Design and microfabrication of flexible neural probes for chronic applications
In the last decades, the clinical applications of neural devices have increased exponentially. Accommodated by the ever increasing miniaturization and affordability of sensors and circuitry more and more developments transitioned from the field of experimental research towards clinical practice. Nowadays, we possess a wide variety of tools that can be used to assess different aspects of the central and peripheral nervous system. These include non-invasive tools to monitor brain activity, such as electroencephalography, and more invasive penetrating devices such as cochlear implants and brain stimulators.
While adequate long-term performance was demonstrated in the above mentioned applications, more advanced neural interfacing devices still face significant challenges concerning chronic reliability. After digging through several decades of research it became clear that the immune response, which is evoked by the implantation of the device, plays a crucial role in the performance of the neural electrode. In chapter 2 of this dissertation we take a closer look at the electrode-tissue interaction and identify the factors that are responsible for the premature failure of implanted neural devices.
In an attempt to minimize the evoked effects and increase the electrode lifetime there is a noticeable evolution towards the use of flexible materials. Using softer, more compliant, materials with mechanical properties resembling those of the brain tissue attenuates the so-called foreign body reaction, and improves the chronic applicability of the implanted devices. Apart from its beneficial effect on electrode lifetime, flexible materials bring along several other opportunities. Chapter 3 of this dissertation describes the development of the ‘flower’ electrode which was designed to drape the inside of an abnormal brain cavity and record neural activity. Due to the deep location of the target cavity, a bespoke implantation procedure was developed with the goal of minimizing damage to the tissue surrounding the implantation trajectory. During this procedure we take advantage of the electrode’s flexibility by temporarily folding it onto itself and packaging it in a cannula. After implantation the electrode is pushed through the cannula and into the cavity, where it unfolds and takes on a three-dimensional shape conform to the cavity wall. Due to its design, the planar structure can take on a hemispherical shape without inducing any stress or wrinkling. An in vivo experiment was performed to validate the developed implantation procedure and the correct operation of the electrode. Analysis of the recorded data indicated that it is possible to record signals of biological origin.
Chapter 4 of this dissertation focuses on the practical problems associated with the use of highly flexible neural probes. The thin polymer-based implants are often too flexible for implantation and a mechanical reinforcement is needed to temporarily increase the probe stiffness. In the quest to find a suitable material, dextran came forward as an ideal candidate as it is cheap, easily accessible and its chemical composition (polymeric carbohydrate) allowed tuning of the coatings dissolution rate. Practically, this means that a fast dissolution time allows the electrode to regain its highly flexible state within minutes after implantation, and thus limits the evoked immune response. These hypotheses were analysed by conducting a long-term in vivo experiment. Not only did the results show that the amount of glial scarring was strongly reduced, but the area that was initially taken up by the dextran coating was re-occupied with active neurons. Additionally, there was no noticeable decrease in neuronal density in the vicinity of the implant.
In addition to using highly flexible materials, the foreign body response can be minimized by integrating bioactive components which play an active role in the suppression of the evoked immune response and the regeneration of the neurons that were damaged during the implantation. In chapter 5 we take a closer look at how these bio-active components influence the electrode-tissue interaction and we can use them to increase the lifetime of neural devices. The design and microfabrication process of a miniaturized neurotrophic electrode is presented. The electrode consists of a hollow tubes which is filled with a growthfactor loaded hydrogel. After implantation a foreign body response will be elicited. Apart from phagocytising the cellular debris resulting from the implantation the activated microglia will also start to enzymatically degrade the hydrogel in the tube, thereby slowly releasing growthfactors in the surrounding environment. The resulting chemical gradient will promote neuroregeneration and supress further astrocyte recruitment, limiting glial scarring at the site of implantation. A secondary advantage is the directional regeneration of damaged neurons into the tubes. As a result the electrical activity of the ingrown neurons can be recorded while isolating the signal from any interference caused by surrounding active neurons, drastically improving the signal-to-noise ratio.
The sixth and final chapter presents the main conclusions of this work.