Analytic modeling of neural tissue: II. Nonlinear membrane dynamics.

Computational modeling of neuroactivity plays a central role in our effort to understand brain dynamics in the advancements of neural engineering such as deep brain stimulation, neuroprosthetics, and magnetic resonance electrical impedance tomography. However, analytic solutions do not capture the fundamental nonlinear behavior of an action potential. What is needed is a method that is not constrained to only linearized models of neural tissue.

Soft, Conductive, Brain-Like, Coatings at Tips of Microelectrodes Improve Electrical Stability under Chronic, In Vivo Conditions.

Several recent studies have reported improved histological and electrophysiological outcomes with soft neural interfaces that have elastic moduli ranging from 10 s of kPa to hundreds of MPa. However, many of these soft interfaces use custom fabrication processes. We test the hypothesis that a readily adoptable fabrication process for only coating the tips of microelectrodes with soft brain-like (elastic modulus of ~5 kPa) material improves the long-term electrical performance of neural interfaces.

Biomechanical micromotion at the neural interface modulates intracellular membrane potentials.

. Respiration and vascular pulsation cause relative micromotion of brain tissue against stationary implants resulting in repetitive displacements of 2-4m (due to vascular pulsation) and 10-30m (due to breathing) in rats. However, the direct functional impact of such tissue micromotion on the cells at the neural interface remains unknown.

Optogenetic modulation of cortical neurons using organic light emitting diodes (OLEDs).

Objective: There is a need for low power, scalable photoelectronic devices and systems for emerging optogenetic needs in neuromodulation. Conventional light emitting diodes (LEDs) are constrained by power and lead-counts necessary for scalability. Organic LEDs (OLEDs) offer an exciting approach to decrease power and lead-counts while achieving high channel counts on thin, flexible substrates that conform to brain surfaces or peripheral neuronal fibers.

Advances in Implantable Microelectrode Array Insertion and Positioning.

Objectives: Microelectrode arrays offer a means to probe the functional circuitry of the brain and the promise of cortical neuroprosthesis for individuals suffering from paralysis or limb loss. These devices are typically comprised of one or more shanks incorporating microelectrode sites, where the shanks are positioned by inserting the devices along a straight path that is normal to the brain surface. The lack of consistent long-term chronic recording technology has driven interest in novel probe design and approaches that go beyond the standard insertion approach that is limited to a single velocity or axis.

Engineering microscale systems for fully autonomous intracellular neural interfaces.

Conventional electrodes and associated positioning systems for intracellular recording from single neurons in vitro and in vivo are large and bulky, which has largely limited their scalability. Further, acquiring successful intracellular recordings is very tedious, requiring a high degree of skill not readily achieved in a typical laboratory. We report here a robotic, MEMS-based intracellular recording system to overcome the above limitations associated with form factor, scalability, and highly skilled and tedious manual operations required for intracellular recordings.

Design and Development of Microscale Thickness Shear Mode (TSM) Resonators for Sensing Neuronal Adhesion.

The overall goal of this study is to develop thickness shear mode (TSM) resonators for the real-time, label-free, non-destructive sensing of biological adhesion events in small populations (hundreds) of neurons, in a cell culture medium and subsequently in the future. Such measurements will enable the discovery of the role of biomechanical events in neuronal function and dysfunction. Conventional TSM resonators have been used for chemical sensing and biosensing applications in media, with hundreds of thousands of cells in culture.

Remote Stimulation of Sciatic Nerve Using Cuff Electrodes and Implanted Diodes.

We demonstrate a method of neurostimulation using implanted, free-floating, inter-neural diodes. They are activated by volume-conducted, high frequency, alternating current (AC) fields and address the issue of instability caused by interconnect wires in chronic nerve stimulation. The aim of this study is to optimize the set of AC electrical parameters and the diode features to achieve wireless neurostimulation.

Autonomous control for mechanically stable navigation of microscale implants in brain tissue to record neural activity.

Emerging neural prosthetics require precise positional tuning and stable interfaces with single neurons for optimal function over a lifetime. In this study, we report an autonomous control to precisely navigate microscale electrodes in soft, viscoelastic brain tissue without visual feedback. The autonomous control optimizes signal-to-noise ratio (SNR) of single neuronal recordings in viscoelastic brain tissue while maintaining quasi-static mechanical stress conditions to improve stability of the implant-tissue interface.

Finite element modeling of human brain response to football helmet impacts.

The football helmet is used to help mitigate the occurrence of impact-related traumatic (TBI) and minor traumatic brain injuries (mTBI) in the game of American football. While the current helmet design methodology may be adequate for reducing linear acceleration of the head and minimizing TBI, it however has had less effect in minimizing mTBI. The objectives of this study are (a) to develop and validate a coupled finite element (FE) model of a football helmet and the human body, and (b) to assess responses of different regions of the brain to two different impact conditions - frontal oblique and crown impact conditions.

Compliant intracortical implants reduce strains and strain rates in brain tissue in vivo.

Objective: The objective of this research is to characterize the mechanical interactions of (1) soft, compliant and (2) non-compliant implants with the surrounding brain tissue in a rodent brain. Understanding such interactions will enable the engineering of novel materials that will improve stability and reliability of brain implants.

Approach: Acute force measurements were made using a load cell in n = 3 live rats, each with 4 craniotomies.

Long-term changes in the material properties of brain tissue at the implant-tissue interface.

Objective: Brain tissue undergoes dramatic molecular and cellular remodeling at the implant-tissue interface that evolves over a period of weeks after implantation. The biomechanical impact of such remodeling on the interface remains unknown. In this study, we aim to assess the changes in the mechanical properties of the brain-electrode interface after chronic implantation of a microelectrode.

Voltage Preconditioning Allows Modulated Gene Expression in Neurons Using PEI-complexed siRNA.

We present here a high efficiency, high viability siRNA-delivery method using a voltage-controlled chemical transfection strategy to achieve modulated delivery of polyethylenimine (PEI) complexed with siRNA in an in vitro culture of neuro2A cells and neurons. Low voltage pulses were applied to adherent cells before the administration of PEI-siRNA complexes. Live assays of neuro2a cells transfected with fluorescently tagged siRNA showed an increase in transfection efficiency from 62 ± 14% to 98 ± 3.

High efficiency, site-specific transfection of adherent cells with siRNA using microelectrode arrays (MEA).

The discovery of RNAi pathway in eukaryotes and the subsequent development of RNAi agents, such as siRNA and shRNA, have achieved a potent method for silencing specific genes for functional genomics and therapeutics. A major challenge involved in RNAi based studies is the delivery of RNAi agents to targeted cells. Traditional non-viral delivery techniques, such as bulk electroporation and chemical transfection methods often lack the necessary spatial control over delivery and afford poor transfection efficiencies.

Electrothermal Microactuators With Peg Drive Improve Performance for Brain Implant Applications.

This paper presents a new actuation scheme for in-plane bidirectional translation of polysilicon microelectrodes. The new Chevron-peg actuation scheme uses microelectromechanical systems (MEMS) based electrothermal microactuators to move microelectrodes for brain implant applications. The design changes were motivated by specific needs identified by the testing of an earlier generation of MEMS microelectrodes that were actuated by the Chevron-latch type of mechanism.

Multi-modal biochip for simultaneous, real-time measurement of adhesion and electrical activity of neurons in culture.

Recent evidence suggests that integrin-mediated adhesion of neurons has immediate functional implications for learning and memory. In addition, adhesion of neurons to artificial substrates often determines the effectiveness and life of implants in the brain and peripheral nervous system. In this study, we present a novel biochip capable of simultaneous, quantitative, real-time monitoring of integrin-mediated adhesion and electrophysiology of primary neurons in vitro.

Packaging and Non-Hermetic Encapsulation Technology for Flip Chip on Implantable MEMS Devices.

We report here a successful demonstration of a flip-chip packaging approach for a microelectromechanical systems (MEMS) device with in-plane movable microelectrodes implanted in a rodent brain. The flip-chip processes were carried out using a custom-made apparatus that was capable of the following: 1) creating Ag epoxy microbumps for first-level interconnect; 2) aligning the die and the glass substrate; and 3) creating non-hermetic encapsulation (NHE). The completed flip-chip package had an assembled weight of only 0.

Novel First-Level Interconnect Techniques for Flip Chip on MEMS Devices.

Flip-chip packaging is desirable for microelectro-mechanical systems (MEMS) devices because it reduces the overall package size and allows scaling up the number of MEMS chips through 3-D stacks. In this report, we demonstrate three novel techniques to create first-level interconnect (FLI) on MEMS: 1) Dip and attach technology for Ag epoxy; 2) Dispense technology for solder paste; 3) Dispense, pull, and attach technology (DPAT) for solder paste. The above techniques required no additional microfabrication steps, produced no visible surface contamination on the MEMS active structures, and generated high-aspect-ratio interconnects.

Adaptive movable neural interfaces for monitoring single neurons in the brain.

Implantable microelectrodes that are currently used to monitor neuronal activity in the brain in vivo have serious limitations both in acute and chronic experiments. Movable microelectrodes that adapt their position in the brain to maximize the quality of neuronal recording have been suggested and tried as a potential solution to overcome the challenges with the current fixed implantable microelectrodes. While the results so far suggest that movable microelectrodes improve the quality and stability of neuronal recordings from the brain in vivo, the bulky nature of the technologies involved in making these movable microelectrodes limits the throughput (number of neurons that can be recorded from at any given time) of these implantable devices.

Highly doped polycrystalline silicon microelectrodes reduce noise in neuronal recordings in vivo.

The aims of this study are to 1) experimentally validate for the first time the nonlinear current-potential characteristics of bulk doped polycrystalline silicon in the small amplitude voltage regimes (0-200 μV) and 2) test if noise amplitudes ( 0-15 μV ) from single neuronal electrical recordings get selectively attenuated in doped polycrystalline silicon microelectrodes due to the above property. In highly doped polycrystalline silicon, bulk resistances of several hundred kilo-ohms were experimentally measured for voltages typical of noise amplitudes and 9-10 kΩ for voltages typical of neural signal amplitudes ( > 150-200 μV). Acute multiunit measurements and noise measurements were made in n=6 and n=8 anesthetized adult rats, respectively, using polycrystalline silicon and tungsten microelectrodes.

Long-Term Neural Recordings Using MEMS Based Movable Microelectrodes in the Brain.

One of the critical requirements of the emerging class of neural prosthetic devices is to maintain good quality neural recordings over long time periods. We report here a novel MEMS (Micro Electro Mechanical Systems) based technology that can move microelectrodes in the event of deterioration in neural signal to sample a new set of neurons. Microscale electro-thermal actuators are used to controllably move microelectrodes post-implantation in steps of approximately 9 mum.

Flexible Chip Scale Package and Interconnect for Implantable MEMS Movable Microelectrodes for the Brain.

We report here a novel approach called MEMS microflex interconnect (MMFI) technology for packaging a new generation of Bio-MEMS devices that involve movable microelectrodes implanted in brain tissue. MMFI addresses the need for (i) operating space for movable parts and (ii) flexible interconnects for mechanical isolation. We fabricated a thin polyimide substrate with embedded bond-pads, vias, and conducting traces for the interconnect with a backside dry etch, so that the flexible substrate can act as a thin-film cap for the MEMS package.

Early onset of electrical activity in developing neurons cultured on carbon nanotube immobilized microelectrodes.

In this study, we test the hypothesis that increased surface roughness due to carbon nanotubes (CNTs) enhances neuronal adhesion and consequently electrical excitability of single neurons. Neurons are grown on CNT modified microelectrode arrays (MEAs). Multi-unit activity was seen as early as 4 days after seeding compared to 7 days in control cultures on microelectrodes without CNTs.

Assessment of gliosis around moveable implants in the brain.

Repositioning microelectrodes post-implantation is emerging as a promising approach to achieve long-term reliability in single neuronal recordings. The main goal of this study was to (a) assess glial reaction in response to movement of microelectrodes in the brain post-implantation and (b) determine an optimal window of time post-implantation when movement of microelectrodes within the brain would result in minimal glial reaction. Eleven Sprague-Dawley rats were implanted with two microelectrodes each that could be moved in vivo post-implantation.

Optoelectronic energy transfer at novel biohybrid interfaces using light harvesting complexes from Chloroflexus aurantiacus.

In nature, nanoscale supramolecular light harvesting complexes initiate the photosynthetic energy collection process at high quantum efficiencies. In this study, the distinctive antenna structure from Chloroflexus aurantiacusthe chlorosomeis assessed for potential exploitation in novel biohybrid optoelectronic devices. Electrochemical characterization of bacterial fragments containing intact chlorosomes with the photosynthetic apparatus show an increase in the charge storage density near the working electrode upon light stimulation and suggest that chlorosomes contribute approximately one-third of the overall photocurrent.