title: Ultrasoft microwire neural electrodes improve chronic tissue integration.
abstract: Chronically implanted neural multi-electrode arrays (MEA) are an essential technology for recording electrical signals from neurons and/or modulating neural activity through stimulation. However, current MEAs, regardless of the type, elicit an inflammatory response that ultimately leads to device failure. Traditionally, rigid materials like tungsten and silicon have been employed to interface with the relatively soft neural tissue. The large stiffness mismatch is thought to exacerbate the inflammatory response. In order to minimize the disparity between the device and the brain, we fabricated novel ultrasoft electrodes consisting of elastomers and conducting polymers with mechanical properties much more similar to those of brain tissue than previous neural implants. In this study, these ultrasoft microelectrodes were inserted and released using a stainless steel shuttle with polyethyleneglycol (PEG) glue. The implanted microwires showed functionality in acute neural stimulation. When implanted for 1 or 8weeks, the novel soft implants demonstrated significantly reduced inflammatory tissue response at week 8 compared to tungsten wires of similar dimension and surface chemistry. Furthermore, a higher degree of cell body distortion was found next to the tungsten implants compared to the polymer implants. Our results support the use of these novel ultrasoft electrodes for long term neural implants.
  
  
  
  One critical challenge to the translation of neural recording/stimulation electrode technology to clinically viable devices for brain computer interface (BCI) or deep brain stimulation (DBS) applications is the chronic degradation of device performance due to the inflammatory tissue reaction. While many hypothesize that soft and flexible devices elicit reduced inflammatory tissue responses, there has yet to be a rigorous comparison between soft and stiff implants. We have developed an ultra-soft microelectrode with Young's modulus lower than 1MPa, closely mimicking the brain tissue modulus. Here, we present a rigorous histological comparison of this novel ultrasoft electrode and conventional stiff electrode with the same size, shape and surface chemistry, implanted in rat brains for 1-week and 8-weeks. Significant improvement was observed for ultrasoft electrodes, including inflammatory tissue reaction, electrode-tissue integration as well as mechanical disturbance to nearby neurons. A full spectrum of new techniques were developed in this study, from insertion shuttle to in situ sectioning of the microelectrode to automated cell shape analysis, all of which should contribute new methods to the field. Finally, we showed the electrical functionality of the ultrasoft electrode, demonstrating the potential of flexible neural implant devices for future research and clinical use.
authors.affiliation: Department of Bioengineering, University of Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, University of Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, USA; Shenzhen Key Lab of Neuropsychiatric Modulation, CAS Center for Excellence in Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
authors.forename: Zhanhong Jeff
authors.initials: ZJ
authors.lastname: Du
authors.affiliation: Department of Bioengineering, University of Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, University of Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, USA; Systems Neuroscience Institute, University of Pittsburgh, PA, USA.
authors.forename: Christi L
authors.initials: CL
authors.lastname: Kolarcik
authors.affiliation: Department of Bioengineering, University of Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, University of Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, USA; NeuroTech Center of Brain Institute, University of Pittsburgh, PA, USA.
authors.forename: Takashi D Y
authors.initials: TDY
authors.lastname: Kozai
authors.affiliation: Boulder Scientific Company, Longmont, CO,USA.
authors.forename: Silvia D
authors.initials: SD
authors.lastname: Luebben
authors.affiliation: Aei Corporation, Littleton, CO,USA.
authors.forename: Shawn A
authors.initials: SA
authors.lastname: Sapp
authors.affiliation: Department of Bioengineering, University of Pittsburgh, PA, USA.
authors.forename: Xin Sally
authors.initials: XS
authors.lastname: Zheng
authors.affiliation: Department of Aerospace Engineering Sciences, University of Colorado, Boulder, CO,USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Nabity
authors.affiliation: Department of Bioengineering, University of Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, University of Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, USA. Electronic address: xic11@pitt.edu.
authors.forename: X Tracy
authors.initials: XT
authors.lastname: Cui
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects / Q000737:chemistry; D001812:Blood-Brain Barrier; D004553:Electric Conductivity; D004558:Electric Stimulation; D004567:Electrodes, Implanted / Q000009:adverse effects; D005549:Foreign-Body Reaction / Q000517:prevention & control; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D008422:Materials Testing; D008839:Microelectrodes / Q000009:adverse effects; D009474:Neurons / Q000502:physiology*; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D012826:Silicone Elastomers; D020531:Subthalamic Nucleus / Q000502:physiology / Q000601:surgery; D014414:Tungsten / Q000009:adverse effects
chemical_list: D001672:Biocompatible Materials; D011108:Polymers; D012826:Silicone Elastomers; D014414:Tungsten
keywords: Composite bio-electrodes; Conducting elastomer; Deep brain stimulation; Neural electrode