Abstract
Neuroengineering methods can be effectively used in the design of new approaches to treat central nervous system and brain injury caused by neurotrauma, ischemia, or neurodegenerative disorders. During the last decade, significant results were achieved in the field of implant (scaffold) development using various biocompatible and biodegradable materials carrying neuronal cells for implantation into the injury site of the brain to repair its function. Neurons derived from animal or human induced pluripotent stem (iPS) cells are expected to be an ideal cell source, and induction methods for specific cell types have been actively studied to improve efficacy and specificity. A critical goal of neuro-regeneration is structural and functional restoration of the injury site. The target treatment area has heterogeneous and complex network topology with various types of cells that need to be restored with similar neuronal network structure to recover correct functionality. However, current scaffold-based technology for brain implants operates with homogeneous neuronal cell distribution, which limits recovery in the damaged area of the brain and prevents a return to fully functional biological tissue. In this study, we present a neuroengineering concept for designing a neural circuit with a pre-defined unidirectional network architecture that provides a balance of excitation/inhibition in the scaffold to form tissue similar to that in the injured area using various types of iPS cells. Such tissue will mimic the surrounding niche in the injured site and will morphologically and topologically integrate into the brain, recovering lost function.
Highlights
In the field of regenerative medicine, neural tissue regeneration can be performed with implantation of 3D scaffold structures containing progenitor cells
Such structures composed of biodegradable materials provide integration of cells in the central nervous system (CNS) and the brain with defined cellular density, dissolving after a few days and leaving only the cells in the site of injury (Ovsianikov et al, 2011; Wang et al, 2012; Akopova et al, 2015; Carlson et al, 2016; Jin et al, 2016; Timashev et al, 2016; Venugopalan et al, 2016; Balyabin et al, 2017; Chen et al, 2018)
Proposed methods and experimental results can be further used to develop new types of functional scaffolds with the biologically inspired cellular network architecture of induced pluripotent stem (iPS) cells that can be implemented in 3D structure and tested on rodents for the ability to regenerate or recover in response to brain lesions
Summary
In the field of regenerative medicine, neural tissue regeneration can be performed with implantation of 3D scaffold structures containing progenitor cells. We propose a new type of heterogeneous structure of the scaffold, in which various types of cells form biologically realistic networks with unidirectional synaptic connectivity mimic injured brain regions with functional integration, thereby potentially recovering cognitive behavior (Figure 1). The first steps of such method development can be performed using planar neuronal cultures grown in multichamber microfluidic devices Such devices contain several chambers for cell plating that are connected by microchannels of asymmetric shape to promote unidirectional axonal growth between cultures (Figure 2) and to promote the formation of synapses with pre-defined spatial locations in pre- and post-synaptic neurons. Note that high-density cultures of approximately 15,000 ± 20,000 cells/mm with four to five layers of cells that are closer to in vivo conditions may induce rhythmic activity (Gladkov et al, 2018) In such multichamber microfluidic devices, one can mimic neurotransplantation and implant integration using an already developed network. Various types of cells can be tested to examine such integration
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