Tech Overview: Neuroprosthetics Part 1
Introduction – Therapeutic Potential
Since the 1960s, neural interfaces have been used to record neural activity or stimulate neural tissue in humans and animals 1. Millions of people worldwide are affected by neurological disorders which disrupt connections within the brain and between brain and body causing impairments of primary functions and paralysis. Such a number is likely to increase in the next years and current assistive technology is limited. The response to such disabilities, offered by the neuroscience community, is given by Brain-Machine Interfaces (BMIs) and Neuroprostheses.
Today, implantation of macro- and micro-devices into the brain is increasingly used for treatment of neurological disorders 2 3 4. For instance, electrical stimulation of the brain can alter brain function by injecting electrical signals into neurons. A deep brain stimulator (DBS) implant is a remarkable treatment that manipulates basal ganglia to relieve the rigidity of Parkinson’s disease 5. However, this device does not establish a communication link with the patient.
Electric Neural Interface Prosthetics
Neural interfaces are connections that enable two-way exchange of electrical information with the peripheral and central nervous systems (PNS and CNS). This communication is via implantable electrodes that transduce electric signals to and from bioelectric signals (Figure 1) 6. These interfaces can occur at multiple levels, including with peripheral nerves, with the spinal cord, or with the brain; in many instances, fundamental biophysical and biological challenges are shared across these levels.
The primary requirements of these electrodes include communication with as many individual neurons as possible with a high degree of signal-to-noise ratio (SNR) for specific time periods that may extend from hours to years 7 8.
This translates toward a requirement for new electrode materials to develop high-density neural probes that are biologically transparent and biocompatible 9, support seamless integration with neurons 8, and remain functional for long period of time 10. Many materials that were not originally developed for neural interfaces have been recently applied for neural recording and stimulation.
The challenges to develop functional neuroprosthetics require a highly multidisciplinary approach, involving very different and disperse scientific communities, making it fundamental to create connections and to join research efforts.
To design neuroprosthetic devices, six main research topics are typically involved:
- Interfacing of neural systems at different levels of architectural complexity (from in vitro neuronal ensembles up to the intact human brain).
- Bio-artificial interfaces for stimulation and recording.
- Innovative signal processing tools for coding and decoding of neural activity.
- Biomimetic artificial neural networks and neural network modelling.
- Functional communication with the nervous system.
- Creation of a new generation of neuroprostheses, including closed-loop systems.
Multi-Site Electrical Recording
Current electrical recording technologies in Neuroscience research are held back by the difficulty of fabrication. An electrode is connected to a plug, which is connected to a pre-amplifier, which is then connected to digitization equipment. These components are fabricated separately and then assembled by hand, limiting their minimum size. For that reason, the number of simultaneously recorded neurons have in the past not scaled with Moore’s law (doubling every 2 years), as it arguably should, but far slower (doubling every 7 years). While there are some systems under development aimed at locally multiplexing of neural signals, they are still generally based on specialized hardware unlikely to scale efficiently.
Figure 1. Ways that neural interfaces communicate with the nervous system via implantable electrodes 11. a) Eight-channel silicon substrate acute Michigan electrode 12 b) High-magnification photograph illustrating four different types of sites layouts for Michigan electrode (NeuroNexus Technologies) 12. c) SEM image of a single gold site of Michigan electrode 13. d) BrainGate microelectrode array (i.e. Utah array) connected by a 13 cm ribbon cable to percutaneous Ti pedestal 14. e) High-magnification image of an electrode of Utah array 15. f) Multiple boards stacked up to form arrays with up to 128 microwires 10. g) SEM image of a microwire, showing Au tip coated with parylene. h) SEM image of 100 microelectrodes of Utah electrode array 14. i) An epiretinal vision prosthesis, final implant with parylene C and silicone rubber encapsulation. j) Heat molded and annealed retinal electrode array with retained spherical curvature (arrow denotes retinal tack hole) 16. k) Fully assembled electrode array. The diameter of the coin is 16 mm. l) Optical image of silk-supported polyimide electrode arrays of a 25 μm mesh wrapped onto a glass hemisphere 17. m) Schematic cross-section of the channel pattern showing the structure neutral plane (strain & 0%) at the electrode layer 18. n) Transversal intrafascicular multichannel electrode 19. o) Enlarged view of the sieve portion of the regenerative electrodes, with nine ring electrodes around via holes and a larger counter electrode 20. p) Fabricated PDMS-substrate MEA wrapped around a wire of similar diameter (2 mm) to that of the neonatal intact or hemisected juvenile in vitro rat spinal cord 21. q) Distal aspect of paddle-style epidural electrode prepared with a 3–0 suture passed and knotted through the tip. The knot serves as a fixation point for wire snare 22.
Materials used in the manufacture of neuroprosthetics
Since these prostheses are implanted directly into the brain, biocompatibility is a very important obstacle to overcome. Crossing the blood–brain barrier (BBB) can introduce pathogens or other materials that may cause an immune response. The brain has its own immune system that acts differently from the immune system of the rest of the body. The failure of chronic neural implants has been linked to the biocompatibility of the interface, which induces a foreign body response of the neural tissue to the implanted electrodes leading to local inflammation and cell death. The biocompatibility of the interface ultimately relies on the specifics of the material properties to enable a long-lasting functional interface 9 10 23.
During the manufacturing process and development of neural interfaces, several considerations must therefore be addressed:
- Materials used in the housing of the device
- Electrode material
- Electrode insulation
- Electrode-tissue interfaces
- Subject to International Standards and therefore the relevant International Organization for Standardizations (ISOs)
The current state of neural prosthetic devices clearly indicates significant advances in materials science approaches have taken place over the last several years. These strategies include:
- Optimizing the size, shape, tip geometry, texture, flexible substrate, and biodegradable coating to minimize initial trauma and micromotion damage to the brain.
- Employing metals, metal oxides, conducting polymers, carbon nanotubes, silicon nanowires, graphene, and composites to decrease the initial impedance of the electrode.
- Applying bioactive coatings such as neurotrophins to enhance the growth of neuronal processes and the systemic or local delivery of anti-inflammatory drugs to reduce the reactive tissue response and gliosis.
Electrode substrate materials
Several materials have been explored for the electrode substrate, including: silicon, ceramic, glass, sapphire, and polymers 24 25 23. For targeting specific regions of the brain, microwires and glass micropipette electrodes have been used. Later, silicon shafts were utilised and then even more complex micromachined silicon and polyimide flexible recording systems capable of monitoring neuron networks with improved temporal and spatial resolution 26 27.
Table 1 summarizes the materials that have been utilized for neural interface technologies:
Table 1. Comparison of microelectrode technologies 11
Latest developments in manufacturing methodology
Recent advances in additive manufacturing methods have enabled the rapid production of static 3D structures 39. However, they exhibit some limitations that restrict their utility. First, they cannot easily generate structures with freely moving parts. Moving components, such as valves and pumps, require control in fabrication in the z axis, followed by the alignment and integration of unattached components. Second, current methods have limitations in constructing entirely biocompatible medical devices.
Implantable microelectromechanical systems (iMEMS) devices 40 41 feature moving parts manufactured with methods developed for silicon and metals: thin-film deposition, photolithography, and etching 42, but silicon-based materials present challenges as implantable devices because of their low biocompatibility 43. This limitation extends to implantable electronic devices that use silicon-based transistor circuits, which further require a reliable power supply via either a toxic battery or electronic interconnects between the interior and exterior of the body.
Although there are various wireless modes of activation of iMEMS-based devices (such as electromagnetic methods, body-energy harvesting techniques, and ultrasonic powering), most reported methods involve the incorporation of electronic components that are non-biocompatible 44.
However, more recently, poly(ethylene glycol) (PEG)–based hydrogels (Figure 2) have been used 45 because:
- They exhibit very high biocompatibility.
- They have surface properties that make them insusceptible to contamination.
- Exhibit high flexibility.
- Allow conformal contact to surrounding tissues.
- Some have demonstrated safety in humans, with approval by the U.S. Food and Drug Administration (FDA) 46.
- Some PEG-based hydrogels are biodegradable or can be synthetically modified to be biodegradable.
- Can be chemically modified or grafted with proteins, forming bioactive sites.
Figure 2. Three-dimensional fabrication of implantable micromachines (iMEMS) 45.
Neural interface devices have a large design space in terms of size, shape, and function; distinct and diverse neural targets prohibit a one-size-fits-all approach. In the next 3-5 years, there is potential for significant progress for neural interface technologies. Continued application-driven advances will increase the selectivity, sensitivity, precision, bandwidth, reliability, and functional lifetimes of implantable neuroprosthetics. This will be discussed in more detail in the second part of this fascinating topic.
- Evarts, E. V. Pyramidal tract activity associated with a conditioned hand movement in the monkey. J. Neurophysiol. 29, 1011 LP-1027 (1966).
- Lebedev, M. A. & Nicolelis, M. A. L. Brain–machine interfaces: past, present and future. Trends Neurosci. 29, 536–546 (2017).
- Wolpaw, J. R., Birbaumer, N., McFarland, D. J., Pfurtscheller, G. & Vaughan, T. M. Brain&computer interfaces for communication and control. Clin. Neurophysiol. 113, 767–791 (2017).
- Velliste, M., Perel, S., Spalding, M. C., Whitford, A. S. & Schwartz, A. B. Cortical control of a prosthetic arm for self-feeding. Nature 453, 1098–1101 (2008).
- Benabid, A. L., Chabardes, S., Mitrofanis, J. & Pollak, P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol. 8, 67–81 (2017).
- Wise, K. D. Silicon microsystems for neuroscience and neural prostheses. IEEE Engineering in Medicine and Biology Magazine 24, 22–29 (2005).
- Hochberg, L. R. et al. Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature 485, 372–375 (2012).
- Buzsaki, G. Large-scale recording of neuronal ensembles. Nat Neurosci 7, 446–451 (2004).
- Polikov, V. S., Tresco, P. A. & Reichert, W. M. Response of brain tissue to chronically implanted neural electrodes. J. Neurosci. Methods 148, 1–18 (2005).
- Nicolelis, M. A. L. et al. Chronic, multisite, multielectrode recordings in macaque monkeys. Proc. Natl. Acad. Sci. 100, 11041–11046 (2003).
- Fattahi, P., Yang, G., Kim, G. & Abidian, M. R. A Review of Organic and Inorganic Biomaterials for Neural Interfaces. Adv. Mater. 26, 1846–1885 (2014).
- Kipke, D. R. et al. Advanced Neurotechnologies for Chronic Neural Interfaces: New Horizons and Clinical Opportunities. J. Neurosci. 28, 11830 LP-11838 (2008).
- Cui, X. & Martin, D. C. Electrochemical deposition and characterization of poly(3,4-ethylenedioxythiophene) on neural microelectrode arrays. Sensors Actuators B Chem. 89, 92–102 (2003).
- Hochberg, L. R. et al. Neuronal ensemble control of prosthetic devices by a human with tetraplegia. Nature 442, 164–171 (2006).
- Negi, S., Bhandari, R., Rieth, L., Van Wagenen, R. & Solzbacher, F. Neural electrode degradation from continuous electrical stimulation: Comparison of sputtered and activated iridium oxide. J. Neurosci. Methods 186, 8–17 (2010).
- Rodger, D. C. et al. Flexible parylene-based multielectrode array technology for high-density neural stimulation and recording. Sensors Actuators B Chem. 132, 449–460 (2008).
- Kim, D.-H. et al. Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics. Nat Mater 9, 511–517 (2010).
- Lacour, S. P. et al. Flexible and stretchable micro-electrodes for in vitro and in vivo neural interfaces. Med. Biol. Eng. Comput. 48, 945–954 (2010).
- Hassler, C., Boretius, T. & Stieglitz, T. Polymers for neural implants. J. Polym. Sci. Part B Polym. Phys. 49, 18–33 (2011).
- Negredo, P., Castro, J., Lago, N., Navarro, X. & Avendaño, C. Differential growth of axons from sensory and motor neurons through a regenerative electrode: A stereological, retrograde tracer, and functional study in the rat. Neuroscience 128, 605–615 (2004).
- Meacham, K. W., Giuly, R. J., Guo, L., Hochman, S. & DeWeerth, S. P. A lithographically-patterned, elastic multi-electrode array for surface stimulation of the spinal cord. Biomed. Microdevices 10, 259–269 (2008).
- MacDonald, J. D. & Fisher, K. J. Technique for Steering Spinal Cord Stimulator Electrode. Oper. Neurosurg. 69, ons83-ons87 (2011).
- Rousche, P. J. et al. Flexible polyimide-based intracortical electrode arrays with bioactive capability. IEEE Transactions on Biomedical Engineering 48, 361–371 (2001).
- Kuperstein, M. & Whittington, D. A. A Practical 24 Channel Microelectrode for Neural Recording in Vivo. IEEE Transactions on Biomedical Engineering BME-28, 288–293 (1981).
- Blum, N. A., Carkhuff, B. G., Charles, H. K., Edwards, R. L. & Meyer, R. A. Multisite microprobes for neural recordings. IEEE Transactions on Biomedical Engineering 38, 68–74 (1991).
- Biran, R., Martin, D. C. & Tresco, P. A. The brain tissue response to implanted silicon microelectrode arrays is increased when the device is tethered to the skull. J. Biomed. Mater. Res. Part A 82A, 169–178 (2007).
- Abidian, M. R., Corey, J. M., Kipke, D. R. & Martin, D. C. Conducting-Polymer Nanotubes Improve Electrical Properties, Mechanical Adhesion, Neural Attachment, and Neurite Outgrowth of Neural Electrodes. Small 6, 421–429 (2010).
- Salcman, M. & Bak, M. J. Design, Fabrication, and In Vivo Behavior of Chronic Recording Intracortical Microelectrodes. IEEE Transactions on Biomedical Engineering BME-20, 253–260 (1973).
- Nicolelis, M. A. L. Brain-machine interfaces to restore motor function and probe neural circuits. Nat Rev Neurosci 4, 417–422 (2003).
- Qing, Q. et al. Nanowire transistor arrays for mapping neural circuits in acute brain slices. Proc. Natl. Acad. Sci. 107, 1882–1887 (2010).
- Robinson, J. T. et al. Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits. Nat Nano 7, 180–184 (2012).
- Hoogerwerf, A. C. & Wise, K. D. A three-dimensional microelectrode array for chronic neural recording. IEEE Transactions on Biomedical Engineering 41, 1136–1146 (1994).
- Wise, K. D. et al. Microelectrodes, Microelectronics, and Implantable Neural Microsystems. Proceedings of the IEEE 96, 1184–1202 (2008).
- Branner, A., Stein, R. B., Fernandez, E., Aoyagi, Y. & Normann, R. A. Long-term stimulation and recording with a penetrating microelectrode array in cat sciatic nerve. IEEE Transactions on Biomedical Engineering 51, 146–157 (2004).
- Muthuswamy, J., Okandan, M. & Jackson, N. Single neuronal recordings using surface micromachined polysilicon microelectrodes. J. Neurosci. Methods 142, 45–54 (2005).
- Hofmann, P. N. and M. K. and A. M. and K. Y. and U. G. A 32-site neural recording probe fabricated by DRIE of SOI substrates. J. Micromechanics Microengineering 12, 414 (2002).
- Raupp, K.-K. L. and J. H. and A. S. and S. M. and G. E. and B. K. and G. Polyimide-based intracortical neural implant with improved structural stiffness. J. Micromechanics Microengineering 14, 32 (2004).
- Cheung, K. C., Renaud, P., Tanila, H. & Djupsund, K. Flexible polyimide microelectrode array for in vivo recordings and current source density analysis. Biosens. Bioelectron. 22, 1783–1790 (2007).
- Tumbleston, J. R. et al. Continuous liquid interface production of 3D objects. Science (80-. ). 347, 1349 LP-1352 (2015).
- Al-Sarawi, A. C. T. and M. F. and S. F. Secure wireless actuation of an implanted microvalve for drug delivery applications. Smart Mater. Struct. 20, 105011 (2011).
- Gensler, H., Sheybani, R., Li, P.-Y., Lo, R. & Meng, E. An Implantable MEMS Micropump System for Drug Delivery in Small Animals. Biomed. Microdevices 14, 483–496 (2012).
- GRAYSON, A. C. R. et al. A BioMEMS review: MEMS technology for physiologically integrated devices. Proceedings of the IEEE 92, 6–21 (2004).
- Voskerician, G. et al. Biocompatibility and biofouling of MEMS drug delivery devices. Biomaterials 24, 1959–1967 (2003).
- Hannan, M. A., Mutashar, S., Samad, S. A. & Hussain, A. Energy harvesting for the implantable biomedical devices: issues and challenges. Biomed. Eng. Online 13, 79 (2014).
- Chin, S. Y. et al. Additive manufacturing of hydrogel-based materials for next-generation implantable medical devices. Sci. Robot. 2, (2017).
- Hoare, T. R. & Kohane, D. S. Hydrogels in drug delivery: Progress and challenges. Polymer (Guildf). 49, 1993–2007 (2008).