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WO2013014206A1 - Procédé et dispositif pour la stimulation/l'enregistrement de cellules - Google Patents

Procédé et dispositif pour la stimulation/l'enregistrement de cellules Download PDF

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Publication number
WO2013014206A1
WO2013014206A1 PCT/EP2012/064630 EP2012064630W WO2013014206A1 WO 2013014206 A1 WO2013014206 A1 WO 2013014206A1 EP 2012064630 W EP2012064630 W EP 2012064630W WO 2013014206 A1 WO2013014206 A1 WO 2013014206A1
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layer
electrode
cnts
atop
electrodes
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PCT/EP2012/064630
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English (en)
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Silke MUSA
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Imec
Katholieke Universiteit Leuven
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0526—Head electrodes
    • A61N1/0529—Electrodes for brain stimulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0031—Implanted circuitry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6867—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive specially adapted to be attached or implanted in a specific body part
    • A61B5/6868—Brain
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0285—Nanoscale sensors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • A61B2562/125—Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes

Definitions

  • This present invention is situated in the field of implantable devices for the stimulation and recording of cells. More in particular it is situated in the field of implantable neural microsystems.
  • Electrical recording and stimulation of the central nervous system is used in basic neuroscience to study brain functions and in clinical practice to treat conditions such as epilepsy, Parkinson's disease, and chronic pain.
  • Device engineers are increasingly confronted with demands from neuroscientists and clinicians alike to develop implantable microsystems that may provide both stimulation and recording capabilities on one platform. Resolutions down to cellular (10-50 um) and even subcellular dimensions ( ⁇ 10 ⁇ ) should allow bidirectional interaction with the brain at different levels of neural organization.
  • dense arrays with ⁇ -sized electrodes for parallel and high-fidelity recording and selective stimulation of single neurons or neuronal populations are envisaged.
  • such strict device specifications can only be met by using advanced Cu-CMOS technology capable of addressing large electrode arrays in a reliable way.
  • Electrode impedance which scales inversely with the electrochemical interface capacitance, may be too high - on the order of several MOhms - for small electrodes based on thin-film materials to offer sufficient recording sensitivity.
  • the high driving voltages required to supply sufficient stimulation charge with small electrodes may damage the electrode and surrounding tissue. Solutions to mitigate these limitations aim at increasing the effective surface area (and hence capacitance) of the electrodes by coating them with rough or porous materials such as Pt black, iridium oxide (IrO,), conducting polymers, and recently also carbon nanotubes (CNTs).
  • Pt black suffers from poor mechanical stability, while IrO, and conducting polymers, such as poly(3,4-ethylenedioxythiophene) and polypyrrole, can degrade under electrical stimulation leading to impedance fluctuations and loss of charge injection capacity.
  • the long-term electrode viability is expected to improve significantly by using CNTs, which are chemically inert and stable against degradation under prolonged potential cycling. They furthermore exhibit excellent electrical conductivity and, most importantly, biocompatibility towards neurons.
  • the major challenge in this regard relates to the mechanical stability of the CNTs during implantation in tissue such as e.g. brain tissue. Due to their vertical structure, CVD-grown CNTs may be susceptible to lateral abrasive forces during probe implantation, leading to damaged or collapsed CNTs. The latter is problematic for dense electrode arrays where collapsed CNTs may form electric shorts across neighboring electrodes. In the usual top-down approach described for microelectrode arrays, CNTs are selectively grown in electrode openings defined in the dielectric that covers the interconnects. Here, the CNT growth can be the last fabrication step, which is advantageous for preserving the as-grown CNT properties.
  • an appropriate embedding and lateral confinement of the CNTs helps to overcome the problem of lateral abrasive forces during probe implantation which could damage the CNTs.
  • the electrode for stimulation and recording of tissue, e.g. brain tissue, is presented.
  • the electrode comprises:
  • an insulating layer e.g. an oxide layer such as a Si0 2 layer, atop the subtrate;
  • a second layer atop the insulating layer and atop the plurality of carbon nanotubes (5); and an opening (8) in the second layer for providing access to the plurality of carbon nanotubes (4).
  • a hermetic electrode for stimulation and recording of tissue comprises:
  • an insulating layer e.g. an oxide layer such as a Si0 2 layer, atop the subtrate.
  • a second layer which is located atop the insulating layer and atop the plurality of carbon nanotubes; - atop the second layer, a third layer, e.g. a biocompatible layer such as a layer comprising or consisting of Parylene C or SiN or any other suitable material that is resistang to sodium ions and moisture,; and an opening in the second layer and the third layer for providing access to the plurality of carbon nanotubes.
  • a biocompatible layer such as a layer comprising or consisting of Parylene C or SiN or any other suitable material that is resistang to sodium ions and moisture
  • a implantable device comprising:
  • a plurality of bondpads connected to the plurality of cell stimulation electrodes via a plurality of interconnections.
  • the implantable device may comprise additional (packaged) circuitry to drive the bondpads.
  • the implantable device may be a neural probe for electrical stimulation and recording of brain tissue.
  • a method is presented to manufacture an electrode for stimulation and recording of tissue as described in the first aspect of the present invention.
  • the method comprises:
  • an insulating layer e.g. an oxide layer such as a Si0 2 layer, atop the subtrate
  • a method is provided to manufacture a hermetic electrode for tissue stimulation and recording as described in the first aspect of the present invention.
  • the method comprises:
  • the third layer provides a hermetic layer to the electrode device.
  • the third layer is preferably made of a biocompatible material such as SiN, Parylene C or any other suitable material that is resistant to to sodium ions and moisture.
  • the third layer protects the second layer from disintegration.
  • the second layer serves also as a protection layer for the CNTs during the plasma etch of the third (hermetic) layer for creating the opening.
  • the second layer may be a Si0 2 layer or another suitable material.
  • FIG. 1 is a schematic of a process flow for the CNT (g), TiN (g 7 ) and Pt (g") electrode arrays;
  • FIG. 2 (a) is an optical micrograph of an electrode array after CNT growth on top of the electrodes;
  • FIG. 2(b) is a cross-sectional scanning electron micrograph (SEM) image of the as-grown CNTs;
  • FIG. 2(c) is a SEM image of an electrode and
  • FIG.2(d) is a close-up of the same after conformal CVD Si0 2 coating;
  • FIG. 2(e) is an overview SEM image o an electrode after etching of the Parylene C and removal of the CVD Si0 2 in buffered HF;
  • FIG. 2(f) is an overview SEM image of a typical electrode edge partially encased in Parylene C;
  • FIG. 2(g) is a combined FIB/SEM image showing details of the final CNT-Parylene C interface at an electrode opening;
  • FIG. 2(h) is a combined FIB/SEM image showing details of the final CNT-Parylene C interface at the outermost electrode edge;
  • FIG.3 illustrates cyclic voltammograms of Ft, TiN and CNT electrodes of 5 mm diameter
  • FIG.4 illustrates average Bode plots with impedance magnitude,
  • FIG.5(a) illustrates impedance magnitude (with standard deviation) at 1 kHz a a function of the electrode diameter for the Pt, TiN and CNT electrodes;
  • FIG.5(b) illustrates an equivalent circuit to fit the impedance spectra
  • FIG.6 is a graph illustrating the baseline-corrected transmittance infrared spectra of (a) as-grown CNTs, (b) of Si0 2 -coated CNTs after a BHF treatment, and (c) of CNTs after BHF treatment. The corresponding contact angles for the three substrates are shown on the righthand side;
  • FIG.7 illustrates SEM images of primary rat hippocampal neurons 5 days in vitro on fabricated CNT substrates
  • FIG.8 schematically illustrates a structural CNT electrode according to embodiments of the present invention.
  • FIG.9 schematically illustrates a structural and hermetic CNT electrode according to embodiments of the present invention.
  • FIG. 10 illustrates an implantable probe for stimulation/recording of cells according to embodiments of the present invention.
  • FIG. 11 illustrates implementations of probes.
  • an insulation layer is deposited after the CNT growth, and electrode openings are defined lithographically or possibly also by chemo-mechanical polishing.
  • the insulation material serves a protective purpose whereby contamination of theCNTswith toxic materials during fabrication is avoided.
  • the insulation prevents the contamination of the CNTs with toxic materials such as photoresist or metal traces during fabrication.
  • the fabrication of individually addressable passive microelectrodes of cellular and subcellular dimensions coated with vertically-aligned CNTs is demonstrated.
  • preserving the mechanical integrity of the CNTs during prospective implantation becomes a key objective. Therefore, a bottom-up approach is presented to encase the vertical CNT microelectrode for improved mechanical stability.
  • FIG.8 and FIG.9 A final device as obtained in accordance with embodiments of the present invention is schematically illustrated in FIG.8 and FIG.9. Both embodiments illustrate a CNT electrode in accordance with embodiments of the present invention, comprising a substrate 1, e.g. a Si substrate, an insulating layer, e.g an oxide such as S1O2, an electrode layer 3 which may be suitably patterned so as to comprise one or more electrodes, a seed layer 4 to grow CNTs, e.g. a TiN or TiN/Ni layer, and a plurality of CNTs 5 grown on the seed layer 4.
  • Such dielectric layer 6 protects the CNTs 5 against mechanical impacts when introducing the electrodes into tissue for stimulation and recording.
  • the embodiment illustrated in FIG.9 furthermore shows, on top of the dielectric layer 6, a protective layer 7.
  • This protective layer 7 preferably is made from biocompatible material, and protects the dielectric layer 6 from disintegration when implanted and in contact with sodium ions and moisture.
  • an opening 8 is provided, in the layer 6 and optionally, when present, in the layer 7, for providing access to the CNTs.
  • the CNTs are protected by the encasing formed by the dielectric layer 6 and optionally the protective layer 7.
  • the encasing provides protection for the CNTs.
  • the encasing provides a solution for inserting the CNTs in tissue. In accordance with embodiments of the present invention, this was achieved using a coating stack comprising a dielectric layer such as e.g. S1O2, and a protective layer such as Parylene C, with lithographically defined electrode openings.
  • the CNTs were grown using low-temperature (425 C) plasma-enhanced CVD (PECVD) optimized for back-end-of-line (BEOL) Cu-CMOS processing.
  • PECVD plasma-enhanced CVD
  • the CNT electrodes were characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) and benchmarked against co-fabricated Pt and TiN electrodes.
  • CV cyclic voltammetry
  • EIS electrochemical impedance spectroscopy
  • the impact of processing on the CNT functional chemistry and wettability was analyzed by Fourier-transform infrared spectroscopy (FTI ) and contact angle measurements, respectively.
  • FTI Fourier-transform infrared spectroscopy
  • SEM scanning electron microscopy
  • FIG. 10 illustrates an implantable probe for stimulation and recording of cells according to embodiments of the present invention.
  • implantable probe comprises a tip 13 for introducting the probe into tissue of which cells are to be stimulated and of which cell activity is to be recorded.
  • This tip 13 is provided at an extremity of a shaft 10 comprising at least one, preferably a plurality of, CNT cell stimulation and recording electrodes 12 in accordance with embodiments of the present invention.
  • the shaft 10 may be connected to a wider portion of the probe, which is not to be implanted, and which is provided with bondpads 14 for making electrical connections to other pieces of circuitry, either integrated on the probe or external thereto.
  • Electrical interconnections 11 are provided on the probe for electrically interconnecting the CNT electrodes 12 with the bondpads 14.
  • FIG. 11 illustrates implementations of such probes.
  • FIG. 11 (c) illustrates a probe comprise additional packaged circuitry 15 for driving the bondpads 14.
  • microelectrode arrays were fabricated on semiconductor wafers 1, e.g. Si wafers, such as 200 mm Si, wafers, according to the scheme depicted in FIG. 1. Briefly, for all investigated electrode materials, interconnects 3 were defined by lift-off of sputter- deposited Pt (FIG. la). Electrode arrays based on TiN 4 and CNTs 5 had an additional TiN layer on top of the electrode areas of the interconnects 3, the additional TiN layer being patterned by means of a second lift-off step (FIG. lb).
  • CNTs 5 were selectively grown on the electrodes by a suitable low-temperature process (such as below 600°C, e.g. 425 C), for example a PECVD process using a 2 nm (nominal) thick Ni layer 4 as catalyst (FIG. lc and FIG. 2a).
  • a suitable low-temperature process such as below 600°C, e.g. 425 C
  • PECVD process using a 2 nm (nominal) thick Ni layer 4 as catalyst
  • FIG. lc and FIG. 2a The resulting multiwalled CNTs had a homogeneous height of ⁇ 2 ⁇ , an average diameter of 34 nm (determined by SEM), and a density of approximately 2-10 11 cm “2 (FIG. 2b). This CNT height was opted for in order to avoid too high topographies on the wafer surface and hence to ensure a reliable lithography.
  • the CNTs 5 were embedded in a dielectric layer 6, e.g. a si0 2 layer, such as a 300 nm Si0 2 layer, to serve as a protection and etch stop layer during subsequent fabrication steps.
  • a dielectric layer 6 e.g. a si0 2 layer, such as a 300 nm Si0 2 layer, to serve as a protection and etch stop layer during subsequent fabrication steps.
  • the Si0 2 was deposited by CVD at 150 C (FIG. Id) and formed a conformal coating on top of the CNTs as seen from the SEM images in FIG.2c and FIG. 2d.
  • an additional biocompatible layer 7 was provided, e.g. evaporated on top of the dielectric layer 6.
  • 1 um of Parylene C was evaporated (FIG. le).
  • the bond pads 9 were opened by suitable methods, e.g. reactive ion etching (RIE) of the biocompatible layer 7, e.g. Parylene C, and the dielectric layer 6, e.g. Si0 2 (FIG. If).
  • RIE reactive ion etching
  • the biocompatible layer 7, e.g. Parylene C, on the electrode areas was opened. The etch time was adjusted to stop on top of the dielectric layer 6, e.g.
  • FIG. lg The corresponding stack profiles for the TiN and Pt electrodes are shown in FIG. lg") and FIG. lg"), respectively.
  • steps b), c) and d) of FIG. 1 were omitted.
  • steps c) and d) were omitted.
  • the wafers were diced and the chips were wirebonded onto custom printed circuit boards.
  • the Si0 2 layer on top of the CNT electrodes was removed by dipping the packaged chips in buffered hydrofluoric acid (BHF).
  • BHF buffered hydrofluoric acid
  • FIG. 2e displays an electrode after RIE of Parylene C and removal of the Si0 2 in BHF. Due to this wet treatment and subsequent drying of the chips, capillary action caused a clustering of the CNTs, resulting in the formation of dense microbundles.
  • a typical electrode edge partly encased in Parylene C is shown in the overview SEM image in FIG. 2f.
  • the Parylene C encasement is higher than the CNTs and should hence provide sufficient protection of the CNT electrodes from abrasive forces that may arise during implantation.
  • Focussed ion beam (FIB) combined with SEM was employed to analyze the details of the CNT-Parylene C interface at an electrode edge.
  • a cross-sectional FIB/SEM image of the final electrode edge shows the CNT-Parylene C interface at the electrode opening (FIG. 2g). Dotted lines indicate the different layers, which are (from top to bottom): Parylene C, CNTs, TiN, Ft, and thermal Si0 2 .
  • CSC charge-storage capacity
  • cathodic neural stimulation is preferred over anodic stimulation because cathodic activation thresholds are lower.
  • This cathodic CSC (CSC,) is frequently employed to estimate the ability of an electrode material to supply sufficient charge for neural excitation. It has to be noted, however, that voltage limits determined by CV may differ significantly from the electrode polarization that is tolerable under stimulation. The reason is that the transient response of electrodes under stimulation is characterized by a highly nonlinear voltage-time behavior with a differential "sweep rate" of more than 1 kV/s.
  • FIG. 3 shows typical voltammograms obtained with Pt, TiN, and CNT electrodes of 5 ⁇ diameter. Scans were performed at 0.1 V/s in phosphate buffered saline. For better clarity. For better clarity, a vertical offset is introduced for the Ft curve (right y-axis), and the values of the TiN curve (left y-axis) have been multiplied by 50.
  • the Pt voltammogram exhibits the typical features of H adsorption and desorption between - 0.6 V and -0.3 V and a broad Pt oxidation band between 0.25-0.9 V. The large current step in the cathodic sweep between 0-0.2 V is due to the reduction of dissolved 0 2 .
  • Electrodes based on TiN show a strong blocking behavior in the potential region -0.5-1.1 V where current flow is mostly capacitive in nature.
  • two large bands centered around -0.85 V and -0.4 V can be observed and are attributed to the oxidation of H 2 gas and chemisorbed H, respectively.
  • Due to the lack of distinct H adsorption features in the cathodic scan the onset potential for H 2 evolution cannot be identified. Thus, this is set at -0.75 V for the TiN electrodes.
  • an oxidative wave near 1.2 V was attributed to the formation of a surface oxynitride and/or oxide phase.
  • the reductive shoulders visible at approximately 0 V and -0.25 V are considered to correspond to the reduction of this oxynitride and/or oxide layer.
  • the signal at 1.1 V in the cathodic sweep may be related to the reduction of 0 2 which evolved in the preceding anodic scan.
  • Electrodes coated with CNTs show a strong capacitive response as evidenced by the large area under the CV curve and the lack of large faradaic features. Besides a well-defined reductive peak at -0.25 V and a weaker shoulder at -0.6 V, only ill-defined broad oxidation bands can be discerned.
  • the overall redox activity of the CNT electrodes including the reductive peak at -0.25 V, bears a strong resemblance to the voltammetric response of the bare TiN electrodes. This may indicate that the CNTs do not form a fully closed layer above the TiN substrate and that the electrolyte is able to enter the CNT matrix and spread over the TiN. This result is of great importance since it implies a good wettability of the CNT matrix.
  • similar voltammetric features have also been reported for singlewalled CNT sheets and were attributed to oxygen-containing functional groups present in the CNT sidewalls. Thus, it remains unclear whether the observed redox activity is solely due to the TiN underlayer or is also caused by the CNTs.
  • Table 1 summarizes the CSCc values (mean ⁇ standard deviation) for all investigated electrode sizes and materials obtained from ne different electrodes. Also provided are the CSCc values normalized by the respective value of the 25 ⁇ -diameter electrode, CSC25c, and the voltage ranges of the water window. The CSCc obtained with the CNT electrodes is more than 2 orders of magnitude larger than that of the Pt and TiN electrodes of the same diameter. It also appears that more charge per unit area is available with decreasing electrode diameter as indicated by the CSC 2 ⁇ .
  • n is the number of electrons
  • D is the diffusion coefficient
  • C* is the bulk analyte concentration
  • re is the electrode radius.
  • the water window for Pt was considerably smaller than for the other materials, which can be attributed to the electrocatalytic nature of Pt towards hydrogen and oxygen evolution.
  • the CNTs provide the best combination of both properties.
  • Table 1 Values for the CSC C , CSC ⁇ c, and water window of Pt, TiN and CNT electrodes.
  • Electrochemical impedance spectra were recorded for all electrode sizes and materials at their respective equilibrium potentials.
  • the EIS data was analyzed by fitting of physically meaningful equivalent circuit models and by parameter extraction.
  • the linear frequency response of an electrode-electrolyte interface can be modeled in terms of an equivalent circuit where the individual circuit elements describe the various relaxation phenomena occurring at the interface.
  • the interface behaves like a parallel C circuit, where the resistance represents the faradaic response of the system, termed the charge- transfer resistance, and the capacitance provides information on the interfacial charge distribution known as the double layer capacitance, C d .
  • CPE constant-phase element
  • ⁇ is the angular frequency
  • a CPE is a measure of the magnitude of Z CPE
  • a is considered to depend on the roughness of an electrode material and decreases with increasing roughness.
  • FIG. 4 shows the Bode plots of all measured electrode sizes and materials averaged over n e measurements from n e different electrodes (see Table 2 for the values of n e ).
  • the amplitude of recorded neural signals is adversely affected by a large electrode-electrolyte interface impedance.
  • a qualitative indicator for the efficiency of a recording electrode is its impedance at 1 kHz, which is the characteristic frequency in the power spectrum of a neural action potential with a duration of 1 ms.
  • the CNT electrode impedance at 1 kHz is 3 orders of magnitude lower compared to the Pt and TiN electrodes.
  • the TiN electrodes exhibit a clear minimum of
  • Electrodes coated with CNTs behave capacitively at low frequencies and resistively at higher frequencies similar to an electronic high-pass filter. Least-square fitting of the spectra reveals that this effect originates from various relaxation processes involving chemical modifications at the CNT surface and a low R a combined with the occurrence of diffusion.
  • the equivalent circuit is provided in FIG. 5b.
  • the series resistance, R s accounts for the ohmic behavior of the solution and metal wires.
  • an additional capacitance, Co is included in series with R a.
  • the pseudocapacitance a small fraction of the interfacial capacitance is faradaic rather than electrostatic in nature and is termed the pseudocapacitance. It is considered to originate from functional groups (defects) present at the tip and sidewalls of the CNTs which are redox active. In general, pseudocapacitances can arise due to chemisorption or redox reactions occurring at electrode surfaces. The charge that is transferred in these electrode processes is some function of the electrode potential, and as such resembles the behavior of a capacitance.
  • this kind of capacitance is faradaic in nature, rather than being associated with a potential-dependent distribution of electrostatic charge as for the C dL
  • the pseudocapacitance is represented as a capacitance, C 3 ⁇ 4 in series with R a
  • C x may be related to the presence of an insulating oxide and/or oxynitride layer on top of the electrodes introduced during the electrode opening by RIE.
  • an additional distributed element, the Warburg impedance, Z w was required to account for diffusion effects in the porous matrix. It is connected in series with R a and C x .
  • the R s shows a strong dependence on the electrode material and is up to 3 orders of magnitude higher for the Pt and TiN electrodes as compared to the CNT electrodes.
  • the series resistance R s of the CNT electrodes is largely determined by the low solution resistance (the metal resistance can be neglected), which is a direct consequence of the large distributed surface area of the CNTs, and can be described in terms of a porous electrode:
  • the average diameter of a nanotube in this context is 34 nm.
  • the actual pore radius r p for a 25 ⁇ -diameter electrode is therefore about 4 times larger than estimated.
  • the bare TiN electrodes show an unexpected high series resistance Rs. This may be due to a higher intrinsic resistivity of the TiN layer possibly caused by oxidation during RIE.
  • the charge-transfer resistance R a for the Pt and TiN electrodes is 4-6 orders of magnitude higher than for the CNT electrodes.
  • charge-transfer occurs much easier at the CNTs than at the Pt or TiN electrodes, which also explains why diffusional involvement in the form of the Warburg impedance Z w was mostly observed for the CNT electrodes.
  • the extent to which this enhanced reactivity of the CNTs may or may not be beneficial for neural recording and stimulation remains to be determined.
  • the low impedance of the CNT electrodes is a direct consequence of their large interfacial capacitance. This is reflected by A CPE values in Table 2 which are 2-3 orders of magnitude higher than for the Pt and TiN electrodes.
  • the constant-phase element C PE power factor, a, of the Pt electrodes is close to unity and thus resembles the behavior of an ideal capacitor.
  • the TiN and CNT electrodes have a smaller power factor a, which indicates a higher roughness/porosity. The roughness of TiN is caused by its microcolumnar morphology.
  • the CNT pseudocapacitance, C X is of the same order of magnitude as AQ>E and therefore directly related to the large specific surface area of the CNTs. Although faradaic and not electrostatic in nature like the constant-phase element C PE , a large pseudocapacitance C X may similarly improve the quality of the signal transduction across the electrode-tissue interface and enhance charge injection during stimulation. On the other hand, the influence of the Warburg impedance, Z W , on the performance of neural electrodes is not evident. Finally, the C, is one order of magnitude higher for the CNT electrodes. Here, additional parasitic coupling compared to the planar Pt and TiN electrodes may occur through the Parylene C encasement of the vertical electrodes (see FIG. lg and FIG. 2f ).
  • FIG. 6 shows the baseline-corrected FTIR spectra and contact angles determined from as- grown CNTs, BHF-treated CNTs, and BHF-treated Si0 2 -coated CNTs similar to the fabrication sequence of the real devices. The exposure to BHF was always 1.5 min.
  • All spectra contain a broad band with a maximum near 3258 cm- 1 originating from stretching modes related to various O-H containing surface groups.
  • a weak band centered around 2700 cm- 1 may be caused by O-H and C-H stretching modes.
  • Signals in the region 1400-1000 cm- 1 are assigned to O-H bending and/or C-0 stretching modes.
  • a strong peak in this region at 1097 cm- 1 was observed for the BHF-treated sample.
  • the band at approximately 850 cm- 1 is attributed to C-H bending modes Clearly, the BHF treatment introduces additional O-containing functional groups.
  • the spectrum of the BHF-treated Si02- coated CNTs does not reveal any significant changes to the as-grown CNTs, which indicates that the BHF exposure time is sufficient to remove the oxide and leave the CNTs unaltered.
  • the results also indicate that functional groups are to some extent present in the as-grown CNTs.
  • the contact angle is lowest for the BHF-treated Si0 2 -coated CNTs.
  • the BHF treatment of the as-grown CNTs only marginally improved their wettability, which is unexpected considering the largest I signal increase due to hydrophilic functional groups.
  • the improved wettability of the BHF-treated Si0 2 -coated CNTs is rather physical than chemical in nature. It was indeed shown that a better hydrophilicity can be achieved with CNT films that have an open microtexture as opposed to closed unmodified CNT films. The appearance of microbundles on the BHF-treated Si0 2 -coated CNTs may hence account for the reduced contact angle. On the other hand, no microbundles were observed after BHF treatment of the as-grown CNTs. This demonstrates that the presence of the Si0 2 is advantageous for mediating the BHF into the CNT matrix and eventually forming the microbundles which improve the wettability.
  • FIG. 7 shows SEM images of neurons grown on fabricated CNT-based substrates after 5 days in vitro. The neurons readily formed equally branched neural networks on top of the Parylene C and on the exposed CNT areas as shown in FIG. 7a and FIG. 7b. Visible neurite ruptures are an artifact caused by sample preparation. The neuronal bodies did not make conformal contact with the underlying CNT microbundles, but rather seemed suspended on the surface (FIG. 7b and FIG. 7c).
  • Low-temperature, e.g. below 600°C, (such as 425°C) PECVD was employed to grow vertically- aligned multiwalled CNTs on passive arrays comprising microelectrodes with cellular and subcellular dimensions of 25, 10, and 5 ⁇ diameter.
  • PECVD Low-temperature, e.g. below 600°C, (such as 425°C) PECVD was employed to grow vertically- aligned multiwalled CNTs on passive arrays comprising microelectrodes with cellular and subcellular dimensions of 25, 10, and 5 ⁇ diameter.
  • the demand for high-density and high-resolution electrode arrays can only be met by using advanced Cu-CMOS technology. Therefore, all process temperatures employed in experiments relating to embodiments of the present invention were compatible with BEOL Cu-CMOS processing ( ⁇ 450°C).
  • a coating stack comprising a dielectric, e.g. Si0 2 , and a biocompatible material, e.g. Parylene C, was employed with lithographically defined electrode openings where the biocompatible material, e.g. Parylene C, partly overlapped the CNT film.
  • the coating stack also provided an effective coverage of the potentially toxic catalytic film, e.g. Ni film, present on the wafer surface.
  • this coating stack provides also a biocompatible packaging, therefore making it suitable to be implanted.
  • the functionality and performance of the fabricated and packaged devices was evaluated by CV and EIS and compared against co-fabricated Pt and TiN microelectrodes. For all electrode diameters, the CNT electrode impedance at 1 kHz was reduced by 3 orders of magnitude compared to the Pt and TiN electrodes. In addition, an improvement by a factor of 10 could be achieved for the 5 ⁇ -diameter electrodes compared to reported CNT electrodes of similar size which were realized at a higher CVD growth temperature than in the process according to embodiments of the present invention. This allows the conclusion that high-quality CNT electrode can be realized at low processing temperatures.
  • the CNT electrodes outperformed the Pt and TiN electrodes in terms of the CSCc by 2 orders of magnitude.
  • CNT electrodes even with sub-micron dimensions are a realistic scenario for future neural implants.
  • FTI revealed that the different fabrication steps did not alter the chemical fingerprint of the CNTs. This will provide more flexibility with post-processing treatments for specific modifications of the CNTs.
  • cell viability on fabricated CNT substrates was successfully demonstrated with primary rat hippocampal neurons indicating that CNTs were not afflicted by toxic compounds or modifications introduced during processing. The proposed fabrication process can therefore be employed to realize future biocompatible neural implants.
  • processing was carried out on 200 mm Si wafers 1 with 300 nm thermal oxide 2 on both the front and back sides.
  • Metal interconnects 3, bond pads 9, and electrode areas were defined by lift-off of sputterdeposited Ti/Pt/Ti (20 nm/200 nm/20 nm) (Nimbus XP, Nexx Systems, USA) using LOR10A (Microchem, USA) as the under-layer and 1X845 (JSR-Micro, USA) as the photoresist.
  • TiN 100 nm; Nimbus XP, Nexx Systems, USA
  • F sputtering of a thin, 2 nm thick (nominal) Ni layer (A610 sputter system, Alcatel, USA)
  • Multiwalled CNTs 5 were grown in a 200 mm microwave (2.45 GHz) PECVD chamber (TEL, Japan).
  • the microwave plasma source was located remotely from the wafer surface to avoid excessive ion-bombardment favoring CNT formation over fiber-like structures.
  • the CNT growth temperature was fixed at 425°C to be compatible with Cu- BEOL CMOS processing.
  • Ni is an effective catalyst for CNT growth because it is reduced to its catalytically active metallic state.
  • this Ni film was transformed into active metal nanoparticles in a NH 3 plasma for 5 min.
  • the CNTs 5 were then grown in a gas atmosphere of C2H4/H2 at 3 Torr for 30 min resulting in a CNT density of 2 ⁇ 10 11 cm "2 , a height of 2 ⁇ , and an average nanotube diameter of 34 nm.
  • Parylene C 7 As an effective and biocompatible insulation material, 1 ⁇ of Parylene C 7 (PDS 2010 Labcoater 2, SCS, USA) has been evaporated.
  • the bond pads 9 were opened by RIE (SPTS, UK) of the Parylene C 7 (130 s; 30 seem SF 6 , 200 seem 0 2 , 100 torr, 250 W) and Si0 2 6 (90 s; 10 seem 0 2 , 100 seem SF 6 , 100 torr, 200 W) using a resist etch mask (1X845, JSR-Micro, USA).
  • RIE resist etch mask
  • the Parylene C 7 on top of the contact areas was etched, thus providing openings 8.
  • An etch time of 130 s was sufficient to remove the Parylene C and leave the Si0 2 coating intact.
  • the singulated chips were wire-bonded onto custom PCBs and sealed with epoxy (353ND-T, Epotek, USA).
  • epoxy 353ND-T, Epotek, USA.
  • the Si0 2 layer on top of the CNT electrodes was removed by dipping the packaged chips in BHF for 1.5 min. Inspection was performed by SEM (SU8000, Hitachi, Japan) and combined FIB/SEM analysis (Nova 600 Dual-Beam, FEI, USA).
  • Electrochemical measurements were performed in PBS (0.150 M NaCI, 0.016 M Na 2 HP0 4 , 0.004 M KH 2 P0 4 , pH 7.4). All chemicals were analytical grade and used as delivered (Sigma-Aldrich, USA). Experiments were conducted in a glass beaker using a three-electrode configuration placed inside a Faraday cage. A commercial double-junction Ag
  • ECD Ecochemie, Netherlands
  • OriginPro 8.5 Optlab, USA
  • ZView Surbner, USA
  • the experimental sequence for all electrodes consisted of an initial electrochemical cleaning step where the electrode potential was cycled at 2 V/s between the respective limits of gas evolution until a stable and reproducible response was observed, followed by 10 slow-sweep CV cycles at 0.1 V/s and the EIS with a 10 mV (rms) AC signal applied between 1 -10 s Hz.
  • the CSCc was obtained from the 10th slow-sweep CV cycle.
  • FTIR analysis has been performed on as-grown CNTs synthesized as described above on wafers uniformly coated with TiN/Ni (100 nm/2 nm), on CNTs immersed in BHF for 1.5 min, and on CNTs coated with CVD Si0 2 (300 nm) and immersed in BHF for 1.5 min. All spectra were collected in transmittance (%) mode (IFS 66 v/S, Bruker Optics, Germany) over the wavenumber range of 500 - 4000cm "1 . Recorded spectra were corrected for baseline and analyzed using OriginPro 8.5 (Originlab, USA).
  • chips For biocompatibility testing, chips have been prepared according to the process sequence displayed in FIG. 1; however, the two lift-off steps ((a) and (b)) have been omitted and an unpatterned metal stack of Ti/Pt/Ti/TiN (20 nm/200 nm/20 nm/100 nm) has been used instead.
  • the CNTs were grown according to the procedure described above. Cell viability was tested with primary hippocampal neurons isolated from embryonic rats. Unpackaged chips were sterilized in 70% ethanol and incubated with poly L-lysine prior to cell plating.
  • samples were removed from the incubator, fixated with formaldehyde, and treated with a 2% Os0 4 solution (Sigma-Aldrich, USA) for increased contrast during SEM analysis (SU8000, Hitachi, Japan). Finally, the samples were rinsed with PBS, dehydrated in solutions of increasing ethanol concentration, and subjected to critical point drying (Tousimis, USA).

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Abstract

Afin d'intégrer de façon fiable des nanotubes de carbone (NTC) alignés verticalement utilisés comme matière d'électrode dans des futures sondes neurales à haute résolution implantables, un enrobage correct des électrodes à base de NTC est essentiel pour maintenir leur intégrité mécanique pendant l'implantation. L'invention porte sur une nouvelle approche pour fabriquer des microélectrodes à base de NTC fonctionnelles enrobées d'un revêtement protecteur en couches comprenant du SiO2 et du Parylène C doté d'ouvertures d'électrode formées par lithographie. Les NTC alignés verticalement ont été amenés à croître sur des ensembles passifs de microélectrodes individuellement adressables à l'aide d'un dépôt chimique en phase vapeur assisté par plasma à basse température (425°C) compatible avec un traitement Cu-CMOS à l'échelle d'une tranche.
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