Ivan R. Minev

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

A Microchannel Neuroprosthesis for Bladder Control After Spinal Cord Injury in Rat

An electronic interface for recording and stimulating nerves that innervate the bladder helps to restore normal bladder function in rats with spinal cord injury. Getting to the Root of Bladder Control Injury to the spinal cord typically results in loss of conscious bladder emptying and the sensation of fullness. Currently, only limited treatment options are available, with most of the patients receiving catheterization. However, this is cumbersome and leads to urological complications including unsolicited episodes of bladder contraction, leading to inappropriate emptying. In a new study, Chew et al. design a “closed-loop” electronic device that can accurately record bladder filling from sensory nerves after spinal cord injury in rat. Using this information, bladder emptying can be artificially stimulated on demand by electrically modulating nerve firing. It is traditionally difficult to record robust neuronal activity from peripheral nerves in vivo. Typically, cuff electrodes are used to record from whole nerves, but produce poor signal quality and provide little indication of bladder filling. Through nerve microdissection, Chew et al. implanted fine-diameter nerves (“rootlets”) into insulated microchannels, recording action potential firing that accurately encoded bladder filling. The device had multiple microchannels for concurrent recording, greatly improving the resolution. Using this sensory information and by manipulating stimulation characteristics, the authors prevented the rat bladder from emptying inappropriately, and bladder contraction was initiated when desired. This work opens a new avenue for the design of a neuroprosthesis for bladder control after spinal cord injury. A severe complication of spinal cord injury is loss of bladder function (neurogenic bladder), which is characterized by loss of bladder sensation and voluntary control of micturition (urination), and spontaneous hyperreflexive voiding against a closed sphincter (detrusor-sphincter dyssynergia). A sacral anterior root stimulator at low frequency can drive volitional bladder voiding, but surgical rhizotomy of the lumbosacral dorsal roots is needed to prevent spontaneous voiding and dyssynergia. However, rhizotomy is irreversible and eliminates sexual function, and the stimulator gives no information on bladder fullness. We designed a closed-loop neuroprosthetic interface that measures bladder fullness and prevents spontaneous voiding episodes without the need for dorsal rhizotomy in a rat model. To obtain bladder sensory information, we implanted teased dorsal roots (rootlets) within the rat vertebral column into microchannel electrodes, which provided signal amplification and noise suppression. As long as they were attached to the spinal cord, these rootlets survived for up to 3 months and contained axons and blood vessels. Electrophysiological recordings showed that half of the rootlets propagated action potentials, with firing frequency correlated to bladder fullness. When the bladder became full enough to initiate spontaneous voiding, high-frequency/amplitude sensory activity was detected. Voiding was abolished using a high-frequency depolarizing block to the ventral roots. A ventral root stimulator initiated bladder emptying at low frequency and prevented unwanted contraction at high frequency. These data suggest that sensory information from the dorsal root together with a ventral root stimulator could form the basis for a closed-loop bladder neuroprosthetic.

Microstructured Silicone Substrate for Printable and Stretchable Metallic Films

Stretchable electronics (i.e., hybrid inorganic or organic circuits integrated on elastomeric substrates) rely on elastic wiring. We present a technique for fabricating reversibly stretchable metallic films by printing silver-based ink onto microstructured silicone substrates. The wetting and pinning of the ink on the elastomer surface is adjusted and optimized by varying the geometry of micropillar arrays patterned on the silicone substrate. The resulting films exhibit high electrical conductivity (∼11 000 S/cm) and can stretch reversibly to 20% strain over 1000 times without failing electrically. The stretchability of the ≥200 nm thick metallic film relies on engineered strain relief in the printed film on patterned PDMS.

Localization of Folds and Cracks in Thin Metal Films Coated on Flexible Elastomer Foams

Thin metal films coated on soft elastomeric foam substrates exhibit enhanced electromechanical performance. The open-cell foam structure conveys highly anisotropic mechanical properties within the top, thin capping elastomer at the surface of the foam. Upon stretching, large strain fields inducing cracks and folds localize above the foam cells, while the surrounding cell ligaments remain almost strain-free, enabling stable electrical conduction in the metallic coating.

Corticospinal neuroprostheses to restore locomotion after spinal cord injury

In this conceptual review, we highlight our strategy for, and progress in the development of corticospinal neuroprostheses for restoring locomotor functions and promoting neural repair after thoracic spinal cord injury in experimental animal models. We specifically focus on recent developments in recording and stimulating neural interfaces, decoding algorithms, extraction of real-time feedback information, and closed-loop control systems. Each of these complex neurotechnologies plays a significant role for the design of corticospinal neuroprostheses. Even more challenging is the coordinated integration of such multifaceted technologies into effective and practical neuroprosthetic systems to improve movement execution, and augment neural plasticity after injury. In this review we address our progress in rodent animal models to explore the viability of a technology-intensive strategy for recovery and repair of the damaged nervous system. The technical, practical, and regulatory hurdles that lie ahead along the path toward clinical applications are enormous - and their resolution is uncertain at this stage. However, it is imperative that the discoveries and technological developments being made across the field of neuroprosthetics do not stay in the lab, but instead reach clinical fruition at the fastest pace possible.

Concurrent recordings of bladder afferents from multiple nerves using a microfabricated PDMS microchannel electrode array

In this paper we present a compliant neural interface designed to record bladder afferent activity. We developed the implants microfabrication process using multiple layers of silicone rubber and thin metal so that a gold microelectrode array is embedded within four parallel polydimethylsiloxane (PDMS) microchannels (5 mm long, 100 μm wide, 100 μm deep). Electrode impedance at 1 kHz was optimized using a reactive ion etching (RIE) step, which increased the porosity of the electrode surface. The electrodes did not deteriorate after a 3 month immersion in phosphate buffered saline (PBS) at 37 °C. Due to the unique microscopic topography of the metal film on PDMS, the electrodes are extremely compliant and can withstand handling during implantation (twisting and bending) without electrical failure. The device was transplanted acutely to anaesthetized rats, and strands of the dorsal branch of roots L6 and S1 were surgically teased and inserted in three microchannels under saline immersion to allow for simultaneous in vivo recordings in an acute setting. We utilized a tripole electrode configuration to maintain background noise low and improve the signal to noise ratio. The device could distinguish two types of afferent nerve activity related to increasing bladder filling and contraction. To our knowledge, this is the first report of multichannel recordings of bladder afferent activity.

Impedance spectroscopy on stretchable microelectrode arrays

We are reporting on the fabrication and electrical characterization of stretchable polydimethylsiloxane (PDMS) based microelectrode arrays for recording of neuronal action potentials. Electrodes are immersed in phosphate buffered saline solution. Their electrical impedance spectra are recorded as a function of uniaxial macroscopic strain applied using a custom built automated stretcher. We propose a model to account for the physical phenomena responsible for electrical conduction in the bulk electrode and at the metal–electrolyte interface. Electrodes with active area dimensions of 100×140 μm2 maintain an impedance of approximately 1 MΩ at 1 kHz when cycled to 20% strain.

Generation and detection of broadband airborne ultrasound with cellular polymer ferroelectrets

Cellular polypropylene ferroelectrets are useful for broadband airborne ultrasound generation and detection up to the fundamental thickness extension resonance. The authors show that the coupling of ferroelectrets to air alters the electromechanical resonance of the foam. In an acoustical cavity, Fabry-Perot resonances are obtained, which is in excellent agreement with the plane wave model calculations. For material assessment in airborne ultrasound applications, a figure of merit is used based on the electromechanical coupling factor and acoustical impedance of the material. The good coupling of ferroelectrets to gases results from the small acoustical impedance of the material.

Interaction of glia with a compliant, microstructured silicone surface.

Soft bioengineered surfaces offer a route towards modulating the tissue responses to chronically implanted devices and may enhance their functionality. In this communication we fabricate microtopographically rich and mechanically compliant silicone surfaces for use in soft neural interfaces. We observe the interaction of primary rat microglia and astroglia with arrays of tall and short (4.7 and 0.5μm) vertically oriented polydimethylsiloxane (PDMS) micropillars and a flat PDMS surface in vitro. With the pillar size and spacing that we use (1.3μm diameter and 1.6μm edge to edge), glia are found to engulf and bend tall pillars. The cytoskeleton of cells adhering to the pillar arrays lacks actin stress fibers; instead we observe actin ring formations around individual pillars. Tall, but not short pillar arrays are inhibitory to migration and spreading for both microglia and astrocytes. When compared to a flat PDMS surface and short pillar arrays, tall micropillar arrays cause nearly a 2-fold decrease in proliferation rates for both cell types. The antimitotic properties of tall pillar arrays may be useful for reducing the density of the glial capsule around brain-implanted devices.

Research Update: Platinum-elastomer mesocomposite as neural electrode coating

Platinum is electrochemically stable and biocompatible, and remains the preferred material for the fabrication of implantable neural electrodes. In a foil or film format, platinum is mechanically stiff compared to interfaced biological tissue. We report a soft, highly stable platinum-elastomer composite that offers both mechanical compliance and the electrochemical properties of platinum. We demonstrate the high-performance of the novel mesocomposite printed on stretchable microelectrodes both in vitro and in vivo. The platinum-elastomer composite is a new promising coating for chronic neural interfaces.