Engineering Vascularized Bone Grafts With Adipose Derived Stem Cells

tissue engineering;bone;vascularization;adipose-derived stem cells;regenerative medicine;Biomedical Engineering

Hutton, Daphne L.Mao, Hai-Quan ;

Johns Hopkins University

关键词: tissue engineering;    bone;    vascularization;    adipose-derived stem cells;    regenerative medicine;    Biomedical Engineering;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39336/HUTTON-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Tissue engineered bone grafts could potentially revolutionize treatments for massive bone defects, offering greater tissue quantities and graft customization over the gold standard autograft. However, scale-up of cell-seeded grafts requires rapid vascularization in order to maintain high cell viability and function after implantation. Engineering vasculature inside the graft may greatly accelerate blood perfusion of the whole tissue, rather than relying solely on slow angiogenic ingrowth. Development of a complex tissue graft poses several challenges, including the concurrent stimulation of two lineages, as well as the selection of clinically relevant cell source(s). Therefore, the objective of this thesis was to develop a protocol to engineer vascularized bone grafts with a single, clinically relevant cell source: adipose-derived stem cells (ASCs). ASCs can be harvested autologously via liposuction with very high yield and are unique in that they have both osteogenic and vascular potential, making them a promising cell source to supply key components of a vascularized bone graft.This body of work describes a multistep approach towards the aforementioned objective. First, the potential of ASCs to form functional vasculature networks was explored. By increasing the direct physical interactions amongst cells, it was demonstrated that small lingering sub-populations of vascular cells are capable of spontaneously proliferating and self-assembling into three-dimensional pericyte-stabilized vascular networks. The next two chapters describe the development of a step-wise in vitro protocol to induce vascularized bone by recapitulating the biochemical environment of native bone repair. This study highlighted factors derived from platelets and inflammatory cells that promote vascular growth and stability, as well as osteogenic mineralization.Lastly, the effects of hypoxia on vascular assembly and stability were studied to understand how ASC-seeded grafts may behave in an ischemic bone injury environment. This investigation revealed that hypoxia severely inhibits de novo vascular assembly, but promotes growth and stability of pre-formed vessels. Taken together, these findings have significant implications for how ASCs could be applied clinically for bone regeneration.