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PhD Defense, Yongkuk Park, "“Development of in vitro bone model for the recapitulation of bone complexity”."

Date/Time: 

Thursday, March 24, 2022 - 1:00pm

Location: 

N410 LSL and via Zoom (please email wallace@ecs.umass.edu for a link)

Details: 

Chair:  Jungwoo Lee

ABSTRACT

 

Osteoporosis is a skeletal disorder that thins and weakens the bones. Bone aging is one of the major causes of osteoporosis, 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 and dimensions. Traditional bone cell culture offers high accessibility and analytical power to study cell behavior in vitro. In addition, considerable efforts have been made to generate physiologically relevant models by using synthetic and biomaterial-based 3D scaffolds. These models represent opportunities to reproduce essential bone microenvironments and cellular processes in vitro. 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. This material is mechanically durable, semitransparent with 20-µm thickness, and has a controlled surface area. 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. Osteoclast lineage cells were observed to locally interact through with the group of osteogenic cells and regulate their bone formation. Additionally, a fully humanized bone model was developed to examine the efficacy and potency of osteoporosis drugs inducing osteoclast apoptosis or upregulated bone formation. A proof-of-concept study demonstrated that phenotypic changes by drug treatment can be quantified by high- throughput imaging analysis. 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 biological significance of mechanotransduction in promoting bone tissue formation and osteocytogenesis. Mechanical stimulations significantly increased mineral deposition by osteoblasts on DBPs, which was resulting in osteocyte population increase within the 3D bone organoids. Taken together, these results suggest that the physical factors of bone microenvironment play an important role in osteocytogenesis and bone maturation.

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. Established models and assays also can be readily applicable to other important aspects of bone tissue biology including bone metastasis, bone aging, bone marrow hematopoiesis, etc. We envision many enabling opportunities with DBP-based bone organoid models in basic and applied bone studies.

 
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