Tech Overview: Neuroprosthetics Part 2
Implantable neural interfaces have achieved remarkable medical advances in the treatment of the most challenging conditions, starting with the introduction of the first implantable pacemaker in 1958. Increasing demand for innovation in existing and novel implantable devices is fuelled by the growing ageing population and the increased prevalence of chronic diseases.
Chapter I provided an overview of the implantable neural interface ecosystem, including the fabrication strategies of neural interfaces and the materials used in their manufacture. This chapter concluded by summarizing the latest developments in manufacturing methodology. Chapter II highlights novel research developments, and discusses challenges and opportunities for translation of new innovative implants enabled by microtechnologies and microfabrication.
Current Neural Interface Technologies
Previous implantable electrodes for neurobiology research or clinical use were metal wire bundles and arrays 1. Most of these were fabricated using conducting metals, including platinum, gold, tungsten, iridium and stainless steel, and their surfaces (except for the tip) were coated with a non-cytotoxic insulator material 2. Subsequently developed implantable neural electrodes, predominantly silicon-based needle arrays, have become standard tools in neuroscience research; some have been implanted in humans in first-of-their-kind clinical trials 3.
Recent progress in neural engineering, materials science and microtechnology has helped provide novel concepts for directly linking the nervous system to external devices 4. One of the highest priorities among required technologies is an implantable electrode with mechanical properties similar to those of soft tissue 5. These electrodes serve a pivotal role – interfacing with the tissue at one end and with electronics at the other to deliver a stimulus or record bioelectrical signals. For practical use, these devices should be chronically implantable, biocompatible and biostable, and they should be small enough to allow signals from a focused region of the brain or nerve to be measured. However, in most cases, microelectrodes inserted in the brain fail to record signals after several months to a few years after implantation 2, 6. This loss of signal is thought to result primarily from the inflammatory response evoked by electrode insertion and subsequent relative motion, both of which are crucial problems associated with implantable electrodes that must be addressed 7.
The applications of diverse implantable electrodes are at present limited to health monitoring, diagnosis and treatment of diseases and prosthetics. In the future, these devices could be extended to applications such as military use, consumer electronic products, authentication and car-driver interfaces 8 (Figure 1). As implantable electrode technology progresses and most associated problems—including biocompatibility, foreign body responses and integration of diverse functions through microfabrication technology—are addressed, this technology will come to transcend the limits of wearable devices, ultimately enhancing the quality of life and opening new industries.
Figure 1. Schematic illustration of possible future work on implantable electrode applications. During combat, implantable electrodes can notify soldiers’ biopotentials and the signals can augment survival rate of the soldiers by personal bio-information management. Using biopotential information, a private informatics security service can be extended by applying precise biopotential signals such as ECG and EEG from soft material based implantable electrodes. Consumers can be better connected to their cars, pets, electronic devices, and houses by sending and receiving bio-potential signals, allowing for deeper personalization. Human diseases can be detected and prevented in advance by detection of specific biopotentials from implantable electrodes 8.
Emerging Trends and Future Applications (0-5 years)
Neural Recording and Stimulation
Large-scale recordings from neurons reveal the information available from the interaction of the neuronal ensembles. In addition, recording from many neurons will reduce the number of animals and their husbandry costs. However, massive parallel recording from multiple single neurons requires high-density neural electrode arrays 9. Furthermore, recording from hundreds or even thousands of neurons using these electrodes increases tissue damage. Thus, an ideal recording electrode needs to have a small volume to minimize tissue damage, many recording sites to monitor multiple single neurons, and small surface geometry recording sites to increase the selectivity to individual neurons 10. However, these competing requirements are difficult to achieve using present technology.
Ideally, innovative large-scale chronic neural electrodes should be:
- Stable electrical properties.
- Low impedance at the electrode-electrolyte interface.
- Have low stray
- Have a high signal to noise ratio (SNR) through stable conduction and insulation 10.
- Self-charging, therefore removing the need for costly and risky surgeries to change implant batteries.
- Appropriate mechanical properties such as softness and flexibility to minimize the mechanical trauma during electrode insertion and brain micromotion 11.
- Acceptable chemical and physical properties to promote the biocompatibility of the electrode-tissue interface 12.
Building on the potential of additive manufacturing for human health applications, implantable microelectromechanical systems (iMEMS) technology works with biomaterials that are well tolerated in the human body. However, current methods for 3D printing of hydrogels 13 are limited to spatial resolutions of >200μm and cannot easily assemble structures with separate individual components, which may be needed for moving parts. The construction and demonstration of the in vivo function of the hydrogel-based iMEMS 14, which features an intricate design wherein a driving gear must correctly engage a driven gear, strongly suggest that hydrogel materials, although often soft and compliant, can be tuned such that they make suitable materials for constructing complex MEMS-like devices.
The iMEMS strategy addresses several fundamental considerations in building biocompatible neuroprosthetics:
- How to power small robotic devices? (because batteries are toxic)
- How to make small biocompatible moveable components? (because silicon has limited biocompatibility)
- How to communicate wirelessly once implanted? (because radio frequency microelectronics require power, are relatively large, and are not biocompatible) 15 3.
The ability to manufacture spatially complex biocompatible components, including freely moving parts, which can respond magnetically, enables continuous control and powering of the implanted microdevices without the need for on-board electronics or a battery. In the near future, such microscale components can be used for MEMS, larger devices (ranging from drug delivery to cardiac pacemakers) 16, and soft robotics 17.
Finally, actuation of implanted components by magnetism could be particularly useful for interventions close to the skin surface, such as subcutaneous delivery (such as delivery of therapies for melanomas, wound healing, and scar prevention) or control over other superficially implanted systems (such as cerebral shunt systems). Potentially, the iMEMS fabrication strategy could incorporate small implantable components responsive to other stimuli (such as temperature, pH, and light) as well as ultrasound, which could penetrate deep into the tissue of interest 18.
Once the neural probe is implanted in our brain, the insertion site is constantly damaged due to micromotion of the brain. Micromotion of the brain is caused by changes in blood pressure induced by cardiac pulsation and breathing. The first soft material that was explored was polyimide 19, 20, 21 which was initially used as a coating material in the early stage of development. With the advent of soft lithography, polyimide is now often used as the main substrate material. The work on all-polyimide neural probes demonstrated less immunoreactivity around the implant. However, no long-term chronic recording data was provided to conclude any direct relationship between the use of polyimide to chronic reliability 22. In fact, over the past decade, neural probes based on a vast number of soft materials such as parylene-C 23, 24, polycarbonate 25, SU-8 26, and benzocyclobutene (BCB) 27 have been reported.
Future directions (5 years +)
In the mid- to long-term it is possible that ultralow-power wireless neural interface systems will become widely used which are life-lasting, fully integrated and support bidirectional data flow with high bandwidth.
Interfaces with the PNS
Reliable neural interfaces between peripheral nerves and implantable devices are at the center of advanced neural prosthetics and bioelectronic medicine. Recording from and stimulating peripheral nerves is an area of increasing importance, especially for restoring control of paralyzed limbs or for dexterous control of advanced bionic limbs 28 and 29. Due to many physiological and anatomical difficulties in accessing small nerves, the precise targeting and modulation of neural signals in the PNS has remained elusive.
One method is to use flexible split ring electrodes that consist of two layers of biocompatible polyimides with Au/Pt electrodes sandwiched in a split ring-shaped geometry. Due to its unique design, split ring electrodes can be used for quick and easy implantation at any desired position on peripheral nerves, and therefore be used effectively for neuromodulation.
Enhancing cognitive function
Augmentation of normal function has been an emerging trend in the field of neural interfaces. The use of electrical stimulation can be used not only to repair lost function, but also to enhance some types of cognitive function, such as spatial memory. For example, in 2012, researchers at the University of California used a technique similar to DBS to enhance spatial memory 30. Based on the idea that the medial temporal structures, including the hippocampus and the entorhinal cortex, are critical to our ability to transform daily experience into lasting memories, they applied DBS at these specific sites while subjects were taught to navigate a virtual city environment with a joystick, picking up passengers and delivering them to specific stores. Appropriate electrical stimulation to the brain during the game task increased their speed and accuracy in accomplishing the task 31.
Wireless Technology and Packaging
To perform a stable chronic recording, the neural probe must be packaged and secured to the head of the animal using an adhesive or dental cement 32. This tether on the skull exerts a tangential force not only at the tip of the neural probe but also at the surface of the brain to the tip of the neural probes 33. Thus, a flexible interconnect and printed circuit board (PCB) have been proposed 22. Another strategy was to use a Teflon sheet between the implant and the dura and Gore-Tex® between the dura and cranium to prevent adhesion between the dura and the arrays. Plugging and unplugging of cables from the external head stage is another source of strain exerted between the neural probe and the surrounding tissue 34. In addition, a wired connection is undesirable for clinical applications 35. Thus, wireless transmission systems for the neural probes are continuously being developed to achieve a larger number of channel interfaces, higher bit rates, and low power consumption 36.
The neural dust design promises to overcome a serious limitation of current invasive neural interfaces: the lack of an implantable neural interface system that remains viable for a lifetime 37.
The neural dust system has three basic elements:
- Thousands of low-power CMOS chips — “neural dust” — are embedded (via fine-wire arrays that are then removed) into the cortex between neurons. They detect extracellular electrophysiological signals via an electrode and a piezoelectric sensor converts the signals into ultrasonic signals.
- A subdural ultrasonic transceiver (transmitter + receiver) receives ultrasonic signals from the neural dust. It also powers the neural dust with ultrasonic energy.
- A battery-powered external transceiver communicates via ultrasound with the subdural transceiver and transmits the data to an external computer.
Embedded ~2 mm into the brain, the powered neural dust chips can be as small as tens of microns. Ultrasound is attractive for in-tissue communication given its short wavelength and low attenuation. The design also uses more efficient “backscattering”: instead of transmitting energy, the chips passively modulate ultrasonic energy from the sub-dural transceiver and reflect it back (Figure 2).
Figure 2. The Neural dust system. The ultrasonic transceiver is placed under the skull, the neural dust sensing nodes dispersed throughout the brain and the external transceiver on top of the skull 37.
Although soft electrode technology has rapidly progressed, fabrication of electrodes with precise geometry and spacing, which is vital for neuroscience research, is still challenging. Despite these challenges, the diversity of new materials has led to enhancements in the flexibility of electrode shape, surface modification (e.g., for improved biocompatibility) and function (e.g., drug release), and has thus extended the range of their biomedical applications. As such, these newly developed soft materials play a key role in enhancing the performance of neural interfaces (21).
Current issues that need to be resolved
In understanding the neural code, there is a long way to go. We need not only better tools for detecting signals from brain, but also more precise tools for sending information back, in addition to a different understanding of how different kinds of neurons work and how complex circuits work together. The fMRI brain images that have become so popular, have poor resolution and have been under criticism for its high rate of false positive results 38. Firstly, they measure changes not in electrical activity but in local blood flow, an imperfect surrogate of actual neural activity. Secondly, they have poor resolution. Each three-dimensional pixel (or “voxel”) in a brain scan contains a half-million to one million neurons. We still do not know how individual neurons work together to form circuits that translate into perception, consciousness and memory.
Neural probe technology has advanced over the past 50 years. The biological processes that are involved in the electrode-tissue interface have been extensively examined and investigated to improve chronic reliability of the interface. Although the exact effects of various design factors on the long-term recording capability are still unknown, several desired features have been identified based on a large amount of studies: small dimensions, flexibility, and biocompatibility. However, the status of the chronic performance is still in the order of weeks while many clinical applications such as neuroprosthetics require a long-term reliability in the order of years or decades. Although the maximum required period for animal studies is different from the clinical studies, at least 12 weeks of chronic recording data should be provided to fully account for the chronic immune response. With continuous innovations in the field and the strong scientific drive to understand the brain, the neural probe technology will advance in the near future to meet the stringent requirements of many interesting chronic applications.
Innovations in molecular biology, neuroscience and material science are almost certainly going to lead, in time, to implants that are smaller, safer and more energy-efficient. Coupled with powerful computers, advances in artificial intelligence (AI) and tools to decode the massive information received, these devices will be able to interpret directly the electrical activity inside the brain. Soon, they will transition from being used exclusively for severe problems such as paralysis, amnesia and mental disorders and start being used by people with less traumatic disabilities and even enhancing and augmenting human performance. They will be used to improve memory, concentration, sensory perception and mood. However, the ethical considerations of these advances must be carefully considered, as these cutting-edge biomedical technologies become more available and its consequences less predictable.
In conclusion, seamless physiological integration of neural probes with the CNS and PNS has the potential to revolutionize our understanding of the brain and spinal cord and to significantly enhance the quality of life in individuals with compromised neural and motor function due to disease or trauma.
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