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theses

Large bone defects resulting from trauma, tumor resection, congenital abnormalities or reconstructive surgery remain significant clinical problems that affect millions of people. The current treatments are autologous or allogeneic bone grafts; each has drawbacks including donor site morbidity, limited available quantity, or risk of viral transmission and immunogenicity respectively. Alternatively, bone graft substitutes (BGS) have been developed as promising substrates for bone repair. However, the current BGS are often fabricated from simple laboratory processes that are never optimized or scaled-up. Most of them are only evaluated in vitro and if they are evaluated in vivo, only small animals models such as rats and rabbits are used. Therefore, none of the approaches proposed thus far have proved very effective. There remains a clinical demand for BGS that can treat large bone defects. This dissertation supports effective and innovative solutions to this familiar problem in orthopedic surgery by (1) optimizing and scaling-up a fabrication process for scaffolds based on E1001(1k), a member of large combinatorial library of tyrosine-derived polycarbonates. (2) Enhancing the osteoconductivity of the scaffolds by adding a variety of calcium phosphates (CaP) including beta-tricalcium phosphate (β-TCP), hydroxyapatite (HA), and dicalcium phosphate dehydrate (DCPD) into the scaffolds. (3) Assessing the bone regeneration capacity of the scaffolds progressively from small animals (rabbit calvarial non-critical size defect and rat subcutaneous model) to a large animal model (goat calvarial critical size defect). The fabrication process was optimized and scaled-up and is ready for transfer to a third party contractor under Good Manufacturing Practice. Scaffolds with homogeneous, consistent and optimized structure including unique bimodal pore size distribution, high porosity, surface area and interconnectivity were produced. In vitro characterization using human mesenchymal stem cells revealed that E1001(1k)-CaP scaffolds supported cell attachment, proliferation and osteogenic differentiation. In vivo evaluation of the scaffolds in small animal models demonstrated excellent biocompatibility and osteoconductivity. Furthermore, the preclinical evaluation in the goat calvarial critical size defects revealed performance superiority of E1001(1k)-CaP scaffolds over chronOS, a commercial BGS. Treatment with E1001(1k)-CaP scaffolds provided complete bridging of the 2 cm human size defects without supplemental osteogenic growth factor, which is of significant importance and has never been reported in the literature. These results suggest that E1001(1k)-CaP scaffold could be the next-generation synthetic bone graft substitute for large bone defect repair.

ETD_6917

Ph.D.

Includes bibliographical references

by Shuang Shuang Chen

doi:10.7282/T3JM2CQ0

ETD doctoral

The author owns the copyright to this work.