Abstract
With the increasing prevalence of neurodegenerative diseases, improved models of the central nervous system (CNS) will improve our understanding of neurophysiology and pathogenesis, whilst enabling exploration of novel therapeutics. Studies of brain physiology have largely been carried out using in vivo models, ex vivo brain slices or primary cell culture from rodents. Whilst these models have provided great insight into complex interactions between brain cell types, key differences remain between human and rodent brains, such as degree of cortical complexity. Unfortunately, comparative models of human brain tissue are lacking. The development of induced Pluripotent Stem Cells (iPSCs) has accelerated advancement within the field of in vitro tissue modelling. However, despite generating accurate cellular representations of cortical development and disease, two-dimensional (2D) iPSC-derived cultures lack an entire dimension of environmental information on structure, migration, polarity, neuronal circuitry and spatiotemporal organisation of cells. As such, researchers look to tissue engineering in order to develop advanced biomaterials and culture systems capable of providing necessary cues for guiding cell fates, to construct in vitro model systems with increased biological relevance. This review highlights experimental methods for engineering of in vitro culture systems to recapitulate the complexity of the CNS with consideration given to previously unexploited biophysical cues within the cellular microenvironment.
Highlights
Disorders of the central nervous system (CNS) bear significant economic and social burdens [1]
heterogeneous environmental cues is necessary for recreating the hierarchical structure of living tissues
This is compounded by the fact that the development and approval processes
Summary
Disorders of the CNS bear significant economic and social burdens [1]. This is compounded by the fact that the development and approval processes for drugs that target the CNS take considerably longer than non-CNS counterparts [2]. The self-organising nature of organoids means vascular components are often disorganised and incomplete, recent advances in neurovascular models provide great promise [61] Organoids offer both cellular and structural complexity necessary for modelling human tissues in vitro; tissue engineering approaches including microfabrication and biomaterials are required to guide organoid morphology and architecture, with advancement enabling improved 3D culture with reduced variability. Environmental cues within hydrogels for CNS modelling include the presence of biochemical molecules (growth factors, proteins, small molecules) and bulk material properties (stiffness, conductivity, porosity), and more complex heterogeneous aspects such as multicomponent structuring, dynamic or stimuli-responsive properties, and multiscale spatiotemporal topographical patterning to modulate cell behaviour. The maturation of stem cell derived neuronal cultures and methods to enable functional interrogation in 3D may hamper attempts to fully utilise these model systems and will require significant optimisation
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