Inflammatory Foreign Body Response Induced by Neuro-Implants in Rat Cortices Depleted of Resident Microglia by a CSF1R Inhibitor and Its Implications

Aviv Sharon; Maciej M Jankowski; Nava Shmoel; Hadas Erez; Micha E Spira

doi:10.3389/fnins.2021.646914

Inflammatory Foreign Body Response Induced by Neuro-Implants in Rat Cortices Depleted of Resident Microglia by a CSF1R Inhibitor and Its Implications

Front Neurosci. 2021 Mar 26:15:646914. doi: 10.3389/fnins.2021.646914. eCollection 2021.

Authors

Aviv Sharon^{1

2}, Maciej M Jankowski^{1

2

3}, Nava Shmoel^{1

2

4}, Hadas Erez^{1

2

4}, Micha E Spira^{1

2

4}

Affiliations

¹ Department of Neurobiology, The Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem, Israel.
² The Charles E. Smith Family and Prof. Joel Elkes Laboratory for Collaborative Research in Psychobiology, The Hebrew University of Jerusalem, Jerusalem, Israel.
³ Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁴ The Harvey M. Kruger Family Center for Nanoscience, The Hebrew University of Jerusalem, Jerusalem, Israel.

Abstract

Inflammatory encapsulation of implanted cortical-neuro-probes [the foreign body response (FBR)] severely limits their use in basic brain research and in clinical applications. A better understanding of the inflammatory FBR is needed to effectively mitigate these critical limitations. Combining the use of the brain permeant colony stimulating factor 1 receptor inhibitor PLX5622 and a perforated polyimide-based multielectrode array platform (PPMP) that can be sectioned along with the surrounding tissue, we examined the contribution of microglia to the formation of inflammatory FBR. To that end, we imaged the inflammatory processes induced by PPMP implantations after eliminating 89-94% of the cortical microglia by PLX5622 treatment. The observations showed that: (I) inflammatory encapsulation of implanted PPMPs proceeds by astrocytes in microglia-free cortices. The activated astrocytes adhered to the PPMP's surfaces. This suggests that the roles of microglia in the FBR might be redundant. (II) PPMP implantation into control or continuously PLX5622-treated rats triggered a localized surge of microglia mitosis. The daughter cells that formed a "cloud" of short-lived (T ₁ _/ ₂ ≤ 14 days) microglia around and in contact with the implant surfaces were PLX5622 insensitive. (III) Neuron degeneration by PPMP implantation and the ensuing recovery in time, space, and density progressed in a similar manner in the cortices following 89-94% depletion of microglia. This implies that microglia do not serve a protective role with respect to the neurons. (IV) Although the overall cell composition and dimensions of the encapsulating scar in PLX5622-treated rats differed from the controls, the recorded field potential (FP) qualities and yield were undistinguishable. This is accounted for by assuming that the FP amplitudes in the control and PLX5622-treated rats were related to the seal resistance formed at the interface between the adhering microglia and/or astrocytes and the PPMP platform rather than across the scar tissue. These observations suggest that the prevention of both astrocytes and microglia adhesion to the electrodes is required to improve FP recording quality and yield.

Keywords: CSF1R; PLX5622; bioelectronics; field potential recordings; foreign body response; microglia; neural interface; neuro-implant.

Grants and funding

U01 NS099687/NS/NINDS NIH HHS/United States