Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes.

Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclodextrin polymer (pCD) local delivery approach presented herein, both in vitro and in vivo. The pCD displayed an extended resveratrol release for 100 days, as well as 60 days of free radical scavenging activity in vitro. In vivo results indicated that our pCD delivery system successfully delivered resveratrol to the brain with a sustained release for the entire short-duration study (up to 7 days). Interestingly, significantly greater concentrations of resveratrol metabolites were found at the intracortical probe implantation site compared to the systemic administration of resveratrol. Together, our pilot results provide support for the possibility of improving the delivery of resveratrol in an attempt to stabilize long-term neural interfacing applications.

In Vivo Characterization of Intracortical Probes with Focused Ion Beam-Etched Nanopatterned Topographies.

(1) Background: Intracortical microelectrodes (IMEs) are an important part of interfacing with the central nervous system (CNS) and recording neural signals. However, recording electrodes have shown a characteristic steady decline in recording performance owing to chronic neuroinflammation. The topography of implanted devices has been explored to mimic the nanoscale three-dimensional architecture of the extracellular matrix. Our previous work used histology to study the implant sites of non-recording probes and showed that a nanoscale topography at the probe surface mitigated the neuroinflammatory response compared to probes with smooth surfaces. Here, we hypothesized that the improvement in the neuroinflammatory response for probes with nanoscale surface topography would extend to improved recording performance. (2) Methods: A novel design modification was implemented on planar silicon-based neural probes by etching nanopatterned grooves (with a 500 nm pitch) into the probe shank. To assess the hypothesis, two groups of rats were implanted with either nanopatterned (n = 6) or smooth control (n = 6) probes, and their recording performance was evaluated over 4 weeks. Postmortem gene expression analysis was performed to compare the neuroinflammatory response from the two groups. (3) Results: Nanopatterned probes demonstrated an increased impedance and noise floor compared to controls. However, the recording performances of the nanopatterned and smooth probes were similar, with active electrode yields for control probes and nanopatterned probes being approximately 50% and 45%, respectively, by 4 weeks post-implantation. Gene expression analysis showed one gene, Sirt1, differentially expressed out of 152 in the panel. (4) Conclusions: this study provides a foundation for investigating novel nanoscale topographies on neural probes.

Comparative assessment of iridium oxide and platinum alloy wires using an in vitro glial scar assay.

The long-term effect of chronically implanted electrodes is the formation of a glial scar. Therefore, it is imperative to assess the biocompatibility of materials before employing them in neural electrode fabrication. Platinum alloy and iridium oxide have been identified as good candidates as neural electrode biomaterials due to their mechanical and electrical properties, however, effect of glial scar formation for these two materials is lacking. In this study, we applied a glial scarring assay to observe the cellular reactivity to platinum alloy and iridium oxide wires in order to assess the biocompatibility based on previously defined characteristics. Through real-time PCR, immunostaining and imaging techniques, we will advance the understanding of the biocompatibility of these materials. Results of this study demonstrate iridium oxide wires exhibited a more significant reactive response as compared to platinum alloy wires. Cells cultured with platinum alloy wires had less GFAP gene expression, lower average GFAP intensity, and smaller glial scar thickness. Collectively, these results indicated that platinum alloy wires were more biocompatible than the iridium oxide wires.

Development of a Slow-Degrading Polymerized Curcumin Coating for Intracortical Microelectrodes.

Intracortical microelectrodes are used with brain-computer interfaces to restore lost limb function following nervous system injury. While promising, recording ability of intracortical microelectrodes diminishes over time due, in part, to neuroinflammation. As curcumin has demonstrated neuroprotection through anti-inflammatory activity, we fabricated a 300 nm-thick intracortical microelectrode coating consisting of a polyurethane copolymer of curcumin and polyethylene glycol (PEG), denoted as poly(curcumin-PEG1000 carbamate) (PCPC). The uniform PCPC coating reduced silicon wafer hardness by two orders of magnitude and readily absorbed water within minutes, demonstrating that the coating is soft and hydrophilic in nature. Using an in vitro release model, curcumin eluted from the PCPC coating into the supernatant over 1 week; the majority of the coating was intact after an 8-week incubation in buffer, demonstrating potential for longer term curcumin release and softness. Assessing the efficacy of PCPC within a rat intracortical microelectrode model in vivo, there were no significant differences in tissue inflammation, scarring, neuron viability, and myelin damage between the uncoated and PCPC-coated probes. As the first study to implant nonfunctional probes with a polymerized curcumin coating, we have demonstrated the biocompatibility of a PCPC coating and presented a starting point in the design of poly(pro-curcumin) polymers as coating materials for intracortical electrodes.

Neuroinflammatory Gene Expression Analysis Reveals Pathways of Interest as Potential Targets to Improve the Recording Performance of Intracortical Microelectrodes.

Intracortical microelectrodes are a critical component of brain-machine interface (BMI) systems. The recording performance of intracortical microelectrodes used for both basic neuroscience research and clinical applications of BMIs decreases over time, limiting the utility of the devices. The neuroinflammatory response to the microelectrode has been identified as a significant contributing factor to its performance. Traditionally, pathological assessment has been limited to a dozen or so known neuroinflammatory proteins, and only a few groups have begun to explore changes in gene expression following microelectrode implantation. Our initial characterization of gene expression profiles of the neuroinflammatory response to mice implanted with non-functional intracortical probes revealed many upregulated genes that could inform future therapeutic targets. Emphasis was placed on the most significant gene expression changes and genes involved in multiple innate immune sets, including Cd14, C3, Itgam, and Irak4. In previous studies, inhibition of Cluster of Differentiation 14 (Cd14) improved microelectrode performance for up to two weeks after electrode implantation, suggesting CD14 can be explored as a potential therapeutic target. However, all measures of improvements in signal quality and electrode performance lost statistical significance after two weeks. Therefore, the current study investigated the expression of genes in the neuroinflammatory pathway at the tissue-microelectrode interface in Cd14-/- mice to understand better how Cd14 inhibition was connected to temporary improvements in recording quality over the initial 2-weeks post-surgery, allowing for the identification of potential co-therapeutic targets that may work synergistically with or after CD14 inhibition to improve microelectrode performance.

Investigation of the Feasibility of Ventricular Delivery of Resveratrol to the Microelectrode Tissue Interface.

(1) Background: Intracortical microelectrodes (IMEs) are essential to basic brain research and clinical brain-machine interfacing applications. However, the foreign body response to IMEs results in chronic inflammation and an increase in levels of reactive oxygen and nitrogen species (ROS/RNS). The current study builds on our previous work, by testing a new delivery method of a promising antioxidant as a means of extending intracortical microelectrodes performance. While resveratrol has shown efficacy in improving tissue response, chronic delivery has proven difficult because of its low solubility in water and low bioavailability due to extensive first pass metabolism. (2) Methods: Investigation of an intraventricular delivery of resveratrol in rats was performed herein to circumvent bioavailability hurdles of resveratrol delivery to the brain. (3) Results: Intraventricular delivery of resveratrol in rats delivered resveratrol to the electrode interface. However, intraventricular delivery did not have a significant impact on electrophysiological recordings over the six-week study. Histological findings indicated that rats receiving intraventricular delivery of resveratrol had a decrease of oxidative stress, yet other biomarkers of inflammation were found to be not significantly different from control groups. However, investigation of the bioavailability of resveratrol indicated a decrease in resveratrol accumulation in the brain with time coupled with inconsistent drug elution from the cannulas. Further inspection showed that there may be tissue or cellular debris clogging the cannulas, resulting in variable elution, which may have impacted the results of the study. (4) Conclusions: These results indicate that the intraventricular delivery approach described herein needs further optimization, or may not be well suited for this application.

Differential expression of genes involved in the acute innate immune response to intracortical microelectrodes.

Higher order tasks in development for brain-computer interfacing applications require the invasiveness of intracortical microelectrodes. Unfortunately, the resulting inflammatory response contributes to the decline of detectable neural signal. The major components of the neuroinflammatory response to microelectrodes have been well-documented with histological imaging, leading to the identification of broad pathways of interest for its inhibition such as oxidative stress and innate immunity. To understand how to mitigate the neuroinflammatory response, a more precise understanding is required. Advancements in genotyping have led the development of new tools for developing temporal gene expression profiles. Therefore, we have meticulously characterized the gene expression profiles of the neuroinflammatory response to mice implanted with non-functional intracortical probes. A time course of differential acute expression of genes of the innate immune response were compared to naïve sham mice, identifying significant changes following implantation. Differential gene expression analysis revealed 22 genes that could inform future therapeutic targets. Particular emphasis is placed on the largest changes in gene expression occurring 24 h post-implantation, and in genes that are involved in multiple innate immune sets including Itgam, Cd14, and Irak4. STATEMENT OF SIGNIFICANCE: Current understanding of the cellular response contributing to the failure of intracortical microelectrodes has been limited to the evaluation of cellular presence around the electrode. Minimal research investigating gene expression profiles of these cells has left a knowledge gap identifying their phenotype. This manuscript represents the first robust investigation of the changes in gene expression levels specific to the innate immune response following intracortical microelectrode implantation. To understand the role of the complement system in response to implanted probes, we performed gene expression profiling over acute time points from implanted subjects and compared them to no-surgery controls. This manuscript provides valuable insights into inflammatory mechanisms at the tissue-probe interface, thus having a high impact on those using intracortical microelectrodes to study and treat neurological diseases and injuries.

Focused Ion Beam Lithography to Etch Nano-architectures into Microelectrodes.

With advances in electronics and fabrication technology, intracortical microelectrodes have undergone substantial improvements enabling the production of sophisticated microelectrodes with greater resolution and expanded capabilities. The progress in fabrication technology has supported the development of biomimetic electrodes, which aim to seamlessly integrate into the brain parenchyma, reduce the neuroinflammatory response observed after electrode insertion and improve the quality and longevity of electrophysiological recordings. Here we describe a protocol to employ a biomimetic approach recently classified as nano-architecture. The use of focused ion beam lithography (FIB) was utilized in this protocol to etch specific nano-architecture features into the surface of non-functional and functional single shank intracortical microelectrodes. Etching nano-architectures into the electrode surface indicated possible improvements of biocompatibility and functionality of the implanted device. One of the benefits of using FIB is the ability to etch on manufactured devices, as opposed to during the fabrication of the device, facilitating boundless possibilities to modify numerous medical devices post-manufacturing. The protocol presented herein can be optimized for various material types, nano-architecture features, and types of devices. Augmenting the surface of implanted medical devices can improve the device performance and integration into the tissue.

Investigating the Association between Motor Function, Neuroinflammation, and Recording Metrics in the Performance of Intracortical Microelectrode Implanted in Motor Cortex.

Long-term reliability of intracortical microelectrodes remains a challenge for increased acceptance and deployment. There are conflicting reports comparing measurements associated with recording quality with postmortem histology, in attempts to better understand failure of intracortical microelectrodes (IMEs). Our group has recently introduced the assessment of motor behavior tasks as another metric to evaluate the effects of IME implantation. We hypothesized that adding the third dimension to our analysis, functional behavior testing, could provide substantial insight on the health of the tissue, success of surgery/implantation, and the long-term performance of the implanted device. Here we present our novel analysis scheme including: (1) the use of numerical formal concept analysis (nFCA) and (2) a regression analysis utilizing modern model/variable selection. The analyses found complimentary relationships between the variables. The histological variables for glial cell activation had associations between each other, as well as the neuronal density around the electrode interface. The neuronal density had associations to the electrophysiological recordings and some of the motor behavior metrics analyzed. The novel analyses presented herein describe a valuable tool that can be utilized to assess and understand relationships between diverse variables being investigated. These models can be applied to a wide range of ongoing investigations utilizing various devices and therapeutics.

Toward Standardization of Electrophysiology and Computational Tissue Strain in Rodent Intracortical Microelectrode Models.

Progress has been made in the field of neural interfacing using both mouse and rat models, yet standardization of these models' interchangeability has yet to be established. The mouse model allows for transgenic, optogenetic, and advanced imaging modalities which can be used to examine the biological impact and failure mechanisms associated with the neural implant itself. The ability to directly compare electrophysiological data between mouse and rat models is crucial for the development and assessment of neural interfaces. The most obvious difference in the two rodent models is size, which raises concern for the role of device-induced tissue strain. Strain exerted on brain tissue by implanted microelectrode arrays is hypothesized to affect long-term recording performance. Therefore, understanding any potential differences in tissue strain caused by differences in the implant to tissue size ratio is crucial for validating the interchangeability of rat and mouse models. Hence, this study is aimed at investigating the electrophysiological variances and predictive device-induced tissue strain. Rat and mouse electrophysiological recordings were collected from implanted animals for eight weeks. A finite element model was utilized to assess the tissue strain from implanted intracortical microelectrodes, taking into account the differences in the depth within the cortex, implantation depth, and electrode geometry between the two models. The rat model demonstrated a larger percentage of channels recording single unit activity and number of units recorded per channel at acute but not chronic time points, relative to the mouse model Additionally, the finite element models also revealed no predictive differences in tissue strain between the two rodent models. Collectively our results show that these two models are comparable after taking into consideration some recommendations to maintain uniform conditions for future studies where direct comparisons of electrophysiological and tissue strain data between the two animal models will be required.

Neural engineering: the process, applications, and its role in the future of medicine.

OBJECTIVE: Recent advances in neural engineering have restored mobility to people with paralysis, relieved symptoms of movement disorders, reduced chronic pain, restored the sense of hearing, and provided sensory perception to individuals with sensory deficits. APPROACH: This progress was enabled by the team-based, interdisciplinary approaches used by neural engineers. Neural engineers have advanced clinical frontiers by leveraging tools and discoveries in quantitative and biological sciences and through collaborations between engineering, science, and medicine. The movement toward bioelectronic medicines, where neuromodulation aims to supplement or replace pharmaceuticals to treat chronic medical conditions such as high blood pressure, diabetes and psychiatric disorders is a prime example of a new frontier made possible by neural engineering. Although one of the major goals in neural engineering is to develop technology for clinical applications, this technology may also offer unique opportunities to gain insight into how biological systems operate. MAIN RESULTS: Despite significant technological progress, a number of ethical and strategic questions remain unexplored. Addressing these questions will accelerate technology development to address unmet needs. The future of these devices extends far beyond treatment of neurological impairments, including potential human augmentation applications. Our task, as neural engineers, is to push technology forward at the intersection of disciplines, while responsibly considering the readiness to transition this technology outside of the laboratory to consumer products. SIGNIFICANCE: This article aims to highlight the current state of the neural engineering field, its links with other engineering and science disciplines, and the challenges and opportunities ahead. The goal of this article is to foster new ideas for innovative applications in neurotechnology.

Nano-Architectural Approaches for Improved Intracortical Interface Technologies.

Intracortical microelectrodes (IME) are neural devices that initially were designed to function as neuroscience tools to enable researchers to understand the nervous system. Over the years, technology that aids interfacing with the nervous system has allowed the ability to treat patients with a wide range of neurological injuries and diseases. Despite the substantial success that has been demonstrated using IME in neural interface applications, these implants eventually fail due to loss of quality recording signals. Recent strategies to improve interfacing with the nervous system have been inspired by methods that mimic the native tissue. This review focusses on one strategy in particular, nano-architecture, a term we introduce that encompasses the approach of roughening the surface of the implant. Various nano-architecture approaches have been hypothesized to improve the biocompatibility of IMEs, enhance the recording quality, and increase the longevity of the implant. This review will begin by introducing IME technology and discuss the challenges facing the clinical deployment of IME technology. The biological inspiration of nano-architecture approaches will be explained as well as leading fabrication methods used to create nano-architecture and their limitations. A review of the effects of nano-architecture surfaces on neural cells will be examined, depicting the various cellular responses to these modified surfaces in both in vitro and pre-clinical models. The proposed mechanism elucidating the ability of nano-architectures to influence cellular phenotype will be considered. Finally, the frontiers of next generation nano-architecture IMEs will be identified, with perspective given on the future impact of this interfacing approach.

Implantation of Neural Probes in the Brain Elicits Oxidative Stress.

Clinical implantation of intracortical microelectrodes has been hindered, at least in part, by the perpetual inflammatory response occurring after device implantation. The neuroinflammatory response observed after device implantation has been correlated to oxidative stress that occurs due to neurological injury and disease. However, there has yet to be a definitive link of oxidative stress to intracortical microelectrode implantation. Thus, the objective of this study is to give direct evidence of oxidative stress following intracortical microelectrode implantation. This study also aims to identify potential molecular targets to attenuate oxidative stress observed postimplantation. Here, we implanted adult rats with silicon non-functional microelectrode probes for 4 weeks and compared the oxidative stress response to no surgery controls through postmortem gene expression analysis and qualitative histological observation of oxidative stress markers. Gene expression analysis results at 4 weeks postimplantation indicated that EH domain-containing 2, prion protein gene (Prnp), and Stearoyl-Coenzyme A desaturase 1 (Scd1) were all significantly higher for animals implanted with intracortical microelectrode probes compared to no surgery control animals. To the contrary, NADPH oxidase activator 1 (Noxa1) relative gene expression was significantly lower for implanted animals compared to no surgery control animals. Histological observation of oxidative stress showed an increased expression of oxidized proteins, lipids, and nucleic acids concentrated around the implant site. Collectively, our results reveal there is a presence of oxidative stress following intracortical microelectrode implantation compared to no surgery controls. Further investigation targeting these specific oxidative stress linked genes could be beneficial to understanding potential mechanisms and downstream therapeutics that can be utilized to reduce oxidative stress-mediated damage following microelectrode implantation.

Rodent Behavioral Testing to Assess Functional Deficits Caused by Microelectrode Implantation in the Rat Motor Cortex.

Medical devices implanted in the brain hold tremendous potential. As part of a Brain Machine Interface (BMI) system, intracortical microelectrodes demonstrate the ability to record action potentials from individual or small groups of neurons. Such recorded signals have successfully been used to allow patients to interface with or control computers, robotic limbs, and their own limbs. However, previous animal studies have shown that a microelectrode implantation in the brain not only damages the surrounding tissue but can also result in functional deficits. Here, we discuss a series of behavioral tests to quantify potential motor impairments following the implantation of intracortical microelectrodes into the motor cortex of a rat. The methods for open field grid, ladder crossing, and grip strength testing provide valuable information regarding the potential complications resulting from a microelectrode implantation. The results of the behavioral testing are correlated with endpoint histology, providing additional information on the pathological outcomes and impacts of this procedure on the adjacent tissue.

Inhibition of the cluster of differentiation 14 innate immunity pathway with IAXO-101 improves chronic microelectrode performance.

OBJECTIVE: Neuroinflammatory mechanisms are hypothesized to contribute to intracortical microelectrode failures. The cluster of differentiation 14 (CD14) molecule is an innate immunity receptor involved in the recognition of pathogens and tissue damage to promote inflammation. The goal of the study was to investigate the effect of CD14 inhibition on intracortical microelectrode recording performance and tissue integration. APPROACH: Mice implanted with intracortical microelectrodes in the motor cortex underwent electrophysiological characterization for 16 weeks, followed by endpoint histology. Three conditions were examined: (1) wildtype control mice, (2) knockout mice lacking CD14, and (3) wildtype control mice administered a small molecule inhibitor to CD14 called IAXO-101. MAIN RESULTS: The CD14 knockout mice exhibited acute but not chronic improvements in intracortical microelectrode performance without significant differences in endpoint histology. Mice receiving IAXO-101 exhibited significant improvements in recording performance over the entire 16 week duration without significant differences in endpoint histology. SIGNIFICANCE: Full removal of CD14 is beneficial at acute time ranges, but limited CD14 signaling is beneficial at chronic time ranges. Innate immunity receptor inhibition strategies have the potential to improve long-term intracortical microelectrode performance.

Status Epilepticus due to Intraperitoneal Injection of Vehicle Containing Propylene Glycol in Sprague Dawley Rats.

Published reports of status epilepticus due to intraperitoneal injection containing propylene glycol in rats are sparse. In fact, there are no reports specifying a maximum safe dose of propylene glycol through intraperitoneal administration. We report here a case of unexpected seizures in Sprague Dawley rats after receiving an intraperitoneal injection containing propylene glycol. Nine-week-old, 225-250 gram male rats were reported to experience tremor progressing to seizures within minutes after given injections of resveratrol (30 mg/kg) dissolved in a 40 : 60 propylene glycol/corn oil vehicle solution by direct intraperitoneal (IP) slow bolus injection or via a preplaced intraperitoneal catheter. The World Health Organization suggests a maximum dose of 25 mg/kg/day of propylene glycol taken orally and no more than 25 mg/dL in blood serum, whereas the animals used in our study got a calculated maximum 0.52 g/kg (25 times lower dose). Blood tests from the seizing rat support a diagnosis of hemolysis and lactic acidosis which may have led to the seizures, all of which appeared to be a consequence of the propylene glycol administration. These findings are consistent with oral and intravenous administration of propylene glycol toxicity as previously reported in other species, including humans. To our knowledge, this report represents the first published case of status epilepticus due to an IP injection containing propylene glycol.

Microelectrode implantation in motor cortex causes fine motor deficit: Implications on potential considerations to Brain Computer Interfacing and Human Augmentation.

Intracortical microelectrodes have shown great success in enabling locked-in patients to interact with computers, robotic limbs, and their own electrically driven limbs. The recent advances have inspired world-wide enthusiasm resulting in billions of dollars invested in federal and industrial sponsorships to understanding the brain for rehabilitative applications. Additionally, private philanthropists have also demonstrated excitement in the field by investing in the use of brain interfacing technologies as a means to human augmentation. While the promise of incredible technologies is real, caution must be taken as implications regarding optimal performance and unforeseen side effects following device implantation into the brain are not fully characterized. The current study is aimed to quantify any motor deficit caused by microelectrode implantation in the motor cortex of healthy rats compared to non-implanted controls. Following electrode insertion, rats were tested on an open-field grid test to study gross motor function and a ladder test to study fine motor function. It was discovered that rats with chronically indwelling intracortical microelectrodes exhibited up to an incredible 527% increase in time to complete the fine motor task. This initial study defines the need for further and more robust behavioral testing of potential unintentional harm caused by microelectrode implantation.

Hippocampal vulnerability and subacute response following varied blast magnitudes.

Clinical outcomes from blast neurotrauma are associated with higher order cognitive functions such as memory, problem solving skills and attention. Current literature is limited to a single overpressure exposure or repeated exposures at the same level of overpressure and is focused on the acute response (<3 days). In an attempt to expand the understanding of neuropathological and molecular changes of the subacute response (7 days post injury), we used an established rodent model of blast neurotrauma. Three pressure magnitudes (low, moderate and high) were used to evaluate molecular injury thresholds. Immunohistochemical analysis demonstrated increased cleaved caspase-3 levels and loss of neuronal population (NeuN+) within the hippocampus of all pressure groups. On the contrary, selective activation of microglia was observed in the low blast group. In addition, increased astrocytes (GFAP), membrane signal transduction protein (Map2k1) and calcium regulator mechanosensitive protein (Piezo 2) were observed in the moderate blast group. Results from gene expression analysis suggested ongoing neuroprotection, as brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF) and Mn and CuZn superoxide dismutases (SOD) all increased in the low and moderate blast groups. Ongoing neuroprotection was further supported by increased SOD levels observed in the moderate group using immunohistochemistry. The gene expression level of glutamate aspartate transporter (GLAST) was upregulated in the low, but downregulated in the high blast group, while no changes were found in the moderate group. Overall, the data shown here provides evidence of a diverse neuroprotective and glial response to various levels of blast exposure. This mechanistic role of neuroprotection is vital in understanding ongoing cellular stress, both at the gene and protein levels, in order to develop interventional studies for the prognosis of injury.

Examining the inflammatory response to nanopatterned polydimethylsiloxane using organotypic brain slice methods.

A long-term effect of chronically implanted neural electrodes is the formation of a glial scar made up of reactive astrocytes, microglia and the matrix proteins they generate. Studies have shown glial fibrillary acidic protein (GFAP) and cytokines interleukin-1beta (IL-1ß), tumor necrosis factor alpha (TNFα), and transforming growth factor beta 1 (TGFß1) are involved with the initial and modulation phases of reactive astrogliosis. In the present study, nanopatterning of polydimethylsiloxane (PDMS) was attempted as a method for reducing the inflammatory response of glial cells. A unique feature of this study is the use of in vitro brain slice cultures (organotypic cultures) in order to more accurately depict the native response. The aim of the study was to determine whether nanotopography could reduce inflammatory signals typically resultant from neural electrode implantation. Specifically, observation of cell alignment and surveillance of GFAP, IL-1ß, TNFα, and TGFß1 gene expression around the PDMS pins was performed. Results of this study confirm nanopatterning not only influences cell morphology, but some of the molecular signals as well. These results collectively indicate nanopatterning improves the biocompatibility of PDMS by reducing inflammatory markers such as GFAP, IL-1ß, TGFß1 and TNFα compared to the non-patterned PDMS pins.

Nanopatterning effects on astrocyte reactivity.

An array of design strategies have been targeted toward minimizing failure of implanted microelectrodes by minimizing the chronic glial scar around the microelectrode under chronic conditions. Current approaches toward inhibiting the initiation of glial scarring range from altering the geometry, roughness, size, shape, and materials of the device. Studies have shown materials which mimic the nanotopography of the natural environment in vivo will consequently result in an improved biocompatible response. Nanofabrication of electrode arrays is being pursued in the field of neuronal electrophysiology to increase sampling capabilities. Literature shows a gap in research of nanotopography influence in the reduction of astrogliosis. The aim of this study was to determine optimal feature sizes for neural electrode fabrication, which was defined as eliciting a nonreactive astrocytic response. Nanopatterned surfaces were fabricated with nanoimprint lithography on poly(methyl methacrylate) surfaces. The rate of protein adsorption, quantity of protein adsorption, cell alignment, morphology, adhesion, proliferation, viability, and gene expression was compared between nanopatterned surfaces of different dimensions and non-nanopatterned control surfaces. Results of this study revealed that 3600 nanopatterned surfaces elicited less of a response when compared with the other patterned and non-nanopatterned surfaces. The surface instigated cell alignment along the nanopattern, less protein adsorption, less cell adhesion, proliferation and viability, inhibition of glial fibrillary acidic protein, and mitogen-activated protein kinase kinase 1 compared with all other substrates tested.