Reducing surface area while maintaining implant penetrating profile lowers the brain foreign body response to chronically implanted planar silicon microelectrode arrays.

A consistent feature of the foreign body response (FBR), irrespective of the type of implant, is persistent inflammation at the biotic-abiotic interface signaled by biomarkers of macrophage/microglial activation. Since macrophage-secreted factors shape the foreign body reaction, implant designs that reduce macrophage activation should improve biocompatibility and, with regard to recording devices, should improve reliability and longevity. At present, it is unclear whether the goal of seamless integration is possible or whether electrode developers can modulate specific aspects of the FBR by intentionally manipulating the constitutive properties of the implant. To explore this area, we studied the chronic brain FBR to planar solid silicon microelectrode arrays and planar lattice arrays with identical penetrating profiles but with reduced surface area in rats after an 8-week indwelling period. Using quantitative immunohistochemistry, we found that presenting less surface area after equivalent iatrogenic injury is accompanied by significantly less persistent macrophage activation, decreased blood brain barrier leakiness, and reduced neuronal cell loss. Our findings show that it is possible for implant developers to modulate specific aspects of the FBR by intentionally manipulating the constitutive properties of the implant. Our results also support the theory that the FBR to implanted electrode arrays, and likely other implants, can be explained by the presence of macrophages at the biotic-abiotic interface, which act as a sustained delivery source of bioactive agents that diffuse into the adjacent tissue and shape various features of the brain FBR. Further, our findings suggest that one method to improve the recording consistency and lifetime of implanted microelectrode arrays is to design implants that reduce the amount of macrophage activation at the biotic-abiotic interface and/or enhance the clearance or impact of their released factors.

[1]  Patrick A Tresco,et al.  The brain tissue response to implanted silicon microelectrode arrays is increased when the device is tethered to the skull. , 2007, Journal of biomedical materials research. Part A.

[2]  D. Edell,et al.  Factors influencing the biocompatibility of insertable silicon microshafts in cerebral cortex , 1992, IEEE Transactions on Biomedical Engineering.

[3]  P. Peterson,et al.  Glia, cytokines, and neurotoxicity. , 1995, Critical reviews in neurobiology.

[4]  David C. Martin,et al.  Chronic neural recordings using silicon microelectrode arrays electrochemically deposited with a poly(3,4-ethylenedioxythiophene) (PEDOT) film , 2006, Journal of neural engineering.

[5]  Del Bigio Mr.  Biological Reactions to Cerebrospinal Fluid Shunt Devices: A Review of the Cellular Pathology , 1998 .

[6]  J. Bernaudin,et al.  Permeability of the normal rat brain, spinal cord and dorsal root ganglia microcirculations to immunoglobulins G , 1990 .

[7]  M. Block,et al.  Microglia-mediated neurotoxicity: uncovering the molecular mechanisms , 2007, Nature Reviews Neuroscience.

[8]  P. Sharp,et al.  Effect of anti‐macrophage inflammatory protein‐1α on leukocyte trafficking and disease progression in experimental autoimmune uveoretinitis , 2003, European journal of immunology.

[9]  G. Rizzolatti,et al.  Seven Years of Recording from Monkey Cortex with a Chronically Implanted Multiple Microelectrode , 2010, Front. Neuroeng..

[10]  Henrik Jörntell,et al.  Implant Size and Fixation Mode Strongly Influence Tissue Reactions in the CNS , 2011, PloS one.

[11]  Y. Agid,et al.  Parkinson's disease, subthalamic stimulation, and selection of candidates: A pathological study , 2003, Movement disorders : official journal of the Movement Disorder Society.

[12]  M. D. Del Bigio,et al.  Treatment of recurrent ventriculoperitoneal shunt failure associated with persistent cerebrospinal fluid eosinophilia and latex allergy by use of an "extracted" shunt. , 2008, Journal of neurosurgery. Pediatrics.

[13]  L. Pitts,et al.  Immunocytochemical localization of immunoglobulins in the rat brain: Relationship to the blood‐brain barrier , 1994, The Journal of comparative neurology.

[14]  C. E. Stiles,et al.  Tissue response to single-polymer fibers of varying diameters: evaluation of fibrous encapsulation and macrophage density. , 2000, Journal of biomedical materials research.

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

[16]  V. Fung,et al.  Postmortem analysis of bilateral subthalamic electrode implants in Parkinson's disease , 2002, Movement disorders : official journal of the Movement Disorder Society.

[17]  R L Schultz,et al.  The ultrastructure of the sheath around chronically implanted electrodes in brain , 1976, Journal of neurocytology.

[18]  A. Koch,et al.  Perforation holes in ventricular catheters—is less more? , 2010, Child's Nervous System.

[19]  Suzanne S. Stensaas,et al.  Histopathological evaluation of materials implanted in the cerebral cortex , 1978, Acta Neuropathologica.

[20]  W. Cammer.  Effects of TNFα on immature and mature oligodendrocytes and their progenitors in vitro , 2000, Brain Research.

[21]  Christine Haberler,et al.  No tissue damage by chronic deep brain stimulation in Parkinson's disease , 2000, Annals of neurology.

[22]  Eduardo Fernández,et al.  Long-term stimulation and recording with a penetrating microelectrode array in cat sciatic nerve , 2004, IEEE Transactions on Biomedical Engineering.

[23]  H. Kettenmann,et al.  Microglia: active sensor and versatile effector cells in the normal and pathologic brain , 2007, Nature Neuroscience.

[24]  S S Stensaas,et al.  The reaction of the cerebral cortex to chronically implanted plastic needles. , 1976, Acta neuropathologica.

[25]  K. Horch,et al.  Biocompatibility of silicon-based electrode arrays implanted in feline cortical tissue. , 1993, Journal of biomedical materials research.

[26]  R. Bakay,et al.  Postmortem study of deep brain stimulation of the anterior thalamus: case report. , 2008, Neurosurgery.

[27]  J. Forrester,et al.  Leukocyte trafficking in experimental autoimmune uveitis: breakdown of blood-retinal barrier and upregulation of cellular adhesion molecules. , 2003, Investigative ophthalmology & visual science.

[28]  J. Muthuswamy,et al.  Thin microelectrodes reduce GFAP expression in the implant site in rodent somatosensory cortex , 2007, Journal of neural engineering.

[29]  Jerald D. Kralik,et al.  Chronic, multisite, multielectrode recordings in macaque monkeys , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  P.R. Kennedy,et al.  Computer control using human intracortical local field potentials , 2004, IEEE Transactions on Neural Systems and Rehabilitation Engineering.

[31]  Jon A. Mukand,et al.  Neuronal ensemble control of prosthetic devices by a human with tetraplegia , 2006, Nature.

[32]  C. Bjarkam,et al.  Chronic subthalamic high‐frequency deep brain stimulation in Parkinson's disease – a histopathological study , 2007, European journal of neurology.

[33]  D.B. McCreery,et al.  Evaluation of the stability of intracortical microelectrode arrays , 2006, IEEE Transactions on Neural Systems and Rehabilitation Engineering.

[34]  G. Percheron,et al.  Long‐term thalamic stimulation in Parkinson's disease , 1994, Neurology.

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

[36]  E. Manuelidis,et al.  Histopathological changes produced by implanted electrodes in cat brains; comparison with histopathological changes in human and experimental puncture wounds. , 1957, Journal of neurosurgery.

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

[38]  Florian Solzbacher,et al.  A comparison of the tissue response to chronically implanted Parylene-C-coated and uncoated planar silicon microelectrode arrays in rat cortex. , 2010, Biomaterials.

[39]  X Liu,et al.  Stability of the interface between neural tissue and chronically implanted intracortical microelectrodes. , 1999, IEEE transactions on rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society.

[40]  R. L. Rennaker,et al.  A comparison of chronic multi-channel cortical implantation techniques: manual versus mechanical insertion , 2005, Journal of Neuroscience Methods.

[41]  T. Aziz,et al.  Electron microscopy of tissue adherent to explanted electrodes in dystonia and Parkinson's disease. , 2004, Brain : a journal of neurology.

[42]  Patrick A Tresco,et al.  Chronic response of adult rat brain tissue to implants anchored to the skull. , 2004, Biomaterials.

[43]  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.

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

[45]  W. Scheld,et al.  Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor. , 1991, The Journal of clinical investigation.

[46]  R. J. Seitz,et al.  The mouse blood-brain barrier and blood-nerve barrier for IgG: A tracer study by use of the avidin-biotin system , 2004, Acta Neuropathologica.

[47]  B Bioulac,et al.  Minimal tissue damage after stimulation of the motor thalamus in a case of chorea-acanthocytosis , 2002, Neurology.

[48]  J Miller,et al.  Minocycline increases quality and longevity of chronic neural recordings , 2007, Journal of neural engineering.

[49]  Gordon H Baltuch,et al.  Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy. Case report. , 2004, Journal of neurosurgery.