This thesis presents an extensive exploration of neuroelectronic interfaces, focusing on microfabrication, in silico modeling, and their applications in designing and fabricating devices for neural interfacing. The research encompasses both peripheral nerve interfaces (PNIs) for in vivo applications and three-dimensional MicroElectrode Arrays (MEAs, also known as MultiElectrode Arrays) for in vitro studies with neural organoids and spheroids.

Initially, the thesis introduces neuroelectronic interfaces, outlining their importance in fundamental and translational neuroscience and neurotechnology. It traces the evolution from traditional neuroelectronic interfaces to advanced silicon-based microelectronics and flexible polymeric devices, enhancing biointegration. The role of Finite Element Modeling (FEM) in improving implant design through simulating mechanical and electrical properties is emphasized.

The second part explores PNIs, categorizing them by invasiveness and interaction mechanisms. It addresses chronic integration challenges like foreign body reactions and the nerve-implant mechanical mismatch. Finite Element Modeling is proposed for optimizing invasive PNI mechanics, using a model simulating a rat's sciatic nerve with an intraneural implant. The model evaluates factors such as implant modulus and design, guiding implant material and design choices to minimize the mechanical footprint.

Leveraging the results from the preceding chapter, the third section presents a hybrid implant model combining intrafascicular and extraneural components, aiming to reduce mechanical stresses on the nerve and improve anchoring. This section introduces the Hybrid Extraneural Intrafascicular Directional Implant (HEIDI) for acute in vivo rat studies, assessing its selectivity and testing new directional stimulation protocols.

The fourth chapter focuses on 3D neural tissue cultures like brain spheroids and organoids. It introduces the e-Flower, a 3D MEA platform for non-destructive electrophysiological recordings on brain spheroids. The e-Flower's design incorporates guidelines from Finite Element Modeling and integrates hydrogel-polymer bilayers as actuating building block, proving effective in recording neural activity on brain spheroid surfaces.

The thesis concludes with ongoing research and future directions for enhancing neuroelectronic devices, including advanced in vitro PNI modeling, development of novel soft materials compatible with microfabrication technologies, and potential applications of both HEIDI and 3D MEAs based on the e-Flower technology.

In summary, this thesis emphasizes the significance of design, modeling, fabrication, and testing in advancing 3D neuroelectronic interfaces, offering innovative solutions for both in vivo and in vitro applications.