Active ultra-flexible, high-density electrode arrays for chronic deep brain neural interfacing

Neurologic disorders and brain diseases are becoming the number one global health burden. Together with an increasing mortality rate, the cost and pressure on the healthcare system is growing annually. Action must be taken now to limit the number of neurological disease cases in the future. That is why there is such a strong motivation in neuroscience to find cures and patient-specific treatments for nervous system-related diseases and to get a better fundamental understanding of the brain. Brain implants can help in achieving those goals by measuring the brain activity or by correcting brain functioning through electrical stimulation.

For the category of invasive, brain-penetrating implants that interface directly with neural circuits—so-called neural probes—two trends have emerged. First, probes harbor an ever-increasing number of electrodes to increase the amount information that can be obtained from the brain. Second, neural probes are used for extended periods of time (months to years) for longitudinal recordings. State of the art neural probes feature over thousand electrodes on a single probe shank greatly enhancing the neural recording capability. However, such probes are often made from silicon, which is a rigid material with a high Young’s modulus, and requires a relatively high thickness to maintain integrity. These properties lead to a large mechanical mismatch with the soft brain tissue, and due to micromotion between the probe and brain, a severe tissue response induces neuronal loss and probe encapsulation.

In this thesis, ultra-thin neural probes fabricated from highly flexible materials are explored as a promising solution to the downsides of silicon. The main result is a polyimide-based flexible neural probe with up to 128 microelectrodes on a single probe shank. The probe dimensions are designed to be minimally invasive and as conformal with the brain as possible. The probe is constructed from polyimide layers with a final thickness of 3 μm, making it one of the thinnest probes to date. The shank width tapers from 100 μm at the last electrode to 40 μm at the tip electrode. Three different microelectrode materials have been investigated, with iridium oxide providing a tenfold impedance reduction over traditional electrode materials such as gold or platinum. The probe stack contains inorganic material layers—aluminium oxide, hafnium oxide (ALD-3) or amorphous silicon carbide (SiC)—for improving the longevity of the device, which is of interest for chronic applications. The probe early failure mechanisms were obtained using accelerated aging experiments in a heated saline environment in two custom-made testing setups. The following material stacks were analyzed: (1) polyimide-polyimide, with the bottom layer soft baked, (2) polyimide-polyimide, both layers completely baked, (3) polyimide-ALD-3-polyimide, and (4) polyimide-SiC-polyimide. The first aging test was used to determine the adhesion between the different layers and showed that the ALD-3 stack improves the adhesion strength compared to completely baked polyimide layers after 217 d aging at 60 °C which corresponds to almost three years in-vivo. The second aging test was used to measure the impedance of encapsulated lines and showed that structures with a partially baked bottom polyimide layer kept a stable closed line impedance of 189 d at 60 °C.

In addition to the development of flexible neural probes, this thesis describes the development of probe implantation techniques that facilitate the insertion and chronic use of both rigid silicon-based and flexible neural probes. Five different implantation techniques were developed: (1) a clamping mechanism enabled the implantation of a 23 mm long silicon probe. (2) a set of four different reusable fixtures for the chronic implantation and retrieval of Neuropixels probes. By using the fixtures, the probes are reusable at least four times in freely behaving rats and mice. (3) An implantation tray to implant a total of 1024 electrodes in the visual cortex of a non-human primate. (4) A hyperdrive structure comprising an array of 16 independently movable microdrives for the implantation of 15 μm thin flexible probes, and (5) a “stitching” method for implanting 3 μm ultra-thin flexible probes to depths beyond 3 cm.

The ultra-flexible probe is connected to a 128 ch headstage that amplifies, multiplexes, and digitizes the neuronal signals. Eventually those features can be integrated on the probe by connecting a CMOS chip. The initial steps for this connection were established and include the electroplating of gold contact pads on a wafer-scale level and flip chip bonding technique, which was used to connect a 128 ch high-density flexible probe to a flexible cable.

Finally, the developed high-density flexible probes have been validated in rats and a mouse in a chronic recording setup. The setup enabled the parallel readout of 128 channels from the ultra-flexible high-density neural probe. Histology experiments show the minimal invasiveness of the flexible probes. Finally, this thesis advanced the neuroscience field by introducing a high-density flexible neural probe together with different probe insertion methods. Some of these techniques can potentially be used for the development of a clinical neural implant.