Electrical signals recorded from neurons by intracortical electrodes have been used by human patients to communicate with computers and to control robotic limbs. The signal quality and the length of time that useful signals can be recorded are inconsistent. The consensus view of the community is that the inflammatory response to the microelectrode contributes, at least in part, to electrode reliability. Inflammation is initiated when inflammatory cells recognize foreign biologics (i.e. damaged/infiltrating proteins and cells). Serum proteins and blood-derived cells invade the central nervous system following device implantation. Cells and tissue are damaged from the trauma of device implantation. At the electrode surface, accumulation of pro-inflammatory molecules causes neuronal degeneration and increases the permeability of the blood-brain barrier, self-perpetuating the process. The co-receptor cluster of differentiation 14 (CD14) has been shown to coordinate the binding and recognition of pathogens or damaged cells for at least four different toll-like receptors (TLR). Specifically, in cooperation with CD14, both TLR2 and TLR4 have also been shown to become reactive towards serum proteins and necrotic cells. CD14 likely mediates the self-perpetuating neuroinflammatory response to non-biological medical devices through recognition of adsorbed serum proteins and damaged cells and tissue. We have studied the role of CD14, TLR2, and TLR4 in facilitating neuroinflammation in response to implanted intracortical electrodes. Transgenic mice lacking CD14, TLR2 or TLR4 implanted with non- working "dummy" electrodes, showed a time dependent inhibition in the inflammatory response to the implant. Therapeutic administration of a CD14 antagonist also attenuated inflammation to the implant. Further, over stimulation of CD14 pathways with lipopolysaccharide negatively impacted the quality of chronic neural recordings. Therefore, we hypothesize that CD14 inhibition will enable intracortical microelectrodes to more consistently record high quality neural units. We propose to first implant transgenic mice lacking either the CD14 co-receptor with functional microelectrodes. The quality and stability of neural signals will be compared to the performance of identical devices implanted in control wildtype animals for up to 16 weeks. As a step towards clinical use, Aim 2 will establish a time course for systemic inhibition using a CD14 antagonist. Finally, Aim 3 will investigate the efficacy of a local delivery vehicle, to minimize the potential for side effects associated with long-term systemic administration. In all aims, histological evaluation will track both neuroinflammation and blood-brain barrier stability over time, while electrophysiological evaluation will correlate neuroinflammation to device performance.

Public Health Relevance

Intracortical microelectrodes have been hindered, at least in part, by the inflammatory reponse, which yeilds the electrodes incapable of consistent stable interactions with viable neurons. Identification of a dominant mechanism that mediates the inflammatory response would represent a significant step towards clinical use. In this study, we will build on our preliminary findings and investigate the role of cluster of differentiation 14 in mediating the self-perpetuating neural inflammatory responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS082404-01A1
Application #
8632462
Study Section
Special Emphasis Panel (BNVT)
Program Officer
Ludwig, Kip A
Project Start
2013-09-01
Project End
2017-06-30
Budget Start
2013-09-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$450,548
Indirect Cost
$161,821
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Nguyen, Jessica K; Park, Daniel J; Skousen, John L et al. (2014) Mechanically-compliant intracortical implants reduce the neuroinflammatory response. J Neural Eng 11:056014
Potter-Baker, Kelsey A; Ravikumar, Madhumitha; Burke, Alan A et al. (2014) A comparison of neuroinflammation to implanted microelectrodes in rat and mouse models. Biomaterials 35:5637-46
Ravikumar, Madhumitha; Sunil, Smrithi; Black, James et al. (2014) The roles of blood-derived macrophages and resident microglia in the neuroinflammatory response to implanted intracortical microelectrodes. Biomaterials 35:8049-64