Stable softening bioelectronics: A paradigm for chronically viable ester-free neural interfaces such as spinal cord stimulation implants.

Polymer toughness is preserved at chronic timepoints in a new class of modulus-changing bioelectronics, which hold promise for commercial chronic implant components such as spinal cord stimulation leads. The underlying ester-free chemical network of the polymer substrate enables device rigidity during implantation, soft, compliant, conforming structures during acute phases in vivo, and gradual stabilization of materials properties chronically, maintaining materials toughness as device stiffness changes. In the past, bioelectronics device designs generally avoided modulus-changing and materials due to the difficulty in demonstrating consistent, predictable performance over time in the body. Here, the acute, and chronic mechanical and chemical properties of a new class of ester-free bioelectronic substrates are described and characterized via accelerated aging at elevated temperatures, with an assessment of their underlying cytotoxicity. Furthermore, spinal cord stimulation leads consisting of photolithographically-defined gold traces and titanium nitride (TiN) electrodes are fabricated on ester-free polymer substrates. Electrochemical properties of the fabricated devices are determined in vitro before implantation in the cervical spinal cord of rat models and subsequent quantification of device stimulation capabilities. Preliminary in vivo evidence demonstrates that this new generation of ester-free, softening bioelectronics holds promise to realize stable, scalable, chronically viable components for bioelectronic medicines of the future.

Mechanically Robust, Softening Shape Memory Polymer Probes for Intracortical Recording.

While intracortical microelectrode arrays (MEAs) may be useful in a variety of basic and clinical scenarios, their implementation is hindered by a variety of factors, many of which are related to the stiff material composition of the device. MEAs are often fabricated from high modulus materials such as silicon, leaving devices vulnerable to brittle fracture and thus complicating device fabrication and handling. For this reason, polymer-based devices are being heavily investigated; however, their implementation is often difficult due to mechanical instability that requires insertion aids during implantation. In this study, we design and fabricate intracortical MEAs from a shape memory polymer (SMP) substrate that remains stiff at room temperature but softens to 20 MPa after implantation, therefore allowing the device to be implanted without aids. We demonstrate chronic recordings and electrochemical measurements for 16 weeks in rat cortex and show that the devices are robust to physical deformation, therefore making them advantageous for surgical implementation.

Recent advances in neural interfaces-Materials chemistry to clinical translation.

Implantable neural interfaces are important tools to accelerate neuroscience research and translate clinical neurotechnologies. The promise of a bidirectional communication link between the nervous system of humans and computers is compelling, yet important materials challenges must be first addressed to improve the reliability of implantable neural interfaces. This perspective highlights recent progress and challenges related to arguably two of the most common failure modes for implantable neural interfaces: (1) compromised barrier layers and packaging leading to failure of electronic components; (2) encapsulation and rejection of the implant due to injurious tissue-biomaterials interactions, which erode the quality and bandwidth of signals across the biology-technology interface. Innovative materials and device design concepts could address these failure modes to improve device performance and broaden the translational prospects of neural interfaces. A brief overview of contemporary neural interfaces is presented and followed by recent progress in chemistry, materials, and fabrication techniques to improve in vivo reliability, including novel barrier materials and harmonizing the various incongruences of the tissue-device interface. Challenges and opportunities related to the clinical translation of neural interfaces are also discussed.

Electrical Properties of Thiol-ene-based Shape Memory Polymers Intended for Flexible Electronics.

Thiol-ene/acrylate-based shape memory polymers (SMPs) with tunable mechanical and thermomechanical properties are promising substrate materials for flexible electronics applications. These UV-curable polymer compositions can easily be polymerized onto pre-fabricated electronic components and can be molded into desired geometries to provide a shape-changing behavior or a tunable softness. Alternatively, SMPs may be prepared as a flat substrate, and electronic circuitry may be built directly on top by thin film processing technologies. Whichever way the final structure is produced, the operation of electronic circuits will be influenced by the electrical and mechanical properties of the underlying (and sometimes also encapsulating) SMP substrate. Here, we present electronic properties, such as permittivity and resistivity of a typical SMP composition that has a low glass transition temperature (between 40 and 60 °C dependent on the curing process) in different thermomechanical states of polymer. We fabricated parallel plate capacitors from a previously reported SMP composition (fully softening (FS)-SMP) using two different curing processes, and then we determined the electrical properties of relative permittivity and resistivity below and above the glass transition temperature. Our data shows that the curing process influenced the electrical permittivity, but not the electrical resistivity. Corona-Kelvin metrology evaluated the quality of the surface of FS-SMP spun on the wafer. Overall, FS-SMP demonstrates resistivity appropriate for use as an insulating material.

Environmental Dynamic Mechanical Analysis to Predict the Softening Behavior of Neural Implants.

When using dynamically softening substrates for neural implants, it is important to have a reliable in vitro method to characterize the softening behavior of these materials. In the past, it has not been possible to satisfactorily measure the softening of thin films under conditions mimicking body environment without substantial effort. This publication presents a new and simple method that allows dynamic mechanical analysis (DMA) of polymers in solutions, such as phosphate buffered saline (PBS), at relevant temperatures. The use of environmental DMA allows measurement of the softening effects of polymers due to plasticization in various media and temperatures, which therefore allows a prediction of the materials behavior under in vivo conditions.

Characterization of the Neuroinflammatory Response to Thiol-ene Shape Memory Polymer Coated Intracortical Microelectrodes.

Thiol-ene based shape memory polymers (SMPs) have been developed for use as intracortical microelectrode substrates. The unique chemistry provides precise control over the mechanical and thermal glass-transition properties. As a result, SMP substrates are stiff at room temperature, allowing for insertion into the brain without buckling and subsequently soften in response to body temperatures, reducing the mechanical mismatch between device and tissue. Since the surface chemistry of the materials can contribute significantly to the ultimate biocompatibility, as a first step in the characterization of our SMPs, we sought to isolate the biological response to the implanted material surface without regards to the softening mechanics. To accomplish this, we tightly controlled for bulk stiffness by comparing bare silicon 'dummy' devices to thickness-matched silicon devices dip-coated with SMP. The neuroinflammatory response was evaluated after devices were implanted in the rat cortex for 2 or 16 weeks. We observed no differences in the markers tested at either time point, except that astrocytic scarring was significantly reduced for the dip-coated implants at 16 weeks. The surface properties of non-softening thiol-ene SMP substrates appeared to be equally-tolerated and just as suitable as silicon for neural implant substrates for applications such as intracortical microelectrodes, laying the groundwork for future softer devices to improve upon the prototype device performance presented here.

Chronic Intracortical Recording and Electrochemical Stability of Thiol-ene/Acrylate Shape Memory Polymer Electrode Arrays.

Current intracortical probe technology is limited in clinical implementation due to the short functional lifetime of implanted devices. Devices often fail several months to years post-implantation, likely due to the chronic immune response characterized by glial scarring and neuronal dieback. It has been demonstrated that this neuroinflammatory response is influenced by the mechanical mismatch between stiff devices and the soft brain tissue, spurring interest in the use of softer polymer materials for probe encapsulation. Here, we demonstrate stable recordings and electrochemical properties obtained from fully encapsulated shape memory polymer (SMP) intracortical electrodes implanted in the rat motor cortex for 13 weeks. SMPs are a class of material that exhibit modulus changes when exposed to specific conditions. The formulation used in these devices softens by an order of magnitude after implantation compared to its dry, room-temperature modulus of ~2 GPa.

Thin Film Multi-Electrode Softening Cuffs for Selective Neuromodulation.

Silicone nerve cuff electrodes are commonly implanted on relatively large and accessible somatic nerves as peripheral neural interfaces. While these cuff electrodes are soft (1-50 MPa), their self-closing mechanism requires of thick walls (200-600 µm), which in turn contribute to fibrotic tissue growth around and inside the device, compromising the neural interface. We report the use of thiol-ene/acrylate shape memory polymer (SMP) for the fabrication of thin film multi-electrode softening cuffs (MSC). We fabricated multi-size MSC with eight titanium nitride (TiN) electrodes ranging from 1.35 to 13.95 × 10-4 cm2 (1-3 kΩ) and eight smaller gold (Au) electrodes (3.3 × 10-5 cm2; 750 kΩ), that soften at physiological conditions to a modulus of 550 MPa. While the SMP material is not as soft as silicone, the flexural forces of the SMP cuff are about 70-700 times lower in the MSC devices due to the 30 µm thick film compared to the 600 µm thick walls of the silicone cuffs. We demonstrated the efficacy of the MSC to record neural signals from rat sciatic and pelvic nerves (1000 µm and 200 µm diameter, respectively), and the selective fascicular stimulation by current steering. When implanted side-by-side and histologically compared 30 days thereafter, the MSC devices showed significantly less inflammation, indicated by a 70-80% reduction in ED1 positive macrophages, and 54-56% less fibrotic vimentin immunoreactivity. Together, the data supports the use of MSC as compliant and adaptable technology for the interfacing of somatic and autonomic peripheral nerves.

Understanding the Effects of Both CD14-Mediated Innate Immunity and Device/Tissue Mechanical Mismatch in the Neuroinflammatory Response to Intracortical Microelectrodes.

Intracortical microelectrodes record neuronal activity of individual neurons within the brain, which can be used to bridge communication between the biological system and computer hardware for both research and rehabilitation purposes. However, long-term consistent neural recordings are difficult to achieve, in large part due to the neuroinflammatory tissue response to the microelectrodes. Prior studies have identified many factors that may contribute to the neuroinflammatory response to intracortical microelectrodes. Unfortunately, each proposed mechanism for the prolonged neuroinflammatory response has been investigated independently, while it is clear that mechanisms can overlap and be difficult to isolate. Therefore, we aimed to determine whether the dual targeting of the innate immune response by inhibiting innate immunity pathways associated with cluster of differentiation 14 (CD14), and the mechanical mismatch could improve the neuroinflammatory response to intracortical microelectrodes. A thiol-ene probe that softens on contact with the physiological environment was used to reduce mechanical mismatch. The thiol-ene probe was both softer and larger in size than the uncoated silicon control probe. Cd14-/- mice were used to completely inhibit contribution of CD14 to the neuroinflammatory response. Contrary to the initial hypothesis, dual targeting worsened the neuroinflammatory response to intracortical probes. Therefore, probe material and CD14 deficiency were independently assessed for their effect on inflammation and neuronal density by implanting each microelectrode type in both wild-type control and Cd14-/- mice. Histology results show that 2 weeks after implantation, targeting CD14 results in higher neuronal density and decreased glial scar around the probe, whereas the thiol-ene probe results in more microglia/macrophage activation and greater blood-brain barrier (BBB) disruption around the probe. Chronic histology demonstrate no differences in the inflammatory response at 16 weeks. Over acute time points, results also suggest immunomodulatory approaches such as targeting CD14 can be utilized to decrease inflammation to intracortical microelectrodes. The results obtained in the current study highlight the importance of not only probe material, but probe size, in regard to neuroinflammation.

In vitro compatibility testing of thiol-ene/acrylate-based shape memory polymers for use in implantable neural interfaces.

Shape memory polymers (SMPs) based on thiol-ene/acrylate formulations are an emerging class of materials with potential applications as structural and/or dielectric coatings for implantable neural interfaces. Here, we report in vitro compatibility studies of three novel thiol-ene/acrylate-based SMP formulations. In vivo cytotoxicity assays were carried out in accordance with International Organization for Standards (ISO) protocol 10993-5, using NCTC clone 929 fibroblasts as well as embryonic cortical cultures. All three SMP formulations passed standardized cytotoxicity assays (>70% normalized cell viability) using both cell types. Functional neurotoxicity assays were carried out using primary cortical networks cultured on substrate-integrated microelectrode arrays (MEAs). We observed significant reduction in cortical network activity in the case of positive control material, but no significant alterations in activity following incubation with SMP material extracts, indicating functional cytocompatibility. Finally, we assessed cell reactivity at the tissue-material interface by performing an in vitro glial scarring assay. Through immunostaining, we observed similar astrocyte-associated (GFAP) mean intensity ratios near nonsoftening SMP-coated and uncoated stainless steel microwires (1.10 ± 0.06 vs. 1.19 ± 0.10), suggesting similar glial cell reactivity. However, we observed decreased mean intensity ratios in the presence of fully softening SMP-coated microwires (1.02 ± 0.04) suggesting reduced glial cell reactivity. Overall, these results indicate that the thiol-ene/acrylate SMP formulations presented here are neither cytotoxic nor neurotoxic, and suggest that fully softening SMP may reduce foreign body response in terms of glial cell reactivity. These findings support further consideration of this class of materials as backbone or insulating materials for implantable neural stimulating/recording devices. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2891-2898, 2018.

Chronic softening spinal cord stimulation arrays.

OBJECTIVE: We sought to develop a cervical spinal cord stimulator for the rat that is durable, stable, and does not perturb the underlying spinal cord. APPROACH: We created a softening spinal cord stimulation (SCS) array made from shape memory polymer (SMP)-based flexible electronics. We developed a new photolithographic process to pattern high surface area titanium nitride (TiN) electrodes onto gold (Au) interconnects. The thiol-ene acrylate polymers are stiff at room temperature and soften following implantation into the body. Durability was measured by the duration the devices produced effective stimulation and by accelerated aging in vitro. Stability was measured by the threshold to provoke an electromyogram (EMG) muscle response and by measuring impedance using electrochemical impedance spectroscopy (EIS). In addition, spinal cord modulation of motor cortex potentials was measured. The spinal column and implanted arrays were imaged with MRI ex vivo, and histology for astrogliosis and immune reaction was performed. MAIN RESULTS: For durability, the design of the arrays was modified over three generations to create an array that demonstrated activity up to 29 weeks. SCS arrays showed no significant degradation over a simulated 29 week period of accelerated aging. For stability, the threshold for provoking an EMG rose in the first few weeks and then remained stable out to 16 weeks; the impedance showed a similar rise early with stability thereafter. Spinal cord stimulation strongly enhanced motor cortex potentials throughout. Upon explantation, device performance returned to pre-implant levels, indicating that biotic rather than abiotic processes were the cause of changing metrics. MRI and histology showed that softening SCS produced less tissue deformation than Parylene-C arrays. There was no significant astrogliosis or immune reaction to either type of array. SIGNIFICANCE: Softening SCS arrays meet the needs for research-grade devices in rats and could be developed into human devices in the future.

A Mosquito Inspired Strategy to Implant Microprobes into the Brain.

Mosquitos are among the deadliest insects on the planet due to their ability to transmit diseases like malaria through their bite. In order to bite, a mosquito must insert a set of micro-sized needles through the skin to reach vascular structures. The mosquito uses a combination of mechanisms including an insertion guide to enable it to bite and feed off of larger animals. Here, we report on a biomimetic strategy inspired by the mosquito insertion guide to enable the implantation of intracortical microelectrodes into the brain. Next generation microelectrode designs leveraging ultra-small dimensions and/or flexible materials offer the promise of increased performance, but present difficulties in reliable implantation. With the biomimetic guide in place, the rate of successful microprobe insertion increased from 37.5% to 100% due to the rise in the critical buckling force of the microprobes by 3.8-fold. The prototype guides presented here provide a reproducible method to augment the insertion of small, flexible devices into the brain. In the future, similar approaches may be considered and applied to the insertion of other difficult to implant medical devices.

3D, Reconfigurable, Multimodal Electronic Whiskers via Directed Air Assembly.

A batch-assembly technique for forming 3D electronics on shape memory polymer substrates is demonstrated and is used to create dense, highly sensitive, multimodal arrays of electronic whiskers. Directed air flow at temperatures above the substrate's glass transition temperature transforms planar photolithographically defined resistive sensors from 2D precursors into shape-tunable, deterministic 3D assemblies. Reversible 3D assembly and flattening is achieved by exploiting the shape memory properties of the substrate, enabling context-driven shape reconfiguration to isolate/enhance specific sensing modes. In particular, measurement schemes and device configurations are introduced that allow for the sensing of temperature, stiffness, contact force, proximity, and surface texture and roughness. The assemblies offer highly spatiotemporally resolved, wide-range measurements of surface topology (50 nm to 500 µm), material stiffness (200 kPa to 7.5 GPa), and temperature (0-100 °C), with response times of <250 µs. The development of a scalable process for 3D assembly of reconfigurable electronic sensors, as well as the large breadth and sensitivity of complex sensing modes demonstrated, has applications in the growing fields of 3D assembly, electronic skin, and human-machine interfaces.

Metamorphic Superomniphobic Surfaces.

Superomniphobic surfaces are extremely repellent to virtually all liquids. By combining superomniphobicity and shape memory effect, metamorphic superomniphobic (MorphS) surfaces that transform their morphology in response to heat are developed. Utilizing the MorphS surfaces, the distinctly different wetting transitions of liquids with different surface tensions are demonstrated and the underlying physics is elucidated. Both ex situ and in situ wetting transitions on the MorphS surfaces are solely due to transformations in morphology of the surface texture. It is envisioned that the robust MorphS surfaces with reversible wetting transition will have a wide range of applications including rewritable liquid patterns, controlled drug release systems, lab-on-a-chip devices, and biosensors.

Characterization of a Thiol-Ene/Acrylate-Based Polymer for Neuroprosthetic Implants.

Thiol-ene/acrylate shape-memory polymers can be used as base substrates for neural electrodes to treat neurological dysfunction. Neural electrodes are implanted into the body to alter or record impulse conduction. This study characterizes thiol-ene/acrylate polymers to determine which synthesis methods constitute an ideal substrate for neural implants. To achieve a desired Tg between 50 and 56.5 °C, curing conditions, polymer thickness, monomer ratios, and water uptake were all examined and controlled for. Characterization with dynamic mechanical analysis and thermal gravimetric analysis reveals that thin, thiol-ene/acrylate polymers composed of at least 50 mol % acrylate content and cured for at least 1 h at 365 nm are promising as substrates for neural electrodes.

Design and demonstration of an intracortical probe technology with tunable modulus.

Intracortical probe technology, consisting of arrays of microelectrodes, offers a means of recording the bioelectrical activity from neural tissue. A major limitation of existing intracortical probe technology pertains to limited lifetime of 6 months to a year of recording after implantation. A major contributor to device failure is widely believed to be the interfacial mechanical mismatch of conventional stiff intracortical devices and the surrounding brain tissue. We describe the design, development, and demonstration of a novel functional intracortical probe technology that has a tunable Young's modulus from ∼2 GPa to ∼50 MPa. This technology leverages advances in dynamically softening materials, specifically thiol-ene/acrylate thermoset polymers, which exhibit minimal swelling of < 3% weight upon softening in vitro. We demonstrate that a shape memory polymer-based multichannel intracortical probe can be fabricated, that the mechanical properties are stable for at least 2 months and that the device is capable of single unit recordings for durations up to 77 days in vivo. This novel technology, which is amenable to processes suitable for manufacturing via standard semiconductor fabrication techniques, offers the capability of softening in vivo to reduce the tissue-device modulus mismatch to ultimately improve long term viability of neural recordings. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 159-168, 2017.

Design Paradigm Utilizing Reversible Diels-Alder Reactions to Enhance the Mechanical Properties of 3D Printed Materials.

A design paradigm is demonstrated that enables new functional 3D printed materials made by fused filament fabrication (FFF) utilizing a thermally reversible dynamic covalent Diels-Alder reaction to dramatically improve both strength and toughness via self-healing mechanisms. To achieve this, we used as a mending agent a partially cross-linked terpolymer consisting of furan-maleimide Diels-Alder (fmDA) adducts that exhibit reversibility at temperatures typically used for FFF printing. When this mending agent is blended with commercially available polylactic acid (PLA) and printed, the resulting materials demonstrate an increase in the interfilament adhesion strength along the z-axis of up to 130%, with ultimate tensile strength increasing from 10 MPa in neat PLA to 24 MPa in fmDA-enhanced PLA. Toughness in the z-axis aligned prints increases by up to 460% from 0.05 MJ/m(3) for unmodified PLA to 0.28 MJ/m(3) for the remendable PLA. Importantly, it is demonstrated that a thermally reversible cross-linking paradigm based on the furan-maleimide Diels-Alder (fmDA) reaction can be more broadly applied to engineer property enhancements and remending abilities to a host of other 3D printable materials with superior mechanical properties.

High-Tg Thiol-Click Thermoset Networks via the Thiol-Maleimide Michael Addition.

Thiol-click reactions lead to polymeric materials with a wide range of interesting mechanical, electrical, and optical properties. However, this reaction mechanism typically results in bulk materials with a low glass transition temperature (Tg ) due to rotational flexibility around the thioether linkages found in networks such as thiol-ene, thiol-epoxy, and thiol-acrylate systems. This report explores the thiol-maleimide reaction utilized for the first time as a solvent-free reaction system to synthesize high-Tg thermosetting networks. Through thermomechanical characterization via dynamic mechanical analysis, the homogeneity and Tg s of thiol-maleimide networks are compared to similarly structured thiol-ene and thiol-epoxy networks. While preliminary data show more heterogeneous networks for thiol-maleimide systems, bulk materials exhibit Tg s 80 °C higher than other thiol-click systems explored herein. Finally, hollow tubes are synthesized using each thiol-click reaction mechanism and employed in low- and high-temperature environments, demonstrating the ability to withstand a compressive radial 100 N deformation at 100 °C wherein other thiol-click systems fail mechanically.

Direct electrochemistry of cytochrome c immobilized on titanium nitride/multi-walled carbon nanotube composite for amperometric nitrite biosensor.

In this report, titanium nitride (TiN) nanoparticles decorated multi-walled carbon nanotube (MWCNTs) nanocomposite is fabricated via a two-step process. These two steps involve the decoration of titanium dioxide nanoparticles onto the MWCNTs surface and a subsequent thermal nitridation. Transmission electron microscopy shows that TiN nanoparticles with a mean diameter of ≤ 20 nm are homogeneously dispersed onto the MWCNTs surface. Direct electrochemistry and electrocatalysis of cytochrome c immobilized on the MWCNTs-TiN composite modified on a glassy carbon electrode for nitrite sensing are investigated. Under optimum conditions, the current response is linear to its concentration from 1 µM to 2000 µM with a sensitivity of 121.5 µA µM(-1)cm(-2) and a low detection limit of 0.0014 µM. The proposed electrode shows good reproducibility and long-term stability. The applicability of the as-prepared biosensor is validated by the successful detection of nitrite in tap and sea water samples.