The present disclosure relates generally to a device for measuring electrical activity in nerves, and for applying electrical stimulation to nerves. In particular, the disclosure relates to electrodes for measuring sympathetic nerve activity and for applying electrical stimulation to the sympathetic nerves.
Many diagnostic and treatment methods in the fields of medicine and biology rely on measurements of nervous activity in patients and test subjects. Nervous activity in humans and other animals generates electrical signals that are detectable by electronic equipment such as oscilloscopes and other electrical signal processing devices. In order to detect the nerve activity, one or more electrical conductors, or electrodes, are placed in proximity to the nerves being measured. The electrodes may receive the electrical signals for further medical analysis. Various medical treatment methods also use electrodes to deliver electrical signals to the nerves in order to induce a response in the patient.
Cardiac care is one particular area of medical treatment that heavily utilizes measurement of nerve activity. Activity in the autonomic nervous system controls the variability of the heart rate and blood pressure. The sympathetic and parasympathetic branches of the autonomic nervous system modulate cardiac activity. Elevated levels of sympathetic nerve activity (SNA) are known to be correlated with heart failure, coronary artery disease, and may be associated with the initiation of hypertension. Therefore, a diagnostic index of “autonomic tone” produced in accordance with measurement of SNA may have considerable clinical value. As known in the art, clinical utilization of autonomic nervous activity is mostly derived from biochemical perturbations like the use of beta-blockers in high blood pressure management. While elevated levels of SNA are known to be correlated with these medical conditions, more precise analysis of the particular electrical signals produced by sympathetic nerves is needed before sympathetic nerve measurement can become a useful diagnostic or prognostic tool. Deficiencies in current electrode technology result in either poor autonomic signal quality or present some difficulty in integrating implantable electronic enhancements (like telemetry, on-chip amplification, storage memory, and motion sensors).
One challenge to measuring sympathetic nerve activity is that the magnitude of electrical signals in the sympathetic nerves is relatively low, while various other electrical signals present in the patient provide noise that may interfere with isolation and detection of the sympathetic nerve activity. Existing electrodes detect both the nerve activity and other electrical noise generated in the patient's body. Thus, the signal to noise ratio (SNR) of the sympathetic nerve activity measured using electrodes known to the art is low, hindering the accurate detection and characterization of sympathetic nerve activity. For example, known electrodes have measured nerve signals with a voltage of 35 μV while the level of noise in the measuring electrode is 10 μV. Using the following SNR equation
the example signals have an SNR of approximately 10.9 dB. While this signal to noise ratio permits some measurements of relatively large changes in sympathetic nerve activity, the noise level may mask nerve activity having a smaller voltage magnitude. Improvements to electrodes that increase the accuracy of nerve activity measurement, including sympathetic nerve activity measurement, will benefit the fields of medicine and biology.
An electrode for measuring nerve activity has been developed. The electrode includes a first electrical contact having at least one electrically conductive projection extending from a surface of the first electrical contact, and a first electrical lead electrically connected to the first electrical contact to enable signals from the nerve to be received. The at least one electrically conductive projection is configured to engage tissue proximate to at least one nerve to enable the first electrical contact to electrically contact the nerve directly and form an electrically conductive or inductive path between the nerve and the electrical contact.
The description below and the accompanying figures provide a general understanding of the environment for the system and method disclosed herein as well as the details for the system and method. In the drawings, like reference numerals are used throughout to designate like elements. As used herein, the term “electrode” refers to an electrical conductor that is configured to establish an electrical contact with biological tissue such as tissue in a patient or test subject. As used herein, the term “nanoelectrode tip” or “nanoelectrode probe” refers to an electrically conductive electrode probe or needle having a size and shape that enables the nanoelectrode tip to engage a layer of tissue to establish electrical contact with a nerve. The nanoelectrode probes can be formed in various sizes and configurations, with typical sizes of an individual nanoelectrode probe being microscopic. Despite the use of the term “nano,” nanoelectrode probes can be larger than one nanometer and are often several hundred or thousand nanometers long and are tens or hundreds of nanometers in diameter at the tip of the probe.
The terms “nanoelectrode array” or “electrode array” both refer to a plurality of nanoelectrode tips that are electrically connected to one another and arranged in a predetermined pattern. The term “two-terminal nanoelectrode array” refers to an electrode having two electrical contacts where at least one of the contacts is a nanoelectrode array. The term “three-terminal nanoelectrode array” refers to an electrode having three electrical contacts where at least one of the contacts is a nanoelectrode array. As used herein, the term “wafer” refers to a planar material sheet adapted to have multiple repeated instances of a structural pattern formed on and through the surface of the wafer. A common example of a wafer is a silicon wafer used in the fabrication of microelectronic devices. Common examples of these wafers have approximately circular shapes with diameters between 25 mm and 450 mm and thicknesses of approximately 275 μm to 950 μm. While the wafer is often primarily composed of a silicon substrate, wafers may also include planar layers of other materials, such as metals and dielectrics.
Each of the nanoelectrode arrays 108 and 116 includes an electrically conductive layer 128 and 144, respectively. The electrically conductive layers include bonding pads for establishing an electrical connection to one of wires 136 and 148. The nanoelectrode arrays 108 and 116 and the electrical conductors are both formed from single layer of metal in some embodiments. In one embodiment, the electrically conductive layers 128 and 144 are formed from the same material as each nanoelectrode, such as gold, and promote a uniform electrical contact between each of the nanoelectrode tips and the electrical leads.
The electrically insulating adhesive 124 seals openings formed through the silicon layer 106, silicon oxide layer 132, and dielectric layer 138 to prevent fluids, tissue, or other contaminants from a patient or the environment surrounding the electrode 100 from contacting the back side of either of the nanoelectrode arrays 108 and 116. In some configurations, the electrically insulative adhesive 124 does not completely fill the space under the nanoelectrode arrays 108 and 116, but seals an air pocket under each of the nanoelectrode arrays 108 and 106. Suitable adhesive materials include a silicone elastomer with a resistivity of 1.8×1015 Ω·cm and electrically insulative epoxies. One commercially available silicone elastomer is Dow Corning® 3745 RTV sold by the Dow Corning Corporation of Midland, Mich., USA. The electrically insulating adhesive 124, silicon layer 106, and silicon oxide layer 132 electrically isolate the nanoelectrode arrays 108 and 116. Thus, electrical nerve signals generated in the nerve tissue are conducted through the nanoelectrode arrays 108 and 116 through the leads 136 and 148, respectively, and do not form a circuit between the nanoelectrode arrays 108 and 116.
The electrical leads 136 and 148 may be formed from any electrically conductive material suited for use in a medical environment, including copper wires surrounded by an insulated jacket. Remote ends of wires 136 and 148 may connect to a variety of medical diagnostic equipment, including wireless transmitters embedded in the body of a patient. Additionally, the wires may connect to electrical signal generators for application of electrical stimulation to various nerves.
In operation, the two-terminal nanoelectrode array 100 is placed in contact with tissue of a patient or test subject proximate to a nerve undergoing measurement or electrical stimulation. The nanoelectrode tips in nanoelectrode arrays 108 and 116 can detect electrical signals in the nerve tissue in two different ways. First, the nanoelectrode tips penetrate a layer of tissue that is proximate to a nerve while not damaging the nerve. As shown in
A system that measures electrical activity in nervous tissue of a patient can also detect spurious electrical signals, referred to as noise, from other sources than the nerve tissue. Sources of noise include diagnostic equipment connected to the terminals and external electromagnetic signals that generate noise in the electrical leads attached to the terminals. Various techniques known to the art can mitigate some external sources of noise. One source of noise, referred to as the Johnson noise also called Johnson-Nyquist noise, Nyquist noise or thermal noise, is electronic noise generated by the thermal agitation of charge carriers in an electric conductor and occurs regardless of any applied voltage. The Johnson noise level in an electrical circuit can be expressed as a voltage Vj and is expressed with the following equation:
Vj=√{square root over (4kbRTΔf)}
Where kb is Boltzmann's constant, R is the resistance of the circuit (including and dominated by the resistance of the electrodes inserted for measurements in applications like this one) in Ohms, Δf is the frequency bandwidth in Hz of the signal at the terminal and T is the temperature in degrees Kelvin. In a practical situation, the body temperature of a patient provides the temperature T. Additionally, narrowing frequency bandwidth Δf can reduce noise, but leads to a loss of information in the nerve signal being measured by the nanoelectrode. The nanoelectrode terminals in the nanoelectrode array 100 establish electrical contacts with nerves over a broad surface area that have a lower electrical resistance between the nerves and the electrode than electrodes previously known in the art. The reduction of the resistance R also reduces the magnitude of noise voltage Vj and consequently reduces measured noise when measuring nerve activity, without narrowing the frequency bandwidth Δf. The reduction in noise results in improved signal to noise ratios when measuring nerve activity, including sympathetic nerve activity. Thus, the structure of the terminals in the nanoelectrode array 100 enable improved detection of electrical nervous activity over prior art devices.
The arrays of nanoelectrode tips depicted in
In the example of
A lithography process, including electron beam lithography, optical lithography or another suitable lithography process, forms a pattern on the top silicon oxide layer 504 (block 408). Next, a mask layer of a resist material is formed on the pattern formed in the top surface of the wafer (block 412). The mask layer may be formed from a metal placed on the wafer using a lift-off technique. The mask layer is formed in locations of nanotips in the completed nanoelectrode array.
Once the mask is in place, a reactive ion etch removes the unmasked portion of the top silicon oxide layer 504 and a portion of the silicon wafer 106 to form a series of silicon pillars under the masked portion of the top silicon oxide layer 504 and silicon wafer 106 (block 416). In one embodiment, each pillar includes a silicon pillar 504 that is approximately 2 μm tall, with a 500 nm thick silicon oxide top layer 512. The mask material 508 is removed from the tops of the pillars after completion of the etching process.
After forming the pillars 504, the wafer is oxidized to convert a portion of the silicon 504 in each pillar into silicon oxide and leave a nanotip shaped segment of silicon 516 in each pillar (block 420).
Process 400 applies a buffered oxide etch (BOE) solution to the top of the silicon wafer 106 to remove the silicon oxide 520 surrounding each of the silicon nanotips 516 and the silicon oxide layer 518 (block 424).
Process 400 continues by applying etching and lithography to the bottom silicon oxide layer 132 of each sample, which is also referred to as the backside of the wafer 106. Each sample is aligned from the bottom to facilitate etching and lithography from the bottom (block 432). A second mask is applied to the bottom layer of dielectric 138 (block 436), as depicted by the mask layer 528 in
Process 400 next removes the unmasked portions of the bottom silicon oxide layer 132 and portions of the silicon layer 106 including the silicon nanotips 516 with a second wet-etching process (block 440). The second wet-etching process includes two stages. The first stage removes unmasked portions of the bottom dielectric layer 138. The second stage removes unmasked portions of the bottom silicon oxide layer 132 and silicon wafer 106, but does not remove the dielectric cap 524.
Process 400 forms the nanotips 112 using a deposition process applied to the bottom surface of the silicon oxide layer 132, silicon wafer 106, and cap layer 524 in the cavity 540 (block 444 ). The deposition process forms a layer of an electrical conductor, such as a metal or other electrically conductive material. The embodiment of
Prior to the metallization process, a resist layer 546 is placed on selected portions of the bottom silicon oxide layer 132 using lithographic techniques. After deposition of the metalusing a physical vapor deposition technique, such as evaporation or sputtering, a lift-off chemical process involving a photoresist stripper like the PRS-2000™ or a solvent like Acetone is used to remove the resist material 546 and the metal layer covering the resist material 546 (block 448). The lift-off process severs an electrical connection between the two nanotip arrays 108 and 116 as depicted in
After formation of the wafer is cut into multiple nanoelectrode arrays, referred to as samples, according to methods known to the art (block 452). Process 400 continues by filling the cavities 540 in the section of the silicon wafer 106 and bottom silicon oxide layer 132 (block 456) in each sample. Electrical wires 136 and 148 are electrically connected to the electrically conductive metal layers 128 and 144, respectively, in the nanoelectrode arrays 108 and 116. As depicted in
In some embodiments, process 400 concludes after block 456, and the two-terminal electrode array 110 in
In another embodiment, process 400 applies a wet etchant to remove the cap layer 524 after depositing the metal layer to form the metallic nanotips 112 (block 460). The cap layer 524 may be removed either prior to or after filling the cavity 540 as described in block 456. As depicted in
While process 400 is described in conjunction with fabrication of a two-terminal nanoelectrode array, process 400 can also be used to fabricate the three-terminal nanoelectrode array depicted in
While the preferred embodiments have been illustrated and described in detail in the drawings and foregoing description, the same should be considered illustrative and not restrictive. For example, the electrode has been shown as an integrated electrode in which the first electrical contact and the second electrical contact are electrically isolated from one another within a single electrode. The two electrical contacts, each with an extending electrically conductive projection, could be formed in two separate electrodes and electrically connected to the same nerve to form a single electrically conductive path through the two electrodes and the nerve. All changes, modifications, and further applications are desired to be protected.
This invention was made with government support under grant number HL071140 awarded by the National Institutes of Health (NIH). The United States government has certain rights in the invention.
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/US2011/055103 | 10/6/2011 | WO | 00 | 4/1/2013 |
Number | Date | Country | |
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61390541 | Oct 2010 | US |