Invited reviewCuff and sieve electrode (CASE): The combination of neural electrodes for bi-directional peripheral nerve interfacing
Introduction
There are at least 1.6 million people living with limb loss in the United States and an estimated 185,000 new cases occur each year. The number of Americans living with major limb loss is increasing, and expected to double by 2050 (Ziegler-Graham et al., 2008). Hence, considerable technological efforts have been devoted to develop neural prosthesis devices capable of replacing the motor and sensory functions of lost limbs required to return normative function to amputees (Fisher et al., 2009; Hoffer and Loeb, 1980; Johnston et al., 2003; Wang et al., 2010). With state of the art prostheses now capable of emulating a wide range of limb functions that stand to significantly improve the quality of life of many amputees, the push is now on to develop the ultimate control methods for intuitive control. Peripheral nerve interfaces (PNIs) are one particularly attractive method, offering direct connections between the biological peripheral nervous system and the robotic prostheses. PNIs can be broadly categorized into four general schemes based on levels of invasiveness and selectivity: (1) regenerative, (2) intraneural, (3) intrafascicular, and (4) extraneural, as shown in Fig. 1 (Micera and Navarro, 2009). Among these types, the regenerative electrodes (sieve electrodes) are considered to have highest invasiveness and selectivity compared to other types of electrode. Regenerative electrodes are designed to contact the transverse face of a severed nerve, allowing axonal growth through the electrodes sites and providing direct and independent access to the distinct fascicular organisation reducing the amount of current required and providing selective spatial recruitment (MacEwan et al., 2016a; Stieglitz et al., 1997). The major caveat of these devices relates to the compliance mismatch of metal electrodes and delicate axons, which has the potential to cause neuropathic pain through physical damage and inflammatory insult (Navarro et al., 2005). Intraneural and intrafascicular electrodes represent the electrodes which have a next lower level of invasiveness and selectivity. Intraneural electrodes placed within the endoneurium of individual nerve fibers have been developed to improve the selectivity and signal-to-noise ratio of neural recordings. A typical type of intraneural electrodes is “Utah slanted electrode array” (USEA) (Boretius et al., 2010; Clark et al., 2011; Lago et al., 2007; Rossini et al., 2010). USEA have been pneumatically inserted into a peripheral nerve without significantly disturbing nerve function. This method allows selective recording of single unit responses and low-current stimulation of motor fibers. Intraneural electrodes, however, have a rigid structure of the electrodes and the tethering forces by lead wires can cause irreparable physical damage to the nerve. Intrafascicular electrodes are placed within the nerve and are in direct contact with the tissue they are intended to stimulate or record. The most common intrafascicular electrode is the longitudinal intrafascicuclar electrodes (LIFEs) (Badia et al., 2011a; Micera et al., 2008). Recently, thin-film LIFEs have been developed to improve on the mechanical mismatch between metal wires and neural tissue. LIFEs allow more selective interfacing than extraneural electrodes due to proximity of electrodes to axons. They also are less invasive than intraneural electrodes. However, while showing a balance between specificity and reliability (Dhillon and Horch, 2005), the insertion can cause damage to the nerve and the longitudinal orientation of the electrodes limits specificity to more than one fascicle (Boretius et al., 2012). Transverse intrafacicular multichannel electrodes (TIME) represent a comparable alternative to LIFE, that penetrates the nerve transversely, providing selective access of different fascicles and have been used to successfully treat phantom pain in humans (Boretius et al., 2010, Boretius et al., 2012). Extraneural electrodes (cuff electrodes) represent the opposite end of the PNI spectrum, and are regarded as having lowest invasiveness and selectivity. Extraneural electrodes are wrapped around nerves and measure electrical potential from the surface of the epineurium. The major caveat to such devices is the lack of recruitment selectivity and the requirement for high current thresholds (Badia et al., 2011b; Navarro et al., 2005). Extraneural electrodes are the most widely used electrode in clinical applications for their ease of implantation and robustness, while regenerative electrodes are yet to be tested in clinical application and remain largely experimental. Despite the lack of selectivity cuff electrodes provide, there has been a substantial degree of clinical success in both the motor and sensory control of neural prostheses (Matthew et al., 2016). Recently, MacEwan et al. (2016) demonstrated chronic stable implantation of a novel micro-sieve regenerative electrode in rats, assisted by the use of nerve guidance tubes for stability, such as those commonly used in nerve gap repair (Belkas et al., 2004; MacEwan et al., 2016a). Guidance tubes themselves are but a few electrodes away from being an interface of their own, and certainly several novel peripheral interfaces have applied guidance tubes in their design in a tissue engineering approach to peripheral interfacing (Nunamaker et al., 2017b).
Here, we present a combination of cuff and sieve electrodes (CASE) that integrates the advantages of both regenerative and extraneural electrodes for future applications in prosthesis control (Fig. 1). Design and fabrication of the CASE are presented, along with ex vivo and acute in vivo testing towards chronic interfacing applications in the amputee setting. The electrode array of CASE is intended to provide ease of implantation and chronic stability while maximizing electrode contacts as well as flexibility in recording/stimulating paradigms through both cuff and sieve portions. Acute in vitro experiments demonstrate the handling and implantation of CASE, while recording of somatosensory evoked potentials (SSEPs) via a microelectrocorticography (μECoG) device demonstrate the ability to write sensory information from CASE to the central nervous system (Dingle et al., 2019; Park et al., 2014, Park et al., 2016, Park et al., 2018; Schendel et al., 2013, Schendel et al., 2014). As a translator of biological and computational signals, CASE can play a pivotal role for harnessing the full potential of advanced prostheses.
Section snippets
CASE design and fabrication
We developed a novel design of CASE combining multichannel sieve electrodes; through which a sciatic nerve regenerates, and cuff electrodes made of a cylindrical sheath which wraps around the exterior of a sciatic nerve. Both the sieve and cuff portions are intended to provide bidirectional neuronal signal communication with the nervous system, independent of each other or in unison. Sieve electrodes provide direct access to the different fascicles that make up the nerve, ultimately providing
Conclusion
In summary, we have demonstrated the fabrication of a novel thin-film peripheral nerve interface combining both traditional cuff and sieve electrode (CASE) interfaces in a single compact unit suitable for in vivo applications. Furthermore, CASE electrodes are easy to surgically manipulate and implant for applications in nerve repair models such as the one demonstrated in this article, or to terminal nerve ends for application in amputation models. Finally, the generation of somatosensory evoked
Device fabrication
Platinum-based electrode arrays were fabricated on Parylene C coated wafers as illustrated in Fig. 2B. A 4 in. silicon wafer was coated with thick Parylene C (15 μm) using a CVD process (SCS Labcoter 2 Parylene Deposition System). The metal layers Ti (30 nm)/Au (200 nm) /Pt (30 nm) was patterned using photolithography and a lift-off process to form the electrode sites, electrical connection traces, and connection pads. Subsequently, a second Parylene C (10 μm) was coated to encapsulate the
Author contributions
H.K. and A.M.D. contributed equally to this work. H.K., A.M.D., I.-K.L., J.P.N., D.-H.B., N.O.S., J.S.I., W.Z., J.A.P., A.X.T.M., J.B., A.J.S., J.C.W., S.O.P. and Z.M. performed the research. H.K., A.D., J.P.N., D.-H.B., N.O.S., D.-W.P, J.C.W., S.O.P. and Z.M. wrote the manuscript. H.K., A.D., J.C.W., S.O.P. and Z.M. designed the research.
Declaration of Competing Interest
J.C.W. has an equity interest in NeuroOne Medical (Minnetonka, MN) and NeuroNexus (Ann Arbor, MI), companies that manufacture microfabricated electrode arrays for research and clinical applications.
Acknowledgment
This work was supported by Army Research Office (ARO) under the auspices of Dr. James Harvey (and previously Dr. Joe X. Qiu) grant W911NF-14-1-0652 and the Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office (BTO) Hand Proprioception and Touch Interfaces (HAPTIX) program under the auspices of Dr. Doug Weber through the DARPA Contracts Management Office Grant/Contract No. HR0011-15-2-0008. This work was also partly supported by the Basic Science Research Program
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These authors contributed equally to this work.