Controlled release of brain derived neurotrophic factor to promote neuron survival following chronic electrode implantation
Authors:   , Sundarakrishnan Aswin K. , Wheatley Margaret A. , Moxon Karen A. 
Published: July 2021

Chronic electrode implantation in the brain leads to the formation of a glial scar surrounding the implantation site. The glial scar, when formed, severely inhibits the long term in-vivo functionality of neural electrodes. Studies in the past have tried coating the neural electrodes using polymers with or without bioactive agents. However none report any success in alleviating the glial scar or show improvement in electrode recording capability. Previous studies have suggested the use of neurotrophin delivery from electrode coatings to promote neuron survival and improve electrode biocompatibility. In the current work, the feasibility of delivering Brain Derived Neurotrophic Factor (BDNF) from alginate thin film coatings on silicon electrodes was evaluated. Electrode coatings were manufactured via spinner coating using 0.45 [mu]m filtered 2% (w/v) or 4% (w/v) alginate solutions on silicon wafer substrates. To crosslink the alginate two different methods of crosslinking were evaluated, the fast CaCl2 crosslinking and the slow CaCO3-GDL crosslinking method. However CaCl2 crosslinking using an aerosolized spray produced consistent alginate coatings compared to the CaCO3-GDL crosslinking method and was subsequently used for all experiments. Thickness measurements using the profilometer showed that CaCl2 crosslinked alginate coatings in the micron level can be produced by spin coating 0.45 [mu]m filtered, 4% alginate solutions at 1000 rpm for 30-60 seconds. When multiple layers of alginate were applied on top of one another, coatings of thicknesses ranging from 5 [mu]m to 80 [mu]m were produced via spinner coating. To simulate BDNF release, all alginate films were loaded with either model proteins (lysozyme or chymotrypsinogen) or poloxamer (p-188), a polymer that has been shown to have membrane-sealing properties. In-vitro release studies from all loaded films were conducted in PBS (pH 7.4) at 37°C until all protein or poloxamer was released. Results from the release studies showed rapid release profiles for both model proteins and p-188. Complete release of proteins and p-188 took place within the first three hours. This is well short of the anticipated 3-4 day release period required for BDNF. In order to prolong release for BDNF, the effect of addition of a poly-L-ornithine (PLO) coating on the alginate layer was evaluated. PLO coatings at three different concentrations, 0.1(w/v) %, 0.5% and 1% were applied on the surface of alginate films. Subsequent release studies showed very similar release profiles between the PLO-coated and the uncoated films, and were probably due to the detachment of the film from the silicon surface early in the release. The results of this study clearly show the feasibility of manufacturing neurotrophin releasing alginate coatings for silicon electrodes. The versatile coating method can be used to deliver a number of different compounds including proteins like neurotrophins and polymers like p-188. However to achieve controlled release over longer periods of 3-4 days, alternate coating methods will need to be investigated.