Actively controlled release of Dexamethasone from neural microelectrodes in a chronic in vivo study.

Stable interconnection to neurons in vivo over long time-periods is critical for the success of future advanced neuroelectronic applications. The inevitable foreign body reaction towards implanted materials challenges the stability and an active intervention strategy would be desirable to treat inflammation locally. Here, we investigate whether controlled release of the anti-inflammatory drug Dexamethasone from flexible neural microelectrodes in the rat hippocampus has an impact on probe-tissue integration over 12 weeks of implantation. The drug was stored in a conducting polymer coating (PEDOT/Dex), selectively deposited on the electrode sites of neural probes, and released on weekly basis by applying a cyclic voltammetry signal in three electrode configuration in fully awake animals. Dex-functionalized probes provided stable recordings and impedance characteristics over the entire chronic study. Histological evaluation after 12 weeks of implantation revealed an overall low degree of inflammation around all flexible probes whereas electrodes exposed to active drug release protocols did have neurons closer to the electrode sites compared to controls. The combination of flexible probe technology with anti-inflammatory coatings accordingly offers a promising approach for enabling long-term stable neural interfaces.

[1]  Xinyan Tracy Cui,et al.  Electrochemically controlled release of dexamethasone from conducting polymer polypyrrole coated electrode. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[2]  S. Wise,et al.  A neurophysiological study of the premotor cortex in the rhesus monkey. , 1984, Brain : a journal of neurology.

[3]  Volker Tronnier,et al.  A simple implantation method for flexible, multisite microelectrodes into rat brains , 2013, Front. Neuroeng..

[4]  Warren M. Grill,et al.  Signal Considerations for Chronically Implanted Electrodes for Brain Interfacing , 2008 .

[5]  Wolfgang Eberle,et al.  Effect of Insertion Speed on Tissue Response and Insertion Mechanics of a Chronically Implanted Silicon-Based Neural Probe , 2011, IEEE Transactions on Biomedical Engineering.

[6]  A. Michael,et al.  Brain Tissue Responses to Neural Implants Impact Signal Sensitivity and Intervention Strategies , 2014, ACS chemical neuroscience.

[7]  Diane J Burgess,et al.  Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[8]  Seong-Gi Kim,et al.  In vivo two-photon microscopy reveals immediate microglial reaction to implantation of microelectrode through extension of processes , 2012, Journal of neural engineering.

[9]  M. Asplund,et al.  A detailed insight into drug delivery from PEDOT based on analytical methods: Effects and side effects , 2014, Journal of biomedical materials research. Part A.

[10]  Stanislav Herwik,et al.  Brain-computer interfaces: an overview of the hardware to record neural signals from the cortex. , 2009, Progress in brain research.

[11]  T. Stieglitz,et al.  Micromachined, Polyimide-Based Devices for Flexible Neural Interfaces , 2000 .

[12]  M. Jamal Deen,et al.  Microfabricated Reference Electrodes and their Biosensing Applications , 2010, Sensors.

[13]  Abigail N Koppes,et al.  Electrical stimuli in the central nervous system microenvironment. , 2014, Annual review of biomedical engineering.

[14]  W Kenneth Ward,et al.  Controlled release of dexamethasone from subcutaneously-implanted biosensors in pigs: localized anti-inflammatory benefit without systemic effects. , 2010, Journal of biomedical materials research. Part A.

[15]  X. Tracy Cui,et al.  In Vivo Electrochemical Analysis of a PEDOT/MWCNT Neural Electrode Coating , 2015, Biosensors.

[16]  Jochen Guck,et al.  The relationship between glial cell mechanosensitivity and foreign body reactions in the central nervous system. , 2014, Biomaterials.

[17]  P. Renaud,et al.  Demonstration of cortical recording using novel flexible polymer neural probes , 2008 .

[18]  André Mercanzini,et al.  Controlled release nanoparticle-embedded coatings reduce the tissue reaction to neuroprostheses. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[19]  X Tracy Cui,et al.  Dexamethasone retrodialysis attenuates microglial response to implanted probes in vivo. , 2016, Biomaterials.

[20]  Mark L. Homer,et al.  Sensors and decoding for intracortical brain computer interfaces. , 2013, Annual review of biomedical engineering.

[21]  Christina Hassler,et al.  Intracortical polyimide electrodes with a bioresorbable coating , 2016, Biomedical Microdevices.

[22]  Michael D Joseph,et al.  Poly(3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes , 2011, Journal of neural engineering.

[23]  D. Humphrey,et al.  Long-term gliosis around chronically implanted platinum electrodes in the Rhesus macaque motor cortex , 2006, Neuroscience Letters.

[24]  Christina Hassler,et al.  In vivo monitoring of glial scar proliferation on chronically implanted neural electrodes by fiber optical coherence tomography , 2014, Front. Neuroeng..

[25]  G. Buzsáki Large-scale recording of neuronal ensembles , 2004, Nature Neuroscience.

[26]  Thomas Stieglitz,et al.  Improved polyimide thin-film electrodes for neural implants , 2012, 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[27]  David C. Martin,et al.  Sustained release of dexamethasone from hydrophilic matrices using PLGA nanoparticles for neural drug delivery. , 2006, Biomaterials.

[28]  P. Tresco,et al.  Response of brain tissue to chronically implanted neural electrodes , 2005, Journal of Neuroscience Methods.

[29]  Lei He,et al.  New carbon nanotube–conducting polymer composite electrodes for drug delivery applications , 2012 .

[30]  G. Buzsáki,et al.  High-frequency network oscillation in the hippocampus. , 1992, Science.

[31]  D. Kipke,et al.  Neural probe design for reduced tissue encapsulation in CNS. , 2007, Biomaterials.

[32]  Thomas Stieglitz,et al.  Long-Term Stable Adhesion for Conducting Polymers in Biomedical Applications: IrOx and Nanostructured Platinum Solve the Chronic Challenge. , 2017, ACS applied materials & interfaces.

[33]  Carl F. Lagenaur,et al.  The surface immobilization of the neural adhesion molecule L1 on neural probes and its effect on neuronal density and gliosis at the probe/tissue interface. , 2011, Biomaterials.

[34]  F Moussy,et al.  In vivo evaluation of a dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to implantable medical devices. , 2002, Journal of biomedical materials research.

[35]  Tomislav Milekovic,et al.  Low-latency multi-threaded processing of neuronal signals for brain-computer interfaces , 2014, Front. Neuroeng..

[36]  S. Retterer,et al.  Dexamethasone treatment reduces astroglia responses to inserted neuroprosthetic devices in rat neocortex , 2005, Experimental Neurology.

[37]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[38]  Diane J. Burgess,et al.  Evaluation of in vivo-in vitro release of dexamethasone from PLGA microspheres. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[39]  Sanjay Garg,et al.  Electrochemically controlled drug delivery based on intrinsically conducting polymers. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[40]  Warren M Grill,et al.  Implanted neural interfaces: biochallenges and engineered solutions. , 2009, Annual review of biomedical engineering.

[41]  Paras R. Patel,et al.  Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. , 2012, Nature materials.

[42]  Andreas Moser,et al.  An implantation technique for polyimide based flexible array probes facilitating neuronavigation and chronic implantation , 2012 .

[43]  Sophie Demoustier-Champagne,et al.  Dexamethasone electrically controlled release from polypyrrole-coated nanostructured electrodes , 2010, Journal of materials science. Materials in medicine.

[44]  X. Cui,et al.  Poly (3,4-Ethylenedioxythiophene) for Chronic Neural Stimulation , 2007, IEEE Transactions on Neural Systems and Rehabilitation Engineering.

[45]  W M Reichert,et al.  Vascular endothelial growth factor and dexamethasone release from nonfouling sensor coatings affect the foreign body response. , 2007, Journal of biomedical materials research. Part A.

[46]  Justin C. Williams,et al.  Flexible polyimide-based intracortical electrode arrays with bioactive capability , 2001, IEEE Transactions on Biomedical Engineering.

[47]  Kelsey A. Potter,et al.  Curcumin-releasing mechanically adaptive intracortical implants improve the proximal neuronal density and blood-brain barrier stability. , 2014, Acta biomaterialia.

[48]  D. Barber,et al.  Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the striatum and hippocampus: implications for mood disorders , 2001, Neuroscience.

[49]  John B. Matson,et al.  Controlled release of dexamethasone from peptide nanofiber gels to modulate inflammatory response. , 2012, Biomaterials.

[50]  Chang Auck Choi,et al.  An iridium oxide reference electrode for use in microfabricated biosensors and biochips. , 2004, Lab on a chip.

[51]  F. Walsh,et al.  Electrodeposited conductive polymers for controlled drug release: polypyrrole , 2016, Journal of Solid State Electrochemistry.

[52]  Thomas Stieglitz,et al.  Anti-inflammatory polymer electrodes for glial scar treatment: bringing the conceptual idea to future results , 2014, Front. Neuroeng..

[53]  Lian-Jun Guo,et al.  Electrophysiological properties of hippocampal–cortical neural networks, role in the processes of learning and memory in rats , 2014, Journal of Neural Transmission.

[54]  Fotios Papadimitrakopoulos,et al.  Controlling Acute Inflammation with Fast Releasing Dexamethasone-PLGA Microsphere/PVA Hydrogel Composites for Implantable Devices , 2007, Journal of diabetes science and technology.

[55]  M. Abidian,et al.  Conducting‐Polymer Nanotubes for Controlled Drug Release , 2006, Advanced materials.

[56]  Ravi V. Bellamkonda,et al.  Dexamethasone-coated neural probes elicit attenuated inflammatory response and neuronal loss compared to uncoated neural probes , 2007, Brain Research.

[57]  G. Wallace,et al.  Polyterthiophene as an electrostimulated controlled drug release material of therapeutic levels of dexamethasone , 2010 .

[58]  J. Simon,et al.  Immune responses to implants - a review of the implications for the design of immunomodulatory biomaterials. , 2011, Biomaterials.

[59]  S. Retterer,et al.  Controlling cellular reactive responses around neural prosthetic devices using peripheral and local intervention strategies , 2003, IEEE Transactions on Neural Systems and Rehabilitation Engineering.

[60]  R. Bellamkonda,et al.  A Novel Dexamethasone-releasing, Anti-inflammatory Coating for Neural Implants , 2005, Conference Proceedings. 2nd International IEEE EMBS Conference on Neural Engineering, 2005..

[61]  Yahya E Choonara,et al.  A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications. , 2014, Journal of Biomedical Materials Research. Part A.

[62]  J. Hetke,et al.  Surface modification of neural recording electrodes with conducting polymer/biomolecule blends. , 2001, Journal of biomedical materials research.

[63]  K. Djupsund,et al.  Flexible polyimide microelectrode array for in vivo recordings and current source density analysis. , 2007, Biosensors & bioelectronics.

[64]  T. Webster,et al.  Electrically controlled drug release from nanostructured polypyrrole coated on titanium , 2011, Nanotechnology.

[65]  O. Inganäs,et al.  Electroactive polymers for neural interfaces , 2010 .

[66]  David C. Martin,et al.  Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays , 2005, Experimental Neurology.

[67]  Paul E Holtzheimer,et al.  Deep brain stimulation for psychiatric disorders. , 2011, Annual review of neuroscience.

[68]  B. Massoumi,et al.  Electrochemically Controlled Binding and Release of Dexamethasone from Conducting Polymer Bilayer Films , 2002 .

[69]  D. Szarowski,et al.  Brain responses to micro-machined silicon devices , 2003, Brain Research.

[70]  D. J. Warren,et al.  A neural interface for a cortical vision prosthesis , 1999, Vision Research.

[71]  A. Levey,et al.  Implanted neural electrodes cause chronic, local inflammation that is correlated with local neurodegeneration , 2009, Journal of neural engineering.

[72]  Andrew B Schwartz,et al.  Cortical neural prosthetics. , 2004, Annual review of neuroscience.

[73]  Patrick A Tresco,et al.  Quantitative analysis of the tissue response to chronically implanted microwire electrodes in rat cortex. , 2010, Biomaterials.