Abstract
In native tissues, cellular and acellular components are anisotropically organized and often aligned in specific directions, providing structural and mechanical properties for actuating biological functions. Thus, engineering alignment not only allows for emulation of native tissue structures but might also enable implementation of specific functionalities. However, achieving desired alignment is challenging, especially in three-dimensional constructs. By exploiting the elastomeric property of polydimethylsiloxane and fibrillogenesis kinetics of collagen, here we introduce a simple yet effective method to assemble and align fibrous structures in a multi-modular three-dimensional conglomerate. Applying this method, we have reconstructed the CA3–CA1 hippocampal neural circuit three-dimensionally in a monolithic gel, in which CA3 neurons extend parallel axons to and synapse with CA1 neurons. Furthermore, we show that alignment of the fibrous scaffold facilitates the establishment of functional connectivity. This method can be applied for reconstructing other neural circuits or tissue units where anisotropic organization in a multi-modular structure is desired.
Highlights
In native tissues, cellular and acellular components are anisotropically organized and often aligned in specific directions, providing structural and mechanical properties for actuating biological functions
Alignment is important to provide the tissue with appropriate structural and mechanical properties for actuating unique biological functions: parallel layers of myocardial cells and collagen fibres in the heart provide the structural basis for effective contraction[1], bundles of aligned fibrillar extracellular matrix (ECM) and tenoblasts in the tendon enable efficient transmission of force[2], and the highly ordered spatial arrangement of collagen fibrils in corneal stroma is critical for optical transparency[3]
The intricate organization of neuronal somata has been modelled by several approaches, such as a multilayered agarose-alginate scaffold that mimics the layered organization of the neocortex[32], neurospheroid blocks that recapitulate the modular interaction between the cortex and the hippocampus[33] and a silk-collagen composite scaffold that epitomizes the compartmentalized nature of the brain[34]
Summary
Cellular and acellular components are anisotropically organized and often aligned in specific directions, providing structural and mechanical properties for actuating biological functions. By exploiting the elastomeric property of polydimethylsiloxane and fibrillogenesis kinetics of collagen, here we introduce a simple yet effective method to assemble and align fibrous structures in a multi-modular three-dimensional conglomerate Applying this method, we have reconstructed the CA3–CA1 hippocampal neural circuit three-dimensionally in a monolithic gel, in which CA3 neurons extend parallel axons to and synapse with CA1 neurons. We show that alignment of the fibrous scaffold facilitates the establishment of functional connectivity This method can be applied for reconstructing other neural circuits or tissue units where anisotropic organization in a multi-modular structure is desired. This method produces homogeneous alignment of collagen fibrils by altering the shape of a pre-strained polydimethylsiloxane (PDMS) mould containing collagen, before the collagen is fully self-assembled Applying this method, we have reconstructed the hippocampal CA3–CA1 circuit in a monolithic gel, in which collagen scaffolds aligned in 3D serve as contact guidance cues to direct the growth of axons uniformly across multiple compartments. We have found that functional connectivity between CA3 and CA1 neural populations is markedly promoted by structurally organizing the culture platform
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