- Open Access
Recent advances in materials and flexible electronics for peripheral nerve interfaces
© The Author(s) 2018
- Received: 23 January 2018
- Accepted: 3 May 2018
- Published: 23 May 2018
Peripheral nerve interfaces are a central technology in advancing bioelectronic medicines because these medical devices can record and modulate the activity of nerves that innervate visceral organs. Peripheral nerve interfaces that use electrical signals for recording or stimulation have advanced our collective understanding of the peripheral nervous system. Furthermore, devices such as cuff electrodes and multielectrode arrays of various form factors have been implanted in the peripheral nervous system of humans in several therapeutic contexts. Substantive advances have been made using devices composed of off-the-shelf commodity materials. However, there is also a demand for improved device performance including extended chronic reliability, enhanced biocompatibility, and increased bandwidth for recording and stimulation. These aspirational goals manifest as much needed improvements in device performance including: increasing mechanical compliance (reducing Young’s modulus and increasing extensibility); improving the barrier properties of encapsulation materials; reducing impedance and increasing the charge injection capacity of electrode materials; and increasing the spatial resolution of multielectrode arrays. These proposed improvements require new materials and novel microfabrication strategies. This mini-review highlights selected recent advances in flexible electronics for peripheral nerve interfaces. The foci of this mini-review include novel materials for flexible and stretchable substrates, non-conventional microfabrication techniques, strategies for improved device packaging, and materials to improve signal transduction across the tissue-electrode interface. Taken together, this article highlights challenges and opportunities in materials science and processing to improve the performance of peripheral nerve interfaces and advance bioelectronic medicine.
- Peripheral nerve interface
- Flexible electronics
Polymeric substrates for flexible and stretchable electrodes
The current trend in PNI design aims to make these devices flexible, bendable, and stretchable to better interface with soft curvilinear tissues and reduce the mechanical mismatch at the abiotic-biotic interface. Polymer substrates such as polyimide and parylene-based polymers have enabled progress in flexible peripheral nerve interfaces in recent decades (Stieglitz et al., 2000; Stieglitz et al., 2005). Advances in flexible electronics are predicated on innovations in processing and micromachining of polymers (e.g. polyimides and parylenes) that can integrate microscale components and create form factors that are suitable for PNI (Noh et al., 2004a; Noh et al., 2004b; Ziegler et al., 2006). While flexible electronics permit conformal integration of electrodes with curvilinear sub-structures, stretchable electronics can accommodate strains in dynamic environments (Wagner & Bauer, 2012) where PNI are often implanted. Elastomers play a central role in advancing stretchable electronics for PNI. Silicone-based elastomers are attractive for implantable medical devices generally, and for stretchable electronics for neural recording more specifically. From a manufacturing standpoint, silicone-based elastomers such as poly(dimethylsiloxane) are cost-effective, robust, largely chemically inert in physiological environments, and amenable to established microfabrication techniques commonly used in PNI manufacturing such as replica-molding, transfer printing (Guo et al., 2013). Silicones offer desirable mechanical properties for bioelectronics including relatively low (and tunable) values for the Young’s modulus (EPDMS ~ 105 (Stieglitz et al., 2005)–106 Pa), high extensibility, and bulk hydrophobicity (γPDMS = 19.8 mN/m; γPMMA = 41.1 mN/m) (Braley, 1970; Wu, 1971). From a regulatory perspective, silicones are ubiquitous medical materials with a rich history for use implants including PNI, specifically cuff electrodes for peripheral nerve recording and stimulation. Silicone-based devices are used in several clinically approved devices for neuromodulation including vagus nerve Silicones are highly stimulators (VNS Therapy System; Cyberonics, Houston, TX USA) (Espinosa et al., 1999; Schachter, 2002). Silicones are highly permeability to water vapor (PH2O(v)-PDMS = 3600 × 10− 9 cm3(STP)-cm/s-cm2-cm Hg) (Spivack & Ferrante, 1969) compared to other barrier layers such as parylene-C (PH2O(v)-Pary-C = 2 × 10− 9 cm3(STP)-cm/s-cm2-cm Hg)(Spivack & Ferrante, 1969; Charati & Stern, 1998; Favre et al., 1994; Robb, 1968). Despite this potential drawback, silicones continue to serve as the gold standard for substrates in PNI because flexible and stretchable interfaces can potentially exhibit improved biocompatibility compared to rigid probes.
Bioabsorbable substrates and components for stretchable and bioresorbable electrodes
Bioabsorbale elastomers have utility as flexible and stretchable substrate materials for use in transient implantable electronic devices. Bioabsorbable PNI may be used in applications where recording or stimulation timelines may be relatively short – on the order of weeks or months. Bioabsorbable PNI are advantageous because they do not have to be explanted and therefore obviate many challenges associated with chronic implants. Towards this end, bioabsorbable elastomers are often composed of simple metabolizable monomers, hydrolytically active bonds, and hyperbranched amorphous networks to achieve biodegradability and extensibility. Prominent examples of bioabsorbable elastomers include polyurethane-ureas, poly(glycerol-co-sebacate) (PGS), poly(1,8-octanediol-co-citrate), polyurethanes, and their derivatives (Wang et al., 2002; Yang et al., 2004; Bettinger et al., 2008; Bettinger, 2011). Like silicones, bioabsorbable elastomers are extensible, can be synthesized in large quantities, processed into thin films, and are compatible with soft lithography and microfabrication techniques (Bettinger et al., 2006a; Bettinger et al., 2006b) including micromolding (Bettinger et al., 2006a), photocrosslinking (Nijst et al., 2007), and 3D-printing (Hung et al., 2014). Unlike silicones, bioabsorbable elastomers are often hygroscopic and susceptible to degradation through hydrolysis and enzymatic activity (Wang et al., 2003; Bettinger et al., 2009). Bioabsorbable elastomers offer utility as a substrate material for temporary implants that can eventually be resorbed within the body (Kim et al., 2010). Careful consideration must be given to the anticipated time scales of hydrolytic degradation versus desired device lifetime (Kim et al., 2010; Bettinger & Bao, 2010a; Bettinger & Bao, 2010b). Flexible and bioabsorbable substrates are of particular interest because they comprise the majority of the device and therefore determine the prospective toxicity risk of the implant. Much work has recently been pursued to design, engineer, and characterize various other active components for implantable electronics (Hwang et al., 2012; Kim et al., 2012). Active components include biocompatible organic semiconductors, silicon, pigments, biodegradable dielectrics, and metals that can be dissolved and metabolized such as magnesium (Irimia-Vladu, 2013; Hwang et al., 2014). These materials can be assembled into active and passive components such as transistors, capacitors, antennae, and other electronic components that may have utility in peripheral nerve interfaces (Chang et al., 2017). Many bioabsorbable devices have functional lifetimes on the order of weeks or months after implantation, which may be suitable for some acute applications, but less appropriate for situations where long-term stable function is required. Therefore, careful consideration must be granted to the final application of the implant.
Ultracompliant materials for flexible electrode arrays
Extensible electronic components
Several engineering strategies have emerged to confer extensibility to electronic components that are integrated with flexible and stretchable substrate materials. One such strategy is to place active electronic components on mechanically rigid domains that are integrated in a continuous elastomeric domain (Lacour et al., 2006). Deterministic composites with differential Young’s moduli confine large strains to the flexible domains thereby reducing the effective strain on the active components. Metallic interconnects between active components must preserve their electrical conductivity while undergoing considerable tensile strains of > 100%. Non-deterministic composites can preserve electrical conductivity in high strain environments by employing mobile colloidal additives that maintain continuous contact during deformation (Kim et al., 2013; Ding et al., 2016). With respect to deterministic composites, there are several examples of compelling geometries to preserve the conductivity of microstructured metallic interconnects under large tensile strains. For example, serpentine structures can access out-of-plane deformation modes that reduce the intrinsic strain on any one microstructure (Zhang et al., 2013). The performance of serpentine interconnects can be enhanced by including secondary structures such as nested elements and fractal geometries. Other strategies for increasing the extensibility of conductors include fabricating 3D structures using Kirigami or Miura folding (Wang et al., 2017; Xu et al., 2017). Features that increase the extensibility of microfabricated conductors span multiple length scales, are largely complementary, and can be combined to preserve electronic properties under large strains.
Transfer printing of microstructures structures
Integrating functional electronics with polymer-based substrates represents a critical dimension in manufacturing flexible and biointegrated electronic devices for bioelectronic medicine. Recent innovations in soft materials processing and microfabrication can produce low-cost and flexible electronic devices. These techniques include advanced photolithography, ink-jet printing, and 3D-printing (Muth et al., 2014; Jakus et al., 2015). While useful for prototyping, many of these approaches present potential challenges in the scalable manufacturing of high-performance electronic devices such as high unit costs, poor reproducibility, and low yields (Macdonald et al., 2014). Transfer printing is a generalizable strategy for integrating electronic components with many substrate materials including elastomers, biodegradable polymers, protein matrices, and hydrogels. Transfer printing is an attractive approach to manufacture flexible and biointegrated electronics because the fabrication of the active components is fundamentally decoupled from the preparation of the substrate, a material that may not be compatible with processes that use elevated temperatures, vacuum, organic solvents, or corrosive buffers.
Advances in transfer printing and heterogeneous device integration
The central technical challenge is transfer printing of any electronic device is achieving differential adhesion between the active layers and the various substrates. One way to dynamically control the adhesion between elastomeric substrates and thin stacks of active components is by altering the rate of lamination and delamination. This technique, termed kinetic control of adhesion, is used for heterogeneous integration of many inorganic active materials with elastomeric substrates in dry conditions in a scalable and reproducible way (Meitl et al., 2006). Other strategies for tunable adhesion between substrates and devices include altering surface chemistries (Sedó et al., 2013), dynamic control of texture (Wang & Xiao, 2017), or employing stimuli-responsive intermediate films. However, the novelty and relative complexity of many of these approaches prohibits widespread use in advanced manufacturing at present. Flexible and biointegrated electronics can benefit from ultracompliant hygroscopic materials with mechanical properties that match that of the target tissue. Technical challenges facing the heterogeneous integration of electronics with hydrated materials include poor adhesion in wet environments and delamination of components due to swelling and deswelling cycles. To this end, bioinspired materials design strategies enable the transfer printing of electronic structures to hydrogel-based substrates (Wu et al., 2015). Bioinspired adhesive motifs promote interfacial bonding between hydrogel substrates and many electronic materials such as noble metals, oxides, and polymers (Wu et al., 2016).
3D-printing and non-conventional fabrication
3D-printing affords another set of complementary strategies to integrate active electronics into soft materials. Recent achievements include the 3D-printing of conductive inks into shapes with complex topologies (Mannoor et al., 2013) to create biohybrid electronic devices. Flexible conductors with complex topologies can also be fabricated by infusing microstructures with liquid metals (Ladd et al., 2013; Gozen et al., 2014). Liquid metals afford many advantages over solid metallic counterparts including robust extensibility. Potential challenges in deploying liquid metals as stretchable conductors in implantable medical devices include preserving chemical stability in physiological conditions and managing toxicity risk.
Progress in device packaging, hermeticity, and on-board energy storage for PNI will likely emerge as a result of relentless, incremental innovation rather than fundamentally new approaches. Practical innovations in thin film processing, microfabrication, and materials integration will underpin many prospective technologies. Achieving long-term hermeticity in implantable medical electronics is a formidable challenge. This goal is especially challenging in devices that feature flexible and stretchable components. The ideal hermetic packaging would: be composed of a material that is stable in aqueous solutions; exhibit an extremely low liquid water; be insulating to electronic and ionic currents; use thin and conformal form factors that preserve flexibility and minimize the “dead space” between the encapsulation layers and the underlying components; maintain insulating and barrier properties under large strains.
Trends in materials for flexible barrier layers
Chemical vapor deposition is a central materials processing strategy to create hermetic packaging. Conformal thin film barrier layers are desirable because films with submicron thicknesses preserve flexibility while conformal deposition reduces the “dead space” in packaged devices. Chemical vapor deposition is compatible with many reliable packaging materials including oxides, carbon-based materials, and polymers such as parylene and its derivatives. Thin parylene films are desirable packaging materials because they are hydrophobic barrier layers, present limited intrinsic biological activity, offer robust dielectric properties, and preserve mechanical flexibility (Loeb et al., 1977). Despite the relatively large hydraulic permeability of parylene compared to many inorganic films, flexible neural probes encapsulated in parylene-C achieve stable in vivo recordings for 12 months or longer (Hara et al., 2016). Nanoscale diamond is another emerging class of packaging materials (Narayan et al., 2011). Nanoscale diamond films have grain sizes that range from 2 to 5 nm (ultrananocrystalline) up to 100 nm (nanocrystalline diamond). Collectively, coatings composed of nanocrystalline diamond exhibit attractive mechanical and tribological characteristics coupled with excellent barrier and dielectric properties. Atomic layer deposition (ALD) is another versatile chemical vapor deposition technique to deposit films with molecular-scale precision. Thin film oxides deposited using ALD have gained traction as packaging materials for implanted medical electronics because the thickness and composition can be tightly controlled. One challenge is that oxides are susceptible to hydrolysis, albeit at very slow rates. Therefore, chronic implants packaged with some types of metal oxides must be co-encapsulated in other inert materials that limit water uptake into components. Flexible bilayers of nanometer-scale Al2O3 films and micron-scale parylene-C can greatly extend the in vitro stability of neural probes compared to devices encapsulated with parylene alone (Xie et al., 2012; Xie et al., 2014a).
Bilayer and composite strategies for improving the performance of barrier layers
Maintaining impermeable barrier layers under high extensibility is challenging because even small strains can produce critical size defects, propagate cracks, and delaminate films. Inventing new techniques to process novel materials into robust barrier layers will likely require an amalgam of strategies from different disciplines. For example, barrier layers composed of bilayer structures with alternating layers of metal oxides and noble metals can dramatically improve hermeticity. Thin films of noble metals prevent water uptake and eliminate hydrolysis while thin films of oxides serve as a robust dielectric layer. The bilayer approach to improved hermeticiy extends to bilayers of Al2O3 and parylene-C (Xie et al., 2014b; Caldwell et al., 2017). Film delamination represents another critical mode for loss of hermeticity. Insulated electrodes with exposed windows create metal-insulator interfaces that are susceptible to failure and film delamination. Adhesion-promoting strategies are employed to address this issue. However, many bonding strategies are susceptible to the milieu of corrosive and reactive species in the biological environment such as salts, free radicals, and aqueous solutions with non-neutral pH values. Microwave heating of parylene-based encapsulation layers can also support robust bonding of polymer films between inorganic substrates (Noh et al., 2004b).
Future perspectives on device packaging
There are many opportunities to advance the performance of materials and processing techniques for packaging, some of which are described here. Choosing the optimal packaging strategy for implantable devices to administer bioelectronic medicine depends on many factors including the implantation site, desired lifetime, anticipated modes of mechanical deformation, and performance requirements associated with barrier and dielectric properties. Polymers will continue to play a central role in packaging materials for implantable stretchable electronic devices. However, novel materials with improved dielectric properties, reduced permeability, and facile processing over existing commodity polymers will likely be required (Hassler et al., 2011). One particular concern is the performance of the barrier layer under tensile or compressive strain. Substantial strains can generate cracks internal stresses that can lead to delamination. Strategies for engineering stretchable metallic interconnects may be repurposed for the design and processing of packaging materials. Namely, techniques to increase the extensibility of materials with intrinsically high Young’s moduli such as serpentine networks, microstructures with out-of-plane geometries, and geometries that support affine deformations are also widely applicable to packaging materials including metals, oxides, and their composites. For example, one may consider fabricating barrier layers with topographically rich features where out-of-plane structures accommodate stretching and bending without reducing the barrier properties of the material (Wu et al., 2013; Münzenrieder et al., 2015).
Improving the in vivo reliability and performance of chronically implanted PNI is critical to advancing scientific discovery and clinical translation of bioelectronic medicines. Most of the technical challenges that currently limit device performance are multifactorial, complex, and must be addressed by interdisciplinary efforts that span materials science, electrical engineering, mechanical engineering, and biomedical engineering. Many of these challenges arise from the fundamental asymmetries between the physical properties of the nervous system versus that of microfabricated electronic devices (Table 1). PNI reliability has steadily improved in recent decades, bolstered by novel materials processing strategies that have improved packaging, yield, and overall in vivo performance. Fundamental discoveries in polymer science have also expanded the materials toolbox available to engineers that design PNI. New technologies in flexible and biointegrated PNI will also be informed by expanding our collective knowledge of the underlying mechanisms that govern the foreign body response to implanted devices. New strategies to improve reliability may emerge including device miniaturization and bioactive components that either manage the underlying biological responses or more directly promote stable tissue-device integration. Understanding signal transduction at the tissue-device interface is another important dimension of device design that will be informed by fundamental studies of charge transport through biological structures, complex fluids, and functional materials such as conducting polymers. Discovering novel mechanisms for charge transport in soft matter or simply increasing our understanding of the governing principles could establish new paradigms for designing electrodes and interfaces for next-generation PNI.
The author acknowledges the many scientists and engineering working in the area of peripheral nerve interface design whose work could not be included in this article due to space limitations.
The author acknowledges financial support provided by the following organizations: National Institutes of Health (R21NS095250); the Defense Advanced Research Projects Agency (D14AP00040); the National Science Foundation (DMR1542196); and the Carnegie Mellon University School of Engineering.
CJB prepared figures and wrote the manuscript. The author read and approved the final manuscript.
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