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Dang Dissertation.Final.pdf (4.22 MB)

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READILY IMPLANTABLE HIGH DENSITY STEM CELL SYSTEMS WITH CONTROLLED GROWTH FACTOR PRESENTATION FROM BIOACTIVE MICROPARTICLES FOR BONE REGENERATION VIA ENDOCHONDRAL OSSIFICATION

Dang, Phuong Ngoc
http://rave.ohiolink.edu/etdc/view?acc_num=case1421864780

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
The growing socioeconomic burden of musculoskeletal injuries resulting in critical-sized bone defects and drawbacks of current therapies have motivated tissue engineering approaches to generate functional tissues to repair bone. This dissertation aimed to develop a readily implantable system to heal bone defects through investigation of the hypothesis that controlled presentation of inductive factors from microparticles to mesenchymal stem cells (MSCs) in high-density culture can guide endochondral bone formation. First, a cartilage template for endochondral ossification was engineered by incorporating TGF-β1-releasing gelatin microparticles (GM) within MSC aggregates and self-assembled sheets. TGF-β1 presentation from GM is predominantly through cell-mediated microparticle degradation with rates tunable by varying polymer crosslinking. Chondrogenesis was shown to be dependent on TGF-β1 concentration and GM amount. Since hydroxyapatite and BMP-2 can regulate chondrogenesis and osteogenesis, their effects on endochondral ossification within MSC aggregates were investigated. Hydroxyapatite was presented in the form of mineral-coated hydroxyapatite microparticles (MCM) capable of controlled BMP-2 delivery. Alone, BMP-2 and MCM induced osteogenesis and chondrogenesis, respectively. Together, BMP-2 and MCM promoted early chondrogenesis followed by additional mineralization, suggesting the induction of endochondral ossification. MSC aggregates were also locally presented with TGF-β1 and BMP-2 by tailoring GM to release the former early for chondrogenic induction and MCM to deliver the latter in a more sustained manner to promote the replacement with bone. Compared to media supplementation, local delivery of TGF-β1 and BMP-2 promoted enhanced chondrogenesis and ALP activity at week 2 and stronger mineralization by week 5. Compared to TGF-β1 or BMP-2 alone, combined treatment resulted in larger mineralized constructs with higher DNA and GAG/DNA content. The ability of this system to heal bone defects was also examined by implanting two-day-old sheets incorporated with TGF-β1- and BMP-2-loaded microparticles in critical-sized defects in rats. Vascularized bone filled the defects after 4 weeks with complete defect bridging by 8 weeks. Endochondral ossification was confirmed by the presence of types II and X collagen at week 4. These findings demonstrate the strong capacity of this novel microparticle-incorporated MSC system to rapidly form vascularized bone without the need for an initial vascular supply and extended in vitro culture.
Eben Alsberg (Advisor)
343 p.
Biomedical Engineering
bone tissue engineering, high-density cell culture, endochondral ossification, intramembranous ossification, growth factor delivery, mesenchymal stem cells, aggregate, self-assembled sheets

Recommended Citations

Citations

  • Dang, P. N. (2015). READILY IMPLANTABLE HIGH DENSITY STEM CELL SYSTEMS WITH CONTROLLED GROWTH FACTOR PRESENTATION FROM BIOACTIVE MICROPARTICLES FOR BONE REGENERATION VIA ENDOCHONDRAL OSSIFICATION [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1421864780

    APA Style (7th edition)

  • Dang, Phuong. READILY IMPLANTABLE HIGH DENSITY STEM CELL SYSTEMS WITH CONTROLLED GROWTH FACTOR PRESENTATION FROM BIOACTIVE MICROPARTICLES FOR BONE REGENERATION VIA ENDOCHONDRAL OSSIFICATION. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1421864780.

    MLA Style (8th edition)

  • Dang, Phuong. " READILY IMPLANTABLE HIGH DENSITY STEM CELL SYSTEMS WITH CONTROLLED GROWTH FACTOR PRESENTATION FROM BIOACTIVE MICROPARTICLES FOR BONE REGENERATION VIA ENDOCHONDRAL OSSIFICATION." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1421864780

    Chicago Manual of Style (17th edition)

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© 2015, some rights reserved.Creative Commons License READILY IMPLANTABLE HIGH DENSITY STEM CELL SYSTEMS WITH CONTROLLED GROWTH FACTOR PRESENTATION FROM BIOACTIVE MICROPARTICLES FOR BONE REGENERATION VIA ENDOCHONDRAL OSSIFICATION by Phuong Ngoc Dang is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.