Fabrication for ultra-compliant probes for neural and other tissues

Abstract

Methods of fabricating ultra-miniature, ultra-compliant probe arrays through spin coating, wherein a dissolvable material in hydrogel form is dispensed onto an assembled mold with wires. Once the dissolvable material is dispensed onto the mold, centrifuging spin casts the material by evaporating the solvent, forming a dried dissolvable polymer. Finally, a device is used with water to remove excess dissolvable material to obtain a dissolvable needle with wires.

Claims

1. A method of spin coating fabrication of needle for a neural probe comprising: providing a top mold and a bottom mold to form an assembled mold with wires; dispensing a dissolvable material in a hydrogel form onto the assembled mold with the wires; centrifuging the dissolvable material to spin-cast the dissolvable material by evaporating solvent to form a dried dissolvable polymer; and using a wiping device with intermittent applications of water to remove excess dissolvable material to obtain needle shape only in the assembled mold with the wires to form a final dissolvable needle with wires embedded.

2. The method according to claim 1, further comprising the step of using a precision assembly approach to assemble a top mold onto a wired bottom Si mold to form the assembled with the wires.

3. The method according to claim 1, further comprising the step of using a device bonder to assemble a top mold onto a wired bottom mold to form the assembled mold with the wires.

4. The method according to claim 1, wherein the dissolvable material is carboxymethyl cellulose (CMC) or a combination of CMC and at least one of sucrose, glucose, maltodextrin, poly(vinylpyrrolidone), polyvinyl alcohol, maltose, polyactic acid.

5. The method according to claim 1, wherein the hydrogel is prepared by mixing powdered carboxymethyl cellulose (CMC) with water.

6. The method according to claim 1, wherein the solvent is water.

7. The method according to claim 1, wherein the step of centrifuging is performed at 20 deg. C at 4700 rpm spinning speed, and for 5 hours.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1A and 1B show schematics of tissue reaction to prior art neural probes;

(2) FIGS. 2A-D show prior art probe arrays;

(3) FIGS. 3A-D shows prior art probe arrays;

(4) FIGS. 4A-C show schematics of a probe array according to the present invention;

(5) FIGS. 5A-E show SEM images of micromolded CMC needles before and after dissolution;

(6) FIG. 6 shows a schematic plan view of the probe cabling according to the present invention;

(7) FIGS. 7A-C show solid model views of embodiments of the probes according to the present invention;

(8) FIGS. 8A-Z show schematic cross-sections of a process flow for fabrication of the probes according to the present invention with several variations on the flow that result in separate embodiments;

(9) FIGS. 9A-C show plan view schematics of the layout of a single electrode made according to the present invention;

(10) FIGS. 10A and 10B show the meandered wires and electrical output cables prior to encapsulation in a biodegradable and/or biodissolvable polymer;

(11) FIG. 11 shows an X-ray image of a single channel neural probe embedded in a biodissolvable polymer;

(12) FIGS. 12A-B shows various embodiments of the present invention;

(13) FIGS. 13A-C are process flow diagrams of an exemplary probe fabrication process of the present invention;

(14) FIGS. 14A-H are pictorial illustrations of the spin casting method to fabricate the needle of the probe of the present invention;

(15) FIG. 15 is a process flow diagram of an exemplary fabrication process of the needle in the present invention;

(16) FIGS. 16A-H are pictorial illustrations of the top mold fabrication method of the present invention;

(17) FIG. 17 is a process flow diagram of an exemplary top mold fabrication method and top/bottom mold assembly in the present invention.

DETAILED DESCRIPTION OF THE INVENTION

(18) This present invention describes methods, systems and apparatuses of ultra-miniature, ultra-compliant probe arrays. Although the present invention finds applications in many human and animal tissue systems, as a specific focus and example, the application of ultra-compliant probes and probe arrays to intracortical neural probing is described here. The probe array allows design flexibility to match the stiffness of the tissue it is being applied to, such as the brain tissue, in all three axes (x, y and z), with interconnect cross section smaller than cell dimensions (<10 m). This stiffness matching requires specific geometric and fabrication approaches, commonly leading to ultra-thin wires. This invention also allows the sizing of the electrodes for specific cell dimensions, e.g., to reduce glial scar formation. Further enhancement in compliance is obtained by incorporating different geometric features to the electrode, such as meandering the electrode wires. The small thickness and geometric features of the wires commonly result in very low stiffness (as required). Under these circumstances, to enable effective insertion of the probes to the tissue (e.g., brain), the present invention uses stiff bio-disolvable and/or biodegradable polymers, including (but not limited to) single use or combinations of carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PLA) and its co-polymers. The descriptions below consider specifically CMC as the material of choice, but the invention is not limited to the use of CMC, but covers the use of any bio-dissolvable and bio-degradable polymer that encases the electrodes to facilitate the insertion. Furthermore, the invention covers different geometries of the polymer (insertion) needles, such as sharp tips, serrated edges, fillets (for increased mechanical stability), to name a few.

(19) The concept of the probe array of the present invention 10 is illustrated in FIGS. 4A-C. The probes 10 are made from thin-film meandered platinum wiring surrounded by parylene-C (other polymers may be used). In contrast to prior flexible probes, the meandered wiring is compliant in the axial direction as well as in lateral directions. Wiring continues onto an integral parylene cable 12 to move connections away from the probe. The parylene cable 12 is designed to allow suturing or other attachment to the dura (or to the skin in the acute tests on small animals).

(20) A schematic plan view of an envisioned probe array and cabling design is shown in FIG. 6. Wiring 14 coming out from the electrodes 16 is routed to the side to lie down naturally onto tissue. The individual parylene micro-cables 12 gradually widen from 7 m (location A) to 40 m (location B) while meandering to decouple stress from the main cable 18. After 5 mm, the wiring 14 is mechanically brought together onto a single integral parylene cable 18 that will span up to 10 cm. The wiring 14 is routed to a set of through-hole pads 20 with layout geometry that matches male connectors (not shown) used in neural recording hardware, such as Omnetics Nano NPD. A carboxymethyl cellulose (CMC), which is a fast degrading, non-cross-linked natural polymer, tab 22 is included to provide an attachment region for the stereotaxis micromanipulator that is used to manually insert electrodes into animals for the in vivo use. This technique provides a controlled and repeatable insertion for single probes and 1D array probes. The present invention is not restricted to the particular dimensions described. A multitude of designs with wiring of different length, width, thickness and orientation, with electrodes of different numbers, size and location, and with needle arrays of different numbers, size and shape. One embodiment of tab 22 includes two sections: a first section 22A that is thicker than a second section 22B such that the second section 22B dissolves before the first section 22A. One or more needle molds 24 are attached to the second section 22B. The probe wiring 14 is encased in the needle mold 24 of carboxymethyl cellulose (CMC). Use of blends of CMC with other biodegradable polymers, such as sucrose, glucose, maltodextrin, and poly(vinylpyrrolidone, PVP), is also possible to tune stiffness properties. The biodegradable needle temporarily supplies the necessary strength for insertion. Probe length 26 is dictated by the desire to place electrodes within the 1-3 mm thick grey matter 28 (see FIG. 4A) in the gyri 30, but to also access grey matter within the sulci folds 32 on the sides where large densities of motor neurons are located. The folds are up to 8 mm deep (e.g. in primates) and set an upper design limit on the probe length for most neural studies. Other probe lengths are possible and may be appropriate for deep brain stimulation, for example. FIG. 7A is an illustration of probe 10 having meandering wires 14 in each needle 24, wherein the meandering wires 14 are shown continuing into second section 22B of tab 22.

(21) Sodium salt of carboxymethyl cellulose is categorized by the FDA as a generally recognized as safe substance. It has been used as replacement of silicon-based breast implants for over fifteen years and is being researched in direct contact with deep tissues for bone replacement/repair. CMC-alginate mixture-based injectable gels are currently being tested for the in situ formation of scaffolding for repairing CNS damage.

(22) CMC has several distinct advantages over other bio-degradable polymers, including (1) room-temperature preparation, which enables embedding bio-active agents directly into the material, (2) hydro-gel formability, which facilitates molding and spin-casting fabrication, (3) high strength and stiffness, providing required resistance for insertion application, (4) rapid bio-absorbability (dissolution), and (5) no harmful by-products from in vivo degradation. In contrast, PLA and PLGA require high-temperature preparation, and leave acidic by-products that prevent its usage for the needle application. However, depending on the specific tissue application, other biodegradable and dissolvable polymers may be utilized.

(23) The effective stiffness of the CMC-encased probes depends not only on the mechanical properties of the CMC, but also the geometry of the needles. The fabrication conditions of the CMC, including viscosity of the initial hydrogel, molecular weight of the particular sodium-CMC used for fabrication, drying rate, and centrifuge conditions (for spin-casting) must be carefully controlled. Elastic modulus values between 0.7 GPa and 3 GPa can be expected, with tensile strength values between 14 MPa and 100 MPa. Given a set of material properties, the stiffness and effective strength of the needles depends on the needle geometry. Higher aspect ratios (length per diameter) will result in lower strength values. CMC can be blended with other biodegradable polymers to set particular stiffness and molding properties.

(24) To obtain required strength and resistance to buckling and fracture during tissue insertion, the cross-sectional area in initial embodiments of the probes are approximately 100 m100 m or 300 m100 m. A small cross-section is desirable to limit damage to tissue upon insertion. The choice of cross-sectional area is dependent on adequate stiffness for insertion into tissue and probe length must be taken into account. Buckling can be predicted based on the end conditions and needle geometry and materials. Furthermore, enhancements to stiffness and factor-of-safety against failure can be attained in some embodiments by modifying the needle design (e.g., an I-beam design) without an increase in the cross-sectional area. The other factor affecting buckling is the maximum force required for the needle to penetrate the tissue. In some embodiments this is controlled by the needle design. The in-plane dimensions and shape are determined by the designed layout of the needle with one-to-one correspondence so characteristics like the radius of the needle tip and the tip angle can be modified to reduce the maximum force on the needle shaft during insertion. In other embodiments, the phenomenon of aspect ratio dependent etching (ARDE) allows control of the out-of-plane shape and dimension of the needle through the use of sacrificial patterns applied during the formation of the needle mold.

(25) The strength against failure also depends on the stress concentrations. The inclusion of stress-concentration reducing features such as fillets can increase the strength of needles against fracture by an order of magnitude. Examples of micromolded CMC needles made by the inventors are shown in FIGS. 5A-E. The needles show a large amount of dissolution after insertion into human skin explants for 20 minutes (FIGS. 5C and E).

(26) In some embodiments of the present invention, micro-molecules, macro-molecules, and/or particulates can be integrated into the dissolvable polymers (e.g., CMC) to provide additional functionalities or properties. For example, to mitigate the potential inflammatory response due to the insertion of the probes into the CNS, an anti-inflammatory drug, such as dexamethasone sodium phosphate, can be incorporated into CMC.

(27) As another example, other biodegradable and/or non-degradable polymers can be added to the biodegradable polymer base to control/select the mechanical properties (stiffness, strength, etc.) and bio-degradability (dissolution rate) of the probe enclosures. For CMC base, some examples of added polymers include, but are not limited to, PVP, PVA, PLA, PLGA, and PCL. Furthermore, other complex sugars, such as maltose, dextrose, etc., can be added to the CMC matrix to control the needle characteristics. CMC's with different density can be mixed to attain improved dissolution properties. Further, deliberate porosity may be incorporated into CMC needles to accelerate dissolution rate.

(28) Platinum provides low resistance interconnect, it is biocompatible, and it is widely used in neural probe electrodes. The conformal and inert nature of parylene-C is effective in sealing and insulating implantable electronics and wiring for short-term and medium-term use. Hermetic sealing layers, such as alumina or silicon carbide, are deemed important for long-term use. Ideally, the cross-section of the individual wires should be less than the surrounding neural cells; we are targeting an interconnect width including insulation layers of around 7 m, which is a practical lower limit set by conventional contact photolithography. Smaller wiring width is possible with advanced lithography. Wiring becomes wider when brought onto the integral parylene cabling. The resulting wire resistance is on the order of 100 for a 1.5 mm probe.

(29) Now turning to FIG. 9B, a meander amplitude of 50 m (i.e. the width of the meander pattern measured from its axis) results in axial compliance that is less than the tissue and will decouple external probe stress from the electrodes. In one embodiment, the meander is formed from circular arcs, which have lower stress concentrations than other curved shapes of similar amplitude and pitch leading to a design that is fundamentally more robust mechanically and less prone to fatigue failure modes during the continuous mechanical cycling characteristic of pulsatile and respiratory brain micromotion. Since the compliance in the lateral directions is more than two orders of magnitude smaller than the axial compliance, this amount of meandering may not be necessary, but underscores that there is plenty of room in the fabrication method to match the mechanical impedance of brain tissue. Many other designs of meandering geometries and sizes are possible. For example, meander designs can be zig-zag (triangular-wave) shaped, square-wave shaped, or many other periodic or aperiodic shape. Corners of the meanders can be rounded with various radius values. A probe of such large axial compliance could never be inserted without a stiff needle connected mechanically in parallel. Our biodegradable needle solution is effective for this purpose.

(30) In one embodiment of the present invention, as shown in FIG. 7B, sidewall barbs 34 are cast into the CMC needle 24 to keep the needle 24 inserted in the tissue. Parylene tethers 36 hold the wiring 14 in place during the CMC molding (see FIGS. 9A-9C). Necking regions 38 of the tethers 36 (see FIG. 9C) will aid in breaking. The wiring 14 meanders as shown have an amplitude of about 25 m. These meanders provide the low axial and lateral compliance that is unique to our design. Now turning to FIGS. 9A-C illustrating an embodiment for 4.5 m-thick, 7 m-wide, 1.5 mm long parylene electrode wiring 14 with 50 m amplitude and 200 m pitch meanders and assuming E=2.76 GPa, the axial spring constant is 0.35 N/m and lateral spring constants are below 1.1 mN/m. The equivalent reaction stiffness of the brain tissue (E=30 kPa) is estimated to be 0.94 N/m in the axial direction; i.e. the probes 10 are more compliant than brain tissue. FIG. 7C illustrates a magnified view of needle tip 24A showing electrode 16 and tethers 36.

(31) The probe wiring 14, tethers 36, tether necking regions 38 and electrodes 16 will be made using planar fabrication on silicon wafers or substrates. Embodiments of the planar process flow used in fabrication of the probes 10 according to the present invention are shown in FIGS. 8A-8Z and is described in flow chart form in FIGS. 13A-C. FIG. 8A illustrates the lower layer of insulation 38 is deposited on a substrate 39 that enables handling and manipulation during fabrication. The insulation 38 can be deposited in blanket form and patterned photolithographically, or it can be directly deposited in a pattern using techniques like 3D printing. In one embodiment, the insulation 38 is parylene-C, but could be replaced by other organic and inorganic insulating materials, like PDMS or alumina, respectively. Adhesion of parylene to the substrate may be enhanced by XeF.sub.2 etch roughening of the substrate prior to deposition. The minimum thickness of the insulation 38 depends on the quality of the deposited film, and the film type, but could be as thin 100 nm. The maximum thickness is determined by the size of the cells of the tissue into which the device is being implanted. For neural tissue, where cells are on the order of 20 m, the limit on thickness for this insulation layer 38 is 10 m. FIG. 8B illustrates the conducting material 40 that will be patterned to form the electrode 16 and its wire interconnect is deposited on top of the insulator 38. In one embodiment, the conducting material layer 40 is Pt with a thickness of 500 nm. Platinum can be deposited directly onto polyimide with O.sub.2 plasma roughening. This same procedure may be useful for direct adhesion to parylene. The lower limit on thickness of conducting material 40 depends on the resistivity of the material and its film quality, while the upper limit on its thickness is dependent on the thickness of the insulation layers 38, 42 (see FIG. 8E) because the overall thickness must be less than the size of the cells of the tissue into which the probe 10 is being implanted. It is possible for the film to range in thickness from 100 nm to 19 m, depending on the thickness of the insulation 38.

(32) FIG. 8C illustrates that the layout pattern of the wire 14 and the electrode 16 are photolithographically printed in photoresist 41 on the outer surface 40A of the conducting material 40. The patterned photoresist 41 is used as a mask to prevent removal of the conducting material 40 under the photoresist 41 during a selective conducting material 40 removal process shown in FIG. 8D. The photoresist 41 thickness in all cases, is dependent on the thickness of the metal used for the conducting material 40 and the size of the feature to be patterned; however, the typical thickness ranges from 200 nm to 20 m. The removal process can be performed using wet chemicals, or plasmas, depending on the conducting material 40. Following the selective conducting material 40 removal process, the photoresist 41 is removed from the surface of the substrate 39 and the substrate 39 is cleaned in preparation for subsequent depositions as shown in FIG. 8E. After cleaning, a second insulator layer 42 is deposited over the first insulator layer 38 and the patterned conductor 40 as shown in FIG. 8F. The thickness of this layer must not exceed the value that would make the total structure thickness exceed the cellular dimensions. The minimum layer thickness depends on the material choice and the minimum thickness required to ensure electrical insulation.

(33) FIG. 8G illustrates that the insulated wire pattern is photolithographically formed in photoresist 43 on the surface of the upper insulator layer 42. A selective insulator layers 38, 42 removal process shown in FIG. 8H is applied to transfer the insulator pattern into the insulator layers 38, 42. Following the transfer process, the photoresist 43 is removed and the surfaces are cleaned as shown in FIG. 8I. FIG. 8J illustrates a hard mask material 44 is deposited on the top surface of the substrate 39, and the patterned insulator layers with embedded conductor. The material is called hard because of its increased resistance to processes that selectively remove the substrate material and its inorganic composition. Typical hardmask materials are metals, like Al and Cr. The minimum hardmask thickness is determined by the depth of substrate 39 that must be removed and the selectivity of the removal process to the hardmask materials. The minimum thickness of hardmask 44 is typically selected and this is around 100 nm for Al. FIG. 8K illustrates patterning of photoresist 45 with bottom mold pattern on the hardmask 44. FIG. 8L illustrates selective removal of hardmask layer 44 to transfer bottom mold pattern from photoresist 43. FIG. 8M illustrates removal of photoresist 45 and cleaning of surfaces. In one embodiment of the invention the substrate 39 is Si and is selectively removed using a process called Deep Reactive Ion Etch (DRIE) which etches Si only in a vertical direction as shown in FIG. 8N. The depth of the DRIE Si etch is driven by the desired dimensions of the encasement. In one embodiment, the depth of this part of the process is about 40 m. Following DRIE, columns of substrate 38 remain under the insulated wire pattern and electrodes 40. In FIG. 8O illustrates the wire pattern and electrodes 40 being suspended when these regions of substrate 38 are removed using a process that removes material in all directions at the same rate. This isotropic process is performed until there is no Si left under the wires and electrodes 40 and is performed for a length of time dependent on the rate at which Si etches and the width of the wires and electrodes. The depth of the bottom mold is dependent on the desired thickness of the final encasement. In one embodiment the depth of the bottom mold is 60 m, but could range from 5 m to 100 m depending on the desired needle thickness and the desired position of the wire and electrode within the needle. In one embodiment of the present invention, both the top and bottom of the platinum are clad in Ti or TiN to ensure adhesion on both sides. In this case, the platinum electrode would conveniently become exposed during the Si DRIE step illustrated in FIG. 8I, which will also directionally etch Ti. An overlap of parylene around the exposed electrode will be designed to help lock in the electrode 16 and prevent stress-induced etching of the metal-parylene interface. Following electrode formation, its recording and stimulating properties can be enhanced by applying materials such as PEDOT (Poly(3,4-ethylenedioxythiophene)) that reduce the electrical impedance to neural signals. The deposition of materials that modify the electrode surface can be done in several ways, for example, electrochemically or by direct additive deposition using technologies like dip pen nanolithography.

(34) The silicon deep reactive-ion etch (DRIE) and isotropic etch steps are subject to ARDE effects that can be used to create three-dimensional structure in the needle mold. These effects, along with the layout pattern of meandering wires, tethers, tether necking regions and the outline of the needle, define the lower half of the needle shape. In the regions covered by the layout pattern the substrate is not removed until the final etching process shown in FIG. 8N and this results in a shallow 3D structure on the bottom surface of the bottom mold that corresponds to the meandering wires, tethers, and tether necking regions.

(35) The upper needle shape is set by a top mold 46 (see FIG. 8Q) with a shape defined by the outline of the needle, made from an elastomer, such as PDMS or PVS, a resin, such as UV-curable resins, or any other polymer or dissolvable materials. The top mold fabrication is described in FIGS. 16A-H and 17 and uses a technique referred to as the sandwich method. In Step 1 (FIG. 16A), a master mold that includes the needle shape is used. The master mold can be formed in several ways, for example from a PMMA master mold 202 made by mechanical micromilling or from a Si master mold made by patterning a Si substrate with the needle pattern and applying the process steps of Si Deep reactive-ion etching (DRIE) (FIG. 8N), Si isotropic etching (FIG. 8O), and wet strip aluminum mask 44 (FIG. 8P). The depth of the needle-shaped mold area is made to be the same as the target top-mold thickness. In Step 2 (FIG. 16B), an intermediate mold material 204, such as PDMS, is applied onto the master mold 202. In Step 3 (FIG. 16C), the intermediate mold material 204 is cured and separated from the master mold 202 to form intermediate mold 206. In Step 4 (FIG. 16D), the intermediate mold 206 is sandwiched between two glass slides 208, and appropriate force is used to hold the three pieces together. In Step 5 (FIG. 16E), the top mold material 210 is poured between the top glass slide 208 and the intermediate mold 206. In one embodiment, top mold material 210 is an elastomer such as PVS. In another embodiment, the top mold material 210 is a UV-curable resin. In Step 6 (FIG. 16F), the top mold material 210 is cured to form the top mold 46. For example, if UV-curable resin is used, UV rays are emitted from a UV-lamb is used to cure the top mold material 210. The top mold 46 is then separated from the glass slides 208 and the intermediate mold 206. In Step 7 (FIG. 16G), a precision assembly approach is used to assemble the top mold 46 onto the wired Si bottom mold 8A. In one embodiment, a device bonder is used for this assembly. Thus, in Step 8 (FIG. 16H) the assembled top-bottom mold 102 with wires is obtained, which will be subsequently used for spin-casting.

(36) Following completion of the bottom mold 8A, a top mold 46 is applied in one embodiment to form assembled mold 102 as shown in FIG. 8Q. In another embodiment, shown in FIG. 8W, the substrate is etched through so the bottom mold 51 is completely open. Several bottom molds 51 are stacked together as shown in FIG. 8X and the top mold 46 is applied to form a structure in which wires and electrodes are arrayed in a 3-dimensional matrix. FIG. 8Y is an illustration of the molds 46, 51 filled with a hydro-gel of CMC or other dissolvable substance by a process discussed in detail below to form probe 10 in FIG. 8Z.

(37) The hydro-gel of CMC 47 is poured into the PDMS-Si mold (FIG. 8R). A more detailed description of the spin-casting process is included in FIGS. 14A-H and 15. In Step 1 (FIG. 14A), the assembled mold 102 obtained from the sandwich molding is used. In Step 2 (FIG. 14B), a hydrogel 47 of the dissolvable (needle) material is applied on the assembled mold 102 to form hydrogel-dispensed assembled molds 106. In one embodiment, the dissolvable material is CMC, and the hydrogel 47 has 15% concentration of CMC and the rest is water. Other solvents can be used in the process based on the choice of dissolvable polymer. In Step 3 (FIG. 14C), a high-g laboratory centrifuge 108 is used to spin the hydrogel-dispensed assembled molds 106. The centrifuge 108 ensures removal of air pockets from the hydro-gel 47 and the complete filling of the mold 102. In one embodiment, the top of the top mold is completely exposed. In another embodiment, release holes (not shown) on top of the top mold 46 are used. Through the centrifuging, the water is evaporated in controlled low temperature, dry conditions, and the dissolvable needle material (e.g., CMC) 47 is solidified to form solidified layer 48. If needed, to ensure complete filing of the mold, considering the shrinkage of CMC, the application of additional layers of CMC 48 is repeated twice, or more times until the needle reaches the desired dry thickness (FIGS. 8S-8U). The final thickness depends on the required mechanical stiffness of the needle to ensure penetration of the tissue without breakage. In one embodiment, this thickness is 125 m but can range from 50 m to 200 m for insertion into dura-resected brain when the needle length is 1.5 mm. In Step 4 (FIG. 14D), the dried CMC 48 on the assembled mold is obtained. In Step 5 (FIG. 14E), a squeegee method is used to remove the excess CMC. In this method, a wiping device such as a sharp blade with a soft coating (e.g., PDMS) is used, and a number of repeated steps of water application and squeegeeing followed until the excess material is completely removed, as shown in Step 5. Considerable shrinkage of the CMC during this process facilitates easy separation of CMC from the assembled mold 10, as seen in Step 6 (FIG. 14F). In Step 7 (FIG. 14G), a precision assembly approach is used to assemble the top mold 46 onto the wired Si bottom mold 8A. In one embodiment, a device bonder is used for this assembly. Thus, in Step 8 (FIG. 14H) the assembled top-bottom mold 102 with wires is obtained, which will be subsequently used for spin-casting. The batch fabrication allows multiple probe designs to be placed on a single mask set, or to fabricate multiple probes of the same design. FIG. 8V illustrates the final probe 10 after being removed from the molds.

(38) Now returning to FIGS. 13A-C that illustrate in process flow diagrams of an exemplary probe fabrication process of the present invention. The process includes many options:

(39) Step 1a or 1b: The insulator layer 38 can be formed on a substrate 39 by depositing (Step 1a) or by direct patterning (Step 1b);

(40) Next, all above steps continue to Steps 2-5:

(41) Step 2: Depositing of conductor 40 that becomes the electrode and wiring;

(42) Step 3: Patterning of photoresist 41 with electrode and wiring pattern;

(43) Step 4: Selective removal of conductor layer 40 to transfer electrode and wire pattern from photoresist 41;

(44) Step 5: Removal of photoresist 41 and cleaning of surfaces to prepare them for subsequent depositions;

(45) Next, after completion of all the above step the process continues to either Steps 6a-9 or Step 6b: The upper insulator layer 42 can be formed by either of the following steps:

(46) Option 1-Steps 6a-9:

(47) Step 6a: Deposition of upper insulator layer 42;

(48) Step 7: Patterning of photoresist 43 with insulator pattern;

(49) Step 8: Selective removal of all insulator layers 38 42 to transfer electrode and wire pattern from photoresist; and

(50) Step 9: Removal of photoresist 43 and cleaning of surfaces to prepare them for subsequent depositions.

(51) Option 2:Step 6b

(52) Step 6b: Direct patterned deposition of upper insulator layer 42.

(53) Next, all above steps continue to Steps 10-14:

(54) Step 10: Deposition of hard mask layer 44;

(55) Step 11: Patterning of photoresist 45 with bottom mold pattern;

(56) Step 12: Selective removal of hard mask layer 44 to transfer bottom mold pattern from photoresist 43;

(57) Step 13: Removal of photoresist 43 and cleaning of surfaces;

(58) Step 14: Selective directional removal of the rigid substrate 39;

(59) Next, all the above steps will continue to either Step 15a or Step 15b: removal of rigid substrate 39 can be performed by Selective isotropic removal of the rigid substrate 39 for a single layer wire array by retaining bottom surface 39A (Step 15a) or selective isotropic removal of the rigid substrate 39 to form stackable bottom molds by removing bottom surface 39A (Step 15b);

(60) After completion of either Step 15a or Step 15b, the next process step is Step 16: Selective removal of the hard mask layer 44;

(61) Next, after the above step the process continues to either Step 17a-22a (single array of wires) or Step 17b-22b (stack or 3D multiple array of wires)

(62) Option 1:

(63) Step 17a: Placement of a top mold 46 patterned with the bottom mold pattern on top of the bottom mold;

(64) Step 18a: Application of polymer gel 47 to the assembled mold;

(65) Step 19a: Dry polymer 48 after water evaporation;

(66) Step 20a: Application of additional polymer gel 49 on top of original dried polymer 48;

(67) Step 21a: Dried polymer 50 filling the entire needle mold;

(68) Step 22a: Demolded polymer needle with encased wires and electrodes;

(69) Option 2:

(70) Step 18a: Stacking of multiple bottom molds 51 and placement of a top mold 46 patterned with the bottom mold pattern on top of the bottom molds;

(71) Step 18b: Application of multiple layers of polymer gel, followed by drying of the polymer performed until the mold is completely filled with dry polymer;

(72) Step 22b: Demolded polymer needle with encased stacked wires and electrodes;

(73) A detailed single-electrode probe layout with parylene tethers that hold the wiring in place during the CMC molding is shown in FIGS. 9A-C. In this particular embodiment, the meanders are set to 50 m amplitude and 200 m pitch. These meanders provide the axial compliance that is unique to the present invention. By including meanders, the lateral compliance is also enhanced when compared to a straight wire. For 4.5 m-thick, 7 m-wide, 1.5 mm long parylene electrode wiring with 50 m amplitude and 200 m pitch meanders, the axial spring constant is 0.35 N/m, assuming E=2.76 GPa. Lateral spring constants are below 1.1 mN/m. The platinum cross section is smaller (0.5 m-thick, 4 m-wide) and is for the moment neglected in this analysis. Assuming a Young's modulus of brain tissue of 30 kPa and a mechanical stress healing distance of 100 m from the wiring, the equivalent stiffness is estimated to be 0.94 N/m acting in the axial direction on the probe described above. Therefore the equivalent brain stiffness will be larger than that of probes with this sizing (i.e., the probes will be more compliant than the brain tissue).

(74) Multi-electrode probes will either require parylene-encased wiring that becomes wider as it nears the base of the shank or multiple parylene-encased wires to interconnect to multiple electrodes. Various designs are possible according to the present invention to achieve the desired compliance while being adequately tethered. Parylene is listed as a leading embodiment, but other material may be used to encase the wiring.

(75) The shank sidewall definition is set by the sacrificial metal mask layer. A Si etch process that etches all exposed horizontal and vertical Si surfaces at an equal rate, which is called isotropic etching, undercuts the parylene/platinum wiring, tethers and tether necking regions by proceeding for a sufficient time to laterally etch the Si from under the narrow features defined by the sacrificial metal mask, but not long enough to remove the Si from under the large areas of the sacrificial metal mask. The isotropic Si etch is followed by wet etch of the sacrificial metal mask. The neck-down region of the tethers is released after the metal mask etch step as indicated in FIG. 9C. The tethers are designed to break apart upon removal of the CMC shank from the substrate.

(76) The recording electrode size should be made as small as possible with a minimum target of 7 m set by conservative lithography and etch. The target impedance of the electrode-solution interface is 500 k at 1 kHz. The calculated 110 resistance of the 4 m-wide wiring for a 1.5 mm probe is very small compared to the target electrode impedance. Even an 8 mm long probe will have resistance of only around 600. Cable wiring will add to the overall device resistance but still be negligible compared to the interface resistance.

(77) Probes according to the present invention can be made spanning a large design space, including multi-site probes, multi-probe arrays, and different probe lengths, shank widths, shank shapes, wire widths, meander widths and electrode sizes. FIGS. 10A, 10B, 11, and 12A-B are illustrations of various examples of the present invention.

(78) Although the present invention has generally been described in terms of specific embodiments and implementations, the present invention is applicable to other methods, apparatuses, systems, and technologies. The examples provided herein are illustrative and not limiting, and other variations and modifications of the present invention are contemplated. Those and other variations and modifications of the present invention are possible and contemplated, and it is intended that the foregoing specification and the following claims cover such modifications and variations.