Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 11 (5), 056014

Mechanically-compliant Intracortical Implants Reduce the Neuroinflammatory Response

Affiliations

Mechanically-compliant Intracortical Implants Reduce the Neuroinflammatory Response

Jessica K Nguyen et al. J Neural Eng.

Abstract

Objective: The mechanisms underlying intracortical microelectrode encapsulation and failure are not well understood. A leading hypothesis implicates the role of the mechanical mismatch between rigid implant materials and the much softer brain tissue. Previous work has established the benefits of compliant materials on reducing early neuroinflammatory events. However, recent studies established late onset of a disease-like neurodegenerative state.

Approach: In this study, we implanted mechanically-adaptive materials, which are initially rigid but become compliant after implantation, to investigate the long-term chronic neuroinflammatory response to compliant intracortical microelectrodes.

Main results: Three days after implantation, during the acute healing phase of the response, the tissue response to the compliant implants was statistically similar to that of chemically matched stiff implants with much higher rigidity. However, at two, eight, and sixteen weeks post-implantation in the rat cortex, the compliant implants demonstrated a significantly reduced neuroinflammatory response when compared to stiff reference materials. Chronically implanted compliant materials also exhibited a more stable blood-brain barrier than the stiff reference materials.

Significance: Overall, the data show strikingly that mechanically-compliant intracortical implants can reduce the neuroinflammatory response in comparison to stiffer systems.

Conflict of interest statement

The authors have no conflicts of interest related to this work to disclose.

Figures

Figure 1
Figure 1
Images of Michigan-style silicon probes before (A) and after (B) PVAc coating. Dipcoating deposited a PVAc-surface layer of 15 ± 5µm. Scale bar = 50 µm.
Figure 2
Figure 2
(A–E) Predicted strain profiles induced by a tangential tethering force on (A) a bare silicon implant (E’ = 200 GPa), (B) a silicon implant with a 15.5µm PVAc coating (E’ = 78 GPa), (C) an implant created entirely of the PVAc nanocomposite material (63µm × 130µm) in the stiff state (E’ = 5 GPa), (D) an implant created entirely of the PVAc nanocomposite material (63µm × 130µm) in the compliant soft state (E’ = 12 MPa), and (E) a hypothetical implant that matches brain modulus (E’ = 6 kPa). Strain profiles are normalized to the maximum induced strain surrounding the uncoated silicon probe. (F–H) Normalized strain profiles extending in the positive y-direction are taken from the brain surface, the implant’s midpoint and implant’s tip (levels are shown as white dashed lines in (A)). No significant differences were seen between the bare and coated silicon implants and stiff NC. Despite the nanocomposite implant having larger dimensions, the model demonstrated that the compliant nanocomposite implant would induce less strain on the surrounding tissue than both the uncoated and coated Si implants along their entire length. Additionally, no significant differences were seen between the compliant nanocomposite and a (hypothetical) implant with a modulus that matches the one of the cortical tissue at the midpoint and tip levels.
Figure 3
Figure 3
Immunohistochemical analysis of neuronal nuclei (NeuN) around the implant site. Representative fluorescence microscopy images of stained tissue show that neuronal dieback around the stiff PVAc-coated silicon implant was significantly higher than in case of the compliant nanocomposite implant at various time points (3 days (A–B), 2 weeks (C–D), 8 weeks (E–F), 16 weeks (G–H)). The bar graphs show quantification of neuron densities. Statistical analysis identified several regions with significantly different neuron populations, which varied between time points. * Denotes significance between stiff and compliant samples; # Denotes significance between noted implant and age-matched sham control (p < 0.05). Scale bar = 100 µm. The horizontal dashed line represents the 100% neuron level as determined by quantification of age-matched sham animals. Error bars represent standard error.
Figure 4
Figure 4
Immunohistochemical analysis of the astrocytic scar. Representative fluorescence microscopy images of stained tissue show the formation of a more compact scar surrounding mechanically compliant implants (B, D, F, H), compared to the chemically-matched stiff implants (A, C, E, G) beginning at 2 weeks post-implantation. IHC staining for GFAP+ astrocytes after 2 weeks were seen at higher densities with broader distribution following implantation of the stiff implants compared to the mechanically compliant implants (I–L) (p < 0.05). Scale bar = 100 µm. Error bars represent standard error.
Figure 5
Figure 5
Immunohistochemical analysis of total microglia/macrophages populations (Iba1). Representative fluorescence microscopy images of stained tissue show no effect of implant compliance at acute time points (3 days (A–B,I), 2 weeks (C–D,J)), but a significant increase in Iba1 immunoreactivity around stiff implants at chronic time points (8 weeks (E–F,K), 16 weeks (G–H,L)) (p < 0.05). Scale bar = 100 µm. Error bars represent standard error.
Figure 6
Figure 6
Immunohistochemical analysis of CD68, a cellular marker for activated microglia/macrophages. Representative fluorescence microscopy images of stained tissue show a distinct benefit of mechanically compliant implants (B, D, F, H), compared to the chemically matched stiff implants (A, C, E, G). Starting at two weeks post implantation, IHC staining and fluorescent quantification showed increased expression of CD68+ tissue surrounding the stiff implants (I–L) (p < 0.05). Scale bar = 100 µm. Error bars represent standard error.
Figure 7
Figure 7
Immunohistochemical analysis of IgG staining shows that the blood brain barrier integrity is improved for compliant implants, compared to stiff implants. Representative fluorescence microscopy images of IgG immunoreactivity show no difference three days post implantation (A, B). At all subsequent time points, a marked increase in IgG intensity was observed around the stiff implant (D, F, H) compared to the compliant implant (C, E, G). Quantification of the fluorescent intensity indicates significant differences between implants at 2, 8, and 16 weeks post implantation (J–L). (p < 0.05). Scale bar = 100 µm. Error bars represent standard error.
Figure 8
Figure 8
Schematic representation of the tissue response around stiff (A) and compliant (B) implants. Stiff implants induce increased gliosis, BBB permeation, and neurodegeneration in comparison to compliant materials. (C) Graphical representation of the peak intensity of specific inflammatory markers over time, which shows a distinct advantage of compliant materials at chronic time points.

Similar articles

See all similar articles

Cited by 54 articles

See all "Cited by" articles

Publication types

Substances

Feedback