Elsevier

Brain Research

Volume 983, Issues 1–2, 5 September 2003, Pages 23-35
Brain Research

Research report
Brain responses to micro-machined silicon devices

https://doi.org/10.1016/S0006-8993(03)03023-3Get rights and content

Abstract

Micro-machined neural prosthetic devices can be designed and fabricated to permit recording and stimulation of specific sites in the nervous system. Unfortunately, the long-term use of these devices is compromised by cellular encapsulation. The goals of this study were to determine if device size, surface characteristics, or insertion method affected this response. Devices with two general designs were used. One group had chisel-shaped tips, sharp angular corners, and surface irregularities on the micrometer size scale. The second group had rounded corners, and smooth surfaces. Devices of the first group were inserted using a microprocessor-controlled inserter. Devices of the second group were inserted by hand. Comparisons were made of responses to the larger devices in the first group with devices from the second group. Responses were assessed 1 day and 1, 2, 4, 6, and 12 weeks after insertions. Tissues were immunochemically labeled for glial fibrillary acidic protein (GFAP) or vimentin to identify astrocytes, or for ED1 to identify microglia. For the second comparison devices from the first group with different cross-sectional areas were analyzed. Similar reactive responses were observed following insertion of all devices; however, the volume of tissue involved at early times, <1 week, was proportional to the cross-sectional area of the devices. Responses observed after 4 weeks were similar for all devices. Thus, the continued presence of devices promotes formation of a sheath composed partly of reactive astrocytes and microglia. Both GFAP-positive and -negative cells were adherent to all devices. These data indicate that device insertion promotes two responses—an early response that is proportional to device size and a sustained response that is independent of device size, geometry, and surface roughness. The early response may be associated with the amount of damage generated during insertion. The sustained response is more likely due to tissue–device interactions.

Introduction

The development of neuroprosthetic devices to restore nervous system function, lost due to trauma or disease, has been investigated for nearly three decades [1], [2], [16], [22], [23]. Such devices are becoming a practical reality in both the peripheral [9], [20], [21], [30], [31], [32], [45], [46] and central nervous systems [3], [7], [10], [13]. The most notable successes in humans are the alleviation of symptoms due to Parkinson’s disease via deep brain stimulation [3], [10], [13] and deafness using cochlear implants [8]. It is clear that the application of neuroprosthetics, especially in the brain, would substantially benefit from miniaturization. For instance, in the human brain, target regions often have linear dimensions of only a few millimeters. Miniature neuroprosthetics have been fabricated using microfabrication technology developed by the integrated circuit industry [14], [16], [29], [34]. Some of these devices have on-board electronics, including telemetry [24], [26]. Others have been assembled into complex three-dimensional electrode arrays [14], [25], [26], [29], [34], [37], [43]. Typical dimensions for such devices range from 10 to 100s of micrometers making it possible to target specific regions of the brain.

The long-term function of these devices is limited due to cellular encapsulation that electrically and mechanically isolates the prosthesis from the brain [17], [25], [39], [41], [44]. This tissue response occurs following implantation of many materials other than silicon [2], [30], [42], [46], [47]. Encapsulation has generally been described by visualizing reactive gliosis, particularly the hypertrophy and increased expression of glial fibrillary acidic protein (GFAP) by astrocytes [11], [18], [28], [33], [35], [40]. For times of 2 weeks and longer after implantation, we have demonstrated that astrocytes are a major cell type in the cellular sheath around inserted silicon devices [44]. This sheath is extremely dense and appears to contribute substantially to the electrical isolation of implants from the brain [44]. Preliminary results also suggest that microglia were also present [5].

The current study was designed to determine the effects of device features and insertion method on development of this cellular sheath. Reactive responses were compared following insertion of model devices with several cross-sectional areas of 16 900–1450 μm2, devices with angular geometries and micrometer surface roughness, or rounded corners and very smooth surfaces. Some devices were inserted using a microprocessor-controlled instrument others were inserted by hand. Results from these experiments indicate that device size is the major contributing factor to size of the early response, while the sustained response is independent of any of these variables.

Section snippets

Device fabrication and preparation

Devices were fabricated at either the Cornell Nanofabrication Facility (CNF) at Cornell University or the Center for Neural Communication Technology (CNCT) at the University of Michigan. The former is an NSF-sponsored facility. The latter is an NIH, NCRR supported Resource Center. Devices fabricated at the CNF permitted us to alter design features. Devices fabricated at the CNCT have prescribed features and are produced for distribution to the general scientific community.

Two different

Results

All animals recovered from surgery with no apparent adverse effects and all survived for the duration of the experiment. No behavioral, or gross- or micro-pathology including infection were observed. Although CNF and CNCT devices were inserted using different methods, the overall insertion processes appeared to be equivalent.

Discussion

If neuroprostheses are to realize their full potential as tools to study the nervous system and as therapeutic devices used to restore CNS functions lost as a result of trauma or disease in humans, it is critical that devices and procedures be developed to minimize or eliminate the formation of the encapsulating sheath. One approach to this problem is to minimize the tissue damage at the time of insertion by making the prosthesis extremely small with smooth surfaces and rounded corners as

Acknowledgments

This work was partially supported by NIH, NCRR RR10957, and NS9-RO1-NS40977 and the Cornell Nanofabrication Facility, a node of the National Nanofabrication Users Network supported by the NSF. The authors thank the Center for Neural Communication Technology sponsored by NIH, NCRR grant P41-RR09754 for devices. The authors wish to acknowledge the contributions of Mr. Alan Hershenroder and Mr. William Abbt of the Wadsworth Center’s Automation and Instrumentation department who designed and

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