Neuroadhesive L1 coating attenuates acute microglial attachment to neural electrodes as revealed by live two-photon microscopy

Abstract

Implantable neural electrode technologies for chronic neural recordings can restore functional control to paralysis and limb loss victims through brain-machine interfaces. These probes, however, have high failure rates partly due to the biological responses to the probe which generate an inflammatory scar and subsequent neuronal cell death. L1 is a neuronal specific cell adhesion molecule and has been shown to minimize glial scar formation and promote electrode-neuron integration when covalently attached to the surface of neural probes. In this work, the acute microglial response to L1-coated neural probes was evaluated in vivo by implanting coated devices into the cortex of mice with fluorescently labeled microglia, and tracking microglial dynamics with multi-photon microscopy for the ensuing 6 h in order to understand L1’s cellular mechanisms of action. Microglia became activated immediately after implantation, extending processes towards both L1-coated and uncoated control probes at similar velocities. After the processes made contact with the probes, microglial processes expanded to cover 47.7% of the control probes’ surfaces. For L1-coated probes, however, there was a statistically significant 83% reduction in microglial surface coverage. This effect was sustained through the experiment. At 6 h post-implant, the radius of microglia activation was reduced for the L1 probes by 20%, shifting from 130.0 to 103.5 µm with the coating. Microglia as far as 270 µm from the implant site displayed significantly lower morphological characteristics of activation for the L1 group. These results suggest that the L1 surface treatment works in an acute setting by microglial mediated mechanisms.

Glial responses to implanted electrodes in the brain

“…However, the implementation of ‘stealth’ coatings, such as those based on neuronal cell-adhesion molecules, can alleviate the foreign-body response by both promoting neural growth and by reducing gliosis (Fig. 2c,d) 162,193,208 .…”

Enhancing surface immobilization of bioactive moleculesviaa silica nanoparticle based coating

“…20,21 Meanwhile, superoxide dismutase mimics such as Mn( iii )tetrakis(4-benzoic acid)porphyrin and amine functionalized meso -tetra(2-pyridyl)porphine (referred to as iSODm) 22,23 have been covalently bound to the surface of neural implants to reduce harmful reactive oxygen species (ROS) released both acutely after insertion injury and chronically as a component of inflammatory tissue responses. Biomimetic coatings utilizing peptides 24,25 and proteins 10,26,27 exhibit pronounced effects in reducing the inflammatory response and/or encouraging neurite attachment as well as decreasing the activation of glia. Laminin-coated surfaces can modulate the inflammation around the implant, increasing the microglia activation acutely but decreasing the glial scar after 4 weeks.…”

Recent advances in neural electrode–tissue interfaces

“…To catch cellular and vascular dynamics, and correlates changes of tissue characteristics to recording performance in real time, various in vivo live imaging approaches have been developed. Two-photon microscopy (TPM) has been used to visualize vascular damage and remodeling, microglial polarization and migration [48, 49], or shape and activity of the neurons around electrode devices [20, 50] before and after electrode array insertion and over extended periods of time. Compared to technologies like MRI and microCT, multi-photon microscopy offers high spatial resolution for resolving cellular processes, sufficient temporal resolution for tracking calcium activity, and ample cell type specific labeling (Capabilities of various imaging modality is summarized in Table 2).…”

“…More recently an in vivo TPM study revealed that microglia cells send processes to probes coated with L1 immediately after implantation at a similar speed as they do to uncoated controls. However upon arriving at the probe surface, the spreading of microglia processes was significantly reduced by the surface immobilized L1 [49]. This study suggests that there is a window of opportunity to modulate the initial cellular behavior via bioactive surface cues.…”

“…This burst in proinflammatory signaling may aid in acute wound healing and minimize long term tissue damage around the electrode. On the other hand, use of L1, a neuron specific cell adhesion molecule, has resulted in increased neuronal attachment along with decreased gliosis around the implants [38, 49, 92, 93]. More recently an in vivo TPM study revealed that microglia cells send processes to probes coated with L1 immediately after implantation at a similar speed as they do to uncoated controls.…”