Elsevier

Biomaterials

Volume 31, Issue 7, March 2010, Pages 1558-1567
Biomaterials

Quantitative analysis of the tissue response to chronically implanted microwire electrodes in rat cortex

https://doi.org/10.1016/j.biomaterials.2009.11.049Get rights and content

Abstract

Several hypotheses have been proposed to explain how the brain tissue reaction to single unit recording electrodes influences biocompatibility including progressive changes in the spatial distribution of reactive astrocytes, and the loss of neurons over the indwelling period. To examine these hypotheses, the spatial distribution of biomarkers associated with the foreign body response to insulated microwires placed in rat cerebral cortex was analyzed 2, 4, and 12 weeks after implantation using quantitative methods. We observed a stereotypical tissue response that was similar in some aspects to that previously reported for penetrating planar silicon microelectrode arrays with some specific differences including an overall lower degree of cortical tissue reactivity. While we found no evidence that reactive gliosis increases over time or that neuronal loss is progressive, we did find evidence of persistent inflammation and enhanced BBB permeability at the electrode brain tissue interface that extended over the 3 month indwelling period and that exhibited more animal to animal variability at 3 months than at 2 and 4 weeks.

Introduction

Cortically implanted microelectrode arrays are used for assessing neuronal activity. One such example is the microwire array, which has been widely used as a basic science tool, and has potential to contribute to clinical device development [1], [2], [3]. However, following implantation, chronic single unit recording and indeed, recording performance in general, is inconsistent from animal to animal with this class of devices [1], [3], [4], [5], [6], [7], [8], [9]. Available evidence suggests that the reaction the brain mounts against implanted microelectrodes contributes to recording instability, however, the factors that influence the brain tissue response to implanted electrodes remain unclear.

Evidence gathered over the last 50 years indicates that the brain tissue response to penetrating electrodes consists of several major features that are observed regardless of electrode design, species studied, or implantation method, and is similar in many respects to the foreign body response in other soft tissues [6], [10]. In particular, by 4 weeks following implantation, the reaction has a stereotypical organization consisting of hypertrophic astrocytes, fibroblasts, and meningeal cells [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23] that surrounds an activated macrophage/microglial/foreign body giant cell core found immediately adjacent to the implant [15], [17], [22]. Within this region of reactive gliosis, numerous studies have described a decrease in the neuronal population [10], [11], [12], [13], [15], [20], [21], [22], [23], [24]. Quantitative studies have shown that the response is limited to the immediate vicinity of the electrode extending a few hundred microns from the interface into surrounding brain tissue [13], [15]. While many of these features are observed at longer timepoints [10], [11], [13], [14], [15], [16], [19], [21], [23], [24], quantitative studies that examine the spatial distribution of relevant biomarkers as a function of indwelling time are lacking.

Toward this end, we employed a quantitative immunohistochemical approach to describe the spatial distribution of cell type specific markers associated with the foreign body response at 2, 4, and 12 weeks following the implantation of a microwire electrode in rat cortex. A single microwire electrode was chosen as a point of comparison with other such studies that have examined the brain tissue response to a single penetrating planar silicon electrode array [11], [13], [15], [16], [17], [25]. Specifically, the study was designed to address several questions including: a) Does inflammation persist around an implanted microwire electrode?; b) Does the pattern of reactive astrogliosis change as a function of the indwelling period?; and, c) Does the distribution of neurons at the device tissue interface change over a long indwelling period? That is, is there evidence of progressive neuronal degeneration?

Section snippets

Microelectrodes

Single shank, stainless steel microwires were provided by FHC (Bowdoinham, ME). Microwires had a 75 μm diameter shank with a sharp conical tip, approximately 1 μm in diameter, and were 5 mm in total length. The microwires were coated by the manufacturer with Epoxylite insulation, except for the last 25 μm of the tip which constituted the recording site, as is shown in Fig. 1A. All microwire electrodes were cleaned by immersion in 70% ethanol and rinsed several times in sterile DI water, followed by

Quantitative glial and neuronal response

No attached cells were observed on explanted microwires at any timepoint studied (data not shown). The activated microglia/macrophage response to implanted stainless steel microwires consisted of punctate ED-1+ immunoreactivity localized adjacent to and within the electrode track. The ED-1 immunoreactive zone was circular in shape and reflected the geometry of the implanted electrode, and was symmetric along the entire electrode shaft (Fig. 2A). There was also a large number of DAPI+ cells

Discussion

This results of our study show that inflammation persists around a single microwire electrode over a three month indwelling period in rat cortex. At no point in time or in any of the implanted animals was the implantation tract free of ED1 immunoreactivity. We consistently observed the pan-macrophage marker, ED-1, at 2, 4 and 12 weeks following implantation along the electrode tract and near the recording tip that was distributed more or less uniformly along the implant surface. We observed no

Conclusions

In this study, we observed an overall lower degree of cortical tissue reactivity near implanted insulated microwire electrodes than has been reported for planar silicon microelectrodes [10], [13], [15], [17]. We found no evidence to support a growing reactive gliotic response over time or to indicate that neuronal loss was progressive. What we found was evidence of persistent inflammation and enhanced BBB permeability that was more variable at 3 months that at 2 and 4 weeks. Whether these

Acknowledgements

The authors gratefully acknowledge Heather Kavarana for help with tissue processing.The custom LabView-based image analysis program was created by Dr. Michael J. Bridge. The authors also would like to acknowledge funding support by the National Institutes of Health (R01 NS046770).

References (48)

  • B.K. Leung et al.

    Characterization of microglial attachment and cytokine release on biomaterials of differing surface chemistry

    Biomaterials

    (2008)
  • Y.T. Kim et al.

    Chronic response of adult rat brain tissue to implants anchored to the skull

    Biomaterials

    (2004)
  • M. Nedergaard et al.

    New roles for astrocytes: redefining the functional architecture of the brain

    Trends Neurosci

    (2003)
  • G. Azzi et al.

    Permeability of the normal rat brain, spinal cord and dorsal root ganglia microcirculations to immunoglobulins G

    Biol Cell

    (1990)
  • R.M. Smeal et al.

    The influence of substrate curvature on neurite outgrowth is cell type dependent

    Exp Neurol

    (2008)
  • A. Sorensen et al.

    Long-term neurite orientation on astrocyte monolayers aligned by microtopography

    Biomaterials

    (2007)
  • R. Biran et al.

    Directed nerve outgrowth is enhanced by engineered glial substrates

    Exp Neurol

    (2003)
  • M.A. Nicolelis et al.

    Chronic, multisite, multielectrode recordings in macaque monkeys

    Proc Natl Acad Sci U S A

    (2003)
  • B.D. Burns et al.

    Recording for several days from single cortical neurons in completely unrestrained cats

    Electroencephalogr Clin Neurophysiol

    (1974)
  • M. Salcman et al.

    A new chronic recording intracortical microelectrode

    Med Biol Eng

    (1976)
  • E.M. Schmidt et al.

    Long-term implants of parylene-C coated microelectrodes

    Med Biol Eng Comput

    (1988)
  • X. Liu et al.

    Stability of the interface between neural tissue and chronically implanted intracortical microelectrodes

    IEEE Trans Rehabil Eng

    (1999)
  • X. Liu et al.

    Evaluation of the stability of intracortical microelectrode arrays

    IEEE Trans Neural Syst Rehabil Eng

    (2006)
  • J.C. Collias et al.

    Histopathological changes produced by implanted electrodes in cat brains; comparison with histopathological changes in human and experimental puncture wounds

    J Neurosurg

    (1957)
  • Cited by (0)

    View full text