Symposium Organizers
Mohammad Reza Abidian, University of Houston
Stephanie Lacour, Ecole Polytechnique Federale de Lausanne, Switzerland
Kip Ludwig, Mayo Clinic
Laura Poole-Warren, University of New South Wales
SM3.1/SM1.1/SM4.1: Joint Session I
Session Chairs
Mohammad Reza Abidian
Martin Kaltenbrunner
Jonathan Rivnay
Tuesday PM, April 18, 2017
PCC North, 100 Level, Room 121 AB
11:30 AM - *SM3.1.01/SM1.1.01/SM4.1.01
Nano-Bioelectronics: From Biological Sensor Chips to Cyborg Tissues and Seamless Brain-Electronics Implants
Charles Lieber 1 , Jae-hyun Lee 1
1 , Harvard University, Cambridge, Massachusetts, United States
Show AbstractNanoscale materials enable unique opportunities at the interface between the physical and life sciences, for example, by integrating nanoelectronic devices with cells and/or tissue to make possible communication at the length scales relevant to biological function. In this presentation, I will present an overview of bioelectronics, including general questions, primary research results, and future opportunities. First, general questions and issues for developing electronic devices for biological sensors through implants will be introduced. Second, transistor-based nanoelectronic chip-based platforms will be introduced and selected studies detection of biological analytes as well as neuron and cardiac cell action potentials will be briefly reviewed. Third, the design and implementation of new nanoelectronic probes capable of intracellular recording and stimulation at scales heretofore not possible with existing techniques will be discussed, including applications in neuroscience and the prospects of biologically-targeting of nanoscale devices. Fourth, a new concept will be introduced for seamless three-dimensional integration of addressable networks of multi-functional devices in engineered tissue, and exemplified with studies of cyborg cardiac tissue. Last, an ‘out-of-the-box’ approach for seamlessly merging nanoelectronic arrays with brain using syringe-injectable polymer-like mesh electronics will be discussed, including quantitative studies demonstrating unprecedented absence of tissue immune response and stable recording at the single neuron/neural circuit level for more than a year. Finally, the prospects for broad-ranging applications in the life sciences as the distinction between electronic and living systems is blurred in the future will be discussed, as well as future challenges.
12:00 PM - *SM3.1.02/SM1.1.02/SM4.1.02
Soft Wearable Robots Improve Walking Function and Economy after Stroke and Grasping Function after Spinal Cord Injury
Conor Walsh 1
1 , Harvard School of Engineering, Cambridge, Massachusetts, United States
Show Abstract
Stroke-induced hemiparetic gait is characteristically slow and metabolically-expensive. Conventional rehabilitation efforts have had limited effectiveness in restoring normal walking behavior, often relying on gait compensations for the limited gains observed. We sought to determine if a unilateral, soft wearable robot (exosuit) designed to supplement the paretic limb’s residual ability to generate forward propulsion and ground clearance during walking could facilitate more normal walking behavior after stroke. Herein, we evaluate the effects of walking with an exosuit actively assisting the paretic limb of nine individuals in the chronic phase of stroke recovery compared to walking with an exosuit unpowered. Spinal cord injury patients often lose the ability to grasp objects and their poor hand function limits their ability to perform activities of daily living. We sought to determine if lightweight, fabric-based soft fluidic actuators would be capable of applying sufficient assistance when integrated into a glove to improve grasping functions. Herein, we evaluate the effects of grasping when wearing the glove of five individuals who have suffered a spinal cord injury and compared to their baseline ability.
SM3.2/SM1.2/SM4.2: Joint Session II: Bioelectronics
Session Chairs
Mohammad Reza Abidian
Martin Kaltenbrunner
Jonathan Rivnay
Tuesday PM, April 18, 2017
PCC North, 100 Level, Room 121 AB
2:30 PM - *SM3.2.01/SM1.2.01/SM4.2.01
Skin-Inspired Materials, Devices and Applications
Zhenan Bao 1
1 , Stanford University, Stanford, California, United States
Show AbstractIn this talk, I will discuss fabrication of skin-inspired devices and related applications in bioelectronics and robotics.
3:00 PM - *SM3.2.02/SM1.2.02/SM4.2.02
Biocompatible Gel Electrodes and Ultraflexible Organic Devices for Implantable Electronics
Takao Someya 1 , Tsuyoshi Sekitani 2 , Sungwon Lee 3 , Tomoyuki Yokota 1
1 Electrical and Electronic Engineering and Information Systems, University of Tokyo, Tokyo Japan, 2 The Institute of Scientific and Industrial Research, Osaka University, Osaka Japan, 3 , Daegu Gyeongbuk Institute of Science and Technology, Daegu Korea (the Republic of)
Show AbstractWe report recent progress of ultraflexible organic photonic and electronic devices for implantable electronics. In particular, we describe the fabrication of different organic devices such as organic thin-film transistors (OTFTs), organic photodetectors (OPDs), and organic light-emitting diodes (OLEDs) that are manufactured on ultrathin plastic film with the thickness of 1 μm. We also fabricate two types of gels that are patterned on the surface of ultrathin film devices for implantable applications. First, by designing and fabricating smart, stress-absorbing electronic devices with sticky gels that can adhere to wet and complex tissue surfaces, we realize reliable, long-term measurements of vital signals. We fabricated a multielectrode array, which can be attached to the surface of a rat heart, resulting in good conformal contact. Second, a biocompatible highly conductive gel composite comprising multi-walled carbon nanotube-dispersed sheet with an aqueous hydrogel. By using gel composites, we fabricated an ultrathin organic active matrix amplifier on a 1-μm-thick polyethylene-naphthalate film to amplify weak biosignals. This work is financially supported by JST/ERATO Bio-harmonized electronics project.
3:30 PM - *SM3.2.03/SM1.2.03/SM4.2.03
Interfacing with the Brain Using Organic Electronics
George Malliaras 1
1 , ENSM Saint-Etienne, Gardanne France
Show AbstractOne of the most important scientific and technological frontiers of our time lies in the interface between electronics and the human brain. It promises to help elucidate aspects of the brain’s working mechanism and deliver new tools for diagnosis and treatment of a host of pathologies including epilepsy and Parkinson’s disease. The field of organic electronics has made available materials with a unique combination of attractive properties, including mechanical flexibility, mixed ionic/electronic conduction, enhanced biocompatibility, and capability for drug delivery. I will present examples of organic-based devices for recording and stimulation of brain activity, highlighting the connection between materials properties and device performance. I will show that organic electronic materials provide unparalleled opportunities to design devices that improve our understanding of brain physiology and pathology, and can be used to deliver new therapies.
4:00 PM - SM3.2./SM1.2./SM4.2
BREAK
4:30 PM - *SM3.2.04/SM1.2.04/SM4.2.04
Materials and Devices Designs for Flexible, Active Electronic Interfaces to the Brain and the Heart
John Rogers 1
1 , Northwestern University, Evanston, Illinois, United States
Show AbstractAdvanced capabilities in electrical recording and stimulation are essential to the treatment of heart rhythm diseases and brain disorders and to progress in cardiac and brain science. The most sophisticated technologies for this purpose utilize geometrically conformal, active electronics that achieve high speed, high resolution electrophysiological mapping through direct measurement interfaces to adjacent, contacting tissues. Unfortunately, slow penetration of biofluids through the materials of the surface layers and/or through localized defects in them prevent chronic modes of use. Here we present advances in materials for ultrathin biofluid barriers and in actively multiplexed device designs for capacitive signal detection that, together, enable flexible electronic devices with stable, long-term operational capabilities as full implants. Systematic studies, including accelerated in vitro testing that suggests lifetimes of several decades, reveal the fundamental materials considerations and highlight the practical advantages of such platforms. High resolution mapping of cardiac function in Langendorff hearts and of brain activity in live animal models demonstrates the capabilities, with quantitative validation against control measurements. The results establish pathways for use of flexible electronics as long-term implants, with important implications for basic scientific study and future clinical use.
5:00 PM - *SM3.2.05/SM1.2.05/SM4.2.05
Conformal, Microfabricated Electrode Array for Optimization of Spectral Content in the Auditory Brainstem Implant (ABI)
Amelie Guex 1 , Ariel Hight 2 , Daniel Lee 2 , M. Brown 2 , Stephanie Lacour 1
1 , Ecole Polytechnique Federale de Lausanne, Switzerland, Lausanne Switzerland, 2 , Harvard Medical School, Boston, Massachusetts, United States
Show AbstractThe auditory brainstem implant (ABI) is a neuroprosthesis that provides sound sensations to patients who cannot benefit from a cochlear implant (CI) by stimulating the cochlear nucleus (CN) surface, the first auditory processing nucleus in the central nervous system. Compared to the CI however, ABI users lag behind in speech comprehension, which may be due to the poor spatial resolution of its stimulating channels leading to a low spectral resolution.
In this study, we test whether using a flexible microfabricated electrode array with high channel resolution and small contacts (100 µm diameter) coated with conducting polymer PEDOT:PSS can provide significant spectral information, and how the presentation of stimulus current can be optimized (e.g. monopolar or bipolar stimulation, distance and angle between the two electrodes of a pair). Using a rat model of the ABI, we place the electrode array along the length of the dorsal cochlear nucleus (DCN) surface to selectively stimulate different locations, and we record evoked activity along the tonotopic axis of the inferior colliculus (IC), an auditory structure located in the midbrain, to measure the resolution of evoked tonotopic cues.
Initially, we found high variability in the pattern of evoked activity but upon further analysis found two components that revealed tonotopic cues. Specifically, we found that there was a common pattern of evoked activity across all electrodes that masks tonotopic cues, and that early latency spikes following each stimulus pulse are more tonotopic than later spikes. While focusing our analysis on tonotopic cues, we found minimal measured differences between monopolar vs. bipolar stimulation, but found that small inter-electrode distances were better than large ones. These results suggest that modifications in the electrode design, particularly an increase in the density of stimulation electrode sites, could ultimately improve tonotopic cues for ABI users.
5:30 PM - *SM3.2.06/SM1.2.06/SM4.2.06
Interfacing Neurons with Electronic Devices
Andreas Offenhaeusser 1
1 , Forschungszentrum Juelich, Juelich Germany
Show AbstractA challenging issue in Neuroscience is tightly monitoring and controlling of the functionality of neural networks. Direct interfacing of devices based on inorganic and organic semiconductor and (non conventional) electrode material with nerve cells and brain tissue open novel perspective for multifunctional electrophysiological tools in vitro and in vivo with high spatiotemporal resolution and improved sensitivity.
We aim for the fabrication of chip-based sensors that enable an efficient neuro-electronic interface towards precise recording of cellular signals. Within this framework, we have developed a variety of microelectrode array (MEA) designs that enable non-invasive, parallel, multi-site recording of action potentials from primary neurons and cardiomyocyte-like HL-1 cell line. We have modified standard planar 64 electrode MEA design with different geometries ranging from nanometer-sized cavities that allow for cellular protrusion into the sensor to mushroom-shaped 3D electrodes. Furthermore, we investigate various field-effect transistor (FET) designs ranging from silicon nanowires to graphene. Recently we could demonstrate successful interfacing of electrogeneic cells with fully printed and flexible MEA and flexible graphene FETs.
Symposium Organizers
Mohammad Reza Abidian, University of Houston
Stephanie Lacour, Ecole Polytechnique Federale de Lausanne, Switzerland
Kip Ludwig, Mayo Clinic
Laura Poole-Warren, University of New South Wales
SM3.3: Neural Interfaces I
Session Chairs
Mohammad Reza Abidian
Laura Poole-Warren
Wednesday AM, April 19, 2017
PCC North, 100 Level, Room 121 C
9:30 AM - SM3.3.01
Curvature-Dependent Neuronal Membrane Deformation Probed by Correlative Fluorescence and Electron Microscopy
Francesca Santoro 1 , Wenting Zhao 1 2 , Hsin-ya Lou 1 , Bianxiao Cui 1
1 Chemistry, Stanford University, Stanford, California, United States, 2 Material Science and Engineering, Stanford University, Stanford, California, United States
Show AbstractIn recent years, 3D nano and micro-fabricated platforms have been used for multiple in vitro biomedical applications. In particular, nanostructured materials have gained large importance as a valid tool to manipulate cells and record electrical activity (i.e. action potentials) from electrogenic cells1. Effectively, the geometry as well as the material nature of those 3D materials induce cells to have a specific response and often to re-adapt their shapes to the nanostructures2. The main goal of those platforms is to gain very close contact to the cellular membrane for further manipulation. Thus, it is necessary to have an investigation tool to visualize the membrane response to different material/geometries at the nanoscale. Traditional techniques such as fluorescence microscopy do not allow that resolution and typical electron microscopy have major sample preparation issues which lead to membrane damages.
Here, we present a detailed study focused on the characterization of neuronal cellular membrane response on 3D nanopillars, nanoholes and planar surfaces to investigate the role of different material curvatures in respect of membrane deformation. For the first time, we are able to directly correlate fluoresce microscopy investigations of the cell membrane to a high resolution imaging based on scanning electron microscopy/focused ion beam (SEM/FIB). Our innovative method is based on heavy metal staining and resin embedding. In contrast to traditional resin embedding procedure, we developed an ultra-thin resin embedding method of cells as well as the material underneath. Having an extremely thin resin layer on top of cells allows us to first visualize, with conventional SEM, entire cells spreading and growing on nanostructured materials while resolving precisely the cell membrane (its contact point to the surface and its ruffling) which can be damaged by standard SEM preparation techniques (i.e. critical point drying). This process is unlikely to be done with standard techniques such as TEM since the embedding resin is in the order of mm thick so that it is impossible to perform correlated SEM imaging with fluorescence microscopy. In fact, our unique technique allows in situ SEM imaging of whole cells, followed by (spatially controlled) sequential transverse sectioning with FIB in order to visualize the cell membrane in 3D in response to the nanofabricated platforms. From our findings, we can conclude that positive curvature (nanopillars) induce closer cell contact to the material then negative curvature (nanoholes) and zero curvature (planar).
1. Angle, M. R., Cui, B. & Melosh, N. A. Nanotechnology and neurophysiology. Curr. Opin. Neurobiol. 32, 132–140 (2015).
2. Santoro, F. et al. Interfacing Electrogenic Cells with 3D Nanoelectrodes: Position, Shape, and Size Matter. ACS Nano 8, 6713–6723 (2014).
9:45 AM - SM3.3.02
A Novel Polymeric Retinal Prosthesis Restores Vision in a Rat Model of Degenerative Blindness
Maria Rosa Antognazza 1
1 , Istituto Italiano di Tecnologia, Milano Italy
Show AbstractReplacement strategies arise as promising approaches in case of inherited retinal dystrophies leading to blindness. We fabricated a fully organic retinal prosthesis made of conjugated polymers layered onto a silk fibroin substrate. First, we characterized the biophysical and surface properties; then, we assess the long-term biocompatibility by implanting the organic device in the subretinal space of 3-months-old rats over a period of 6 months. The results indicate a good stability of the subretinal implants over time, with preservation of the physical properties of the polymeric layer and of a tight contact with the outer retina. Immunoinflammatory markers detected a modest tissue reaction to the surgical insult and the foreign body that peaked shortly after surgery and progressively decreased with time to normal levels at 5 months after implantation. Importantly, the integrity of the polymeric layer in direct contact with the retinal tissue was preserved after 6 months of implantation. The recovery of the foreign-body tissue reaction was also associated with a normal b-wave in the electroretinographic response. The results demonstrate that the device implanted in non-dystrophic eyes is well tolerated, highly biocompatible and suitable as retinal prosthesis in case of photoreceptor degeneration. Electrophysiological and behavioural analyses reveal a significant and persistent prosthesis-dependent recovery of light-sensitivity and visual acuity up to 6 months after surgery. The rescue of visual functions is accompanied by an increase of the basal metabolic activity in the primary visual cortex, as demonstrated by positron emission tomography neuroimaging. Our results highlight the possibility of developing a new generation of fully organic photovoltaic retinal prostheses for sub-retinal implants that may be of clinical relevance in degenerative blindness.
10:00 AM - *SM3.3.03
CMOS Neural Probes
Ken Shepard 1
1 Electrical Engineering, Columbia, New York, New York, United States
Show AbstractCMOS technology has the opportunity to enable a growing number of tools for studying the brain because of the ability to scale recording and stimulating electronics to very small dimensions, enabling either very small devices or very large numbers of channels. The simplest place to employ this scale is in electrophysiology, where current approaches can simply be scaled to large numbers of electrodes. We will show on-going efforts to employ high-density electronics with passive electrode structures, in the form of penetrating silicon probes and flexible surface recording arrays. More interesting opportunities exist when the CMOS integrated circuit and the electrodes are monolithically integrated and this combination is put into unusual form factors. Active CMOS multielectrode arrays allow electrode densities to exceed 1000 electrodes/mm2, bringing new opportunities to study planar system such as the retina. CMOS technology can also be thinned to the point of pliability making it possible to produce flexible electronics that fully exploits the capabilities of CMOS, improving mechanical compatibility for implanted systems. Examples here include 65,000-channel arrays for surface recording and fully wireless shanks for electrophysiological recording in the brain. The capabilities of CMOS for neural interfaces are also enhanced by employing RF, light, and acoustics for powering, telemetry, and biotic-abiotic interfaces, creating whole new classes of implantable, ingestible, and wearable systems. We will describe several on-going efforts here with applications to neuroscience.
10:30 AM - *SM3.3.04
Stability and Reliability of Neural Implants—A View from Materials to Systems
Thomas Stieglitz 1
1 Laboratory for Biomedical Microtechnology, Department of Microsystems Engineering – IMTEK, University of Freiburg, Freiburg Germany
Show AbstractNeural implants need to establish stable and reliable interfaces to the target structure for chronic application in neurosciences as well as in clinical applications. They have to record electrical neural signals, excite neural cells or fibers by means of electrical stimulation. Metabolic monitoring and detection of neurotransmitter concentrations is also part of the research agenda but not yet mature enough for translation in chronic clinical applications. Proper selection of substrate, insulation and electrode materials is of utmost importance to bring the interface in close contact with the neural target structures, minimize foreign body reaction after implantation and maintain functionality over the complete implantation period. Our work has focused on polymer substrates with integrated thin-film metallization as core of our flexible neural interfaces approach. Micromachining is the main technology for electrode array manufacturing. Designing applications for implants in the peripheral and central nervous system needs integration of components, the connection of cables and connectors to both, electrode arrays and hermetic packages containing electronic circuitry for recording, stimulation and signal processing. Failure of one of the components or connections stops the function of the whole system. We present an exemplary implant system and discuss state of the art materials and manufacturing techniques as well as prominent failure modes. Thin-film substrates and hybrid combinations with silicone rubber substrates serve as neural interfaces. Adhesion layers have been integrated to obtain long term stability of polyimide-platinum sandwiches. Metal electrodes without and with coatings of PEDOT and carbon-based materials have been used for neural recording and stimulation as well as for neurotransmitter monitoring. Reliability data from chronic experiments show the applicability of thin-film implants for stimulation and recording. However, system assembly and interfacing microsystems to robust cables and connectors still is a major challenge in translational research and transition of research results into medical products.
Acknowledgement:
Part of this work was funded by the cluster of excellence BrainLinks-BrainTools (DFG, EXC 1086), and the European Union ("TIME", FP 7, CP-FP-INFSO 224012, “EPIONE”, FP7, FP7-HEALTH-2013-INNOVATIO-1602547, “NEBIAS”, FP7, CP-FP-INFSO 318478).
11:30 AM - *SM3.3.05
Communication with Neurons—New Materials and New Dimensions
Gordon Wallace 1 , David Officer 1
1 ARC Centre of Excellence for Electromaterials Science, Intelligent Polymer Research Institute, AIIM Facility, Innovation Campus, University of Wollongong, Wollongong, New South Wales, Australia
Show AbstractElectrical communication with neuronal systems enables us to both monitor and modulate function.
In recent years the materials inventory available for such purposes has expanded dramatically.
In particular, organic conductors have been shown to bring some unique attributes to this venture. Here we will use examples wherein either graphene or organic conducting polymers are used to stimulate and/or record activity from neuronal systems. The ability to influence stem cell development into neurons using these organic conductors will also be illustrated. Another intriguing finding is that organic conducting polymer platforms may inherently facilitate communications between neurons.
Neural systems are, of course, three dimensional so here we will also explore the ability to create interconnected 3D structures containing neurons using 3D bioprinting.
We will explore our most recent advances in recording from and/or stimulating such structures.
Key References
Sherrell, P.C., Thompson, B.C., Wassei, J.K., Gelmi, A.A., Higgins, M.J., Kaner, R.B., Wallace, G.G. “Maintaining Cytocompatibility of Biopolymers Through a Graphene Layer for Electrical Stimulation of Nerve Cells” Advanced Functional Materials 2014, 24, 769-776.
Thompson, B.C., Murray, E., Wallace, G.G. “Graphite Oxide to Graphene. Biomaterials to Bionics” Advanced Materials 2015, 27, 7563-7582.
Lozano, R., Stevens, L., Thompson, B.C., Gilmore, K.J., Gorkin, R., Stewart, E.M., in het Panhuis, M., Romero-Ortega, M., Wallace, G.G. “Brain on a bench top Cortical neurons within a 3D printed structure” Materials Today 2016, 19 (2), 124-125.
Gu, Q., Tomaskovic-Crook, E., Lozano, R., Chen, Y., Kapsa, R.M., Zhou, Q., Wallace, G.G., Crook, J.M. “Functional 3D Neural Mini-Tissues from Printed Gel-Based Bioink and Human Neural Stem Cells” Advanced Healthcare Materials 2016, 5, 1429-1438.
Stewart, E.M., Wu, Z., Huang, X.F., Kapsa, R.M.I., Wallace, G.G. “Use of conducting polymers to facilitate neurite branching in schizophrenia-related neuronal development” Biomaterials Science 2016 4, 1244-1251.
12:00 PM - SM3.3.06
Fabrication of 3D Neural Probes Using Photolithography in Fibers
Andres Canales 1 , Marc-Joseph Antonini 1 , Gregory Ellson 2 , Yoel Fink 1 , Polina Anikeeva 1
1 , Massachusetts Institute of Technology, Cambridge, Massachusetts, United States, 2 , University of Texas at Dallas, Dallas, Texas, United States
Show AbstractHigh-density mapping of neural circuits in vivo requires neural probes that address multiple brain signaling modalities along with their high spatial resolution and intricate geometry. Decreasing quality of the measured neural activity over time, caused by glial scarring and death of neurons surrounding the device, limits the utility of existing neural probes. One of the hypothesized causes for the probe failure is the mismatch of the mechanical properties between the neural probe and the surrounding tissue. We have applied thermal drawing process to produce flexible minimally invasive neural probes. This process, commonly used in the fabrication of optical fibers, permits straightforward integration of multiple materials into individual probes with arbitrary geometries, therefore allowing the incorporation of multiple functionalities into a single device. Using this method, we have fabricated flexible neural probes, as small as 80 μm in diameter with tens of 5 μm tin electrodes. These devices were used to chronically record isolated action potentials in the brain with an average signal-to-noise ratio of 13. The functional area of these devices, however, is limited to the tip of the fiber. In contrast, the brain is three-dimensional, and interaction between different layers in the brain defines many complex cognitive processes. In order to be able to interface with the brain across multiple depths simultaneously, we have developed a method that combines both thermal drawing and photolithographic processes in a scalable manner. Together these fabrication approaches enabled incorporation of functional features along the length of the probe.
12:15 PM - SM3.3.07
Coupling of Active and Passive 1D Nanostructure Devices to Record Neuronal Activity—From Extra to Intracellular Interfacing
Adrien Casanova 1 , Marie-Charline Blatche 1 , Fabrice Mathieu 1 , Aurelie Lecestre 1 , Laurent Mazenq 1 , Cecile Ferre 2 , Daniel Gonzalez-Dunia 2 , Liviu Nicu 1 , Guilhem Larrieu 1
1 , LAAS-CNRS, Université de Toulouse, CNRS, Toulouse France, 2 INSERM UMR 1043, CNRS UMR 5282, Université Toulouse, Toulouse France
Show AbstractDue to constant aging of world population, the struggle against neurodegenerative diseases is one of the major challenges in the near future and a better understanding of these pathologies goes through an improvement of basic mechanism knowledge involved in neuronal networks. In that scope, miniaturization of electronic components opens new perspectives for addressing such issues and holds great promise to improve the resolution levels. 1D-nanostructures such as NW-FET [1] or NW probes [2], offer real benefits thanks to their very small sections allowing to be less intrusive combined with their high surface-to-volume ratio leading to a higher affinity with cells.
Here, we propose to co-integrate passive and active devices based on 1D nanostructures on the same platform (vertical NW probes and NW-FETs), to accurately compare advantages and drawbacks of each configuration regarding neuron electrical activity measurement. The two nanowire devices are fabricated with a large scale and cost effective top-down approach combining conventional lithography tools, plasma etching and sacrificial oxidation step to tune the nanostructure geometry. A core-shell-type device has been developed with a conductive part at the center, encapsulated by a conformal silicon oxide to insulate the probing nanostructures from liquid. In parallel, silicon NW-FETs are created with a planar NW channel (50 nm) connected by two highly doped low resistive regions. The device operation has been characterized in liquid environment (interface impedance of passive probes and pH sensing for transistors).
Primary rat cortical neuronal cultures have been grown in-vitro with an unprecedented surface functionalization approach to precisely locate single neurons and guide the growth of their extensions. The approach allows the perfect location of somas on devices and the control of neurite growth at sub-micrometer scale. After 10 days in-vitro, we detected for the first time spontaneous mammalian neuron action potentials using passive vertical nanowire probes. Thereafter, several kinds of stimulation protocols have been implemented: (i) at the network level, with chemical stimulations such as KCl depolarization to mimic epileptic synchronization or with more refined stimulation (bicuculline). Local field potentials from few somas and action potentials from single neurons have been successfully recorded with a maximal signal-to-noise ratio of 10 for transistors compared to 40 for passive probes. (ii) At the cell level, where bi-directionality of passive probes have been used to locally trigger neuronal activity under electrical stimulation. Finally, multi-site recordings with vertical probes have been used to compare extra and intracellular probing action potentials of single soma. We will discuss and compare all these results from electrical and technical point of view.
[1] F. Patolsky & al., Science, 313, p 1100 – 1104, (2006).
[2] J. T. Robinson & al, Nature Nano, 7, 180–184, (2012).
12:30 PM - *SM3.3.08
Nano-Fractal Platinum-Iridium Bioelectrodes
James Weiland 1 , John Whalen 2 , Artin Petrossians 1
1 , University of Southern California, Los Angeles, New York, United States, 2 , Platinum Group Coatings, Pasadena, California, United States
Show AbstractNeurological implantable medical devices such as retinal prostheses, deep brain stimulators, spinal cord stimulators and cochlear implants communicate with the brain via microelectrodes by transferring electrical signals to targeted nerve cells. For many current and future neuromodulation devices, smaller electrode size is desired because it allows more precise communication with smaller cell populations thus enabling higher stimulation/recording resolution. Additionally, smaller electrodes enable smaller, less invasive device designs. A major challenge to further decreasing microelectrodes size is increased electrical charge density injection. The electrical and electrochemical properties of the electrode/tissue interface material play major roles in overcoming the charge injection issue.
Previously we have reported on a novel electrochemically deposited 60:40% platinum-iridium (PtIr) electrode material that has improved qualities, namely lower impedance, greater charge injection capacity, and mechanical stability. Here, we provide details of long-term pulse testing done to demonstrate the chronic stability of the material.
We used commercial deep brain stimulation electrodes and pulse generators provided by Medtronic. Electrochemical measurements were taken before PtIr deposition, after PtIr deposition and before continuous pulsing, and after 13 weeks of continuous pulsing. The measurements include cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and electrode current transients during voltage pulsing (pulse). In addition, EIS was measured weekly during pulse testing. All measurements were made in a model of interstitial fluid. Charge/phase was calculated by integrating the current in the leading phase of a biphasic pulse. Implantable pulse generators (Activa RC, Medtronic Inc. USA) were used to apply pulses. Voltage pulses of 2V, 90 us, and 5V for 150 us were applied at 100 Hz, on 8 electrodes for each voltage. All pulsing experiments were performed in a two-electrode configuration. Platinum wire in solution was used as return electrodes in these measurements. The platinum wire was connected to the pulse generator case to complete the circuit. Electrodeposition of PtIr significantly decreased impedance and increased charge storage as measured by EIS and CV, respectively. EIS showed a decrease of two orders of magnitude at 10 Hz. The average charge per pulse across all electrodes increased by 56% (p < 0.0001) for a 2V, 90 us pulse. After 13 weeks of pulsing, the average charge per pulse was still 46% greater vs. control (p < 0.0001). The decrease in charge per pulse comparing before and after pulsing was 6.8% (p = 0.017). In summary, electrodeposited PtIr maintains superior electrical properties after 13 weeks of continuous pulsing in vitro.
SM3.4: Neural Interfaces II
Session Chairs
Wednesday PM, April 19, 2017
PCC North, 100 Level, Room 121 C
3:00 PM - SM3.4.01
From Soft and Stretchable Conductive Materials to a Fully Functional Neuromodulation Device
Mattia Marelli 1 , Alessandro Antonini 1 , Marta Ferri 1 , Cristian Ghisleri 1 , Ilaria Pietta 1 , Laura Spreafico 1 , Luca Ravagnan 1 , Sandro Ferrari 1
1 , WISE, Milan Italy
Show AbstractSoft conductive materials give significant advantages when realizing neuro-electronic interfaces. They are able to comply and closely adhere to involved neural tissues shapes, reduce the possibility of soft tissue damages during movements, and decrease mechanical stress at the tissue-biomaterial interface. Beside a stable neuro-biomaterial interface it is also crucial to provide a stable biomaterial-electronic device connection, in order to effectively convey electrical signals to and from the neural tissue. This is a challenging task towards the fabrication of a complete medical device, due to the mechanical mismatch between soft biomaterials and hard metallic electronic devices. As further technological constraints, all of the fabrication processes have to be industrializable and scalable, the materials must satisfy defined biocompatibility standards, and the outcoming device needs to be compliant with a regulatory environment which is becoming more and more demanding. This variety of boundary conditions should be taken into account and faced by the applied research on biomedical materials.
In this work we are presenting a route that brought a soft metal-rubber nanocomposite material to the maturity of a functional neuromodulation device, meeting the most demanding requirements due to the use in a surgical setting for the cure of neuropathic disorders. The pivotal features of this device are based on the electromechanical properties of the metal-silicone nanocomposite material made by Supersonic Cluster Beam Implantation (SCBI). On one hand, the thin silicone rubber matrix allows the device to closely adapt and comply to the complex shape of brain sulci, stabilizing and improving the electrical coupling with neural tissues. On the other hand, a high charge density can be reached thanks to the high surface area of the nanostructured metallic filler. This allows to exploit non-faradic charge transfer, increasing the electrodes life in stimulation and decreasing their impedance in a range of physiologically meaningful frequencies (less than 200 Ω between 10-103 Hz; stable electrochemical behaviour in stimulation for 75+ M pulses, corresponding to 3+ months in a typical intraoperatorial use).
The device is then completed with highly stretchable leads (sheet resistances Rs < 1 Ω/sq at rest and Rs < 12 Ω/sq at 20% strain) and with an electrical interconnection between the soft conductive material and state of the art medical cables, compatible with the existing clinical recorders and stimulators.
We demonstrate the usability of the device in preclinical testing and its biocompatibility. The latter was achieved by design – carefully selecting materials and fabrication processes of each single component – and subsequently proved according to the most strict regulation requirements for FDA and CE approval.
3:15 PM - SM3.4.02
Investigation of Glassy Carbon Microelectrode Arrays for Multi-Analyte Biosensing Applications
Maria Vomero 1 3 , Danesh Ashouri 1 4 , Calogero Gueli 1 , Sam Kassegne 2 3 , Thomas Stieglitz 1 4
1 IMTEK-BMT, University of Freiburg, Freiburg Germany, 3 , Center for Sensorimotor Neural Engineering, Seattle, Washington, United States, 4 , Exzellenzcluster BrainLinks-BrainTools, Freiburg Germany, 2 Mechanical Engineering, San Diego State University, San Diego, California, United States
Show AbstractCarbon-based materials have lately become of particular interest for manufacturing neural electrodes with biosensing capabilities. Among all, carbon fiber (CF) are known to have high sensitivity and selectivity for neurotransmitters detection, but their low stability and fidelity do not allow them to be considered the best candidates for chronic applications. On the other hand, recent studies have proved glassy carbon (GC) to be a great electrode material, due to its electrochemical stability, biocompatibility, large safe potential window and its tunable mechanical and electrical properties. In addition, using ordinary lithographical process, GC electrodes can be fabricated in a wide range of geometries. In this study we evaluate the biosensing capabilities of GC microelectrode arrays (MEAs) on a Polyimide (PI) substrate for neural applications. Such devices combine the ability to electrophysiologically record and stimulate from the cerebral cortex and the intracortical layers. Additionally, the electrochemical characteristics of GC make these MEAs potential candidates for multi-analyte biosensing applications, e.g. selective dopamine and serotonin detection. The fully flexible PI substrate also has the potential of reducing the tissue reaction to the neural implant, which translates into the increase of its life span. To discuss the capability of the novel devices to monitor neurochemicals, a comparison study is conducted using GC and CF microelectrodes. Fast-scan cyclic voltammetry (FSCV) is used to characterize both CF and GC and provided an evaluation of their sensitivity and selectivity towards various neurotransmitters with varying concentrations. The results show that the fabricated GC electrodes are sensitive to changes of analyte concentration during in-vitro experiments in PBS, and the correlation between analyte concentration and monitored oxidation current is found linear. This ability to simultaneously detect a variety of neurotransmitters and analytes in-vivo as part of a BCI (brain-computer interface) platform has significant implications in furthering our understanding of the correlation between neurotransmitters and electrical signal transduction in neurons along with the associated neural events.
We would like to acknowledge CSNE and BLBT for supporting this research.
4:30 PM - SM3.4.03
Integration of Microfluidic Channels for Hybrid Drug-Delivery Mechanism in Mechanically-Adaptive Neural Probes
Allison Hess-Dunning 1 2 , Joseph Lerchbacker 1 2
1 Rehabilitation Research and Development, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States, 2 , Advanced Platform Technology Center, Cleveland, Ohio, United States
Show AbstractLocalized pharmacological intervention through bio-active and drug-eluting coatings or microfluidic channels integrated into neural probes can significantly inhibit problematic tissue responses to the implant, promote bio-integration, or provide therapeutic benefit to combat disease or injury. Compared to systemic delivery strategies, local drug delivery strategies reduce drug requirements, affect a very limited tissue volume, are not required to cross the blood-brain barrier, and provide immediate benefit. Unfortunately, drug-eluting coatings tend to provide only a short-term benefit as they become completely depleted after only a few days or weeks. In this work, we developed a device that uses integrated microfluidic channels to re-load a polymer-based, drug-eluting neural probe.
A bio-inspired, mechanically-dynamic polymer nanocomposite (NC) is rigid (E = 5 GPa) when dry, then dramatically softens (E = 10 MPa) after becoming water-saturated and heated above its glass transition temperature (Tg ~ 20°C) when implanted into tissue. In previous work, it was shown that by reducing mechanical mismatch between the implant and brain tissue (E ~ 10 kPa), the biological response evoked by NC-based is attenuated. We also previously developed a microfabrication process for NC-based intracortical microelectrode arrays. Molecules loaded into the moisture-absorbent NC matrix can be released by diffusion into tissue after implantation. By integrating microfluidic channels into the NC structure, the NC film can be replenished with pharmacological agents.
Microfluidic channels were integrated into the NC substrate by first laser-etching 40 μm-wide channels into a NC film to a depth of 20 μm. Separately, a cover layer with inlet holes was laser-micromachined into a second NC film. The two films were then plasticized by immersion in DI water, then the cover layer was aligned to the channel layer and set in place. The stack was then heated to 50°C on a hotplate until a bond was formed between the two layers and the channels were sealed. The duration of the bond process was determined with the aid of uv-vis reflection spectra. After bonding, the outer geometry of the probes was laser-micromachined.
Diffusion-based transport rates were measured for an aqueous dye in water-saturated test samples. Optical microscope images were recorded every 2 seconds under constant lighting conditions. Image analysis was performed used a custom MATLAB script to determine the lateral speed of the diffusion front through the NC film, as well as the saturation point. At 60 seconds after filling the microfluidic channel, the dye had diffused 220 μm laterally from the channel. As a proof of concept, dye-loaded NC probes placed into 1.0% agarose gel demonstrated that dye diffuses from the channel through the NC probe and into the gel. This strategy can later be integrated with microelectrode arrays for a multi-functional implant.
4:45 PM - SM3.4.04
Removal of Targeted Pathway on Blood-Derived Immune Cells Improves Intracortical Recordings
Hillary Bedell 1 , Shushen Lin 1 , Ashley Rein 1 , Xujia Li 1 , Emily Molinich 1 , Jeffrey Capadona 1
1 , Case Western Reserve University, Cleveland, Ohio, United States
Show AbstractAction potentials from individual neurons can be recorded from intracortical microelectrodes affording these devices much potential in basic research and rehabilitation applications. Unfortunately, the quality of the neural signal decreases over time. Neuroinflammatory mechanisms play a major role in intracortical microelectrode failure. Two of the biological pathways that contribute to the failure of these devices are the breakdown of the blood brain barrier with subsequent myeloid cell infiltration and the Cluster of Differentiation 14 (CD14) pathway. CD14 is a key co receptor involved in the recognition of extravasated serum proteins and cellular damage in the brain resulting from intracortical microelectrode implantation. This work aims to delineate the role of the CD14 pathway on infiltrating macrophages versus resident microglia.
Bone marrow chimera mice were used to selectively inhibit CD14 from either resident microglia or infiltrating myeloid cells. Intracortical microelectrodes were implanted into wild type (WT) C57/BL6, CD14 knock out mice (Cd14-/-), and bone marrow chimera mice (Cd14-/-+ WT bone marrow and WT + Cd14-/-bone marrow). To evaluate the long-term stability of intracortical microelectrode performance, Cd14-/-, bone marrow chimera mice (Cd14-/- + WT bone marrow and WT + Cd14-/-bone marrow) and WT control mice were implanted with functional intracortical Michigan style microelectrodes in the forelimb-associated motor cortex. Electrophysiological recordings were obtained twice a week to assess function of the electrode. The percent of channels of the electrode that are recording single units and number of single units per channel were tracked over time for 16 weeks post implant as metrics of recording quality. Sixteen weeks post implantation, microglia/macrophage activation, astrocytic encapsulation, blood-brain barrier disruption, and neuronal dieback was assessed via immunohistochemistry
Up to 10 weeks, the four conditions demonstrated comparable percent of channels recording single units for a given day. However, about 10 weeks after implant, the percent of channels recording single units for WT mice significantly decreases compared to Cd14-/- and the two chimeric conditions. Interestingly, the percent of channels recording single units does not significantly decrease over time for the WT + Cd14-/-BM mice. Results will also be reported for the 16 week post implantation immunohistochemistry data detailing microglia/macrophage activation, astrocytic encapsulation, blood-brain barrier disruption, and neuronal dieback.
Our study identifies a clear link between specific inflammatory/immunity pathways and the long-term performance of intracortical microelectrodes. Further, our results suggest that systemic administration of therapeutic agents to inhibit the CD14 receptor-mediated pathway from blood-derived cells can be sufficient to improve chronic intracortical electrode performance.
5:00 PM - *SM3.4.05
Overview of NIH-Funded Material and Device Advances as well as Future Opportunities in Neural Interfaces
Nick Langhals 1
1 , National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, United States
Show AbstractNick B. Langhals, Ph.D. serves as the Program Director for Neural Engineering within the Repair and Plasticity Cluster at the National Institute of Neurological Disorders and Stroke (NINDS), where he manages a portfolio of grants focused on the development and translations of neurotechnologies. He is heavily involved in the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative teams focused on both implantable and non-invasive technologies for recording and modulating neural activity. He also serves as the NINDS lead for the Bioengineering Research and Stimulating Peripheral Activity to Relieve Conditions (SPARC) programs at NIH. Within this talk, he will discuss many of the recent advances in neural interface materials, devices, electronics, and instrumentation that have been developed through NIH funding in many of these areas. Further, he will also discuss a vision for future opportunities in research and development in these areas and where the materials research community could play an active role.
5:30 PM - SM3.4.06
MEASSuRE—A Novel Tool to Mechanically Stretch and Record Electrophysiological Activity and Image Cells, all at the Same Time
Oliver Graudejus 1 2 , Ruben Ponce Wong 2 , Sonali Ahuja 3 , Adam Pak 1 , Sigurd Wagner 4 , Barclay Morrison 3
1 , Arizona State University, Phoenix, Arizona, United States, 2 , BMSEED LLC, Phoenix, Arizona, United States, 3 Biomedical Engineering, Columbia University, New York, New York, United States, 4 Electrical Engineering, Princeton University, Princeton, New Jersey, United States
Show AbstractCells in the body are constantly subject to mechanical forces, with yet poorly understood effects on cell division, gene expression, cell migration, morphogenesis, and ion channel gating. We are developing a commercial tool (MicroElectrode Array Stretching Stimulating und Recording Equipment; MEASSuRE) that provides the capabilities for fundamentally understanding mechanically-induced cellular processes. MEASSuRE mechanically stretches living cells in vitro, while at the same time recording or stimulating electrophysiological activity, and imaging the cells at high frame rate. Existing commercial technologies only allow either the recording of neural activity or the mechanical stretching of a tissue or cell culture, but not both. MEASSuRE can be employed in the development of improved organ systems (organ-on-a-chip) for drug toxicity testing. Another group of applications is the rapid screening of the efficacy of drugs and other treatment strategies on the injury progression in traumatic brain injury, and of other diseases with a similar neuropathology such as Alzheimers Disease. The core technology of MEASSuRE is a stretchable microelectrode array (sMEA) which interfaces with the cell or tissue culture in a growth well at its center, and connects to a data acquisition system at its perimeter. The microelectrodes on the sMEA consist of a gold film, which is made elastically stretchable by deposition on a biocompatible elastomeric substrate. We will report the impedance vs. strain behavior of elastic gold electrodes for (i) linear stretching to strains exceeding 100%, and (ii) radial stretching over up to 100,000 cycles, radial strains of up to 50%, and strain rates of up to 5s-1. We will also show that sMEAs produced with a commercially viable process are capable to record and stimulate electrophysiological activity from hippocampal tissue slice before and after stretching.
Symposium Organizers
Mohammad Reza Abidian, University of Houston
Stephanie Lacour, Ecole Polytechnique Federale de Lausanne, Switzerland
Kip Ludwig, Mayo Clinic
Laura Poole-Warren, University of New South Wales
SM3.5: Neural Interfaces III
Session Chairs
Mohammad Reza Abidian
Laura Poole-Warren
Thursday AM, April 20, 2017
PCC North, 100 Level, Room 121 C
10:00 AM - *SM3.5.01
Molecular Design, Synthesis, Microstructure, Mechanics, and Transport Behavior of Functionalized Conjugated Polymers for Biomedical Devices
David Martin 1 , Vivek Subramanian 1 , Liangqi Ouyang 2 , Jinglin Liu 1 , Bin Wei 1 , Jing Qu 1 , Chin-Chen Kuo 1 , Dimitrios Koutsouras 3 , George Malliaras 3
1 , University of Delaware, Newark, Delaware, United States, 2 , Linkopping University, Linkopping Sweden, 3 Bioelectronics, Ecole des Mines de Saint Etienne, Gardanne France
Show AbstractWe are continuing to examine the design, electrochemical synthesis, mechanical properties, and charge transport behavior of functionalized conjugated polymers intended for the long-term interfacing of electronic biomedical devices with living tissue. These materials include derivatives of poly(3,4-ethylenedioxythiophene) (PEDOT) and poly(3,4-propylenedioxythiophene) (PProDOT). This talk will discuss recent results from our laboratory including multifunctional, crosslinkable thiophene comonomers and corresponding copolymers, in-situ methods for monitoring electrochemical polymerization in the TEM, novel methods for measuring polymer thin film mechanics and adhesion to solid substrates, and charge transport behavior on microfabricated devices with systematic variations in electrode size and shape.
10:30 AM - *SM3.5.02
Biomimetic Neural Implant Design towards Seamless Tissue Interface
Xinyan Cui 1
1 , University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Show AbstractNeural implants are placed in the nervous system to electrically interface with neurons or monitor neurochemicals as research tools or clinical diagnosis and treatment. These devices often experience failures in part due to the electrical, mechanical, and biochemical, mismatch between the artificial device and neural tissue. Several biomaterial strategies are being investigated minimize the mismatches and achieve seamless and stable device-tissue interface. First, various conducting polymer based nanocomposites have been investigated as electrode coatings and facilitate the signal transduction/charge transfer between ionically conductive tissue and electrical device. Secondly, to minimize the mechanical mismatch at the device-brain tissue interface, novel electrode materials are developed. An elastomeric electrically conductive polymer blend is synthesized based on a PEDOT copolymer and medical grade silicone. This conducting elastomer can be fabricated into soft electrodes with Young’s modulus approaching that of neural tissue (less than 1 MPa). Comprehensive host tissue response studies showed significantly reduced glial activation and BBB breach at 8 weeks and reduced cellular deformation around the soft implants in comparison to stiff implants of similar geometry and surface chemistry. The third strategy is to decorate the man-made implant surface with biomolecules derived from the brain or synthetic biomolecule mimics. Surface immobilization with these bioactive molecules significantly improved neuronal health and inhibited the inflammatory tissue response around the implants. Furthermore, therapeutics that control inflammation, neurodegeneration and oxidative stress, can be released directly from the implant surface to further modulate cell-material interaction. The ultimate solution to a reliable neural implants may be a combinatorial approach that takes advantage of multiple biomimetic strategies discussed above and beyond.
11:30 AM - SM3.5.03
All-in-One Fabrication Process of a Rigidified Flexible Neural Probe
Jolien Pas 1 , Marc Ferro 1 2 , George Malliaras 1
1 Bioelectronics, EMSE, Gardanne, Bouche-du-Rhone, France, 2 Materials Science and Engineering and of Photon Science, Stanford University, Stanford, California, United States
Show AbstractNeural depth probes are gaining scientific attention as tool to improve our understanding of the brain. Mechanical mismatch between conventional rigid probes and soft brain tissue causes chronic neuro-inflammation which prevents long-term, stable recordings. This could be circumvented by the use of softer and more flexible materials. However, these novel designed flexible probes lack the necessary stiffness for insertion into the brain.
A mechanical support can help to insert the flexible probes. Bioresorbable polymers are promising candidates to provide stiffness for insertion and have the advantage of being degraded and resorbed once the probe is in longer contact with cerebrospinal fluid. Promising polymer candidates are poly-vinyl pyrrolidone, polyvinyl alcohol and poly(lactic-co-glycolic acid). The challenge is to integrate such bioresorbable polymers on neural probes with an efficient and high-resolution fabrication process.
Here, we show an all-in-one fabrication process of parylene-based PEDOT:PSS neural probes [1] with a bioresorbable polymer support patterned using orthogonal photolithography. We focus on the strategy to integrate a custom-made bioresorbable polymer layer as shuttle for these probes and discuss the biocompatibility and electrophysiology recordings of the flexible neural probe in an animal model. In short, parylene with embedded electronics is manufactured on a substrate wafer using standard photolithography and lift-off. A layer of bioresorbable polymer is then spin-coated or screen-printed at a desired thickness on top of the wafer. The shape of the neural probe is patterned on top of the sample using Orthogonal Inc. photoresist and transferred to the bioresorbable layer through dry-etching. Finally, the remaining photoresist is removed using a hydrofluoroether (HFE) solution, known as a water-immiscible fluorinated solvent[2]. We find that the bioresorbable polymer coating is not affected by the HFE solvent and that the thickness of the polymer is easily adapted to create probes with various stifnesses.
To conclude, we have developed a fabrication process for innovative neural probes by combining traditional photolithography with orthogonal patterning of bioresorbable polymers. Most importantly, the procedure is done in an efficient all-in-one fabrication process and any of the above mentioned bioresorbable polymers can be used to rigidify flexible probes. All together, this is a step towards achieving the ultimate aim of fabricating neural depth probes for long-term recording.
References:
1. Williamson, A., et al., Localized Neuron Stimulation with Organic Electrochemical Transistors on Delaminating Depth Probes. Adv Mater, 2015.
2. Zakhidov, A.A., et al., Hydrofluoroethers as Orthogonal Solvents for the Chemical Processing of Organic Electronic Materials. Advanced Materials, 2008. 20(18): p. 3481-3484.
11:45 AM - SM3.5.04
Conducting Polymer Nanotubes for Axonal Guidance
Milad Khorrami 1 , Mohammad Reza Abidian 1
1 , University of Houston, Houston, Texas, United States
Show AbstractAxonal guidance is vital for wiring of the nervous system. Despite the significant research progress on axonal regeneration, functional regeneration of axons remains a challenge due to complex post-injury environment that may prevents the functional recovery. In this study, conducting polymer (CP) nanotubes have been utilized for (1) promoting axonal outgrowth using topographic contact guidance and (2) enhancing the neural recoding signal-to-noise ratio via reduction of electrode impedance.
The fabrication process of aligned CP nanotubes includes electrospinning of poly(L-lactic acid) (PLLA) and benzyltriethylammonium chloride (BTEAC) on 1.5mm diameter gold substrates attached to a rotating wheel (i.e. 1000 rpm). The PLLA aligned fibers was then coated using electrochemical polymerization of 0.2M pyrrole (Py) and 0.02M 3,4-ethylenedioxythiophene (EDOT) with 0.2M polysyrinsulfunate (PSS) in various deposition time (i.e. 1min to 4min). The CPs-coated PLLA nanofibers were dissolved in chloroform to form the nanotubes.
The size of aligned CP nanotubes was characterized by scanning electron microscopy (i.e. 700±100nm). Impedance Spectroscopy revealed that the impedance of bare gold decreased from 282.1±19.7Ω to 58±3.4Ω at 1 kHz, (~79%) and from 282.1±19.7Ω to 41.9±1.5Ω at 1 kHz, (~85%) for PEDOT nanotubes and PPy nanotubes, respectively. In addition, cyclic voltammetry (CV) showed that charge storage capacity significantly increased from 0.32±0.03mC/cm2 to 16.3±1.5mC/cm2 and from 0.32±0.03mC/cm2 to 4.86±0.24mC/cm2 for PPy nanotubes and PEDOT nanotubes, respectively. We have cultured PC12 cells and dorsal root ganglions on PEDOT and PPy nanotube substrates. We will assess the directionality of neurite outgrowth and cellular elongation using confocal microscopy and will compare with PEDOT and PPy film counterparts. In the future, we will employ gradients of physical and chemical gradient cues to grow axons cell at certain direction.
12:00 PM - SM3.5.05
Conducting Polymers for Axonal Regeneration—Effect of Surface Topography on Neurite Outgrowth
Martin Antensteiner 1 , Mohammad Reza Abidian 1
1 , University of Houston, Houston, Texas, United States
Show AbstractNerve injuries in the peripheral nervous system caused by trauma (i.e. nerve lesions) or debilitating disorders (i.e. Parkinson’s disease) have affected more than 20 million people and are estimated to account for 2.8% of all trauma cases in the United States. Autografts are the clinical gold standard for the treatment of nerve gaps, the disadvantages of which include a limited supply of donor nerve, making it impossible to reconstruct complex nerve gaps, sensory deficits in the distribution of the donor nerve, painful dysesthesias following sensory nerve harvest, and structural/ultrastructural nerve mismatch. To overcome these limitations, artificial conduits have been widely investigated to bridge nerve gaps. However, the functional recovery after nerve injury remains a challenge. Biocompatible Conducting Polymers (CP) can be utilized to guide neurons and eventually repair nerve injuries such as nerve gaps due to their unique, electrical, physical, and chemical properties. Several works have shown that aligned CP structures could improve dendrite outgrowth. However, few works have focused on the effect CP roughness on axonal regeneration. In this work, we have investigated two common CPs, poly(pyrrole) (PPy) and poly(3,4-ethylenedioxythiophene) (PEDOT), fabricated using galvanostatic (GSTAT) and potentiostatic (PSTAT) methods to quantify the surface roughness of these two polymers. PPy is well-known for its excellent biocompatibility, electrical conductivity, and physical stability. PEDOT displays superior chemical stability and electrical conductivity, making it an ideal candidate long term artificial conduits. Aligned poly(lactic acid) (PLA) electrosprayed nanofibers have served as templates for subsequent electrodeposition of PPy and PEDOT on Au electrodes. The electrodeposition was performed from a solution containing EDOT or Py monomers and poly(styrene-sulfonate) in GSTAT mode (i.e. current density from 0.1 to 1.5 mA/cm2), and PSTAT mode (i.e. voltage from 0.5 to 0.95V) over set intervals from 1-10min deposition time. Each sample has been analyzed using scanning electron microscopy (SEM) and atomic force microscopy (AFM) to assess the surface roughness. Dorsal root ganglia (DRG) will be cultured on the aligned CP nanofibers and examined using confocal microscopy. Preliminary data suggests a dual dependence of roughness on both time and current density (3.5nm at 1min, 0.1mA/cm2 to 26.1nm at 10min, 1.5mA/cm2). PPy films formed via PSTAT show much steeper increases in roughness (2.41nm at 1min, 0.5V to 25.7nm at 10min, 0.7V). The knowledge gained here will (1) improve understanding of surface cues on the outgrowth of regenerating axons, (2) increase control over CP films formed via electrodeposition.
12:15 PM - SM3.5.06
Implantable OECT-Based Metabolic Sensors for In Vivo Prediction of Seizure Onset
Mary Donahue 1 , Xenofon Strakosas 1 , Adam Williamson 2 , Marcel Braendlein 1 , Christophe Bernard 2 , George Malliaras 1
1 , ENS Mines-St. Etienne, Gardanne France, 2 Inserm, Aix Marseille University, Marseille France
Show AbstractIn epilepsy, the reasons governing the evolution of a patient’s brain state from healthy to pathological are unclear. However, seizures are fundamentally electrophysiological events and such events require brain-energy resources to begin and to be maintained. Therefore, it is our belief that the change in specific brain-energy substrates could be identified as an effective biomarker to identify seizure onset. The two primary energy-substrates in the brain, specifically glucose and lactate, are identified here as excellent candidates for biomarkers signaling seizure onset.
Transistors-based enzymatic sensor fabrication is combined here on our previously published flexible, non-invasive polymer probes, allowing high-resolution in vivo measurements. The conductive polymer utilized in this technology is PEDOT:PSS {poly(3,4-ethylenedioxythiophene) doped with poly(styrenesulfonate)} providing the basis for our organic electrochemical transistors (OECTs). The gates of these devices are then functionalized by a stable covalent enzyme immobilization process, creating enzymatic sensors for in vivo implant.
This design allows us to sense the biomarkers of interest, glucose and lactate, and at the same time exploit the amplification properties of the OECT, namely much larger currents and increased SNR in comparison to standard electrodes. We then correlate the consumption of glucose and the production of lactate during in vivo seizure onset.
Very clear changes in the slope of lactate increase can be seen preceding the onset of ictal (large seizure) events. This identified change occurring prior to the beginning of the pathological activity could potentially be used to for therapeutic local drug delivery to prevent epileptic seizure.
Additionally, in order to simultaneously monitor the levels of both glucose and lactate, cross-talk via H2O2 production between closely located sensors must be minimized. This has been done by the addition of a second enzyme layer using an ‘enzyme stacking’ process. In vivo use considerably profits from this addition as we additionally demonstrate that H2O2 changes firing patterns by disrupting ATP production in mitochondria.
SM3.6: Neural Interfaces IV
Session Chairs
Thursday PM, April 20, 2017
PCC North, 100 Level, Room 121 C
2:30 PM - *SM3.6.01
Nanofiber-Based Conduits with a Honeycomb Structure for Peripheral Nerve Repair
Younan Xia 1
1 , Georgia Institute of Technology, Atlanta, Georgia, United States
Show AbstractThere is an urgent need to develop conduits for the surgical repair of transected peripheral nerves by restoring their continuity and functions. I will discuss a novel class of nanofiber-based, multi-tubular nerve guidance conduits with a honeycomb structure to closely mimic the anatomy of a thick nerve and thus greatly facilitate its functional recovery. The conduit is constructed by inserting a hexagonal array of seven small, single-tubular conduits into a large conduit. Each individual conduit is fabricated from a tri-layer structure, with the top and bottom layers containing uniaxially aligned and random nanofibers, respectively. A phase-change material (PCM) sensitive to temperature change is applied as a thin, porous layer to glue together the two layers of nanofibers. The PCM can be pre-loaded with Chondroitinase ABC (ChABC) and neurotrophin-3 (NT-3) for controlled release to digest the inhibitory chondroitin sulfate proteoglycan (CSPG) and promote neurite extension, respectively. The inner surface of the conduit can also be seeded with Schwann cells derived from autologous bone mesenchymal stem cells (BMSCs) to support neurite outgrowth. The ultimate goal is to apply this novel class of NGCs to clinics for the successful repair of large gaps in thick nerves.
3:00 PM - SM3.6.02
Conductive Elastomeric Electrodes for Interfacing with Peripheral Nervous System
Kevin Woeppel 1 2 , Sally Zheng 1 , Brady Clapsaddle 3 , Michael Looker 3 , Emily Chang 3 , Xinyan Cui 1 2
1 Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States, 2 Center for Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States, 3 , TDA Research, Inc., Golden, Colorado, United States
Show AbstractChronically implanted neural electrodes fabricated from traditional materials such as tungsten, steel, and silicon trigger a high degree of inflammatory response that often leads to fibrous encapsulation of the device, formation of scar tissue, degeneration of neurons, and ultimate failure of the device. This inflammatory response is believed to be caused in part by the high degree of mechanical mismatch between the electrode and the nervous system tissue, with the Young’s modulus of the traditional electrode material (GPa) being multiple orders of magnitude greater than the surrounding tissue (kPa). In a previous attempt to resolve this mechanical mismatch, we have developed soft neural probes fabricated from a blend of conducting and elastomeric polymers (elongation 60-100%) with young’s modulus approaching that of neural tissue (200-1000 kPa). These probes demonstrated recording viability by recording single unit action potentials in vivo in the rodent visual cortex.
In this work, by changing the geometry of the electrode and modifying the material, we focused on developing electrodes to interface with peripheral nerves. To further improve the mechanical and electrical properties, new electrodes have been created by incorporating multiwall carbon nanotubes (CNT) into the polymer matrix. The addition of CNT has resulted in lower impedance of the soft electrode and better mechanical durability. In vitro toxicity data from direct contact and elution assays showed excellent biocompatibility, while preliminary in vivo studies demonstrated electrical stimulation via the new electrodes to successfully induce muscle contraction in the rat gastrocnemius. Taken together, these results show great promise for conducting elastomer based electrodes for peripheral interface applications.
3:15 PM - SM3.6.03
Hydrogel-Elastomer Hybrid Material with Tunable Mechanical Properties for Intracortical Probe
Jennifer Macron 1 , Aaron Lee 1 , Stephanie Lacour 1
1 , Bertarelli Foundation Chair in Neuroprosthetic Technology, Laboratory for Soft Bioelectronic Interfaces, Centre for Neuroprosthetics, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne Switzerland
Show AbstractThe mechanical mismatch between soft and dynamic neural tissues and stiff and static neural implants is one of the limiting factors to long-term biointegration of implants. Their insertion into the brain triggers bidirectional interactions: man-made implants induce insertion-related trauma to the host biological tissues, acute and then chronic inflammation, gliosis and disruption of the blood–brain barrier. Conversely, the active and reactive biological medium affects the synthetic devices.
To tackle this issue, several groups investigate mechanically-adaptive probes that are initially stiff enough for implantation in the tissue (with moduli in the GPa range) and then soften after being exposed during few minutes to physiological conditions. Based on this concept, we investigate the use of hydrogel as a soft shell hydrophilic material that could fit better with the properties of neural tissues. In the presence of excess water, hydrogels swell to reach equilibrium, leading to a large increase of their volumes and changes in their mechanical properties (1-100 kPa range at swelling equilibrium). To avoid compression of surrounding tissues, we focus on a specific type of gel that has low swelling behavior (less than 10 wt%), thanks to a good balance between its hydrophilic and hydrophobic properties: the poly(hydroxyethyl methacrylate) (PHEMA), mainly known for its use as contact lenses.
We have created a covalently bonded shell of PHEMA around the poly(dimethylsiloxane) (PDMS) elastomer. The multi-stacking was performed following a spin-coating layer-by-layer process. The original step is the modification of the top surface of PDMS with reactive hydrophilic functions that would subsequently get involved during the polymerization of the hydrogel. We will present in more details the different steps of the microfabrication of the hybrid construct, the characterization of the chemical surface modifications and a preliminary study of the biocompatibility of the material. We will also discuss the dynamic modifications of the mechanical properties of the multilayer material from its initial dry state to its swollen state in physiological conditions.
Combined with soft electrode technologies, this gel-elastomer coating offers an exciting avenue for biointegrated intracortical probes.
4:00 PM - *SM3.6.04
Materials-Based, Biologically-Inspired, Anti-oxidative, Anti-Inflammatory Approaches to Enable Next-Generation Intracortical Microelectrodes
Jeffrey Capadona 1 2 , Andrew Shoffstall 2 1 , John Hermann 1 2 , Evon Ereifej 2 1
1 , Case Western Reserve University, Cleveland, Ohio, United States, 2 RR&D, Department of Veterans Affairs, Cleveland, Ohio, United States
Show AbstractOverview:
To ensure long-term consistent neural recordings, next-generation intracortical microelectrodes are being developed with an increased emphasis on reducing the neuro-inflammatory response. The increased emphasis stems from the improved understanding of the multifaceted role that inflammation may play in disrupting both biologic and non-biologic components of the overall neural interface circuit. To combat neuro-inflammation and improve recording quality, the field is actively progressing from traditional inorganic materials towards approaches that either minimizes the microelectrode footprint or that incorporate compliant materials, bioactive molecules, conducting polymers or nanomaterials. However, the immune-privileged cortical tissue introduces an added complexity compared to other biomedical applications that remains to be fully understood. The Capadona Lab utilizes basic science techniques to provide a more complete mechanistic understanding of the molecular and biological-mediated failure modes for intracortical microelectrodes. Their increased understanding provides the framework for the development of targeted materials-based and therapeutic attempts to impact intracortical microelectrode performance. From the onset, the Capadona lab focused on systematic evaluation of leading hypotheses of device compliance (stiffness), inflammatory-mediated oxidative damage to both devices and tissue, and innate immunity pathways associated with neurodegeneration. We have found that each mechanism provides independent and complementary input into the temporal response of the neural tissue to microelectrode implantation. Further, each pathway appears to dominate differentially at various stages of wound healing and chronic inflammation. This talk will provide an overview of the recent highlights and promising strategies to enable long-term clinical successes of intracortical microelectrodes.
Methods:
To assess the chronic neuroinflammatory response to microelectrodes, we utilize both mouse and rat models. Mouse models are used to develop bone marrow chimera and to employ transgenic models for innate immunity receptor contribution to the response. Animals are implant with either recording or non-functioning microelectrode. Intracortical recordings are performed on free moving rats and mice implanted in the primary motor cortex, while functional testing of both fine and gross motor function have been performed on rats. In all animals, post-mortem histology is used to assess the neuroinflammatory response while electron microscopy is used to assess device corrosion, post explantation.
4:30 PM - *SM3.6.05
Organic Mixed Conductors for Bioelectronic Applications
Jonathan Rivnay 1
1 Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, United States
Show AbstractDirect measurement and stimulation of electrophysiological activity is a staple of neural and cardiac health monitoring, diagnosis and/or therapy. Such bi-directional interfacing can be enhanced by the low impedance imparted by organic electronic materials that show mixed conduction properties (both electronic and ionic transport). Organic electrochemical transistors (OECTs) utilize such materials as the transistor channel, and have shown considerable promise as amplifying transducers due to their stability in aqueous conditions and high transconductance. These devices are fabricated in flexible, conformable form factors for in vivo recordings of epileptic activity, and for cutaneous EEG and ECG recordings in human subjects. The majority of high performance devices are based on conducting polymers such as poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS. By investigating PEDOT-based materials and devices, we are able to establish a set of design rules for new formulations/materials. Introducing glycolated side chains to carefully selected semiconducting polymer backbones has enabled a new class high performance bioelectronic materials that feature high volumetric capacitance, transconductance >10mS (device dimensions ca. 10um), and steep subthreshold switching characteristics. A sub-set of these materials outperform PEDOT:PSS and shows significant promise for biocompatible, low power in vitro and in vivo biosensing applications.
5:00 PM - SM3.6.06
Thermal Damage to the Blood-Brain Barrier during Craniotomy Procedure—Implications for Intracortical Recording Microelectrodes
Andrew Shoffstall 2 1 , Jennifer Paiz 1 , David Miller 1 , Mitchell Willis 1 , Griffin Rial 1 , Dhariyat Menendez 1 , Jeffrey Capadona 2 1
2 Advanced Platform Technology Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, United States, 1 Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States
Show AbstractIntracortical recording microelectrodes have tremendous potential for use in both research and medical applications. While the promise is great, widespread adoption is challenged by inconsistent device longevity and performance. Neuroinflammation, initiated by blood-brain barrier (BBB) damage from insertion and perpetuated by the foreign body response, is thought to play a key role in premature recording failure. Here, we report an observation that excessive heat from the implantation procedure may occur under certain conditions and acutely increase BBB permeability, even in the absence of dura penetration or microelectrode insertion. The implantation procedure relies on drilling a small hole through the skull to produce a craniotomy. While some groups take precautions to prevent tissue overheating, methods are inconsistently reported in the literature. Furthermore, it is unclear if reported techniques (e.g., irrigation with saline) are effective at prevention given they are applied superficially, while the most heat transfer takes place at the tip of the drill bit buried in the skull. From orthopedics literature, it is known that drill speed, contact time, feed rate, bit sharp/dullness, and bit size may all influence drilling heat. Our initial observation was that craniotomies that took longer (with continuous drill contact) yielded increased BBB permeability compared to those that were shorter or used pulsed non-continuous application of the drill. Using an infrared camera, we measured maximum bit temperatures and total time of drill application during typical continuous-contact craniotomy procedures at various drill speeds. Increases in bit temperature ranged from +3C to +21C. Time of drill application ranged from 15 seconds to 30 seconds. There was significant trial-to-trial variability in both temperature and time, suggesting that force, feed-rate, angle of application, and other variables inherent in by-hand drilling significantly influence the heating outcome. We recapitulated our findings with direct application of heat to the rat skull to verify that heat, and not other effects from the motorized drill (e.g., vibration), indeed caused the observed increase in BBB permeability. It should be noted that in the absence of Evans Blue dye, the BBB permeability marker used in this study, no overt damage to the brain or vasculature was visible. This study demonstrates the extreme sensitivity of blood-brain barrier permeability to overheating caused by bone drilling. Future work will determine whether the observed acute increase in BBB permeability influences the neuroinflammatory response. Regardless, to ensure that overheating does not impact damage brain tissue or impact BBB permeability, it is recommended that craniotomies be drilled with a pulsed on/off application, or alternatively that craniotomy shams be tested for BBB damage with the use of i.v. Evans Blue dye.
SM3.7: Poster Session: Neural Interfaces
Session Chairs
Mohammad Reza Abidian
Kip Ludwig
Friday AM, April 21, 2017
Sheraton, Third Level, Phoenix Ballroom
9:00 PM - SM3.7.01
Invasive Microscale Probe for Intracellular Measurements
Manjunath Rajagopal 1 , Sanjiv Sinha 1
1 Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States
Show AbstractNeurophysiological parameters like action potentials, synaptic transmissions, and intracellular dopamine concentrations are sensitive to small temperature changes [1]. The thermometry techniques required to analyze such small changes demand a measurement resolution better than 100 mK [2]. Compared to the commonly used non-invasive techniques for intracellular measurements [3], an invasive probe provides high accuracy temperature measurement [4]. In addition, it provides options for local heating, measurements of membrane potential and ion concentrations. Previous reports of invasive probes suggest that they were suitable only for extra-cellular measurements [5]. However, the probes reported here are about 500 μm long with 5 μm wide tips that make them possible to probe cell organelles within a neuron cell. The dimensions of the probe, the materials used, and the thermometry technique allow for a passive measurement with limited tissue damage, preserving the cell milieu. A microscale thermocouple probe is fabricated by forming a metal junction at the tip of an overhanging cantilever. Silicon nitride, a low thermal conductivity material with high stiffness, is used for the cantilever to withstand forces encountered during cell wall penetration. The sensitivity of the measurement based on the Seebeck coefficients is estimated to be around 10 μV/K, with a temperature resolution of about 20 mK. The probe cantilever, and it’s supporting substrate are fabricated to have a converging profile that enables direct measurements in cultured cells placed on a microscope bench. Preliminary measurements taken in invertebrate neuron cells are reported.
[1] Wang, Huan, et al. Frontiers in neuroscience 8 (2014): 307.
[2] Thrippleton, Michael J., et al. NMR in Biomedicine 27.2 (2014): 183-190.
[3] Tanimoto, Ryuichi, et al. Scientific reports 6 (2016): 22071.
[4] Majumdar, A. 1999. Annual Review of Materials Science 29 (1):505-85.
[5] Watanabe, M. S., et al. IEEE Engineering in Medicine and Biology 27th Annual Conference (2005): 4858-4861
9:00 PM - SM3.7.02
Highly Durable PEDOT-Based Medical Coatings for Recording and Stimulating Electrodes
Nandita Bhagwat 1 , Melanie Gupte 1 , Clayton Lepak 1 , Jeff Hendricks 1
1 , Biotectix, Richmond, California, United States
Show AbstractConducting polymers (CPs) are gaining significant scientific and commercial interest as materials for medical electrodes for electrically sensing and stimulating cardiac and nervous tissue. CPs lower the impedance of the traditional metal-based electrodes and allow safe and efficient transfer of electrical signals across the electrode-tissue interface due to enhanced interfacial conductivity. CPs present many possibilities for improving device design and clinical outcome through miniaturization of electrodes and devices, improved power consumption, increased stimulation capabilities, and improved recording signal quality and amplitude.
Poly(3,4-ethylenedioxythiophene) (PEDOT) is the most widely used CP and one of the most promising for medical applications due to its low oxidation potential, good electrochemical and thermal stability, and biocompatibility. PEDOT coating performance can be optimized by a variety of means such as choice of dopant, substrate surface features, and coating solvent system. Some of the most commonly used and reported dopants for PEDOT are poly(styrene sulfonate) (PSS) and p-toluene sulfonate (pTS), a polymeric and small molecule counter-ion, respectively. In spite of their good electrical properties, many publications suggest that PEDOT:PSS and PEDOT:pTS lack durability and mechanical stability for clinical use.
To address these limitations, Biotectix has developed Amplicoat™, a PEDOT-based coating made from a proprietary blend of conducting polymers and biocompatible dopants that provide enhanced durability and conductivity. Amplicoat is currently being used clinically on CE Mark approved cardiac mapping catheters. Here we compare the performance of Amplicoat to the commonly used PEDOT:PSS and PEDOT:pTS coatings by comparing the electrical stability and thermal stability of all three formulations, using methods commonly used in literature. The effects of repeated cyclic voltammetry (CV) and biphasic stimulation on the coatings’ electrical properties were measured. After 1000 CV cycles, Amplicoat exhibited the smallest loss in charge storage capacity (CSC) (11%), followed by PEDOT:pTS (32%), whereas PEDOT:PSS demonstrated the highest loss in CSC (51%). Preliminary results from biphasic stimulation studies indicate that Amplicoat has improved stability compared to both PEDOT:PSS and PEDOT:pTS. The long-term stability of the three coatings in physiological conditions, tested via accelerated thermal aging (conducted at 77°C in PBS), resulted in delamination of PEDOT:PSS after 7 days and delamination of PEDOT:pTS after 14 days. Amplicoat showed no signs of delamination after 21 days of thermal aging at 77°C, which corresponds to close to one year in vivo. Amplicoat showed superior durability compared to both PEDOT:PSS and PEDOT:pTS following thermal aging, aggressive CV testing, and biphasic stimulation, which is indicative of improved performance in long-term physiological conditions.
9:00 PM - SM3.7.03
Rupture Characteristics of Elastically Stretchable Microcracked Gold Conductors for Stretchable Microelectrode Array Applications
Adam Pak 1 , Ruben Ponce Wong 2 , James Abbas 3 , Oliver Graudejus 2 4
1 School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, Arizona, United States, 2 , BMSEED LLC, Phoenix, Arizona, United States, 3 Center for Adaptive Neural Systems, School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona, United States, 4 School of Molecular Sciences, Arizona State University, Tempe, Arizona, United States
Show AbstractStretchable microelectrode arrays (sMEAs) can be fabricated by depositing microcracked gold electrodes between two layers of poly(dimethylsiloxane) (PDMS). sMEAs are able to mechanically and electrically stimulate neural tissue in vitro. They enable physiological and pathological stretching of cells in a controlled environment while simultaneously recording/stimulating electrophysiological activity. The first commercial generation of sMEAs with a total of 28 microelectrodes will soon be available on the market. The next generation of sMEAs will have 60 microelectrodes, i.e., the electrode density will be significantly higher. To achieve this increased density routing, angles or turns need to be introduced into the stretchable conductive pathways. To ensure reliable production of high density sMEAs, we investigated the limits for angles on the leads of the microcracked gold electrodes. The microelectrode pattern was produced by thermal evaporation through a shadow mask, and the mechanical and electrical properties of single non-encapsulated microelectrodes were studied as a function of angle and angle structure. This investigation also examined the shadow effect and characterized defects in the microcracked gold conductors for various sample orientations during the thermal evaporator deposition process. Microcracked gold lines were produced by depositing a metal stack of 3 nm of chromium and 25-100 nm of gold on a PDMS substrate. Structures were 2 cm in length and 100/75 µm in nominal width, with either an angled or rounded turn present at midpoints of 45o, 90o, 135o and 180o lines, which were then subjected to cyclic strains with increasing magnitude. Results show that rupture strain characterized by electrical failure of microcracked gold conductors is independent of angle geometry. Rather, rupture strain depends upon the width of the conductor in the direction that is perpendicular to the direction of the strain, which we have termed ‘effective width’. Recognition of design parameters which influence rupture strain provides guidance for design of stretchable microcracked gold conductors requiring non-straight conductive pathway, such as the next generation of commercial sMEAs.
9:00 PM - SM3.7.04
Therapeutic Inhibition of Innate Immunity to Improve Intracortical Microelectrode Longevity
John Hermann 1 2 , Jeremy Chang 1 , Dawn Taylor 3 2 1 , Jeffrey Capadona 1 2
1 Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States, 2 Rehabilitation Research and Development, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States, 3 Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States
Show AbstractBrain machine interfaces have demonstrated potential for improving the mobility of individuals suffering from paralysis, loss of limbs, and neurodegenerative disorders. Neurological activity recorded with intracortical microelectrodes can be used to control brain machine interfaces, such as robotic arms or prosthetic devices. Unfortunately, intracortical microelectrodes often fail to consistently record neurological activity over long time periods. Intracortical microelectrodes can fail due to various mechanical, material, and biological mechanisms, including downstream effects of neuroinflammation. Neuroinflammation is propagated through the recognition of tissue damage by microglia and macrophages, which release pro-inflammatory cytokines. Innate immunity pathways involving Toll-like receptors recognize general molecular patterns associated with both invading pathogens and endogenous factors released during tissue damage to promote inflammation. Cluster of Differentiation 14 (CD14) coordinates ligand binding to several Toll-like receptors. Thus, we hypothesize that CD14 plays a role in the chronic inflammatory response to intracortical microelectrodes. Further, therapeutic inhibition of CD14 mediated pathways will improve the long-term performance of intracortical microelectrodes.
Planar silicon intracortical microelectrodes (NeuroNexus) were implanted in mice receiving subcutaneous injections of a small-molecule antagonist to CD14 (IAXO-101, Innaxon) and wild type (WT) control mice. Single-unit neural activity was recorded for 16 weeks after implantation and histology was compared at 16 weeks after implantation.
Wild type mice exhibited significant decreases in number of units, channels detecting units, and SNR at several time points, indicating less stable recording quality than IAXO-treated mice. Compared to control mice, mice receiving IAXO had significantly higher SNR and signal amplitude at some but not all time points. Mice receiving IAXO demonstrated no significant histological improvements at 16 weeks post implantation, but trended higher in neuronal survival at intermediate distances from the implanted electrode.
In summary, CD14 plays a role in the chronic inflammatory response to implanted intracortical microelectrodes. Systemically inhibiting CD14 with the small molecule antagonist IAXO improves the performance of intracortical microelectrodes, but other methods of inhibiting CD14 may be needed for optimal results.
9:00 PM - SM3.7.05
Self-Softening Shape Memory Polymers as a Scaffold for Neural Electrodes
Melanie Ecker 1 , Vindhya Danda 2 , Joseph Pancrazio 2 , Walter Voit 1 2
1 Materials Science and Engineering, The University of Texas at Dallas, Richardson, Texas, United States, 2 Department of Bioengineering, The University of Texas at Dallas, Richardson, Texas, United States
Show AbstractShape memory polymers (SMPs) have been proposed as the basis of a new generation of responsive, softening neural interfaces which address problems caused by the mechanical mismatch which exists for traditional devices with tissue.[1] We present the first thermomechanical evidence that photolithographically-defined SMP substrates having thicknesses of about 30 μm undergo softening when transitioning from dry to wet states.[2] Furthermore, we could reliably quantify the degree of softening of these variably processed thin films. In the past, traditional techniques were limited in their ability to measure thin films in aqueous environments to achieve reasonable thermomechanical properties in the wet state including Tg, glassy modulus, rubbery modulus and tangent delta.
The fabrication of thin polymer films involves spin coating of varying thiol-ene and thiol-ene/acrylate polymer solutions followed by photo-curing. In addition, we applied a new approach using photolithography to singulate neural devices and test specimens with controlled thicknesses to exhibit how processing affects the thermomechanical properties of copolymer films.
We have developed a new testing protocol to provide accurate thermomechanical measurements of thin films and demonstrate variable compositions to reliably adjust the Tg from 40 to 90 °C in the dry state. Furthermore, we tested devices in aqueous environments and found that Tg shifts by approximately 10 to 15 °C after plasticization of thin films. Depending on the monomer composition, the polymers were able to undergo various degrees of softening under physiological conditions, ranging from fully softening to non-softening.
In conclusion, we were able to investigate SMP thin films, having the thickness of actual devices, which can undergo different degrees of softening after being immersed in physiological solution. The use of a DMA with immersion system allowed us to mimic in vivo conditions relevant for implantable bioelectronic devices.
[1] Ware, T. et al, J. Biomed. Mater. Res. Part B, 2014, 102, 1.
[2] M. Ecker et al., Macromol. Mater. Eng., 2016, DOI: 10.1002/mame.201600331.
9:00 PM - SM3.7.06
Wet Chemical Synthesis of IrOx Film for Biostimulating Interface
Kuang-Chih Tso 1 , Han Yi Wang 1 , PuWei Wu 2 , Po Chun Chen 3 , Jyh Fu Lee 4
1 National Chiao Tung University, Hsinchu, Taiwan, R.O.C, Graduate Program for Science and Technology of Accelerator Light Source, Hsinchu Taiwan, 2 , Department of Materials Science and Engineering National Chiao Tung University, Hsinchu, Taiwan, R.O.C., Hsinchu Taiwan, 3 , Department of Materials and Mineral Resources Engineering National Taipei University of Technology, Taipei, Taiwan, R.O.C., Taipei Taiwan, 4 , National Synchrotron Radiation Research Center, Hsinchu, Taiwan, R.O.C., Hsinchu Taiwan
Show AbstractIridium oxide is an attractive material for application in bio-stimulating electrodes because of its distinct stability and biocompatibility. Electrostimulation medical devices for neural diseases require electro-stable and biocompatible materials to transmit the electrical signals form electrodes to target neural tissues. In our study, we have developed a formula via a chemical bath deposition process (CBD) to produce iridium oxide film atop of ITO substrate and medical devices. The film thickness can be controlled by adjusting solution recipes from 40 to 110 nm per bath. Surface morphology, crystallinity, and charge storage capacity of iridium oxide are observed. Compared to conventional platinum electrodes which are now widely used in neural prosthetic devices like retina implants, iridium oxide electrodes exhibit a much larger charge storage capacity.
9:00 PM - SM3.7.07
Connected Node Engineering of Neuronal Systems Using Laser Direct Write
Benjamin Vinson 1 , Samuel Sklare 2 , Jayant Saksena 3 , Jabe Curley 3 , Michael Moore 3 , Douglas Chrisey 2
1 Bioinnovation Program, Tulane University, New Orleans, Louisiana, United States, 2 Physics and Engineering Physics, Tulane University, New Orleans, Louisiana, United States, 3 Biomedical Engineering, Tulane University, New Orleans, Louisiana, United States
Show Abstract
In order to elucidate the micro-environmental and intercellular interactions that underlie neuronal behavior, both the ability to recapitulate complex cellular constructs and interface efficiently with those models are required. We have previously demonstrated our ability to utilize the laser direct-write (LDW) technique to reproducibly and accurately pattern viable dorsal root ganglion (DRG) neurons and supportive cells capable of neural outgrowth and network formation. Herein we describe the laser-assisted deposition of neural cells into a fabricated gel matrix-coated PDMS trinodal construct that aims to guide the neuronal growth via physical pathways and chemical cues. Chemical cues were dissolved and then pipetted to coat construct channels. The physical channels were fabricated using precise laser micromachining of the gel matrix. We hope to leverage our increased understanding gained from this experiment to fabricate a similar construct on a microelectrode array in the future. Electrodes will allow us to directly interface with and stimulate the construct.
9:00 PM - SM3.7.08
Investigating the Biostability of Three-Dimensional Graphene Foam for Regenerative Neural Stem Cell Culture
Tanveer Tabish 1 , Sakineh Chabi 2 , David Horsell 1 , Yongde Xia 1 , Chris Scotton 3 , Shaowei Zhang 1
1 College of Engineering Mathematics and Physical Sciences, University of Exeter, Exeter United Kingdom, 2 Department of Chemistry, Florida Institute of Technology, Melbourne, Florida, United States, 3 Institute of Biomedical and Clinical Science, University of Exeter, Exeter United Kingdom
Show AbstractGlobally more than 15 million people suffer a stroke annualy. Of those six million die and another five million are left permanently disabled [1]. Disability may include visual disturbance, loss of speech and paralysis on one side of the body. Neural stem cell (NSC) research holds promise in pushing the boundaries for treatment in neurological disorders [2]. NSC culture requires scaffolds to offer microenvironments for stem cell viability and growth of 3D networks, promoting their biostability, survival and differentiation [2]. Also, biologic corrosion is the silent enemy and it plays a pivotal role in living systems. Undetected, it can be severe enough to compromise the immune system [2]. 3D graphene foam (GF) is a promising candidate for the tissue engineering field; it has a number of superior physic-chemical features compared to conventional biomaterials, such as mechanical strength, superhydrophobic surface, high conductivity and corrosion resistant pathways for charge transport while offering a 3D structure for cell adhesion and cell network integration.
Here, we report the in vitro biologic corrosion, wettability and electrical compliance strategies that will underpin regenerative medicine approaches for NSC applications. GFs were prepared by chemical vapour deposition, using a Ni foam template. GFs were characterized by transmission electron microscope (TEM) and energy dispersive X-ray spectrometry (EDS). The wettability of the GF surface was determined using a contact angle goniometer. The bio stability and corrosion of GF were characterized by Tafel plot, electrochemical stability and cyclic voltammetry (CV) using a CHI 660C Electrochemical Workstation, in simulated body fluid at pH 7.4. EDS spectra showed only one carbon peak at 0.4 KeV, indicating the successful removal of Ni. TEM images demonstrated that the GF is made of large-sized, multi-layered graphene flakes (average size ~4 µm). Tafel curves presented the highest current density indicating the lowest corrosion resistance as compared to those of conventional biomaterials [2]. Corrosion rates based on weight loss indicated that GF has marked resistance to corrosion and high biostability – which is essential in vivo to direct tissue healing prior to biodegradation. GF is a hydrophobic material, with a water contact angle of 1290. Higher wettability could also affect cell functions by interfering protein adsorption. The CV measurements suggested that GF can be controlled electrically and has the potential to deliver electric currents to cells via capacitive charge injection without involving any chemical reaction - which may prove ideal for neural stimulation [3].These findings will further the development of advanced 3D graphene platforms for NSC based therapies.
References: [1] Mackay, J, et al. The atlas of heart disease and stroke. World Health Organization, 2004 [2] Fisher, O. Z, et al. Accounts Chem Res, 2009, 43, 419-428. [3] Tandon, N, et al. Nat Protoc, 2009, 4, 155-173
9:00 PM - SM3.7.09
Architectural Surface Modifications of Intracortical Microelectrode for Reduced Foreign Body Response
Evon Ereifej 2 1 , Cara Smith 2 1 , Seth Meade 2 1 , Keying Chen 2 1 , Jeffrey Capadona 2 1
2 Biomedical Engineering, Case Western Reserve University , Cleveland, Ohio, United States, 1 APT Cen, Veteran Affairs Medical Center, Cleveland , Ohio, United States
Show AbstractIntroduction: Intracortical microelectrodes provide a means to both treat and understand diseases and injuries of the brain/nervous system. A major hurdle to the clinical deployment of microelectrode technologies is recording instability caused by the lack of integration with the native tissue. The initial insertion of these electrodes causes a cascade of inflammation, which leads to a chronic foreign body response and encapsulation of the electrode. Signals recorded from these implanted electrodes get distorted over time due to high noise resulting from the inflammatory reaction to these implants. It is crucial to understand that the in vivo environment is not smooth, in contrast to the currently accepted and used intracortical microelectrodes. The discontinuity between the tissue and the device interface structure/texture results in inflammation of the tissue. This goal of this study is to examine the effects of nanoscale surface modifications, similar to the native in vivo environment, on reducing the inflammatory response compared to a standard, smooth microelectrode surfaces.
Materials and Methods: Non-functional, Michigan-style silicon shank microelectrodes were patterned using focused ion beam (FIB) etching to create nanoscale parallel grooves on the device surface. The width and depth of the nanopattern grooves are 200nm. The grooves are spaced 300nm apart. Non-patterned silicon shanks were used as controls. Patterned or non-patterned shanks were implanted into the cortex of Sprague Dawley rats for two or four weeks. Following which, cortical slices of the brain tissue were analyzed for the presence of astrocytic scarring, activated microglia/macrophages, blood-brain barrier permeability, neuronal survival and oxidative stress. This analysis was performed using immunohistochemical staining in combination with the Matlab image analysis program to quantify the fluorescent intensity values surrounding the site of implantation. Laser capture microdissection and RT-PCR were used to analyze molecular markers for inflammation and oxidative stress in the tissue surrounding the implant site.
Results and Discussion: Rats implanted with topographically modified shanks showed a decrease in inflammation over time, as observed by an increase in neuronal survival and a decrease in activated microglia and astrocytes compared to rats implanted with control shanks. Future studies examining chronic time points are necessary to further examine the acute results observed here.
Acknowledgements: This work was supported by the Dept. of Veterans Affairs Career Development Award 1 (CDA-1) Award #1IK1RX001664, Merit Review (Award # B1495-R), Clinical Translational Science Collaborative of Cleveland, UL1TR000439, APT Center, Swagelock Center and FEI. The contents do not represent the views of the U.S. Department of Veteran Affairs or the United States Government.