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Author ORCID Identifier

https://orcid.org/0000-0003-4481-4287

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemical Engineering

Year Degree Awarded

2022

Month Degree Awarded

May

First Advisor

Jungwoo Lee

Subject Categories

Biomaterials | Biomedical Engineering and Bioengineering | Molecular, Cellular, and Tissue Engineering

Abstract

Osteoporosis is the most common skeletal disorder that thins and weakens the bones, yet the detailed mechanisms remain poorly understood and limited therapeutic options are available. This can be attributed to the lack of relevant experimental models that can recapitulate the bone complexity and bone remodeling. Mouse models have identified many critical genes and molecules regulating bone metabolism but are limited to studying detailed cellular and molecular processes due to anatomical inaccessibility and restricted ability to manipulate bone structure. Considerable efforts have been made to generate physiologically relevant models by using synthetic and biomaterial-based 3D scaffolds. However, there are no widely accepted models since it is difficult to standardize or manipulate the model systems for mechanistic study with high fidelity and analytical power. My dissertation research focuses on developing a new 3D bone tissue model to manipulate bone matrix and devise mechanoculture platforms to recapitulate essential 3D bone tissue complexity and processes. Here, we introduce an osteoid-inspired biomaterial that is developed in a controlled and accessible manner. Demineralized bone paper (DBP) was engineered to generate the in vitro niche retaining the extracellular complexity of bone tissue. First, we explored the DBP-guided mineralization of osteoblasts and their phenotype. Physiologically relevant OPG/RANKL secretion of osteoblasts on DBP faithfully simulates osteoblast-osteoclast interactions in the bone remodeling process. The optical transparency of DBP was leveraged to investigate spatial bone remodeling activities via various imaging techniques in a quantitative manner. Next, we have established two distinct biomimetic strategies to build 3D bone tissue models via stacking and rolling osteoblast-seeded DBPs. Osteoblasts in between multi-layered DBPs progressed from mineralizing cells to mature osteocytes with dendritic cell morphology and upregulated Sost gene expression. We have also prepared two distinct mechanoculture devices, compression and vibration, and demonstrated the biological significance of mechanotransduction in promoting bone tissue formation and osteocytogenesis. Laboratory-grown bone organoid models represent a great opportunity to better understand the complex and dynamic regulation of bone remodeling. The presented models and techniques may suggest a new gold standard for in vitro bone cell assay that aids in the development of bone disease therapies in medical research.

DOI

https://doi.org/10.7275/28526499

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