A three dimensional in vitro glial scar model to investigate the local strain effects from micromotion around neural implants

Abstract

The glial scar formation remains a significant barrier to the long term success of neural probes. Micromotion coupled with mechanical mismatch between the probe and tissue is believed to be a key driver of the inflammatory response. In vitro glial scar models present an intermediate step prior to conventional in vivo histology experiments as they enable the cell-device interactions to be tested on a shorter timescale, with the ability to conduct broader biochemical assays. No established in vitro models have incorporated methods to assess device performance with respect to mechanical factors. In this study, we describe an in vitro glial scar model that combines high-precision linear actuators to simulate axial micromotion around neural implants with a 3D primary neural cell culture in a collagen gel. Strain field measurements were conducted to visualize the local displacement within the gel in response to micromotion. Primary brain cell cultures were found to be mechanically responsive to micromotion after one week in culture. Astrocytes, as determined by immunohistochemical staining, were found have a significant increase in cell area and perimeter in response to micromotion compared to static control wells. These results demonstrate the importance of micromotion when considering the chronic response to neural implants. Going forward, this model provides advantages over existing in vitro models as it will enable critical mechanical design factors of neural implants to be evaluated prior to in vivo testing.

Steerable Microinvasive Probes for Localized Drug Delivery to Deep Tissue

“…Long‐term measurements can also be inaccurate representations of naïve brain tissue due to neuron death and local changes in electrochemical signaling due to gliosis and neuroinflammation . Our group has previously demonstrated reduced glial scarring in response to smaller implant diameters, down to 150 µm . Implants that incorporate highly flexible, low‐diameter materials to reduce associated inflammation are thus termed “microinvasive.” Microinvasive implants are capable of targeting deep‐brain structures with increased spatial resolution and minimal scarring .…”

Double-layer flexible neuronal probe with closely spaced electrodes for high-densityin-vivobrain recordings

“…However, due to the intrinsic stiffness of the silicon substrate, there has been a rising interest in probes that can be fabricated in flexible biocompatible substrate materials with lower mechanical mismatch between probe and brain tissue 4 . Flexible neuronal probes can be highly conformable, thus reducing the extent of brain tissue displacement, damage and glial scaring upon implantation, and providing adaption to brain micro- and macro-motions 4,5,6,7 . These advantages are important for the stability of the brain implant and for improving the quality of the recorded signals, both in acute and chronic in vivo applications 8 .…”

A Mechanically-Adaptive Polymer Nanocomposite-Based Intracortical Probe and Package for Chronic Neural Recording

“…Relative micromotion arising from constant, repetitive displacements in tissue due to respiration and vascular pulsations produce strain on tissue surrounding the implant due to mechanical mismatch at the implant-tissue interface for high modulus implants. The differential strain on tissue is considered to be a primary contributor to glial scar formation [ 21 , 22 ], which is further supported by in vitro studies reporting that components of astroglial scarring proliferate in response to mechanical strain [ 23 ] and high modulus substrates [ 24 ], while neurite outgrowth and extension is stimulated on low-modulus substrates with mechanical properties approaching brain tissue ( E brain ~ 10 kPa) [ 25 ]. Intracortical implants based on a lower modulus material reduce the differential strain on tissue during micromotion [ 26 , 27 ], which may also reduce the problematic neuroinflammatory response.…”