基于硅基电极的脑组织微动损伤仿真

目的:为预测脑组织微动损伤和解决植入电极的长期寿命问题,本研究基于硅基微电极进行建模,并对神经电极-脑组织有限元模型进行数值仿真。 方法:采用超黏弹性模型描述脑组织材料,研究不同微动模式（纵向和横向）、不同物理耦合度下电极附近脑组织应变分布。 结果:纵向载荷分析显示当摩擦系数?增加时,脑组织最大von Mises应变呈降低趋势,并且电极尖端附近的组织应变最大,这表明电极与脑组织之间的物理耦合度对脑组织微动损伤有较大影响。增强电极和脑组织间的黏附程度,可以有效减小脑组织损伤。电极尖端的形状也极大地影响着组织的应变大小。横向载荷分析显示X轴方向的载荷产生的脑组织损伤区域大约为60 ?m,这表明电极之间的间距应大于60 ?m,否则不同电极产生的组织应变会发生重叠,这对于电极之间理想间距的设计和防止重叠应变形成多余的细胞鞘有着重要的意义。 结论:数值仿真模型可以为电极-脑组织界面参数和电极间距设计参数提供参考,从而减少组织损伤,提高电极工作寿命,满足临床应用。     

Intracortical polyimide electrodes with a bioresorbable coating

Polyimide based shaft electrodes were coated with a bioresorbable layer to stiffen them for intracortical insertion and to reduce the mechanical mismatch between the target tissue and the implanted device after degradation of the coating. Molten saccharose was used as coating material. In a proof-of-concept study, the electrodes were implanted into the cortex of Wistar rats and the insertion forces during implantation were recorded. Electrochemical impedance spectroscopy was performed immediately after implantation and up to 13 weeks after implantation to monitor the tissue response to the implanted electrodes. The recorded spectra were modeled with an equivalent circuit to differentiate the influence of the single components. In one rat, a peak in the encapsulation resistance was observable after two weeks of implantation, indicating the peak of the acute inflammatory response. In another rat, the lowest resistances were observed after four weeks, indicating the termination of the acute inflammatory response. Multiunit activity was recorded with an adequate signal to noise ratio to allow spike sorting. Histology was performed after 7, 45 and 201 days of implantation. The results showed the highest tissue reaction after 45 days and confirmed impedance data that acute inflammatory reactions terminate over time.     

Highly-compliant,microcable neuroelectrodes fabricated from thin-film gold and PDMS

Bio-electrodes have traditionally been made of materials such as metal and silicon that are much stiffer than the tissue from which they record or stimulate. This difference in mechanical compliance can cause incomplete or ineffective contact with the tissue. The electrode stiffness has also been hypothesized to cause chronic low-grade injury and scar-tissue encapsulation, reducing stimulation and recording efficiency. As an initial step to resolve these issues with electrode performance, we have developed and characterized electrically-functional, low-Young’s modulus, microcable-shaped neuroelectrodes and demonstrated electrophysiological recording functionality. The microcable geometry gives the electrodes a similar footprint to traditional wire and microwire neuroelectrodes, while reducing the difference in Young’s modulus from nervous tissue by orders of magnitude. The electrodes are composed of PDMS and thin-film gold, affording them a high-level of compliance that is well suited for in vivo applications. The composite Young’s modulus of the electrode was experimentally determined to be 1.81 ± 0.01 MPa. By incorporating a high-tear-strength silicone, Sylgard 186, the load at failure was increased by 92%, relative to that of the commonly used Sylgard 184. The microcable electrodes were also electromechanically tested, with measurable conductivity (220 kΩ) at an average 8% strain (n = 2) after the application of 200% strain. Electrophysiological recording is demonstrated by wrapping the electrode around a peripheral nerve, utilizing the compliance and string-like profile of the electrode for effective recording in nerve tissue.     

Polylysine-Modified PEG-Based Hydrogels to Enhance the Neuro–Electrode Interface

Neural prostheses are a promising technology in the treatment of lost neural function. However, poor biocompatibility of these devices inhibits the formation of a robust neuro–electrode interface. Several factors including mechanical mismatch between the device and tissue, inflammation at the implantation site, and possible electrical damage contribute to this response. Many researchers are investigating polymeric brain mimetic coatings as a means to improve integration with nervous tissue. Specifically, hydrogels, constructs also employed in tissue engineering, have been explored because of their structural and mechanical similarity to native tissue. However, many hydrogel materials (e.g., poly(ethylene glycol) (PEG)) do not support cell adhesion. In this work, we report a technique to enhance the interface between polymeric brain mimetic coatings and neural tissue using adhesion molecules. In particular, polylysine-modified PEG-based hydrogels were synthesized, characterized and shown to promote neural adhesion using a PC12 cell line. In addition, we examined adhesion behavior of a PEG-co-polymer and found that these materials adhere to electrodes for at least 4 weeks. These results suggest that polylysine–PEG hydrogel biomaterials are biocompatible and can enhance stability of chronic neural interfaces.     

Bioactive anti-inflammatory coating for chronic neural electrodes

Chronic electrodes are widely used for brain degenerative and psychiatric daises such as Parkinson's diseases, major depression, and obsessive-compulsive disorder, and for neuronal prosthesis. Brain immune reaction to electrodes in the form of glial scar encapsulates the electrode and reduces the efficacy of deep brain stimulation and neuronal prosthesis. State-of-the-art strategies for improving brain-electrode interface use passive protein coating to "camouflage" the electrode from the immune system. In this study, we actively reduced the brain immune reaction to the chronic electrodes using immune suppressing protein, that is, interleukin (IL)-1 receptor antagonist. IL-1 receptor antagonist-coated electrodes and noncoated electrodes were chronically implanted in rats. An additional group of rats was chronically implanted with IL-1 receptor antagonist- and laminin-coated electrodes (as passive protein). Examination of glial scaring 1ne and 4 weeks after implantation indicated a significant reduction in the amount of glial scar in the vicinity of the IL-1 receptor antagonist-coated electrode in comparison to both noncoated electrode and laminin-coated electrodes. The results strongly suggest that active immune suppressing protein reduces the level of immune reaction to chronic electrodes already after 1 week after implantation and generates less immune reaction then passive protein coating.     

Novel multi-sided,microelectrode arrays for implantable neural applications

A new parylene-based microfabrication process is presented for neural recording and drug delivery applications. We introduce a large design space for electrode placement and structural flexibility with a six mask process. By using chemical mechanical polishing, electrode sites may be created top-side, back-side, or on the edge of the device having three exposed sides. Added surface area was achieved on the exposed edge through electroplating. Poly(3,4-ethylenedioxythiophene) (PEDOT) modified edge electrodes having an 85-μm² footprint resulted in an impedance of 200 kΩ at 1 kHz. Edge electrodes were able to successfully record single unit activity in acute animal studies. A finite element model of planar and edge electrodes relative to neuron position reveals that edge electrodes should be beneficial for increasing the volume of tissue being sampled in recording applications.     

Flexible and stretchable micro-electrodes for in vitro and in vivo neural interfaces

Microelectrode arrays (MEAs) are designed to monitor and/or stimulate extracellularly neuronal activity. However, the biomechanical and structural mismatch between current MEAs and neural tissues remains a challenge for neural interfaces. This article describes a material strategy to prepare neural electrodes with improved mechanical compliance that relies on thin metal film electrodes embedded in polymeric substrates. The electrode impedance of micro-electrodes on polymer is comparable to that of MEA on glass substrates. Furthermore, MEAs on plastic can be flexed and rolled offering improved structural interface with brain and nerves in vivo. MEAs on elastomer can be stretched reversibly and provide in vitro unique platforms to simultaneously investigate the electrophysiological of neural cells and tissues to mechanical stimulation. Adding mechanical compliance to MEAs is a promising vehicle for robust and reliable neural interfaces.     

Characterization of microglial attachment and cytokine release on biomaterials of differing surface chemistry

The clinical usefulness of central nervous system recording electrodes is currently limited by inconsistent long-term performance that is believed to be governed by the brain tissue response to the implant. In this study, we observed persistent macrophage biomarker expression at the biotic-abiotic interface surrounding implanted electrodes over a 12-week indwelling period. Using the cell type-specific marker CD11b to examine the cells attached to electrodes retrieved over the indwelling period, we found that most of the cells were activated microglia, the resident macrophage of brain tissue, indicating that the implanted electrodes behave as a persistent inflammatory stimulus. To determine the potential usefulness of different materials as coatings for implanted electrodes, we examined brain-derived microglial cell attachment and cytokine release on a number of medically relevant materials. Our results suggest that activated microglia attach to many of the materials used as external coatings for electrode manufacture, and likely serve as a source of pro-inflammatory and neurotoxic cytokines that may be responsible for reducing the biocompatibility of such implants. Our results also indicate that low protein-binding coatings may be useful in reducing microglial attachment upon implantation in brain tissue and may provide a means of improving electrode biocompatibility.     

侵入式柔性神经电极的植入策略

侵入式神经电极将人类对神经科学的认识提升到微米与毫秒尺度.由于传统的刚性电极与柔软的脑组织间存在较大的机械不匹配性,柔性电极成为新一代神经电极的发展趋势.神经电极的柔性化更迭降低免疫反应的同时却失去植入刚度.分析神经电极的植入机制并总结目前研究中关于柔性电极的植入策略,旨在帮助解决柔性电极的植入能力丧失以及急性植入损伤...     

Flexible microfluidic devices supported by biodegradable insertion scaffolds for convection-enhanced neural drug delivery

Convection enhanced delivery (CED) can improve the spatial distribution of drugs delivered directly to the brain. In CED, drugs are infused locally into tissue through a needle or catheter inserted into brain parenchyma. Transport of the infused material is dominated by convection, which enhances drug penetration into tissue compared with diffusion mediated delivery. We have fabricated and characterized an implantable microfluidic device for chronic convection enhanced delivery protocols. The device consists of a flexible parylene-C microfluidic channel that is supported during its insertion into tissue by a biodegradable poly(DL-lactide-co-glycolide) scaffold. The scaffold is designed to enable tissue penetration and then erode over time, leaving only the flexible channel implanted in the tissue. The device was able to reproducibly inject fluid into neural tissue in acute experiments with final infusate distributions that closely approximate delivery from an ideal point source. This system shows promise as a tool for chronic CED protocols.     

Chronic response of adult rat brain tissue to implants anchored to the skull

Using quantitative immunohistological methods, we examined the brain tissue response to hollow fiber membranes (HFMs) that were either implanted intraparenchymally, as in a cell encapsulation application, or were attached to the skull as in a biosensor application (transcranially). We found that the reaction surrounding transcranially implanted HFMs was significantly greater than that observed with intraparenchymally implanted materials including increases in immunoreactivity against GFAP, vimentin, ED-1 labeled macrophages and microglia, and several extracellular matrix proteins including collagen, fibronectin, and laminin. In general, these markers were elevated along the entire length of transcranially implanted HFMs extending into the adjacent parenchyma up to 0.5 mm from the implant interface. Intraparenchymal implants did not appear to have significant involvement of a fibroblastic component as suggested by a decreased expression of vimentin, fibronectin and collagen-type I at the implant tissue interface. The increase in tissue reactivity observed with transcranially implanted HFMs may be influenced by several mechanisms including chronic contact with the meninges and possibly motion of the device within brain tissue. Broadly speaking, our results suggest that any biomaterial, biosensor or device that is anchored to the skull and in chronic contact with meningeal tissue will have a higher level of tissue reactivity than the same material completely implanted within brain tissue.     

An intrafascicular electrode for recording of action potentials in peripheral nerves

We are developing a new type of bipolar recording electrode intended for implantation within individual fascicles of mammalian peripheral nerves. In the experiments reported here we used electrodes fabricated from 25 μm diameter Pt wire, 50 μm 90% Pt-10% Ir wire and 7 μm carbon fibers. The electrodes were implanted in the sciatic nerves of rats and in the ulnar nerves of cats. The signal-to-noise ratio of recorded activity induced by nonnoxious mechanical stimulation of the skin and joints was studied as a function of the type of electrode material used, the amount of insulation removed from the recording zone, and the longitudinal separation of the recording zones of bipolar electrode pairs. Both acute and short term (two day) chronic experiments were performed. The results indicate that a bipolar electrode made from Teflon^™-insulated, 25 μm diameter, 90% Pt-10% Ir wire, having a 1–2 mm long recording zone, can be used for recording of peripheral nerve activity when implanted with one wire inside the fascicle and the other lead level with the first lead, but outside the fascicle. No insulating cuff needs to be placed around the nerve trunk.     

Measurement of contact impedance of electrodes used for deep brain stimulation

High frequency electrical stimulation by means of electrodes implanted into the brain has become an accepted technique for treatment of Parkinson's disease. The electrical field distribution normally inserted into the sub thalamic nucleus minimise abnormal brain activity. Square wave pulses of 1–3.6 V with duration of 60–90 μs at a frequency range of 130–185 pps are generally used. Every electrode unit consists of four cylindrical electrodes positioned in a row and can be switched on independently. This paper determines the contact impedance of the electrodes for different frequencies and proposes improvement to reduce the contact impedance between the electrodes and the brain. Measurements were performed by placing the electrodes in a tank filled with saline. Different frequencies were applied on two electrodes via a resistor. The current was measured through the resistor and the voltage was registered between one of the electrodes and a third non current carrying electrode. The obtained values were used to calculate the contact impedance. The result shows large contact impedance for the used frequency compared to the impedance of the treated tissue, which means that variation in contact impedance can result in variation in the electrical field applied to the tissue.     

MRI图像中颅内栅格电极定位算法的研究

在癫痫的手术治疗中,往往需要在患者颅内植入电极,通过记录和分析颅内脑电来精确定位致痫病灶.通常情况下电极植入后,依靠MRI检查来定位这些电极的位置并找到它们和脑组织结构的空间位置关系.但是这些电极定位方法不是需要较多的人工参与就是计算效率较低.为此,本文开发了一种只需要用户很少参与,便可以自动高效地在MRI图像中定位颅内栅格电极的算法.本算法充分利用栅格电极的几何特征以及它在MRI图像中的成像表现来对其定位,之后利用一个光滑曲面模型对结果进行修正,最后在重建的三维人脑结构中标定这些电极的位置,从而帮助实现手术前的规划.应用本算法对数例患者的MRI脑图像进行了实验分析,证明了算法的有效性.     

Characterization of astrocyte reactivity and gene expression on biomaterials for neural electrodes

Neural electrode devices hold great promise to help people with the restoration of lost functions. However, research is lacking in the biomaterial design of a stable, long-term device. Glial scarring is initiated when a device is inserted into brain tissue and an inflammatory response ensues. Astrocytes become hypertrophic, hyperplastic, and upregulate glial-fibrillary acidic protein. This study was designed to investigate the astrocyte proliferation, viability, morphology, and gene expression to assess the reactive state of the cells on different material surfaces. Although platinum and silicon have been extensively characterized both in vivo and in vitro for their biocompatibility with neuronal cells, this study used the novel usage of PMMA and SU-8 in neural electrodes by comparative analysis of materials' biocompatibility. This study has shown evidence of noncytotoxicity of SU-8. We have also confirmed the biocompatibility of PMMA with astrocytes. Moreover, we have established sound guidelines of which neural implant materials should meet to be depicted biocompatible.     

Fabrication and evaluation of conductive elastomer electrodes for neural stimulation

This study explored the feasibility of applying nanocomposites derived from conducting organic polymers and silicone elastomers to fabricate electrodes for neural stimulation. A novel combination of nanoparticulate polypyrrole polymerized within a processable elastomeric silicone host polymer was evaluated in vitro and in vivo. The electrical properties of the elastomeric conductors were strongly dependent on their composition, and mixtures were identified that provided high and stable conductivity. Methods were developed for incorporating conductive polymer–siloxane co-polymer nanocomposite and silicone insulating polymers into thin-layered structures for simple single-poled electrode fabrication. In vitro testing revealed that the materials were stable under continuous pulsing for at least 10 days. Single contact prototype nerve cuff electrodes were fabricated and device functionality was demonstrated in vivo following acute implantation. The results of this study demonstrate the feasibility of conductive elastomers for peripheral nerve stimulating electrodes. Matching the mechanical properties of cuff electrode to those of the underlying neural tissue is expected to improve the long-term tissue response to the presence of the electrode.     

Fabrication and evaluation of conductive elastomer electrodes for neural stimulation

This study explored the feasibility of applying nanocomposites derived from conducting organic polymers and silicone elastomers to fabricate electrodes for neural stimulation. A novel combination of nanoparticulate polypyrrole polymerized within a processable elastomeric silicone host polymer was evaluated in vitro and in vivo. The electrical properties of the elastomeric conductors were strongly dependent on their composition, and mixtures were identified that provided high and stable conductivity. Methods were developed for incorporating conductive polymer-siloxane co-polymer nanocomposite and silicone insulating polymers into thin-layered structures for simple single-poled electrode fabrication. In vitro testing revealed that the materials were stable under continuous pulsing for at least 10 days. Single contact prototype nerve cuff electrodes were fabricated and device functionality was demonstrated in vivo following acute implantation. The results of this study demonstrate the feasibility of conductive elastomers for peripheral nerve stimulating electrodes. Matching the mechanical properties of cuff electrode to those of the underlying neural tissue is expected to improve the long-term tissue response to the presence of the electrode.     

A new technique for implanting a fine-wire microelectrode for chronic recording of unit activity from freely-moving mice

We report here a newly developed chronic implantation technique using an epoxy-coated fine-stainless steel wire (33 microm in diameter) to record single unit activity from the brain of freely-moving mice with as little tissue injury as possible. Since the fine-wire electrode is not capable of staying straight by itself or of penetrating into the brain, a pair of permanent neodymium magnets placed on a micromanipulator as well as below the animal's head was used for stereotaxic implantation to keep the fine-wire straight and strong by the magnetic fields. With those implanted electrodes recording of single units from the hippocampal CA1 of freely-moving mice was performed during sleep and wakefulness.     

Implantation of a newly developed direct optic nerve electrode device for artificial vision in rabbits

The purpose of this study was to investigate the surgical procedures involved in the implantation of a newly developed direct optic nerve electrode device for inducing artificial vision. The electrode device comprised seven wire stimulation electrodes and a return electrode (diameter 50?μm), one manipulation rod (diameter 100?μm), and a cylindrical silicone board (diameter 2.0?mm). The stimulation electrodes and the manipulation rod protruded through the board to allow implantation of the electrode tips into the optic disc of the rabbit eye. The surgical procedures required to insert the device into the vitreous cavity and implant the device into the optic disc were evaluated. When the electrodes were stimulated, electrically evoked potentials (EEPs) were recorded at the visual cortex. The electrode device was inserted into the vitreous cavity with no damage using a trocar through a scleral incision. The device was easily manipulated using vitreoretinal forceps in the vitreous cavity, and the electrode tips were implanted into the optic disc in a single insertion after vitrectomy. When electrical stimulation was applied, EEPs were recorded from all electrode pairs. The newly developed electrode device was inserted into the eye and implanted into the optic nerve disc smoothly and safely, suggesting that these surgical procedures are useful for our artificial vision system.