, 2005). The cortical CH5424802 order tissue response to passive (i.e. unstimulated) electrode insertion and chronic presence has been examined in a variety of experimental conditions involving both animals and humans. Immunohistochemical studies at varying time points after implantation reveal acute and chronic astrocytic and microglial encapsulation of electrodes (Biran et al., 2005, Edell et al., 1992, Kozai et al., 2012 and Szarowski et al., 2003), and chronic inflammation with localized neurodegeneration (Azemi et al., 2011,

Biran et al., 2005 and McConnell et al., 2009) that combine to increase the separation of viable neurons from the electrode surface. Importantly, this response may be highly variable, even within

an individual electrode array. The factors mediating the extent of tissue response are still being characterized, however a number of mechanisms have been examined or proposed. These include the extent of vascular injury occurring during electrode insertion (Bjornsson et al., 2006, House et al., 2006 and Kozai et al., 2010), the amount of strain experienced by cortical tissue during penetration of the pia mater (Bjornsson et al., 2006, Rennaker et al., 2005 and Rousche and Normann, 1992), the geometry of electrodes (Seymour and Kipke, 2007 and Skousen et al., 2011) and micromotion-induced injury due to a stiffness mismatch between electrodes and cortical DAPT tissue, or by electrode tethering (Biran et al., 2007, Freire et al., 2011 and Lind et al., 2010). A variety of approaches are being explored to minimize the extent of glial encapsulation and oxyclozanide chronic neuroinflammation. A reduction in vascular injury may be achieved by careful placement of electrodes deliberately avoiding surface vessels (Kozai et al., 2010), implanting flexible electrodes that can deflect off vascular structures (Bjornsson et al., 2006), or by customizing electrode arrays to account for the distribution of vessels at the cortical surface of the recipient (Ortmann

and Baziyan, 2007). Some disagreement exists about the optimal combination of insertion speed and electrode tip sharpness required to penetrate the pia with minimal tissue compression; Nicolelis et al. (2003) advocate for the ultra-slow insertion (100 µm/min) of arrays containing blunt-tipped electrodes, while Rousche and Normann (1992) suggest that to minimize cortical compression and achieve uniform insertion depth of the 100-electrode Utah Electrode Array (UEA), very high speed (>8.3 m/s) insertions of electrodes with sharp tips are required in cats. Notably, the same group suggest that even higher speeds may be required for implantation of arrays into the larger human brain, with its differing biomechanical properties and thicker pial layer (House et al., 2006).