www.afm-journal.de FULL PAPER © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 3470 www.MaterialsViews.com wileyonlinelibrary.com Taylor Ware, Dustin Simon, David E. Arreaga-Salas, Jonathan Reeder, Robert Rennaker, Edward W. Keefer, and Walter Voit* 1. Introduction Cortical neural interfaces provide a communication platform for direct interaction with the nervous system. [1–4] Communi- cation with the central nervous system has enabled treatment of numerous conditions such as epilepsy and depression, con- trol of prosthetic devices and the advancement of the field of neuroscience. [5–7] However, devices designed to record extracel- lular neural activity generally fail within one year of implanta- tion. [8–10] This failure has been widely attributed to gliosis, the chronic reactive biological response to the foreign probe, which leads to death of neurons and encapsulation of the implant resulting in a loss in the signal-to-noise- ratio over time. [11–15] A number of factors contribute to the timeframe and extent of the observed gliosis: size, stiffness, sur- face chemistry, insertion procedure and mechanical constraints provided by elec- trical contacts have been shown to have a direct effect on glial scarring. [16–18] The focus of this work is to minimize device stiffness, but each parameter must be considered in device development. Neural interfaces are typically made of silicon microneedles, planar electrodes or metal microwires. [19] The extreme mechanical mismatch between these devices (commonly tungsten or silicon) is strongly linked to the extensive gliosis and reduction in signal quality over time. [8,9] Recently much research has focused on the design, manufacture and implantation of flexible probes made from polymers, such as polyimides or Parylene-C, with thin-film conductors defined by photolithography; these devices have a reduced mechanical mismatch between neural tissue and the implants. [9,10,20–27] Polymer probes are stiff enough for implantation into the cortex directly or with the aid of an insertion tool, depending on geometry. [25,28] These polymers are still, however, 5 or 6 orders of magnitude stiffer than the sur- rounding neural tissue. Softening neural interfaces have been demonstrated utilizing the swelling of a nanocomposite pol- ymer film. [29–31] Combining advances in polymer-based probes and shape memory polymers (SMPs) will allow for the further development of devices that are stiff enough for insertion, but undergo orders-of-magnitude reduction of stiffness following insertion. SMPs are a class of mechanically active materials used to store a metastable shape and return to a globally stable shape upon activation by a stimulus, such as temperature, humidity, light or a combination of these stimuli. [32–34] In thermally active SMPs, recovery is induced by heating the polymer through a transition, such as crystalline melting or a glass transition, leading to a considerable drop in modulus. [35] SMP activation by humidity is a variation of thermal activation, where the drop in modulus is triggered by plasticization of the polymer leading to thermal activation at a lower temperature. [36] Many thermally activated SMP biomedical devices have been proposed including cortical probes that self-insert upon recovery of the device. [37,38] Cortical probes fabricated on an SMP specifically tuned to soften after insertion into the brain have not been previously Fabrication of Responsive, Softening Neural Interfaces A novel processing method is described using photolithography to pattern thin-film flexible electronics on shape memory polymer substrates with mechanical properties tailored to improve biocompatability and enhance adhesion between the polymer substrate and metal layers. Standard semi- conductor wafer processing techniques are adapted to enable robust device design onto a variety of softening substrates with tunable moduli. The resulting devices are stiff enough (shear modulus of ≈700 MPa) to assist with device implantation and then soften in vivo ( ≈300 kPa) approaching the modulus of brain tissue ( ≈10 kPa) within 24 h. Acute in vivo studies demon- strate that these materials are capable of recording neural activity. Softening multi-electrode arrays offer a highly customizable interface, which can be optimized to improve biocompatibility, enabling the development of robust, reliable neural electrodes for neural engineering and neuroscience. DOI: 10.1002/adfm.201200200 T. Ware, D. Simon, D. E. Arreaga-Salas, Prof. W. Voit Department of Materials Science and Engineering The University of Texas at Dallas 800 West Campbell RD, Mailstop RL 10, Richardson, TX 75080, USA E-mail: walter.voit@utdallas.edu J. Reeder, Prof. W. Voit Department of Mechanical Engineering The University of Texas at Dallas 800 West Campbell RD, Mailstop RL 10, Richardson, TX 75080, USA R. L. Rennaker II School of Behavioral and Brain Sciences Erik Jonnson School of Engineering The University of Texas at Dallas 800 West Campbell RD, Mailstop RL 10, Richardson, TX 75080, USA E. W. Keefer Plexon Inc., 6500 Greenville Ave., Suite 730, Dallas, TX 75206, USA Adv. Funct. Mater. 2012, 22, 3470–3479