Robust penetrating microelectrodes for neural interfaces realized by titanium micromachining.

Neural prosthetic interfaces based upon penetrating microelectrode devices have broadened our understanding of the brain and have shown promise for restoring neurological functions lost to disease, stroke, or injury. However, the eventual viability of such devices for use in the treatment of neurological dysfunction may be ultimately constrained by the intrinsic brittleness of silicon, the material most commonly used for manufacture of penetrating microelectrodes. This brittleness creates predisposition for catastrophic fracture, which may adversely affect the reliability and safety of such devices, due to potential for fragmentation within the brain. Herein, we report the development of titanium-based penetrating microelectrodes that seek to address this potential future limitation. Titanium provides advantage relative to silicon due to its superior fracture toughness, which affords potential for creation of robust devices that are resistant to catastrophic failure. Realization of these devices is enabled by recently developed techniques which provide opportunity for fabrication of high-aspect-ratio micromechanical structures in bulk titanium substrates. Details are presented regarding the design, fabrication, mechanical testing, in vitro functional characterization, and preliminary in vivo testing of devices intended for acute recording in rat auditory cortex and thalamus, both independently and simultaneously.

Titanium-based multi-channel, micro-electrode array for recording neural signals.

Micro-scale brain-machine interface (BMI) devices have provided an opportunity for direct probing of neural function and have also shown significant promise for restoring neurological functions lost to stroke, injury, or disease. However, the eventual clinical translation of such devices may be hampered by limitations associated with the materials commonly used for their fabrication, e.g. brittleness of silicon, insufficient rigidity of polymeric devices, and unproven chronic biocompatibility of both. Herein, we report, for the first time, the development of titanium-based "Michigan" type multi-channel, microelectrode arrays that seek to address these limitations. Titanium provides unique properties of immediate relevance to microelectrode arrays, such as high toughness, moderate modulus, and excellent biocompatibility, which may enhance structural reliability, safety, and chronic recording reliability. Realization of these devices is enabled by recently developed techniques which provide the opportunity for fabrication of high aspect ratio micromechanical structures in bulk titanium substrates. Details regarding the design, fabrication, and characterization of these devices for eventual use in rat auditory cortex and thalamus recordings are presented, as are preliminary results.

Metallothionein-3 and neuronal nitric oxide synthase levels in brains from the Tg2576 mouse model of Alzheimer's disease.

Using antiserum against the recombinant isoform 3 of mouse brain metallothionein (MT3), the amount of MT3 protein was determined in whole brain homogenates from the Tg2576 transgenic mouse model of Alzheimer's Disease. Twenty-two month old transgenic positive mice showed a 27% decrease of MT3 normalized to the total protein in the extracts compared to same age, control transgenic negative mice. Metallothioneins bind seven molar equivalents of divalent metal ions per mole of protein so metal levels also were measured in these whole brain extracts using inductively coupled plasma atomic absorption (ICP-AA) spectrometry. No significant difference was observed for any metal assayed. Because neuronal nitric oxide synthase (nNOS) is involved in neurodegenerative disease and nitric oxide specifically interacts with MT3, the concentration and total nNOS activity also were evaluated. The transgenic positive mice showed a decrease of 28% in nNOS protein compared to the same age transgenic negative mice. Normalized to the amount of nNOS protein, total NOS activity was higher in the transgenic positive mice. These data showed that protein levels of both MT3 and nNOS were reduced in transgenic positive mice that show many characteristics of Alzheimer's Disease. In vitro studies suggested that MT3 was not a likely candidate for directly affecting nNOS activity in the brain.