As with any material implanted in the body, it is important to minimize or eliminate foreign body response and maximize effectual integration. Neural implants have the potential to increase the quality of life for patients with such disabilities as Alzheimer's, Parkinson's, epilepsy, depression, and migraines. With the complexity of interfaces between a neural implant and brain tissue, adverse reactions such as fibrous tissue encapsulation that hinder the functionality, occur. Surface modifications to these implants can help improve the tissue-implant interface, increasing the lifetime and effectiveness of the implant.
Background on Intracranial Electrodes
Intracranial electrodes consist of conductive electrode arrays implanted on a polymer or silicon, or a wire electrode with an exposed tip and insulation everywhere that stimulation or recording is not desired. Biocompatibility is essential for the entire implant, but special attention is paid to the actual electrodes since they are the site producing the desired function.
Issues with Current Intracranial Electrodes One main physiological issue that current long-term implanted electrodes suffer from are fibrous glial encapsulations after implantation. This encapsulation is due to the poor biocompatibility and biostability (integration at the hard electrode and soft tissue interface) of many neural electrodes being used today. The encapsulation causes a reduced signal intensity because of the increased electrical impedance and decreased charge transfer between the electrode and the tissue. The encapsulation causes decreased efficiency, performance, and durability.
Electrical impedance is the opposition to current flow with an applied voltage, usually represented as Z in units of ohms (Ω). The impedance of an electrode is especially important as it is directly related to its effectiveness. A high impedance causes poor charge transfer and thus poor electrode performance for either stimulating or recording the neural tissue. Electrode impedance is related to surface area at the interface between the electrode and the tissue. At electrode sites, the total impedance is controlled by the double-layer capacitance. The capacitance value is directly related to the surface area. Increasing the surface area at the electrode-tissue interface will increase the capacitance and thus decrease the impedance. The equation below describes the inverse relationship between the capacitance and impedance.
where i is the imaginary unit, w is the frequency of the current, C is capacitance, and R is resistance.
A desirable electrode would have a low impedance meaning a higher surface area. One method to increase this area is coating the electrode surfaces with a variety of materials. Many new materials and techniques are being researched to improve the behavior of neural electrodes. Currently, research is being done to increase the biocompatibility and integration of electrodes in neural tissue; this research is discussed in more detail below.
Importance of Surface Chemistry
Surface chemistry of implantable electrodes proves to be more of a design concern for chronically implanted electrodes as compared to those with only acute implantation times. For acute implantations, the main concerns are laceration damage and degradation of particles left behind after electrode removal. For chronically implanted electrodes the cellular response and tissue encapsulation of the foreign body, regardless of degradation – even for materials that are highly biocompatible – are the primary concerns. Degradation, however, is still undesirable because particles can be toxic to tissue, can spread throughout the body, and even trigger an allergic response. Surface chemistry is an area of science applicable to biological implants. Bulk material properties are important when considering applications, however, it is the materials' surface (top several layers of molecules) that determines the biological response and is therefore the key to implant success. Implants within the central nervous system are unique in their manor of cellular response; there is little room for error. Prosthesis in these areas are typically electrodes or electrode arrays.
Electrochemical Considerations Electrodes, especially stimulating electrodes and the high current density they discharge, can raise electrochemical issues. Electrodes will be surrounded by tissue and electrolytes; stimulation, resultant electric fields, and induced polarizations will change local ion concentrations and local pH which can then cause problems such as material corrosion and electrode fouling.
Pourbiax diagrams will show the phases that a material will take in an aqueous environment, based on electrical potential and pH. The brain maintains a pH of around 7.2 to 7.4, and from the Pourbaix diagram of platinum it can be seen that at around 0.8 volts Pt at the surface will oxidize to PtO2, and at around 1.6 volts, PtO2 will oxidize to PtO3. These voltages do not seem to be outside of reasonable range for neural stimulation. The voltage required for stimulation may change significantly over the life of a single electrode. This change is required to maintain a consistent current output through variations in the surrounding environmental resistance. The changes in resistance may be due to: adsorption of material onto the electrode, corrosion of the electrode, encapsulation of the electrode in fibrous tissue – known as a glial scar, or changes in the chemical environment around the electrode. Ohm's law V = I * R shows the interdependence of voltage, current and resistance. When voltage change causes a crossing of equilibrium lines as seen in a Pourbaix diagram during a stimulation, the changing polarization of the electrode is no longer linear. Undesirable polarization can lead to adverse effects such as corrosion, fouling, and toxicity. Because of this equilibrium potential, pH, and required current density should be considered when making material choice since these can affect the surface chemistry and biocompatibility of the implant.
Corrosion Corrosion is a major issue with neural electrodes. Corrosion can occur because electrode metals are placed in an electrolytic solution, where the presence of current can either increase the rate of corrosion mechanisms or overcome limiting activation energies. Redox reactions are a mechanism of corrosion that can lead to dissolution of ions from the electrode surface. There is a base level of metal ions in tissue, however, when these levels increase beyond threshold values the ions become toxic and can cause severe health problems. In addition, the fidelity of the electrode system can be compromised. Knowing the impedance of an electrode is important whether the electrode is used for stimulation or recording. When degradation of the electrode surface occurs because of corrosion, the surface area increases with its roughness. Calculating a new electrode impedance to compensate for the change in surface area once implanted it is not easy. This computational flaw can skew data from recording or pose a dangerous obstacle limiting safe stimulation.
Electrode Fouling Electrode fouling is a major hindrance on the performance of electrodes. Few materials are completely bioinert, as in they trigger no bodily reaction. Some material that may be bioinert in theory fails to be ideal in practice because of defects in their formation, processing, manufacturing or sterilization. Fouling can be caused by adsorption of proteins, fibrous tissue, trapped cells or dead cell fragments, bacteria, or any other reactive particle. Protein adsorption is influenced by the nature and geometry of domains including hydrophobicity, polar and ionic interactions of the material and surrounding particles, charge distribution, kinetic movement, and pH. Phagocytosis of bacteria and other particles is mainly affected by surface charge, hydrophobicity, and chemical composition of the implant. The initial environment the implant is subjected to after implantation is different and unique compared to the environment after some time has passed since the area will undergo wound repair; the body's natural healing of the trauma will cause changes in local pH, electrolyte concentrations, and the presence and activity of biological compounds.
Properties of Metals For many reasons known and unknown, protein adsorption varies from material to material. Two of the biggest determining factors that have been observed are surface roughness and surface free energy. In the case of exposed electrodes, it is desirable to have the adsorbed protein layer as thin as possible to increase sensitivity and performance. Noble metals are an obvious choice for achieving biocompatibility; however, when acting as electrodes, some of these noble metals will actually participate in the reaction, deteriorate, and trigger adverse effects via lost particles. The most (noble metals) are gold (Au), platinum (Pt), and iridium (Ir).
MaterialNobility (in volts, to the simplified product)Surface free energy , (eV/Å2), in (111) planeRMS roughness @ before exposure; 7; 28 days post exposure (nm) Thickness of protein film (nm) @ 1; 7; 28 days post-exposureGold (Au)1.42 V to Au3+0.0781.4; 22; 68 13; 110; 340Platinum (Pt)1.18 V to Pt2+0.1370.8; 51; x11; 113; xIridium (Ir)1.156 V to Ir3+0.2042.4; 29; 185 7; 108; 420 - An x refers to bad data - Nobility is the measure of potential needed to chemically reduce the material; these were measured against a standard hydrogen electrode. - RMS roughness is a measure of deviation from the mean plane. - Protein was measured in vitro with ellipsometry and step-technique atomic force microscopy, with metal in a dilute plasma solution. This is very similar to extracellular fluid, which is suspected to contain the proteins that make first contact with the surface, and form the first adsorbed layer. As stated before this first layer determines the adsorption from then on out.
= Surface free energy Es = Total energy per unit cell at surface Eb = Total energy per unit cell in bulk of material A = Area of surface
The properties of titanium were also investigated in the study that produced the data for the above table, however, its properties are not listed here since its poor conductive properties make it unsuitable for neural implants. Insight on titanium's surface chemistry may give direction to future research. Titanium has the roughest and most hydrophilic surface of any metal described thus far (the importance of protein adsorption, its mechanisms, and the interplay of hydrophilic properties are discusses further in the hydrogels section of the page). Titanium adsorbed the thickest protein layer after the first day and still after the seventh day, but actually had its thickness reduced by the 28th day. Gold, platinum and iridium's protein layers all continued to grow up until the 28th day, but the rates slowed over time.