Implantable biosensors are valuable scientific tools for basic neuroscience research and clinical applications. Neurotechnologies provide direct readouts of neurological signal and neurochemical processes. These tools are generally most valuable when performance capacities extend over months and years to facilitate the study of memory, plasticity, and behavior or to monitor patients’ conditions. These needs have generated a variety of device designs from microelectrodes for fast scan cyclic voltammetry (FSCV) and electrophysiology to microdialysis probes for sampling and detecting various neurochemicals. Regardless of the technology used, the breaching of the blood–brain barrier (BBB) to insert devices triggers a cascade of biochemical pathways resulting in complex molecular and cellular responses to implanted devices. Molecular and cellular changes in the microenvironment surrounding an implant include the introduction of mechanical strain, activation of glial cells, loss of perfusion, secondary metabolic injury, and neuronal degeneration. Changes to the tissue microenvironment surrounding the device can dramatically impact electrochemical and electrophysiological signal sensitivity and stability over time. This review summarizes the magnitude, variability, and time course of the dynamic molecular and cellular level neural tissue responses induced by state-of-the-art implantable devices. Studies show that insertion injuries and foreign body response can impact signal quality across all implanted central nervous system (CNS) sensors to varying degrees over both acute (seconds to minutes) and chronic periods (weeks to months). Understanding the underlying biological processes behind the brain tissue response to the devices at the cellular and molecular level leads to a variety of intervention strategies for improving signal sensitivity and longevity.

Penetrating cortical neural probe technologies allow investigators to record electrical signals in the brain. Implantation of probes results in acute tissue damage, and microglia density increases around implanted devices over weeks. However, the mechanisms underlying this encapsulation are not well understood in the acute temporal domain. The objective here was to evaluate dynamic microglial response to implanted probes using two-photon microscopy. Using two-photon in vivo microscopy, cortical microglia ∼200 µm below the surface of the visual cortex were imaged every minute in mice with green fluorescent protein-expressing microglia. Following probe insertion, nearby microglia immediately extended processes toward the probe at (1.6 ± 1.3) µm min(-1) during the first 30-45 min, but showed negligible cell body movement for the first 6 h. Six hours following probe insertion, microglia at distances <130.0 µm (p = 0.5) from the probe surface exhibit morphological characteristics of transitional stage (T-stage) activation, similar to the microglial response observed with laser-induced blood-brain barrier damage. T-stage morphology and microglia directionality indexes were developed to characterize microglial response to implanted probes. Evidence suggesting vascular reorganization after probe insertion and distant vessel damage was also observed hours after probe insertion. A precise temporal understanding of the cellular response to microelectrode implantation will facilitate the search for molecular cues initiating and attenuating the reactive tissue response.