Modeling Neurodegenerative Diseases Using In Vitro Compartmentalized Microfluidic Devices

Abstract

The human brain is a complex organ composed of many different types of cells interconnected to create an organized system able to efficiently process information. Dysregulation of this delicately balanced system can lead to the development of neurological disorders, such as neurodegenerative diseases (NDD). To investigate the functionality of human brain physiology and pathophysiology, the scientific community has been generated various research models, from genetically modified animals to two- and three-dimensional cell culture for several decades. These models have, however, certain limitations that impede the precise study of pathophysiological features of neurodegeneration, thus hindering therapeutical research and drug development. Compartmentalized microfluidic devices provide in vitro minimalistic environments to accurately reproduce neural circuits allowing the characterization of the human central nervous system. Brain-on-chip (BoC) is allowing our capability to improve neurodegeneration models on the molecular and cellular mechanism aspects behind the progression of these troubles. This review aims to summarize and discuss the latest advancements of microfluidic models for the investigations of common neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

Addressing blood-brain-tumor-barrier heterogeneity in pediatric brain tumors with innovative preclinical models

“…Drug uptake was significantly improved within the 3D glioblastoma spheroid in combinations with mannitol and gintonin addition which induces BBB permeability (128). With platforms and applications of organ-on-a-chip models now widely accepted for a variety of diseases (129)(130)(131)(132)(133)(134), it is imperative that these models are adapted and transitioned for the study of pediatric brain cancer. These innovative in vitro platforms in conjunction with animal models will be highly important to better understand the molecular mechanism of such ailments and providing novel therapeutics that have been thoroughly tested to target tumors in the presence of a heterogeneous BBTB.…”

Compartmentalized primary cultures of dorsal root ganglion neurons to model peripheral pathophysiological conditions

“…9 Microfluidic chambers (MFC) facilitate the study of interactions between axonal endings and tissue cells such as keratinocytes and immune cells, under physiological or pathological conditions. [10][11][12][13][14][15] They permit the investigation of neuronal excitability, including action potential frequency and velocities. 16,17 Therefore, microfluidic-based, compartmentalized nociceptors primary cultures may provide a suitable preclinical model for investigating the contribution of the neurosensory system to skin pathophysiology and to validate drug candidates that contribute to faster resolution of skin disorders by modulating the neuronal input to the disease.…”

Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson’s Disease

“…Recent uses of micro uidics have enabled more thorough development of disease propagation patterns with the advantage of controlling and guiding the model by controlling the axonal transfer of PFFs, isolating synaptically connected neurons and observing PFF-triggered aggregation [12][13][14]17,18 . These stateof-the-art models are progressive alternatives to conventional in vitro cultures that are not su cient to represent the propagation path 19 . However, the currently used PD models with micro uidics lack integrated functional measurement systems, causing limitations for noninvasive temporal experiments [12][13][14]17,18,20 .…”

“…In summary, previous studies focusing on the functional aspects of PFF-induced α-s aggregation were performed on neuronal cultures from different species with different timelines and in different phases of aggregation with varying results 11,13,14,[21][22][23][24][25] . For this reason, new insights combining micro uidic technology with MEAs 19,26 are needed to provide more comprehensive information on the pathophysiological progress of axonal propagation of aggregated α-s and enable a more robust timeline assessment of its effects on the progression of PD.…”