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.

Deployable, liquid crystal elastomer-based intracortical probes.

Intracortical microelectrode arrays (MEAs) are currently limited in their chronic functionality due partially to the foreign body response (FBR) that develops in regions immediately surrounding the implant (typically within 50-100 µm). Mechanically flexible, polymer-based substrates have recently been explored for MEAs as a way of minimizing the FBR caused by the chronic implantation. Nonetheless, the FBR degrades the ability of the device to record neural activity. We are motivated to develop approaches to deploy multiple recording sites away from the initial site of implantation into regions of tissue outside the FBR zone. Liquid Crystal Elastomers (LCEs) are responsive materials capable of programmable and reversible shape change. These hydrophobic materials are also non-cytotoxic and compatible with photolithography. As such, these responsive materials may be well suited to serve as substrates for smart, implantable electronics. This study explores the feasibility of LCE-based deployable intracortical MEAs. LCE intracortical probes are fabricated on a planar substrate and adopt a 3D shape after being released from the substrate. The LCE probes are then fixed in a planar configuration using polyethylene glycol (PEG). The PEG layer dissolves in physiological conditions, allowing the LCE probe to deploy post-implantation. Critically, we show that LCE intracortical probes will deploy within a brain-like agarose tissue phantom. We also show that deployment distance increases with MEA width. A finite element model was then developed to predict the deformed shape of the deployed probe when embedded in an elastic medium. Finally, LCE-based deployable intracortical MEAs were capable of maintaining electrochemical stability, recording extracellular signals from cortical neurons in vivo, and deploying recording sites greater than 100 µm from the insertion site in vivo. Taken together, these results suggest the feasibility of using LCEs to develop deployable intracortical MEAs. STATEMENT OF SIGNIFICANCE: Deployable MEAs are a recently developed class of neural interfaces that aim to shift the recording sites away from the region of insertion to minimize the negative effects of FBR on the recording performance of MEAs. In this study, we explore LCEs as a potential substrate for deployable MEAs. The novelty of this study lies in the systematic and programmable deployment offered by LCE-based intracortical MEAs. These results illustrate the feasibility and potential application of LCEs as a substrate for deployable intracortical MEAs.

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.

Chronic recording and electrochemical performance of amorphous silicon carbide-coated Utah electrode arrays implanted in rat motor cortex.

OBJECTIVE: Clinical applications of implantable microelectrode arrays are currently limited by device failure due to, in part, mechanical and electrochemical failure modes. To overcome this challenge, there is significant research interest in the exploration of novel array architectures and encapsulation materials. Amorphous silicon carbide (a-SiC) is biocompatible and corrosion resistant, and has recently been employed as a coating on biomedical devices including planar microelectrode arrays. However, to date, the three-dimensional Utah electrode array (UEA) is the only array architecture which has been approved by the food and drug administration (FDA) for long-term human trials. APPROACH: Here, we demonstrate, for the first time, that UEAs can be fabricated with a-SiC encapsulation and sputtered iridium oxide film (SIROF) electrode coatings, and that such arrays are capable of single-unit recordings over a 30 week implantation period in rat motor cortex. Over the same period, we carried out electrochemical measurements, including voltage transients, cyclic voltammetry, and electrochemical impedance spectroscopy (EIS), to evaluate potential failure modes. Furthermore, we evaluated chronic foreign body response via fluorescence immunohistochemistry following device explantation. MAIN RESULTS: During the indwelling period, we observed a reduction in active electrode yield percentage from 94.6 ± 5.4 (week 1) to 16.4 ± 11.5% (week 30). While the average active electrode yield showed a steady reduction, it is noteworthy that 3 out of 8 UEAs recorded greater than 60% active electrode yield at all times through 24 weeks and 1 out of 8 UEAs recorded greater than 60% active electrode yield at all times through the whole implantation period. SIGNIFICANCE: In total, these findings further suggest that a-SiC may serve as a mechanically and electrochemically stable device encapsulation alternative to polymeric coatings such as Parylene-C.

Effect of oxidation on intrinsic residual stress in amorphous silicon carbide films.

The change in residual stress in plasma enhanced chemical vapor deposition amorphous silicon carbide (a-SiC:H) films exposed to air and wet ambient environments is investigated. A close relationship between stress change and deposition condition is identified from mechanical and chemical characterization of a-SiC:H films. Evidence of amorphous silicon carbide films reacting with oxygen and water vapor in the ambient environment are presented. The effect of deposition parameters on oxidation and stress variation in a-SiC:H film is studied. It is found that the films deposited at low temperature or power are susceptible to oxidation and undergo a notable increase in compressive stress over time. Furthermore, the films deposited at sufficiently high temperature (≥325 C) and power density (≥0.2 W cm-2 ) do not exhibit pronounced oxidation or temporal stress variation. These results serve as the basis for developing amorphous silicon carbide based dielectric encapsulation for implantable medical devices. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1654-1661, 2019.

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.

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.

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.