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. Author manuscript; available in PMC: 2021 Jul 15.
Published in final edited form as: J Neurosci Methods. 2020 May 13;341:108762. doi: 10.1016/j.jneumeth.2020.108762

Integration of Flexible Polyimide Arrays into Soft Extracellular Matrix-based Hydrogel Materials for a Tissue-Engineered Electronic Nerve Interface (TEENI)

Benjamin S Spearman 1, Cary A Kuliasha 2,3, Jack W Judy 2,3, Christine E Schmidt 1
PMCID: PMC8086190  NIHMSID: NIHMS1678855  PMID: 32413377

Abstract

Background

Biomimetic hydrogels used in tissue engineering can improve tissue regeneration and enable targeted cellular behavior; there is growing interest in combining hydrogels with microelectronics to create new neural interface platforms to help patient populations. However, effective processes must be developed to successfully integrate flexible but relatively stiff (e.g., 1–10 GPa) microelectronic arrays within soft (e.g., 1–10 kPa) hydrogels.

New Method

Here, a novel method for integrating polyimide microelectrode arrays within a biomimetic hydrogel scaffold is demonstrated for use as a tissue-engineered electronic nerve interface (TEENI). Tygon tubing and a series of 3D printed molds were used to facilitate hydrogel fabrication and implantable device assembly.

Comparison with Existing Methods

Other comparable regenerative peripheral nerve interface technologies do not utilize the flexible microelectrode array design nor the hydrogel scaffold described here. These methods typically use stiff electrode arrays that are affixed to a similarly stiff implantable tube serving as the nerve guidance conduit.

Results

Our results indicate that there is a substantial mechanical mismatch between the flexible microelectronic arrays and the soft hydrogel. However, using the methods described here, there is consistent fabrication of these regenerative peripheral nerve interfaces suitable for implantation.

Conclusions

The assembly process that was developed resulted in repeatable and consistent integration of microelectode arrays within a soft tissue-engineered hydrogel. As reported elsewhere, these devices have been successfully implanted in a rat sciatic nerve model and yielded neural recordings. This process can be adapted for other applications and hydrogels in which flexible electronic materials are combined with soft regenerative scaffolds.

Keywords: tissue-engineered electronic nerve interface, peripheral nerve interface device assembly

Graphical Abstract

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1. Introduction

Hydrogels are networks of crosslinked hydrophilic polymers that can absorb many times their original weight in water; they are used in numerous biomedical applications including cell encapsulation, wound dressing, and soft contact lenses. Furthermore, hydrogels have found wide use as tissue engineering matrices to encourage cellular repair and regeneration of damaged tissue (Hoffman, 2012).

Simultaneously, there has been growth in the use of flexible electronic materials within hydrogels and tissues including neural interfaces (Spearman et al., 2017) and electronic devices (Rong et al., 2018), and to add load-bearing (and other) capabilities to hydrogels (Mehrali et al., 2017).

Neural interfaces are technologies used to connect the central or peripheral nervous system with computers or other electronic devices (Spearman et al., 2017). Peripheral nerve interfaces are of particular interest for robotic prosthetic limbs used by amputees. Prostheses have advanced rapidly with innovations in the field of robotics including integration of pressure and temperature sensors to provide sensory feedback to the patient. However, technology to interface with the nervous system has lagged, and long-term bidirectional control of these prostheses is still absent. One method for improving peripheral nerve interfaces is to combine tissue engineering techniques with microelectronics to create a tissue-engineered electronic nerve interface (TEENI) (Desai et al., 2017; Kuliasha et al., 2018).

Comparable regenerative peripheral nerve interface devices have typically utilized a stiff electrode array, which is affixed to a similarly stiff polyurethane or polysulfone tube that is used as a nerve guidance conduit (Clements et al., 2013; Garde et al., 2009). Some approaches to stimulating and recording in the central nervous system have used hydrogel coatings of electrodes for drug release as either an attractant for neurites (Winter et al., 2006) or to mitigate the foreign body reaction caused by electrode implantation (Pierce et al., 2009). Integration of a pro-regenerative hydrogel scaffold is an approach novel to TEENI with peripheral nerve interfaces. For additional discussion of tissue-engineered neural interface technologies, please see (Spearman et al., 2017).

The TEENI approach described here utilizes a flexible electrode array encapsulated in a soft, pro-regenerative scaffold. The mechanical properties of both components increase assembly challenges compared to the stiffer probes traditionally used in peripheral nerve interfacing. The novel method developed utilizes of a series of 3D printed molds to hold the flexible arrays in place to allow for assembly of implantable TEENI devices.

Implanted TEENI devices can record bioelectronic neural signals using multi-electrode polymer-based threads embedded into tissue-engineered hydrogel scaffolds that promote nerve regeneration, Figure 1A. After implantation into the rat sciatic nerve, tissue regenerates through the gel and around the electronic array resulting in axons within close proximity of recording microelectrode sites (Graham et al., 2017). The hydrogel also acts as a mechanical support for the electrodes in 3D allowing for the arrays to be relatively thin (e.g., 10 μm) and flexible but still implantable by a surgeon. Furthermore, the thin flexible TEENI microelectrode arrays make them more mechanically compatible with surrounding tissue, thus eliminating some of the drawbacks associated with more rigid devices such as sieve electrodes or silicon-based devices (Spearman et al., 2017).

Figure 1:

Figure 1:

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A) Schematic of a TEENI device with a single thread set. Each TEENI device is composed of a polyimide (PI) thread set with multiple threads, each containing multiple electrodes. The thread set is surrounded by hydrogel and the whole implantable region is wrapped in small intestinal submucosa (SIS) to provide the surgeon with a site for suturing the device to the nerve stumps. The PI array leads to a printed circuit board (PCB) connector with a wire bundle running to a headstage used for electrical recordings from TEENI. This image used with permission from (Desai et al., 2017). B) Modulus data of a rat sciatic nerve, a TEENI hydrogel, and the PI threads. Indentation was used to obtain the modulus of the nerve and hydrogel whereas tensile testing was used to quantify the modulus of the PI threads; n = 5 for tensile testing of PI threads and n = 10 for indentation of rat nerve and hydrogel. Error bars shown are standard deviations. C) Magnified images of PI thread set showing 16 electrodes within the 5 mm implant region.

However, a major challenge with TEENI has been how to integrate the soft tissue-engineered hydrogel around the flexible polyimide (PI) electrodes. Although the microelectode arrays are flexible and substantially less stiff than many other peripheral nerve interfaces (e.g., silicon, tungsten), there is still a substantial mechanical mismatch between the microelectrode threads and the hydrogel and native peripheral nerve. Many factors were considered during the development of this assembly process, including organizing the threads centrally within the hydrogel, eliminating potential damage to the hydrogel from mechanical mismatch between the threads and the hydrogel, allowing for UV penetration to crosslink the hydrogel, and assembly using sterile techniques.

Here, we describe a novel process that was developed to integrate thin electronic threads into an implantable device containing a soft pro-regenerative hydrogel scaffold. This process was only briefly described in previous publications on TEENI such as (Kuliasha et al., 2018) and (Graham et al., 2017), so this paper is meant to highlight the methods developed for device assembly for TEENI in a more comprehensive manner.

2. Materials and methods

2.1. TEENI polyimide (PI) thread fabrication

TEENI microelectrode arrays were composed of three or four PI threads (80 μm wide × 10 μm thick) that contained up to 16 electrodes with areas of 400 μm2, Figure 1C. Devices were fabricated in a cleanroom on 100 mm silicon wafer carriers according to (Kuliasha et al., 2018). Briefly, a 5 μm layer of PI precursor (U-Varnish-S, UBE Inc., Japan) was spin coated and cured to 450 °C. Then, 400 nm of sputtered Ti/Pt/Au/Pt/Ti was applied and patterned via lift-off with stoichiometric amorphous silicon carbide used as an adhesion promotor to the PI. A second 5 μm layer of PI was applied and cured as before. RIE dry-etching was used to reveal Pt electrode sites and final device geometries. Microelectrode arrays were electrically connected to printed circuit boards with soldered wires allowing for percutaneous connections during implantation.

2.2. Hydrogel fabrication

A nerve extracellular matrix mimicking hydrogel was developed for TEENI. The hydrogel consists of modified photocrosslinkable hyaluronic acid (HA), collagen I, and laminin. For more information about the hydrogel development and fabrication process, please see (Spearman et al., 2019).

2.2.1. Methacrylation of hyaluronic acid

To synthesize glycidyl methacrylate hyaluronic acid (GMHA), HA was dissolved in a solution of 50% 1X phosphate-buffered saline (PBS) and 50% acetone solution overnight. Triethylamine was added to the solution and following 30 minutes of mixing, glycidyl methacrylate was added and stirred overnight. GMHA solution was precipitated by slowly pouring the dissolved solution into a 20 times larger volume of acetone and stirring with a glass rod to collect the precipitate. After the solution precipitated, GMHA was rinsed with fresh acetone and dissolved in PBS overnight followed by precipitation in acetone again the following day. GMHA solution was then dialyzed against PBS for 3 days with PBS replaced daily. On the third day, the solution was dialyzed against deionized water to remove any residual salt from PBS. GMHA solution was sterile filtered, flash frozen, and lyophilized for long-term storage up to a year.

2.2.2. Hydrogel production

To mimic peripheral nerve extracellular matrix, multi-component hydrogels containing collagen I (Corning 354249, USA), laminin (Trevigen 3446-005-01, USA), and GMHA were made by mixing these components at appropriate concentrations. GMHA concentration was 5 mg/mL, collagen I concentration was 3 mg/mL, and laminin concentration was 1.5 mg/mL. As noted above, GMHA was sterilized prior to lyophilization and was handled under sterile conditions from that point forward. Collagen I and laminin were received sterile. The chemical crosslinker Irgacure 2959 (BASF SE, Germany) was used to crosslink GMHA. Irgacure 2959 was prepared by dissolving in 1X PBS at a concentration of 10 mg/mL with sonication at 40 °C. GMHA was then dissolved in Irgacure solution at the appropriate concentration to produce the final mixtures. The collagen, laminin, and GMHA solutions were then mixed to yield the final pre-hydrogel solution.

2.3. Mechanical characterization

Mechanical characterization of rat sciatic nerve, hydrogel, and polyimide threads was performed to measure mechanical differences between these components of the TEENI device. Indentation was used to quantify rat sciatic nerve and hydrogel while tensile testing was used to quantify the mechanical properties of the polyimide threads.

2.3.1. Rat sciatic nerve isolation for indentation

Isolation of rat sciatic nerve as described here was approved by the Institutional Animal Care and Use Committee at the University of Florida. Three rats were perfused with PBS to remove blood and rat sciatic nerve was harvested from both sides. Following removal, the nerve was immediately tested using the indentation procedure described below.

2.3.2. Indentation for hydrogel and tissue characterization

To measure the mechanical properties of the TEENI PI threads relative to the extracellular matrix-based hydrogel, different techniques had to be used because of the wide disparity in material properties.

For the hydrogel and nerve, indentation was used (Rubiano et al., 2018; Spearman et al., 2019) with n = 10. An 8 mm diameter, 2 mm height cylindrical sample was prepared by pipetting pre-hydrogel solutions into silicone molds (Grace Bio-Labs 622305, USA). The sample was then loaded into the indentation device and indented with a 3 mm hemispherical probe to a depth of 200 μm. Samples were kept hydrated with PBS to minimize the hydrogel from sticking to the surface of the indentation probe. The samples were indented at a rate of 10 μm/s and the relaxation phase was 60 seconds. To obtain a steady-state modulus (the effective modulus following relaxation), the relaxation phase was fit to the standard linear solid model to obtain a steady-state modulus, which is the modulus reported for the hydrogel and nerve. For more information on this technique, please refer to the following reference (Rubiano et al., 2018).

2.3.3. Tensile testing for polyimide thread characterization

PI films were mechanically characterized using tensile tests according to ASTM D638 with n = 5. 10 μm thick samples were fabricated into a standard dogbone shape using RIE dry-etching, and tests were performed using a TA.XT.plus (Stable Micro Systems, UK) tensile load frame with a 5 kg load cell at a rate of 60 mm/min.

2.4. 3D printed mold

As described below, a 3D printed mold was used to aid with the TEENI device assembly process. Design of the 3D printed mold was accomplished using Fusion 360 (Autodesk, USA). The molds were 3D printed with polylactic acid using an Ultimaker 3 3D printer (Ultimaker, Netherlands). Two 3D printed assembly molds were printed to facilitate holding the microelectrode array in a secure manner for device assembly, Figure 2. These assembly molds with the microelectrode threads in place were positioned in a base mold to facilitate the rest of the device assembly process.

Figure 2:

Figure 2:

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The complete process for integrating a hydrogel around microelectrode arrays to create a tissue-engineered electronic nerve interface (TEENI). A) An example TEENI microelectrode array with implantable polyimide threads and attached wire bundle. B) The microelectrode array is placed into the side assembly molds. C) A Tygon tube is wrapped around the implantable region of the microelectrode threads. The Tygon tube is cut to 5 mm to form a 5 mm long hydrogel. D) The assembly molds are placed into the base mold and the construct is ethylene oxide sterilized (not shown). E) Pre-hydrogel solution is pipetted into the tube, followed by F) UV crosslinking of the hydrogel. G) The Tygon tube is carefully removed from the TEENI construct with intact hydrogel. H) A 7 mm piece of SIS (5 mm implant region with 1 mm overhangs for suturing to the rat sciatic nerve) is wrapped around the implantable region and sutured closed. I) The TEENI device is ready for implantation. Black scale bars (A, B, C, D, E, G, and H) = 5 mm; white scale bar (I) = 1 mm.

2.5. Sterilization of TEENI device

Following assembly of the microelectrode array into the 3D printed mold and placing the tube around the threads, the entire construct was placed in a petri dish and sterilized with ethylene oxide. GMHA was sterile filtered after synthesis as described above. Collagen I, laminin, and small intestinal submucosa (SIS) were received sterile. Some equipment such as the sutures and the scalpel (used to cut SIS into the correct size and shape) were received sterile. All other equipment was autoclaved including pipette tips, tools used for device assembly (forceps, needle holder, and microscissors), and PBS. The device was assembled in a horizontal-flow hood that was wiped with 70% ethanol and UV sterilized prior to use.

2.6. TEENI device assembly

To assemble the TEENI device, a series of 3D printed molds were used to aid with the fabrication process. The threads were placed into the side assembly molds using 1 mm diameter dowel pins (Grainger 38DT36, USA) that held the construct and threads together during assembly. The assembly molds were placed into the base mold which had slots to facilitate precise placement of the assembly molds into the base mold. A 5 mm long, 1/16-inch inner diameter Tygon tube (Fisher 14-171-129, USA) was wrapped around the implantable region of the microelectrode array. Pre-hydrogel solution was pipetted into the tube, followed by UV crosslinking of the hydrogel at ~12 mW/cm2 for 5 minutes. The Tygon tube was carefully removed with forceps from the TEENI construct with intact hydrogel. A 7 mm piece of SIS (5 mm implant region with 1 mm overhangs for suturing to the rat sciatic nerve) was wrapped around the implantable region and sutured closed with 9–0 suture (AROSurgical T06A09N14-13, USA). The TEENI device was then ready for implantation. For information on the TEENI device implantation procedure, see (Nunamaker et al., 2017).

3. Results

3.1. Mechanical testing

Mechanical testing was conducted on rat sciatic nerve, the TEENI hydrogel, and the TEENI PI threads, Figure 1B. Because of the difference in mechanical properties between the nerve/hydrogel and PI threads, different mechanical testing methods had to be used. For the sciatic nerve and hydrogel, indentation was used to determine a steady-state modulus, whereas tensile testing was used with PI threads to determine a Young’s modulus. Rat sciatic nerve and the hydrogel had steady-state moduli of 2.47 ± 0.31 and 2.55 ± 0.05 kPa, respectively, whereas the PI threads had a Young’s modulus of 8.31 ± 0.40 GPa. While these methods do not necessarily give completely concurrent data, the substantial difference in mechanical properties is still highlighted. The TEENI hydrogel was mechanically matched to the rat sciatic nerve as described in (Spearman et al., 2019), whereas the PI threads had a modulus that was six orders of magnitude greater. This highlights the design challenge of the TEENI assembly process since the PI threads need to be integrated into the TEENI hydrogel.

4. Discussion

4.1. TEENI Hydrogel Development

For more information about the hydrogel design process, please see (Spearman et al., 2019). HA was selected as the base component for the hydrogel because of its easy chemical modification and established effect of enhancing peripheral nerve regeneration (Wang et al., 1998). Collagen I and laminin were added to the hydrogel to mimic the native extracellular matrix of peripheral nerve. Multiple studies have been conducted and found that both collagen I and laminin (both individually and together) aid with peripheral nerve regeneration (Chen et al., 2000; Labrador et al., 1998). Both proteins provide adhesive sequences for migrating Schwann cells to adhere to during nerve regeneration. In addition, laminin is the primary component of the basal lamina tubes that Schwann cells lay down during regeneration and eventually become the myelin sheaths.

4.2. TEENI Assembly Process

The assembly process for TEENI required many iterations to successfully establish. Initial 3D printed molds were not capable of precisely holding the microelectrode array in place during hydrogel fabrication. In addition, the orientation of the threads parallel to the mold resulted in some blocking of the UV light, which caused incomplete crosslinking of the hydrogel and eventual breakdown of the hydrogel when attempting to wrap the device in SIS. These challenges led to the assembly process shown in Figure 2, which was more robust and reproducible, oriented the electrode array to minimized blocking of UV used for crosslinking, and facilitated SIS wrapping and suturing. The complete process for assembly as shown in the figure are as follows.

The microelectrode array is placed into the side assembly molds using pins that hold the construct together during assembly. The assembly molds are placed into the base mold that has slots to facilitate precise placement between the two molds. A Tygon tube is cut to 5 mm and wrapped around the implantable region of the microelectrode array along the threads. At this point, the assembled 3D printed molds, polyimide threads, and Tygon tube are sterilized with ethylene oxide and the remainder of the assembly process is completed in sterile conditions within a horizontal-flow hood. Pre-hydrogel solution is pipetted into the tube, followed by UV crosslinking through the Tygon tube resulting in a 5 mm long hydrogel tube encapsulating the electrode threads. The Tygon tube is carefully removed with forceps from the TEENI construct. The hydrogel remains intact. A 7 mm section of SIS (5 mm implant region with 1 mm overhangs on each side for suturing to the rat sciatic nerve) is wrapped around the hydrogel. Four suture sites are used to secure the SIS to the TEENI device. Two central sites are used to close the central region as well as to suture the microelectrode array to the SIS, (see suture holes in Figure 1A). Two outer sites approximately 1 mm from either side are used to fully close the SIS around the threads and hydrogel. The TEENI device is ready for implantation.

This process allows for consistent fabrication of implantable TEENI devices. However, removing the Tygon tube without damaging the hydrogel and threads can be difficult for a new user; although with practice the technique can be performed consistently without causing damage to the TEENI device. Future work will implement multiple thread sets within each TEENI device. By increasing the number of thread sets, the number of electrodes within a single TEENI device can be vastly increased, which will improve this device’s potential use for bidirectional control of robotic prostheses.

For more comprehensive results from implanted TEENI devices using this assembly process, see (Graham et al., 2017) and (Kuliasha et al., 2018).

Highlights.

  • TEENI integrates a flexible electrode array with a soft regenerative hydrogel

  • Novel process for integration of flexible electrodes with soft hydrogel developed

  • Series of 3D printed molds facilitate TEENI device assembly process

Acknowledgements

The authors would like to acknowledge Chancellor Shafor, Vidhi Desai, Eric Atkinson, James Graham, Elizabeth Nunamaker, and Kevin Otto for their early assistance and feedback on the TEENI device assembly process described here. The authors would also like to acknowledge the rest of the TEENI team for their critical role in this project. Research reported in this manuscript was supported by the BTO of the Defense Advanced Research Projects Agency. No. HR0011-15-2-0030.

Footnotes

Conflicts of interest

None.

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