Organ-On-A-Chip in vitro Models of the Brain and the Blood-Brain Barrier and Their Value to Study the Microbiota-Gut-Brain Axis in Neurodegeneration

Abstract

We are accumulating evidence that intestinal microflora, collectively named gut microbiota, can alter brain pathophysiology, but researchers have just begun to discover the mechanisms of this bidirectional connection (often referred to as microbiota-gut-brain axis, MGBA). The most noticeable hypothesis for a pathological action of gut microbiota on the brain is based on microbial release of soluble neurotransmitters, hormones, immune molecules and neuroactive metabolites, but this complex scenario requires reliable and controllable tools for its causal demonstration. Thanks to three-dimensional (3D) cultures and microfluidics, engineered in vitro models could improve the scientific knowledge in this field, also from a therapeutic perspective. This review briefly retraces the main discoveries linking the activity of gut microbiota to prevalent brain neurodegenerative disorders, and then provides a deep insight into the state-of-the-art for in vitro modeling of the brain and the blood-brain barrier (BBB), two key players of the MGBA. Several brain and BBB microfluidic devices have already been developed to implement organ-on-a-chip solutions, but some limitations still exist. Future developments of organ-on-a-chip tools to model the MGBA will require an interdisciplinary approach and the synergy with cutting-edge technologies (for instance, bioprinting) to achieve multi-organ platforms and support basic research, also for the development of new therapies against neurodegenerative diseases. Keywords: microbiota-gut-brain axis, neurodegenerative diseases, in vitro modeling, microfluidics, brain, bloodbrain barrier THE MICROBIOTA-GUT-BRAIN AXIS AND ITS INVOLVEMENT IN NEUROLOGICAL DISEASES Research on microbiota is rooted in Antonie van Leeuwenhoek's pioneering work (XVII century) (Bardell, 1983), but in recent years it has aroused a growing interest. In particular, the gut microbiota has strongly emerged as a key player both in physiological and pathological conditions (Jia et al., 2008). The gut microbiota is a complex and dynamic population of tens of trillions of microbes residing in the gastrointestinal (GI) tract, with a mutualistic relationship with the host. Bacterial genera Brain disease References 5-Hydroxytryptamine (5-TH)

Multiplexed blood–brain barrier organ-on-chip

“…16,17 Over the last decade, researchers have been able to fabricate chips for studying the BBB, and other organs demonstrating the ability of OOC to capture physiologically relevant conditions in vitro. [18][19][20][21][22] To date, most reported microfluidic models of the BBB are fabricated using the biocompatible polydimethylsiloxane (PDMS) organic polymer. The permeability to CO 2 and O 2 of this polymer makes it ideal for cell studies.…”

A miniaturized hydrogel-based in vitro model for dynamic culturing of human cells overexpressing beta-amyloid precursor protein

“…For embedded cells, we compared the results to those from 5.1-mm-thick samples. For the layered condition, we plated 2.34 × 10 4 H4-SW cells/cm 2 neurodegeneration, whose figures are rapidly growing worldwide. In fact, AD affects one out of nine people aged 65 and older, but this figure increases to one out of three for people aged 85 and older.…”

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

“…Furthermore, the advantages offered by novel experimental models (co-cultures, 3D cultures, organoids, CRISPR/Cas9 gene editing) may aid in simulating these network systems for better analysis. For instance, organ-on-a-chip modeling was recently proposed as a candidate tool for future investigation of the gut–brain axis [ 380 ]. The system consists of chips serially connected through microfluidic devices.…”