Turning Neural Prosthetics Into Viable Products

Academic researchers concentrate on the scientific and technological feasibility of novel treatments. Investors and commercial partners, however, understand that success depends even more on strategies for regulatory approval, reimbursement, marketing, intellectual property protection and risk management. These considerations are critical for technologically complex and highly invasive treatments that entail substantial costs and risks in small and heterogeneous patient populations. Most implanted neural prosthetic devices for novel applications will be in FDA Device Class III, for which guidance documents have been issued recently. Less invasive devices may be eligible for the recently simplified “de novo” submission routes. We discuss typical timelines and strategies for integrating the regulatory path with approval for reimbursement, securing intellectual property and funding the enterprise, particularly as they might apply to implantable brain-computer interfaces for sensorimotor disabilities that do not yet have a track record of approved products.

Interaction of micropatterned topographical and biochemical cues to direct neurite growth from spiral ganglion neurons

Functional outcomes with neural prosthetic devices, such as cochlear implants, are limited in part due to physical separation between the stimulating elements and the neurons they stimulate. One strategy to close this gap aims to precisely guide neurite regeneration to position the neurites in closer proximity to electrode arrays. Here, we explore the ability of micropatterned biochemical and topographic guidance cues, singly and in combination, to direct the growth of spiral ganglion neuron (SGN) neurites, the neurons targeted by cochlear implants. Photopolymerization of methacrylate monomers was used to form unidirectional topographical features of ridges and grooves in addition to multidirectional patterns with 90° angle turns. Microcontact printing was also used to create similar uni- and multi-directional patterns of peptides on polymer surfaces. Biochemical cues included peptides that facilitate (laminin, LN) or repel (EphA4-Fc) neurite growth. On flat surfaces, SGN neurites preferentially grew on LN-coated stripes and avoided EphA4-Fc-coated stripes. LN or EphA4-Fc was selectively adsorbed onto the ridges or grooves to test the neurite response to a combination of topographical and biochemical cues. Coating the ridges with EphA4-Fc and grooves with LN lead to enhanced SGN alignment to topographical patterns. Conversely, EphA4-Fc coating on the grooves or LN coating on the ridges tended to disrupt alignment to topographical patterns. SGN neurites respond to combinations of topographical and biochemical cues and surface patterning that leverages both cues enhance guided neurite growth.

Typical somatomotor physiology of the hand is preserved in a patient with an amputated arm

Electrophysiological signals in the human motor system may change in different ways after deafferentation, with some studies emphasizing reorganization while others propose retained physiology. Understanding whether motor electrophysiology is retained over longer periods of time can be invaluable for patients with paralysis (e.g. ALS or brainstem stroke) when signals from sensorimotor areas may be used for communication or control over neural prosthetic devices. In addition, a maintained electrophysiology can potentially benefit the treatment of phantom limb pains through prolonged use of these signals in a brain-machine interface (BCI).Here, we were presented with the unique opportunity to investigate the physiology of the sensorimotor cortex in a patient with an amputated arm using electrocorticographic (ECoG) measurements. While implanted with an ECoG grid for clinical evaluation of electrical stimulation for phantom limb pain, the patient performed attempted finger movements with the contralateral (lost) hand and executed finger movements with the ipsilateral (healthy) hand.The electrophysiology of the sensorimotor cortex contralateral to the amputated hand remained very similar to that of hand movement in healthy people, with a spatially focused increase of high-frequency band (65-175Hz; HFB) power over the hand region and a distributed decrease in low-frequency band (15-28Hz; LFB) power. The representation of the three different fingers (thumb, index and little) remained intact and HFB patterns could be decoded using support vector learning at single-trial classification accuracies of >90%, based on the first 1-3s of the HFB response. These results demonstrate that hand representations are largely retained in the motor cortex. The intact physiological response of the amputated hand, the high distinguishability of the fingers and fast temporal peak are encouraging for neural prosthetic devices that target the sensorimotor cortex.

The human primary somatosensory cortex encodes imagined movement in the absence of sensory information

Classical systems neuroscience positions primary sensory areas as early feed-forward processing stations for refining incoming sensory information. This view may oversimplify their role given extensive bi-directional connectivity with multimodal cortical and subcortical regions. Here we show that single units in human primary somatosensory cortex encode imagined reaches in a cognitive motor task, but not other sensory–motor variables such as movement plans or imagined arm position. A population reference-frame analysis demonstrates coding relative to the cued starting hand location suggesting that imagined reaching movements are encoded relative to imagined limb position. These results imply a potential role for primary somatosensory cortex in cognitive imagery, engagement during motor production in the absence of sensation or expected sensation, and suggest that somatosensory cortex can provide control signals for future neural prosthetic systems.

Hybrid Chemomechanical Promotion of PEDOT Adhesion onto Flexible Microelectrode Arrays for Chronic Neural Stimulation

Advances in neural prosthetic technologies demand ever increasing novelty in material composition to enhance the mechanical and electrochemical properties of existing microelectrode arrays. Conductive polymers present advantages such as mechanical flexibility, outstanding biocompatibility, remarkable electrical properties and, most of all, cellular agreement. However, for long-term chronic applications, they fall short in their electrochemical endurance and mechanical adhesion to their substrate materials. Multiple electrochemical approaches have been investigated to improve the adherence of Poly(3,4-ethylenedioxythiophene) (PEDOT) to underlying metallic thin films. In this work, an electrochemical treatment of diazonium salt on platinum microelectrodes is incorporated as an electrochemical adhesion promoter for PEDOT and it is further combined with using the highly microporous geometry of Platinum Grey (Pt-Grey); a technology developed by Second Sight Medical Products Inc (SSMP). The intertwined mechanical integration of Pt-Grey and PEDOT molecules together with the covalent binding agency of diazonium salt demostrate a composite coating technology with long-term stability of more than 452 days while providing >70× enhancement to the interfacial capacitive impedance.

Stability Performance Analysis of Various Packaging Materials and Coating Strategies for Chronic Neural Implants under Accelerated, Reactive Aging Tests

Reliable packaging for implantable neural prosthetic devices in body fluids is a long-standing challenge for devices’ chronic applications. This work studied the stability of Parylene C (PA), SiO2, and Si3N4 packages and coating strategies on tungsten wires using accelerated, reactive aging tests in three solutions: pH 7.4 phosphate-buffered saline (PBS), PBS + 30 mM H2O2, and PBS + 150 mM H2O2. Different combinations of coating thicknesses and deposition methods were studied at various testing temperatures. Analysis of the preliminary data shows that the pinholes/defects, cracks, and interface delamination are the main attributes of metal erosion and degradation in reactive aging solutions. Failure at the interface of package and metal is the dominating factor in the wire samples with open tips.

Distributed processing of movement signaling

Basic neurophysiological research with monkeys has shown how neurons in the motor cortex have firing rates tuned to movement direction. This original finding would have been difficult to uncover without the use of a behaving primate paradigm in which subjects grasped a handle and moved purposefully to targets in different directions. Subsequent research, again using behaving primate models, extended these findings to continuous drawing and to arm and hand movements encompassing action across multiple joints. This research also led to robust extraction algorithms in which information from neuronal populations is used to decode movement intent. The ability to decode intended movement provided the foundation for neural prosthetics in which brain-controlled interfaces are used by paralyzed human subjects to control computer cursors or high-performance motorized prosthetic arms and hands. This translation of neurophysiological laboratory findings to therapy is a clear example of why using nonhuman primates for basic research is valuable for advancing treatment of neurological disorders. Recent research emphasizes the distribution of intention signaling through neuronal populations and shows how many movement parameters are encoded simultaneously. In addition to direction and velocity, the arm’s impedance has now been found to be encoded as well. The ability to decode motion and force from neural populations will make it possible to extend neural prosthetic paradigms to precise interaction with objects, enabling paralyzed individuals to perform many tasks of daily living.

Neural Prosthetics:A Review of Empirical vs. Systems Engineering Strategies

Implantable electrical interfaces with the nervous system were first enabled by cardiac pacemaker technology over 50 years ago and have since diverged into almost all of the physiological functions controlled by the nervous system. There have been a few major clinical and commercial successes, many contentious claims, and some outright failures. These tend to be reviewed within each clinical subspecialty, obscuring the many commonalities of neural control, biophysics, interface materials, electronic technologies, and medical device regulation that they share. This review cites a selection of foundational and recent journal articles and reviews for all major applications of neural prosthetic interfaces in clinical use, trials, or development. The hard-won knowledge and experience across all of these fields can now be amalgamated and distilled into more systematic processes for development of clinical products instead of the often empirical (trial and error) approaches to date. These include a frank assessment of a specific clinical problem, the state of its underlying science, the identification of feasible targets, the availability of suitable technologies, and the path to regulatory and reimbursement approval. Increasing commercial interest and investment facilitates this systematic approach, but it also motivates projects and products whose claims are dubious.