Development of highly biocompatible neuro-electronic interfaces towards monitoring authentic neuronal signaling in the brain

Background: To understand how the neuronal circuits in the brain process information there is a need for novel
neuro-electronic interfaces that can interact chronically with brain tissue with minimal disturbance of the
physiological conditions in the tissue, in awake and freely moving animals. For this, there is a need for implantable
neuro-electronic interfaces that are mechanically compliant with the tissue and that can remain positionally stable
with respect to the neurons, despite the continuous micromotions in the brain. To reach this goal it is also
important to be able to conduct a detailed analysis of the tissue reactions in the juxtapositional tissue around the
implant as well as to incorporate additional strategies such as adding tissue modifying drugs to the implant.
Aim: To this end, two different types of implantable neuro-electronic interfaces, addressing the issue of
mechanical compliance with two different approaches, as well as a novel method of sustained drug delivery from
the neural implants were designed, manufactured and evaluated in vivo.
Method: First, arrays of thin gold leads, flexible in 3D, were cut from a 4 μm thin gold sheet, insulated with a thin
layer of Parylene-C (4 μm) and then embedded and structurally locked in a stiff gelatin matrix that dissolves after
implantation. These arrays were implanted in rats and evaluated electrophysiologically for 3 weeks. Second, a
novel tube-like electrode with an opening on the side, comprising a conducting lead embedded in glucose
enveloped by a thin layer of Parylene-C, was developed. After implantation the glucose in this protoelectrode
dissolves transforming the protoelectrode into a highly flexible and low density electrode inside the tissue. Such
tube electrodes were implanted in rats and evaluated by means of immunofluorescence microscopy after 6 weeks.
Further, minocycline loaded nanoparticles were embedded into a gelatin matrix surrounding neural implants and
the tissue reactions were evaluated in genetically modified mice exhibiting fluorescent microglia by means of
immunofluorescence microscopy 3 and 7 days after implantation.
Results: The developed 3D arrays were found to be implantable with preserved conformation and
electrophysiological recordings showed relatively stable recordings, with spike amplitudes over 400 μV. The tube
electrode proved to be sliceable in the brain without dislocating, making it possible to analyze the tissue right
outside the recording site, showing minute glia reactions and no significant loss of neurons as compared to
baseline tissue, even in the inner most zone (0-20 μm). The minocycline loaded nanoparticles where successfully
incorporated in gelatin-coatings of neural implants, and histological analysis showed a significant attenuation of
glia reactions.
Conclusion: Two new types of mechanically compliant neuro-electronic interfaces and implantation methods, as
well as a compatible embedding method of local delivery of drug content, has been successfully developed and
evaluated, showing very promising biocompatibility and stability in the tissue.