3D Bioprinted Neurospheroid Niche Models for Neurological Disease Modeling

Yasamin Jodat, PhD
Department of Medicine
Division of Engineering in Medicine
Poster Overview

To develop effective drugs for various neurological diseases such as Alzheimer’s, it is important to build an accurate model of the architecture of the brain and its biochemical reactions. The common procedure for this process is to create and grow these models on petri-dishes. However, these dishes do not allow the cells to interact with each other properly as they would do in the 3D natural brain environment. We have made a 3D cellular environment using 3D bioprinting and a composite of biofriendly engineered gels to create a brain-like construct patterned with neural cells. We show that the cells embedded in these printed mini brains can grow and form neurons and other brain cells and interact with their neighboring cells in 3D. The materials and printing method can be tuned to capture different stiffnesses, patterns and cellular interactions. In the future, these constructs can be further engineered into a reproducible platform for modeling neurological diseases and drug testing.

Scientific Abstract

A crucial step in creating reliable in vitro platforms for neural development and disorder studies is the reproduction of the multicellular three-dimensional (3D) brain microenvironment and the capturing of cell-cell interactions within the model. The power of self-organization of diverse cell types into brain spheroids could be harnessed to study mechanisms underlying brain development trajectory and diseases. A challenge of current 3D organoid and spheroid models grown in petri-dishes is the lack of control over cellular localization and diversity. To overcome this limitation, neural spheroids can be patterned into customizable 3D structures using microfabrication. We developed a 3D brain-like co-culture construct using embedded 3D bioprinting as a flexible solution for composing heterogenous neural populations with neurospheroids and glia. Specifically, neurospheroid-laden free-standing 3D structures were fabricated in an engineered astrocyte-laden support bath resembling a neural stem cell niche environment. A photo-crosslinkable bioink and a thermal-healing supporting bath were engineered to mimic the mechanical modulus of soft tissue while supporting the formation of self- organizing neurospheroids within elaborate 3D networks. Moreover, bioprinted neurospheroid- laden structures exhibited the capability to differentiate into neuronal cells. These brain-like co- cultures could provide a reproducible platform for modeling neurological diseases, neural regeneration, and drug development and repurposing.

Clinical Implications
Modeling neural stem cell niches in two-dimensional petri-dishes poses challenges as these platforms do not accurately recapitulate the complex biological behavior of the native 3D brain tissue and lack the functional aspects of 3D cell-cell interactions. Proposed brain-like co-culture constructs could provide a means to studying and engineering of a heterogenous neural stem cell niche. Additive manufacturing techniques and the selection and engineering of smart biomaterials could considerably push organoid- and spheroid-based research towards a streamlined and reproducible platform where the fabrication of these structures could be conveniently scaled up to allow for high throughput analyses. By building a diverse bank of organoids and spheroids based on reprogrammed induced pluripotent stem cell (iPSC) lines, we could ultimately combine this technology with automated multi-material printing systems for the rapid manufacturing of complex amalgamated microarchitectures for organ-organ interactions using the organoid building blocks. These platforms could serve as major stepping stones towards modeling the stem cell niche in the brain, which has not yet been fully established. Finally, the proposed 3D bioprinted platform could robustly be assimilated into an automated culture pipeline to directly manufacture, assemble, culture and test the neurospheorid- and organoid-laden constructs in a scalable fashion with reduced variability.
Research Areas
Authors
Yasamin A. Jodat*, Yi-Chen Ethan Li*, Roya Samanipour*, Mina Hoorfar, Su Ryon Shin
Principal Investigator
Su Ryon Shin

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