Abstract
Intracortical electrodes for brain–machine interfaces rely on intimate contact with tissues for recording signals and stimulating neurons. However, the long-term viability of intracortical electrodes in vivo is poor, with a major contributing factor being the development of a glial scar. In vivo approaches for evaluating responses to intracortical devices are resource intensive and complex, making statistically significant, high throughput data difficult to obtain. In vitro models provide an alternative to in vivo studies; however, existing approaches have limitations which restrict the translation of the cellular reactions to the implant scenario. Notably, there is no current robust model that includes astrocytes, microglia, oligodendrocytes and neurons, the four principle cell types, critical to the health, function and wound responses of the central nervous system (CNS). In previous research a co-culture of primary mouse mature mixed glial cells and immature neural precursor cells were shown to mimic several key properties of the CNS response to implanted electrode materials. However, the method was not robust and took up to 63 days, significantly affecting reproducibility and widespread use for assessing brain-material interactions. In the current research a new co-culture approach has been developed and evaluated using immunocytochemistry and quantitative polymerase chain reaction (qPCR). The resulting method reduced the time in culture significantly and the culture model was shown to have a genetic signature similar to that of healthy adult mouse brain. This new robust CNS culture model has the potential to significantly improve the capacity to translate in vitro data to the in vivo responses.
Highlights
Investigating the biocompatibility of brain interfacing devices using animal models is expensive, time consuming (Gilmour et al, 2016) and data yield from each animal can be limited by the tissue processing and histological methods used within a study (Woolley et al, 2011)
Both the layered and concurrent co-culture methods resulted in dense myelinated neural networks which grew for 35 days
As mixed glial cells (MGCs) were only revived once a mouse was successfully time mated this resulted in 100% success rate for the modified co-culture methods significantly reducing animal breeding costs
Summary
Investigating the biocompatibility of brain interfacing devices using animal models is expensive, time consuming (Gilmour et al, 2016) and data yield from each animal can be limited by the tissue processing and histological methods used within a study (Woolley et al, 2011). For neural cell culture models to be mimetic of the CNS in health and disease, mimicking cell–cell interactions is essential. Interactions both within and between individual glial and neural cell types are critical for the development, function and dysfunction of the CNS (Jäkel and Dimou, 2017). Glial cells change roles from promoting development of neural networks and myelination, to maintaining the complex function of the adult CNS. In response to injury in the mature CNS, glial cells within the wound parenchyma transition to a reactive state (Silver and Miller, 2004; Anderson et al, 2014; Gilmour et al, 2016). Immature glial cells from fetal or neonatal origins lack the ability to undergo reactive gliosis-like reactions in vivo and in vitro (Schwartz et al, 1989; Wu and Schwartz, 1998)
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