Nanofabricating neural networks: Strategies, advances, and challenges

Abstract

Nanofabrication can help us to emulate natural intelligence. Forward-engineering brain gained enormous momentum but still falls short in human neurodegenerative disease modeling. Here, organ-on-chip (OoC) implementation of tissue culture concepts in microfluidic formats already progressed with the identification of our knowledge gap in toxicology and drug metabolism studies. We believe that the self-organization of stem cells and chip technology is a key to advance such complex in vitro tissue models, including models of the human nervous system as envisaged in this review. However, current cultured networks of neurons show limited resemblance with the biological functions in the real nervous system or brain tissues. To take full advantage of scaling in the engineering domain of electron-, ion-, and photon beam technology and nanofabrication methods, more research is needed to meet the requirements of this specific field of chip technology applications. So far, surface topographies, microfluidics, and sensor and actuator integration concepts have all contributed to the patterning and control of neural network formation processes in vitro. However, when probing the state of the art for this type of miniaturized three-dimensional tissue models in PubMed, it was realized that there is very little systematic cross-disciplinary research with biomaterials originally formed for tissue engineering purposes translated to on-chip solutions for in vitro modeling. Therefore, this review contributes to the formulation of a sound design concept based on the understanding of the existing knowledge and the technical challenges toward finding better treatments and potential cures for devastating neurodegenerative diseases, like Parkinson's disease. Subsequently, an integration strategy based on a modular approach is proposed for nervous system-on-chip (NoC) models that can yield efficient and informative optical and electronic NoC readouts in validating and optimizing these conceptual choices in the innovative process of a fast growing and exciting new OoC industry.

Microengineered neuronal networks: Enhancing brain-machine interfaces

“…Soft lithography is another method which involves transferring features from a template to an elastomeric material, enabling the creation of small structures quickly, easily, and affordably 5 . The development of organs-on-chips and multiorgan MPS involves incorporating patterns mimicking neuronal tissue structures, utilizing soft materials as scaffolds, implementing nano-topography, and ensuring long-term stability in functionality 12 . Recent advancements in MPS have been facilitated by the discovery of biocompatible materials with minimal adverse effects, such as polydimethylsiloxane (PDMS), and the application of methods like PDMS-free microchips designed through computer-aided processes and flow profile characterization 4 .…”

Bioinspired micro- and nano-structured neural interfaces

“…Focal adhesion proteins can transduce the topographical details of the ECM into specific biomolecular instructions, triggering the activation of the cell cytoskeleton, and mechano-activated intracellular cascades, which lastly regulate cell adhesion and behavior [63][64][65]. From when it was firstly observed at the beginning of the 20th century [48,49], the amount of information available on contact guidance has exponentially grown, owing largely to the introduction of new fabrication techniques and the development of micro-and nanostructured substrates [66]. It has also become clear that if microscale features which are comparable in size to cellular features typically result in whole-cell contact guidance phenomena, nanoscale features, approaching the size of individual cell receptors (i.e.…”

In situ biosensing technologies for an organ-on-a-chip

“…nutrients, growth factors, and oxygen) and recapitulate the 3D organ microenvironment [6][7][8][9]. Organs-on-chips can be designed to mimic almost any organ, and the responses of organs to external stimuli or drugs can be simulated in vitro [10][11][12][13][14]. Presently, more promising and complex organ-on-a-chip systems are being developed using organoids that are generated via the differentiation of human stem cells and self-organization [15][16][17][18][19].…”