Name: fabrication of high contact-density, flat-interface nerve electrodes for recording and stimulation applications
Uploaded: 2016-10-04T14:00:00
Description: Watch this Scientific Journal Video about Fabrication of High Contact-Density, Flat-Interface Nerve Electrodes for Recording and Stimulation Applications at JoVE.com

This work was sponsored by the Defense Advanced Research Projects Agency (DARPA) MTO under the auspices of Dr. Jack Judy and Dr. Doug Weber through the Space and Naval Warfare Systems Center, Pacific Grant/Contract No.N66001-12-C-4173. We would like to thank Thomas Eggers for his help in the fabrication process, and Ronald Triolo, Matthew Schiefer, Lee Fisher and Max Freeburg for their contribution in the development of the composite nerve cuff design.

1. Electrode Components Preparation
<ol>
	<li>Gather four electrode components that require precision cut (laser-cut was used, Please refer to the Materials List) prior to the manufacturing process. These components are (Figure 1): 
	Contacts array frame: This frame is made out of 125 &#181;m thick Polyether ether ketone (PEEK) sheet. It covers the entire width of the cuff and holds the middle contacts and has serpentine-shaped edges (Figure 1B). The middle contacts are wrapped in...

<ol>
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B., Hayes, G. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Experimental+improvements+in+the+use+of+elastic+cuff+for+peripheral+nerve+repair.">Experimental improvements in the use of elastic cuff for peripheral nerve repair.</a> J N Sur. 28, 582-587 (1968).</li><li>Tan, D. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+neural+interface+provides+long-term+stable+natural+touch+perception.">A neural interface provides long-term stable natural touch perception.</a> S T Med. 6, (2014).</li><li>Branner, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Long-term+stimulation+and+recording+with+a+penetrating+microelectrode+array+in+cat+sciatic+nerve.">Long-term stimulation and recording with a penetrating microelectrode array in cat sciatic nerve.</a> Bio Med Eng, IEEE Trans. 1, 146-157 (2004).</li><li>Micera, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Decoding+information+from+neural+signals+recorded+using+intraneural+electrodes:+toward+the+development+of+a+neurocontrolled+hand+prosthesis.">Decoding information from neural signals recorded using intraneural electrodes: toward the development of a neurocontrolled hand prosthesis.</a> P IEEE. 98, 407-417 (2010).</li><li>Kozai, T. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ultrasmall+implantable+composite+microelectrodes+with+bioactive+surfaces+for+chronic+neural+interfaces.">Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces.</a> N Mat. 11, 1065-1073 (2012).</li><li>Sinha, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Charged+by+GSK+investment,+battery+of+electroceuticals+advance.">Charged by GSK investment, battery of electroceuticals advance.</a> Nat Med. 19, 654-654 (2013).</li><li>Tyler, D. J., Durand, D. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chronic+response+of+the+rat+sciatic+nerve+to+the+flat+interface+nerve+electrode.">Chronic response of the rat sciatic nerve to the flat interface nerve electrode.</a> A Biom Eng. 31, 633-642 (2003).</li><li>Schiefer, M. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selective+stimulation+of+the+human+femoral+nerve+with+a+flat+interface+nerve+electrode.">Selective stimulation of the human femoral nerve with a flat interface nerve electrode.</a> J N Eng. 7, 026006 (2010).</li><li>Edell, D. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+peripheral+nerve+information+transducer+for+amputees:+long-term+multichannel+recordings+from+rabbit+peripheral+nerves.">A peripheral nerve information transducer for amputees: long-term multichannel recordings from rabbit peripheral nerves.</a> Bio med Eng, IEEE Trans. 2, 203-214 (1986).</li><li>Schuettler, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fabrication+of+implantable+microelectrode+arrays+by+laser+cutting+of+silicone+rubber+and+platinum+foil.">Fabrication of implantable microelectrode arrays by laser cutting of silicone rubber and platinum foil.</a> J N Eng. 2, 121 (2005).</li><li>Pudenz, R. H., Bullara, L. 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The manufacturing method described in this article requires dexterous and fine movements in order to ensure the quality of the final cuff. The recording contacts must be placed precisely in the middle of the two reference electrodes. This placement has been shown to significantly reduce interferences from surrounding muscles electrical activity27. Any imbalance in the relative position of the contact during the fabrication can degrade the rejection of common mode interfering signals generated outside the cuff....

Interfacing with the peripheral nervous system (PNS) provides access to highly-processed neural command signals as they travel to different structures within the body. These signals are generated by axons confined within fascicles and surrounded by tightly-jointed perineurium cells. The magnitude of the measurable potentials resulting from the neural activities is affected by the impedance of the various layers within the nerve such as the highly resistive perineurium layer that surrounds the fascicles. Consequently, two interface approaches have been explored depending on the recording location with respect to the perineurium layer, namely intrafascicular and extrafascicular approaches. Intra-fascicular approaches place the electrodes inside the fascicles. Examples of these approaches are the Utah array17, the Longitudinal Intra-fascicular Electrode (LIFE)18, and the transverse intra-fascicular multichannel electrode (TIME)32. These techniques can record selectively from the nerve but have not been shown to reliably retain functionality for long periods of time in vivo, likely due to the size and the compliance of the electrode12.
Extra-fascicular approaches place the contacts around the nerve. The cuff electrodes used in these approaches do not compromise the perineurium nor the epineurium and have been shown to be both a safe and robust means of recording from the peripheral nervous system12. However, extra-fascicular approaches lack the ability to measure single unit activity&#160;&#8212; compared to intra-fascicular designs. Neuroprosthetic applications that utilize nerve cuff electrodes include activation of the lower extremity, the bladder, the diaphragm, treatment of chronic pain, block of neural conduction, sensory feedback, and recording electroneurograms1. Potential applications to utilize peripheral nerve interfacing include restoring movement to victims of paralysis with functional electrical stimulation, recording motor neuron activity from residual nerves to control powered limb prostheses in amputees, and interfacing with the autonomic nervous system to deliver bio-electronic medicines20.
A design implementation of the cuff electrode is the flat-interface nerve electrode (FINE)21. This design reshapes the nerve into a flat-cross section with larger circumference compared to a round shape. The advantages of this design are increased number of contacts that can be placed on the nerve, and the close proximity of the contacts with the rearranged internal fascicles for selective recording and stimulation. Furthermore, upper and lower extremity nerves in large animals and human can take various shapes and the reshaping generated by the FINE does not distort the natural geometry of the nerve. Recent trials have shown that FINE is capable of restoring sensation in the upper extremity16 and restoring movement in the lower extremity22 with functional electrical stimulation in humans.
The basic structure of a cuff electrode consists of placing several metal contacts on the surface of a nerve segment, and then insulating these contacts along with the nerve segment within a nonconductive cuff. To achieve this basic structure, several designs have been proposed in previous studies including:
(1) Metal contacts embedded into a Dacron mesh. The mesh is then wrapped around the nerve and the resulting cuff shape follows the nerve geometry4, 5.
(2) Split-cylinder designs which use pre-shaped rigid and non-conductive cylinders to fix the contacts around the nerve. The nerve segment that receives this cuff is reshaped into the cuff&#39;s internal geometry6-8.
(3) Self-coiling designs where the contacts are enclosed between two insulation layers. The internal layer is fused while stretched with an external un-stretched layer. With different natural resting lengths for the two bonded layers causes the final structure to form a flexible spiral that wraps itself around the nerve. The material used for these layers have typically been polyethylene9 polyimide10, and silicone rubber1.
(4) Uninsulated segments of the lead wires placed against the nerve to serve as the electrode contacts. These leads are either woven into silicone tubing11 or molded in silicone nested cylinders12. A similar principle was used to construct FINEs by arranging and fusing insulated wires to form an array, and then an opening through the insulation is made by stripping a small segment through the middle of these joined wires13. These designs assume a round nerve cross section and conform to this assumed nerve geometry.
(5) Flexible polyimide based electrodes33 with contacts formed by micromachining polyimide structure, and then integrating into stretched silicone sheets to form self-coiling cuffs. This design also assumes a round nerve cross section.
Cuff electrodes should be flexible and self-sizing in order to avoid stretching and compressing the nerve that can cause nerve damage3. Some of the known mechanisms by which cuff electrodes can induce these effects are the transmission of forces from adjacent muscles to the cuff and hence to the nerve, mismatch between the cuff&#39;s and nerve&#39;s mechanical properties, and the undue tension in the cuff&#39;s leads. These safety issues lead to specific set of design constraints on the mechanical flexibility, geometric configuration, and size1. These criteria are particularly challenging in the case of a high contact count FINE because the cuff must be at the same time stiff in the transverse direction to reshape the nerve and flexible in the longitudinal direction to prevent damage as well as accommodating multiple contacts. Self-sizing spiral designs can accommodate multiple contacts cuff14, but the resulting cuff is somewhat rigid. Flexible polyimide design can accommodate a high number of contacts but are prone to delamination. The wire array design13 produces a FINE with flat cross section, but in order to retain this geometry the wires are fused together along the length of the cuff producing stiff faces and sharp edges making then unsuitable for long term implants.
The fabrication technique described in this article produces a high contact density FINE with flexible structure that can be made by hand with consistently high precision. It uses a rigid polymer (Polyether ether ketone (PEEK)) to allow precise placement of the contacts. The PEEK segment maintains a flat cross section at the center of the electrode while remaining flexible in the longitudinal direction along the nerve. This design also minimizes the overall thickness and stiffness of the cuff since the electrode body does not have to be rigid in order to flatten the nerve or secure the contacts.

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		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Platinum-Iridium foil</td>
			<td style="width:223px;">Alfa Aesar</td>
			<td style="width:279px;">41802</td>
			<td style="width:225px;">90%Platinum Iridium&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">DFT wires</td>
			<td style="width:223px;">Fort Wayne Metals</td>
			<td style="width:279px;">35N LT-DFT-28%Ag</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:241px;">Lead connector</td>
			<td style="width:223px;">Omnetics Connector Corporation</td>
			<td style="width:279px;">MCS-27-SS</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Silicone sheet</td>
			<td style="width:223px;">Speciality Silicon Fabricator</td>
			<td style="width:279px;">0.005&#34;x12&#34;x12&#34; Silicone Sheet</td>
			<td>High durometer, vulcanized&#160;</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:241px;">Polyether ether ketone (PEEK) sheet</td>
			<td style="width:223px;">Peek-Optima</td>
			<td style="width:279px;">0.005 sheet LT3 grade</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">polyester stabelizing mesh</td>
			<td style="width:223px;">Surgicalmesh</td>
			<td style="width:279px;">PETKM2002</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:241px;">Silicon tubing (0.04&#34; I.D. 0.085&#34; O.D.)</td>
			<td style="width:223px;">Silcon Medical/NewAge Industries.</td>
			<td style="width:279px;">2810458</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:241px;">Outer shielding layer</td>
			<td style="width:223px;">Alfa Aesar, A Johnson Matthey</td>
			<td style="width:279px;">MFCD00003436 (11391)</td>
			<td>Gold foil, 0.004&#34; thick</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Transparency sheet</td>
			<td style="width:223px;">APOLLO</td>
			<td style="width:279px;">APOCG7060</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Ultrasonic bath cleaner</td>
			<td style="width:223px;">Terra Universal</td>
			<td style="width:279px;">2603-00A-220</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Isotemp standard lab oven</td>
			<td style="width:223px;">Fisher Scientific</td>
			<td style="width:279px;">13247637G</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Optical microscope</td>
			<td style="width:223px;">Fisher Scientific</td>
			<td style="width:279px;">15-000-101</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Tweezers</td>
			<td style="width:223px;">Technik</td>
			<td style="width:279px;">18049USA (2A-SA)</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Surgical blade handles</td>
			<td style="width:223px;">Aspen Surgical Products</td>
			<td style="width:279px;">371031</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Base frame&#160;</td>
			<td style="width:223px;">McMaster-Carr</td>
			<td style="width:279px;">9785K411</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Support beam</td>
			<td style="width:223px;">McMaster-Carr</td>
			<td style="width:279px;">9524K359</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Two parts silicone</td>
			<td style="width:223px;">Nusil</td>
			<td style="width:279px;">MED 4765</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Soldering Flux</td>
			<td style="width:223px;">SRA Soldering Products</td>
			<td style="width:279px;">FLS71</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Tape</td>
			<td style="width:223px;">3M Healthcare</td>
			<td style="width:279px;">1535-0 (SKUMMM15350H)</td>
			<td>Paper, hypoallergenic surgical tape</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:241px;">Spot welding machine</td>
			<td style="width:223px;">Unitek</td>
			<td style="width:279px;">125 Power Supply with 101F Welding Head</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:241px;">Laser cutting platform</td>
			<td style="width:223px;">Universal Laser Systems</td>
			<td style="width:279px;">PLS6.150D</td>
			<td>150 watts laser</td>
		</tr>
	</tbody>
</table>

fabrication of high contact-density, flat-interface nerve electrodes for recording and stimulation applications

Many attempts have been made to manufacture multi-contact nerve cuff electrodes that are safe, robust and reliable for long term neuroprosthetic applications. This protocol describes a fabrication technique of a modified cylindrical nerve cuff electrode to meet these criteria. Minimum computer-aided design and manufacturing (CAD and CAM) skills are necessary to consistently produce cuffs with high precision (contact placement 0.51 &#177; 0.04 mm) and various cuff sizes. The precision in spatially distributing the contacts and the ability to retain a predefined geometry accomplished with this design are two criteria essential to optimize the cuff&#39;s interface for selective recording and stimulation. The presented design also maximizes the flexibility in the longitudinal direction while maintaining sufficient rigidity in the transverse direction to reshape the nerve by using materials with different elasticities. The expansion of the cuff&#39;s cross sectional area as a result of increasing the pressure inside the cuff was observed to be 25% at 67 mm Hg. This test demonstrates the flexibility of the cuff and its response to nerve swelling post-implant. The stability of the contacts&#39; interface and recording quality were also examined with contacts&#39; impedance and signal-to-noise ratio metrics from a chronically implanted cuff (7.5 months), and observed to be 2.55 &#177; 0.25 k&#8486; and 5.10 &#177; 0.81 dB respectively.

Recording neural activity was performed with a customized pre-amplifier using super-&#946; input instrumentation amplifier (700 Hz - 7 kHz bandwidth and total gain of 2,000). An example of the fabricated FINE electrode with the presented protocol is shown in Figure 3. Implanting the FINE around the nerve is done by suturing the two free edges together. A demonstration of the cuff&#39;s flexibility (Figure 3B) indicates that the cuff flattens the nerve while retaining flexibility in the l...

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Fabrication of High Contact-Density, Flat-Interface Nerve Electrodes for Recording and Stimulation Applications

This article provides a detailed description on the fabrication process of a high contact-density flat interface nerve electrode (FINE). This electrode is optimized for recording and stimulating neural activity selectively within peripheral nerves.

Many attempts have been made to manufacture multi-contact nerve cuff electrodes that are safe, robust and reliable for long term neuroprosthetic ...

The overall goal of this protocol is to fabricate flat-interface cuff electrodes to use in neural interface applications. The use of flat-interface cuff electrodes can help solve problems in the field of neuroprosthetics, such as how to record the intent to move a limb from the nerves. Even though the cuff electrodes have submillimeter features, they can still be made by hand reliably.And the design is flexible. It can be easily customized to many different neural interface applications. Start with a CAD software to produce a true scale diagram of the electrode.This diagram will determine the dimensions of the electrode and the placement sites of the various electrode components. Similarly, create an additional CAD file of the contacts and electrode components, in order for them to be produced using laser cutting machinery. In preparation, place the center contacts under the microscope and bond them to the lead using a spot welder.Hold down the contact to make an initial bend at an approximately 45 degree angle, and then fold it around the contact's frame. Alternate the contact leads on each side of the array frame. Next, place a transparency sheet over the guiding diagram and tape it to the baseplate.Now, to start the build, cut a five cm square piece out from a five mil thick silicon sheet. Place it on the baseplate without trapping air bubbles. Then, prepare two grams of uncured silicon and de-gas it in a vacuum chamber for three minutes.Release and reapply the vacuum periodically so trapped air can escape. Now, apply a thin line of uncured silicon at the locations of the spacer segments according to the guide. Then, adhere the prepared spacer components onto their designated regions by pressing them onto the silicon sheet.Now, place the silicon in a preheated 130 degree Celsius isotemp oven for 30 minutes followed by cooling for 10 minutes. Now, place the reference contacts in their designated locations, with the weld points up and the contact leads routed towards the midline of the cuff to exit at the far end. After ensuring correct positioning, press the contacts down onto the silicon layer and deposit uncured silicon into the thru holes.Next, temporarily secure the leads with tape, and cure the silicon at 130 degrees Celsius for 90 minutes, or overnight at room temperature. Once the reference contacts are secured with silicon, use the same technique to attach the center contact array. Importantly, the center contacts must be placed precisely to get a high-quality recording.Proper routing of the leads to the designated exit sites is also critical. Cut a one cm by five cm transparency sheet, and use it to cover the center contact arrays. Then tape it down to the baseplate.Place the small fixture bar across the center of the electrode and clamp it down to the baseplate to secure the middle contacts in place while the silicon cures. Once cured, removed the small fixture bar. Then, remove all the tape securing the leads for the references and metal contacts, and gently remove the transparent sheet to expose the metal contact arrays.Now, cut a square piece of transparency that has the same width as the electrode and is five cm in length. Then, cut a square piece of silicon sheet that can cover the entire electrode surface. Now, lay this silicon over the piece of transparency, and stretch it flat to remove any irregularities and to prevent air bubbles from being trapped.Next, cut four pieces of silicon tubing, each five cm long, and place them at the exit sites following the diagram. Leave a two mm gap between the edge of the electrode and the tube. While holding down each pair of tubes with tweezers, tape down the tubes starting at one mm away from the tube end.Now, arrange the leads of the middle contacts and the references into bundles. Then, pass them through the corresponding tube near the exit sites. Do this for all the tubes.Next, from a vacuumed mixing container, or a syringe, slowly deposit a generous amount of uncured silicon over the entire electrode body. Now, place the silicon and transparency structure onto the uncured silicon. Align the transparency piece with the electrode while keeping the silicon sheet adhered to it.Then, tape down the transparency and apply light pressure to remove any trapped air bubbles. Finally, place the large fixture bar across the center of the electrode and over the transparency segment. Then clamp it down to the baseplate with moderate pressure and fully cure the silicon.To add a shielding layer, remove the large fixture bar, and remove the transparency piece with tweezers. Then place the shielding sheet in the center of each face of the electrode, and gently press it into the electrode. Then deposit some uncured silicon into the thru holes and partially cure it for 30 minutes at 130 degrees Celsius.Once cooled to room temperature, place adhesive tape over the outer ends of the electrode and over the closing flanges to keep silicon out of these segments. Then, repeat the process of adding a layer of silicon to cover the entire electrode body. Follow this by placing silicon and transparency sheets over the electrode, and then secure them with a large fixture bar and cure the silicon.After curing, to complete the process, remove the excess silicon and the tape. Then, cut windows through the silicon to expose the spacer segments, and use tweezers to remove the spacer segments. Next, under a microscope, remove the tape and silicon over the tubes until it is level with the electrode body.Then, carefully cut around the perimeter of the electrode down to the baseplate. Now, taking caution to not damage the electrode, follow the guide diagram to shape the lead's exit sites. Cut out a triangle between each tube pair that goes completely through the electrode layers and onto the outer side.Now, cut windows into the silicon that covers the shielding layer. Then, glide the polypropylene suture between the electrode base and the adjacent transparent layer and use it to delaminate the nearly finished cuff electrode. Finally, cut windows out of the silicon to expose the center contacts and reference contacts.The fabricated FINE electrode was used to record the activity of the sciatic nerve in a dog over 7.5 months. A customized pre-amplifier and a super-beta input instrumentation amplifier were implemented. The electrode was implanted around the nerve by suturing the two free edges together.The cuff flattens the nerve while retaining flexibility in the longitudinal direction. The electrode response to increasing pressure levels inside the cuff was measured. At the diastolic pressure level of 67 mm mercury, the cuff was expanded to 1.25 its initial cross-section area.This expansion can be employed to compensate for nerve swelling after the implant procedure. Several parameters were periodically measured during the chronic implant duration. Signal to noise stayed steady for the entire 7.5 months.Contact impedance, measured at 1 kHz, also remained stable. Finally, there were never more than two inactive contacts which were observed to have occurred due to bad connections across the animal's skin. After watching this video, you should have a good understanding of how to fabricate similar multi-channel nerve electrodes, and be able to adjust the design to meet your end application requirements.The use of these electrodes has paved the way for researchers in the field of neuroprosthetics to record voluntary signals from nerves.

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