The field of neuroprosthetics has important applications in medicine and science. In clinical settings, neural stimulation and recording implants promise to introduce new capabilities in restoring functions of the central nervous system (CNS) lost to trauma or disease. In basic research settings, neuroprosthetic devices remain one of the most important tools for those neuroscientists who work to elucidate the brain’s functions. Clinical therapies using neural stimulation include cochlear stimulation for the deaf; epidural spinal stimulation for the treatment of pain ; cortical or vagus nerve stimulation for epilepsy; and several other emerging indications including retinal stimulation for the blind.
Neural stimulation in the brain has an established clinical history and has helped many patients lead a normal life. Deep brain stimulation, for example, targets the subthalamic nucleus to treat Parkinson’s disease and has also been shown efficacious for depression and obesity. In neuroscience, neuroprostheses have been used primarily as neural recording elements, which permit the acquisition of signals from a large number of single units or neuron ensembles in order to study network behaviour or control robotic prostheses. Many of these clinical and scientific applications have been enabled by, or can be improved with, the small size and density of electrode sites that microfabrication technology enables.
Modern microfabrication techniques have been applied to make devices employed in a wide variety of biomedical applications. The small size attainable with this technology enables the manufacture of microelectrodes and microfluidic channels that are used to make unique neuroprosthetic systems. Smaller recording sites can capture more localized neural activity and single unit-cell activity. Smaller stimulation electrodes can activate more defined volumes within tissue. Scaling limits apply to the size of both microelectrodes and microfluidic channels. Therapeutically efficient electrical stimulation levels must be maintained while providing safe charge transfer from metal electrodes. Similarly, therapeutic amounts of fluid must be delivered at safe hydraulic pressures from microfluidic based neuroprostheses.
A major obstacle to the clinical use of microfabrication-based neuroprostheses is the tissue reaction around such devices, associated with the implantation procedure and subsequent chronic injury around the device. The advantages gained in reducing the size of microelectrodes and catheters in these devices are quickly lost as the tissue reaction progresses around the implant. The widespread clinical use of implantable neural probes will be limited unless solutions are developed to counteract the tissue response to electrodes implanted in the brain. This inflammatory response degrades the electrical characteristics of the recording or stimulation site with time. Soon after implantation, a cellular encapsulating sheath forms, composed of glial cells and collagen. This sheath creates a high electrical resistance between the electrodes and tissue and may render the device unusable a few weeks following implantation. As the density and number of glial cells progresses, there is an increase in impedance for stimulation applications, and a decrease in the signal-to-noise ratio, Thus complicating the recording of single unit activity and neural ensembles. This tissue reaction is a major hindrance to the progress of translational research in microfabricated neuroprosthetics.
Ultimately the success of neuroprosthetics in clinical use will be decided on the quality, safety and uniqueness of the technology platforms used to make research devices. By helping neuroscientists ask fundamental questions about the brain, particular insight is gained about the clinical relevance of the treatment of disease and trauma. The diseases of the CNS remain some of the most underserved, and CNS drug compounds are among the most expensive and risky to develop. It is hoped that the field of neuroprosthetics will soon address many of the world’s most debilitating neurological diseases, and that the technologies and methods described in this book will form part of the foundation for the future success of neuroprosthetics.
Problem statement: the tissue reaction to implanted neuroprostheses
The most prominent problem for chronically implanted neuroprostheses is the gradual degradation of the recording or stimulation quality due to tissue reactions around the implant. For biocompatible electrodes implanted in the cortex, the tissue reaction is based on two phenomena; the damage upon insertion, and the continual presence of the implant. The central nervous system (CNS) stages a tissue reaction to implants which is dominated by gliosis resulting from the activation of astrocytes, resulting in the formation of a dense sheath around the implant. Nonlocal cells that have bypassed the bloodbrain-barrier through injured vasculature also surround the implant. The formation of this capsule is not to be misunderstood as non-biocompatibility, it is a normal response to injury in the CNS. Data indicates that device insertion promotes two responses – an initial response that is proportional to device size and insertion damage; and a sustained response that is independent of device size and geometry. The sheath electrically isolates the electrodes from the tissue they are meant to be monitoring and stimulating. The following sections describe what is currently known about the tissue reaction and the problems it causes for neuroprostheses.
The initial response
During the implantation of a cranial neuroprosthesis, blood vessels, neurons and glial cells in the path of the device are damaged. Microhemorrhage occurs and the blood-brain-barrier (BBB) is disrupted. The wound healing response is a cascade of signalling events which is not yet fully understood. The first step of the initial inflammatory response is the covering of the implant’s polymer surface by proteins. Subsequently, fibroblasts and macrophages infiltrate through the disrupted blood-brain-barrier. Activated microglia from the brain also rapidly move to the implantation site. The release of cytokines ensues and foreign body giant cells (FBGC) derived from macrophages may form on the implant’s surface.
Once attached to the material surface, the microglia and macrophages are believed to release neurotoxic molecules – such as nitric oxide and several cytokines – which will activate the astrocytes. A loose encapsulation of cells of up to 200 μm in thickness forms around the device, creating a region in which few neurons are found. The astrocytes extend processes toward and around the injury. After a few weeks, this sheath becomes denser, and a heavy astrocyte presence is observed within 100 μm of the implantation site.
The functionality of a device implanted in the CNS depends on the formation of electrical connections with neuronal axons, and, to a lesser extent, with neuronal dendrites and somas. The electrical connection must be able to record field and single-unit potentials, or stimulate small volumes of neural tissue. However, the regrowth of neuronal processes near the implant, which may have been damaged during implantation, is slower than the gliosis. The sheath prevents neuronal processes from growing towards and contacting the electrodes, forming a high impedance interface between the device and the brain.
During this initial response phase, it is clear that electrode size, shape, and insertion technique can contribute to limiting the extent of the injury. Reducing the initial response requires good device design and insertion technique. Investigators have compared electrode shape and insertion techniques and observed whether electrode size and shape make a difference in the tissue reaction. While histology performed in the first two weeks following implantation did demonstrate a difference in tissue reaction, histology performed several months after implantation showed no correlation between electrode shape and the degree of the tissue reaction. Therefore, electrode size, shape and implantation technique do not determine the long term characteristics of the tissue reaction.
The sustained response
The formation of the cellular sheath is a result of an inflammatory process, intended to prevent ongoing tissue damage; to isolate and destroy the foreign material; and to activate repair processes. The CNS stages an immunological response that is distinct from the rest of the body, involving both different cells and mechanisms. The sustained response is more likely due to chronic tissue-device interactions and results in the formation of a tight cellular sheath around the electrode. Astrocytes, the most prevalent type of glial cell, play a major role in the scar formation around neuroprostheses. The sheath engulfing the neuroprosthesis consists of astrocytes, microglia and a thin layer of collagen, which is probably synthesized by non-CNS cells displaced during the implantation procedure. The microglia are mobile cells that digest fragments of damaged cells. The final layer of the sheath is composed of collagen. Several weeks after implantation, the cellular sheath becomes denser and thinner, typically consisting of 4 to 6 layers of tightly packed glial cells. This thin encapsulating sheath renders the probe electrically unusable in many cases.
Effect of tissue reaction on recording and stimulation
The main objective of neuroprosthetic devices is to record from and stimulate neural tissue. However, the tissue reaction described above limits these functionalities. The negative effect on recording capabilities occurs because the tissue reaction isolates neurons from the electrodes through a dense, highimpedance cellular sheath. In an extensive study on singleand multi-unit recordings, Nicolelis et al. have reported recordings from as many as 247 separately recorded neurons in the first weeks after implantation in a macaque cortex, with a decrease to 58 recorded neurons 18 months after implantation.
In neurostimulation systems, the sheath increases the amplitude of the stimulation signal necessary for activation. It alters the signal waveform when stimulating with constant voltage, and it decreases the specificity of the volume of tissue stimulated. Higher amplitude signals will more quickly deplete the battery of implantable pulse generators. The electrical stimulation threshold may ultimately become too great for the electrode material to function at safe reversible current densities.
Microelectrode array-based neuroprostheses are the most advantageous technology for accessing neuron volumes in different applications. However, because of the size of microelectrodes, the tissue reaction is particularly detrimental to their operation. One study from a University of Michigan group that produces silicon-microelectrode arrays has reported good long-term recording capabilities for 52 weeks. However, it is well known in practice – as several independent studies have shown – that silicon-based neuroprostheses can only record action potentials successfully for one to three weeks.
There are a limited number of in vivo results that demonstrate how the tissue reaction affects the signal-to-noise ratio and single unit recordings of microelectrodes, but these do not quantitatively characterize the extent of the reaction. Furthermore, different animal models will have different tissue reaction mechanisms, potentially exhibiting different degrees of tissue reaction. Several groups have performed impedance measurements on implanted devices, but their methods do not offer thorough tissue characterisation. Until now, there has been no quantitative method to determine the time progression of the tissue reaction and its specific electrical characteristics, and how these affect the recording and stimulation capabilities of neuroprostheses…