Scaffold guided 3D brain organoid models
File(s)
Author(s)
Ritzau-Reid, Kaja
Type
Thesis
Abstract
The intrinsic self-organisation properties of stem cells provide a unique opportunity to derive 3D in vitro models of organs, known as organoids. In recent years brain organoids have emerged as in vitro model systems that recapitulate certain functional and organisational properties of embryonic brain development. This nascent technology holds enormous promise to investigate human brain development and disease and has already shown success in modelling certain features of some neurodevelopmental and neurodegenerative brain disorders. Yet, major challenges remain. In particular, the lack of organoid reproducibility, lack of regional patterning, shape heterogeneity and the absence of a proper vasculature system currently hinder the advancement of this technology.
Combining expertise from stem cell biology and bioengineering offers a promising approach to address some of these limitations. Here, a bioengineering platform is developed to guide 3D stem cell and brain organoid growth. This thesis is separated into three sections, exploring: (i) The design and fabrication of biomaterial scaffolds for stem cell culture, where it is shown that scaffold geometry is a key determinant of stem cell self-organisation and collective tissue growth; (ii) The generation of a new method for controlled high-throughput brain organoid formation using
the scaffold-culture platform; (iii) Growth factor functionalisation of scaffolds and microfluidic gradients to direct the regional patterning of scaffold-cultured brain organoids. Taken together, these strategies provide the opportunity to guide brain organoid morphogenesis, utilising scaffold geometry and exploiting the material to incorporate biochemical cues. Importantly, this scaffold mediated process maintains the intrinsic cell autonomous property of self-organisation that is inherent to organoid development. It is hoped that these strategies will be adapted to other organoid systems in the future, allowing for more controlled, complex organoid formation.
Combining expertise from stem cell biology and bioengineering offers a promising approach to address some of these limitations. Here, a bioengineering platform is developed to guide 3D stem cell and brain organoid growth. This thesis is separated into three sections, exploring: (i) The design and fabrication of biomaterial scaffolds for stem cell culture, where it is shown that scaffold geometry is a key determinant of stem cell self-organisation and collective tissue growth; (ii) The generation of a new method for controlled high-throughput brain organoid formation using
the scaffold-culture platform; (iii) Growth factor functionalisation of scaffolds and microfluidic gradients to direct the regional patterning of scaffold-cultured brain organoids. Taken together, these strategies provide the opportunity to guide brain organoid morphogenesis, utilising scaffold geometry and exploiting the material to incorporate biochemical cues. Importantly, this scaffold mediated process maintains the intrinsic cell autonomous property of self-organisation that is inherent to organoid development. It is hoped that these strategies will be adapted to other organoid systems in the future, allowing for more controlled, complex organoid formation.
Version
Open Access
Date Issued
2022-06-06
Date Awarded
01/01/2023
License URL
Advisor
Stevens, Molly
Sponsor
Engineering and Physical Sciences Research Council
Rosetrees
Grant Number
EP/L016737/1
Publisher Department
Materials
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)