by method steps comprising: providing a conductive microwire comprising a distal end portion having a tip; depositing a conductive diamond layer on at least the distal end portion of the conductive microwire; depositing a biocompatible insulating layer over the conductive microwire and the conductive diamond layer; and selectively removing part of the insulating layer overlying the conductive diamond layer to expose one or more sensor areas of the conductive diamond layer.
Once the surface of the microwire is prepared for diamond deposition, e.g. by steps of roughening (lapping or bead blasting) or chemical etching, a layer of conductive diamond is deposited thereon. For example, the diamond layer may comprise boron doped UNCD deposited by Hot Filament Chemical Vapour deposition from a reactant gas mixture comprising methane and hydrogen (CH4/H2) with a boron dopant gas, such as trimethyl borane.
The layer of conductive diamond may be deposited to a thickness in the range from 50 nm to 3000 nm, although for some embodiments the diamond layer may be deposited to a thickness greater than 1500 nm or 1.5 μm.
The NCD/UNCD diamond deposition process is optimized to avoid pin holes and reduce stress and graphite deposition. Pin holes through the diamond to certain substrates metals such as tungsten or titanium may produce undesirable signals or variations or cause deterioration to the substrate. Pin holes expose the metal underneath the diamond coatings which increases the background charging current and affects sensitivity. Optimization of grain size and diamond layer or film thickness can reduce the occurrence of these pin holes.
Graphite can also cause interference to readings due to its inferior electrochemical properties compared to the conductive diamond. Increased graphite deposition is often a result of non-uniform temperatures in the local deposition area or catalytic activity as a result of other materials exposed in the deposition process. Adjustments to the reactor configuration may help in providing more uniform temperatures. Also, operation at higher temperatures (such as >730° C.) and longer processing times (>25 minutes) may further provide for temperature uniformity.
The diamond film 104 stress will directly affect the adhesion of the diamond to the substrate 101. For deposition or NCD and UNCD by HFCVD, the CH4/H2 ratio can be reduced to generate more atomic hydrogen which enhances filament decarburization, raises substrate temperatures and reduces stress in the as-deposited film
If required, the diamond surface may be modified once the diamond film is deposited. For example, a post treatment with atomic hydrogen or oxygen may be used, e.g. to improve the selectively of the diamond surface to neuroactive analytes.
An insulating layer comprising a suitable biocompatible material is then formed onto the microwire and overlying the diamond film. The insulating layer leaves one or more areas of the conductive diamond layer exposed to define each sensing area. There are many biocompatible insulating materials that may be used for this insulating material. These include aluminum oxide, a polymer such as parylene, glass and a non-conductive diamond layer. Beneficially, the insulating layer is a good insulator that may be deposited to a thickness of 5 μm or less.
For simple structures with one sensing area at the tip, the insulating material may be selectively deposited on the diamond coated wire in a manner to leave the tip exposed. In other embodiments, surfaces of the microwire may be coated with the insulating material and then the insulating material is selectively removed to form openings defining sensor areas.
There are many methods that may be employed to selectively remove the insulation to form openings defining sensing areas of the conductive diamond surface. The methods may be selected depending on the insulating material used. Removal methods may include mechanical abrasion, chemical etching (i.e. wet etching of an oxide layer) and laser etching. Most of the material may be removed with an etching process but in some embodiments, a further cleaning process may be needed to remove any residual insulating material. Such processes may include electrochemical cleaning or a more rigorous oxygen plasma cleaning process. The latter cleaning process is preferably applied when it is desired to improve the attainable signal-to-noise ratio (S/N) to at least 25.
In some embodiments, e.g as shown in
In variants of these embodiments, the tip may be a blunt or cylindrical tip (examples shown in
Surface Treatments
In some embodiments, it may be beneficial if the conductive diamond is further surface treated or additional layers may be deposited. Surface treatment may be done prior to applying the insulating layer or surface treatment of the exposed sensing areas or it may be done after the selective removal of the insulating layer to open windows defining the sensing areas. The surface treatment may be a surface modification or deposition of a surface layer, e.g. enzymes or other bio layers. This additional treatment may be provided to improve selective detection of non-electroactive chemicals.
Micro-Electrode Sensor Arrays
In another embodiment, several electrodes in an in vivo sensor array may be used to provide spatial sensing, e.g. for an area of the brain tissue. A common configuration is a 4×4 multi micro-electrode array. With the use of FSCV and high speed multiplexing methods, individual data can be collected for each of the electrodes and then analyzed, producing a 3-D spatial sensing of the tissue area.
Individual probes may be combined to produce the array or, in alternative embodiments, a plurality of electrodes may be patterned on a single substrate. This substrate may include the microwires.
In other embodiments of a micro-electrode array, the array may further comprise some neurostimulation electrodes. These electrodes may be used for stimulating the local brain tissue to provide a response for the detection of neurochemical/neurotransmitter sensors. This provides a “stimulation-recording-detection” capability to the array. With the combination of stimulation and sensing or recording electrodes in an array, this array may be part of a universal platform for many applications requiring stimulation, recording, and sensing functions.
In some embodiments, the exposed conductive diamond surfaces forming the sensor areas may be treated with ultraviolet light (UV) to enhance the detection of the neurotransmitters.
Conductive diamond micro-electrode sensors and sensor arrays according to embodiments of the present invention are provided which are suitable for in vivo chemical sensing. Also provided is a method of fabrication of individual micro-electrode sensors and sensor arrays. Reliable, sensitive and selective chemical micro-sensors may be constructed for real-time, continuous monitoring of neurotransmitters and neuro-active substances in vivo. In preferred embodiments, each sensor comprises conductive microwire, having a distal end comprising a tip, coated with nanocrystalline or ultrananocrystalline conductive diamond, and an overlying insulating layer. Active sensor areas of the conductive diamond layer are defined by openings in the insulating layer at the distal end. Multiple sensor areas may be defined by a 2 or 3 dimensional pattern of openings near the tip. Particular arrangements of defined conductive diamond sensor areas limits interference from surrounding areas for improved signal to noise ratio, sensitivity and selectivity. For example, for applications such as fast-scan cyclic voltammetry, multiple sensors can be arrayed and operated using high speed multiplexers, to provide 3-D spatial sensing with near real-time monitoring.
Although embodiments of the invention have been described and illustrated in detail, it is to be clearly understood that the same is by way of illustration and example only and not to be taken by way of limitation, the scope of the present invention being limited only by the appended claims.
This application claims priority from U.S. provisional patent application Ser. No. 61/705,715 entitled “UNCD Microsensors for In Vivo Monitoring of Neurotransmitters”, filed Sep. 26, 2012, which is incorporated herein by reference, in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US13/61958 | 9/26/2013 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61705715 | Sep 2012 | US |
