The development of an active implantable neural probe system for chronic use

Abstract

The alleviation of symptoms of debilitating neural conditions via neural probes is an increasingly important area of research. However, the effectiveness of these probes decreases over time due to the formation of a glial scar around them. In order to design probes that can function long-term, this research study developed two main approaches to reduce the inflammatory response: one focusing on reducing the inflammatory response around the probe via a coating with controllable surface topography and drug delivery capabilities and the other on designing a neural probe utilising cooling as an alternative therapy to electrical stimulation to reduce the inflammatory response at the functioning tip. In order to assess material topographical effects in vitro, PC12 cells, primary neuronal cells from rats and human astrocytes were plated onto hydroxyapatite (HA) discs of various degrees of roughness. A method of encapsulating astrocytes in a gelatin methacryloyl (GelMA) hydrogel was also devised in order to allow studies of over a week to be carried out. HA was found to be non-cytotoxic, with PC12 and primary neuronal cells surviving and attaching to the moderately rough surface best, implying there is an optimum roughness to promote neuronal survival. This was further corroborated by astrocytes, as they exhibited the highest expression of inflammatory cytokines TNF-α and IL-6 when plated on the very rough surfaces. As topographical control alone was found to be insufficient to significantly reduce the inflammatory response, a drug eluting coating was also developed. This consisted of a dual layered microfluidic system capable of delivering multiple anti-inflammatory factors to brain tissue long term. This system offered the added benefit of being able to be inserted in its thin dry state before reswelling to provide anchorage against micromotion. Diffusion tests showed the system could release cytokines over a 4 day period from one infusion and could release small drugs with minimal burst release. Repeated infusions of IL-4 upregulated anti-inflammatory M2 phenotype macrophages and downregulated the expression of pro-inflammatory markers in astrocytes over a 3 week period. An experimentally validated thermal model was created in Comsol® to assess temperature profiles around a cooling probe in the human brain. This was linked with a Peltier chip and heat sink model in order to create a tool allowing for the prediction of Peltier and heat sink settings required to deliver a desired temperature at the probe tip. A 4mm probe consisting of silver core coated with HA was suggested as the current best method of ensuring therapeutic temperatures at the tip. This probe would also offer mild cooling along the probe length to reduce glial activation and therefore the formation of a glial scar. These two strategies were initially proposed as complementary ideas, however, the results of the investigations indicated that the cooling along the length of the cooling probe and the potential to release anti-inflammatory factors preferentially at the functioning tip of the probe resulted in an overlap in function between the two strategies. They are therefore presented as two separate solutions – a novel cooling probe or alternatively a coating system to increase the efficacy of current electrodes. With further work, both of these probe designs have the potential in the future to be clinically relevant and improve the lives of patients with neurological conditions.