Emerging Brain‐Pathophysiology‐Mimetic Platforms for Studying Neurodegenerative Diseases: Brain Organoids and Brains‐on‐a‐Chip

Abstract

Neurodegenerative diseases are a group of disorders characterized by progressive degeneration of the structural and functional integrity of the central and peripheral nervous systems. Millions of people suffer from degenerative brain diseases worldwide, and the mortality continues to increase every year, causing a growing demand for knowledge of the underlying mechanisms and development of therapeutic targets. Conventional 2D‐based cell culture platforms and animal models cannot fully recapitulate the pathophysiology, and this has limited the capability for estimating drug efficacy. Recently, engineered platforms, including brain organoids and brain‐on‐a‐chip, have emerged. They mimic the physiology of brain tissue and reflect the fundamental pathophysiological signatures of neurodegenerative diseases, such as the accumulation of neurotoxic proteins, structural abnormalities, and functional loss. In this paper, recent advances in brain‐mimetic platforms and their potential for modeling features of neurodegenerative diseases in vitro are reviewed. The development of a physiologically relevant model should help overcome unresolved neurodegenerative diseases.

Nanoscale Patterning of In Vitro Neuronal Circuits

“…Due to the large number of replicates typically needed for in vitro neuroscience experiments, scalability of the fabrication method was an additional requirement. Soft lithography, the most used method for neuron guidance in vitro , , has the potential to meet these requirements, but resolution limits in both the master mold and the polymer need to be addressed. Conventional photolithography using either photomasks or direct laser writing, while able to generate wafer-scale molds quickly, is unable to do so reliably at resolutions of 1 μm or below (Figure S2).…”

“…Historically, studies using low-density neuronal cultures have revealed fundamental properties of synaptic plasticity, such as spike timing-dependent plasticity (STDP). , However, the morphological and functional complexity of these seemingly random neuronal networks makes the systematic study of their connectivity challenging. So-called “brain-on-a-chip” technologies have improved in terms of high-throughput capabilities in the past few years, particularly for disease modeling and pharmacological testing (reviewed in refs − ). For the interrogation of neuronal circuits, these devices may also be engineered to gain better control over neuronal network topology and connectivity .…”

Engineered Neutral Phosphorous Dendrimers Protect Mouse Cortical Neurons and Brain Organoids from Excitotoxic Death

“…Organoids recapitulate several of the characteristics of the human brain, such as 3D organization achieved through self-organization of the developing organoids, making them an attractive model for the human brain by maintaining mechanical and cellular topographical relationships that generate close-to-physiological microenvironments [51]. This makes them more useful in providing information about the effect of possible therapeutic compounds on the specific human-pathogenic-signaling cascades involved in neuronal death than two-dimensional neuronal culture or animal models of neurologic disease [52]. Here, we show that NMDA induces excitotoxic death in human brain organoids.…”

Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays?

“…Therefore, to create a more physiologically and structurally relevant in vitro model of the human brain and, thus, a tauopathy model, recent research has focused on creating 3D-based cell culture models including brain organoids. In comparison to 2D models, 3D models of the brain allow for interactions between different neural cell types, and they are also capable of mimicking perfusion (and diffusion-based molecular transport) something that is impossible to model in 2D culture [ 143 ]. Moreover, a brain organoid development process closely mimics that of the developing human brain as it organizes into an anatomically-specific structure [ 144 ].…”