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Marian Hettiaratchi
PhD Defense Presentation
Date: Friday, September 16, 2016
Time: 10:00 am
Location: Petit Institute Suddath Seminar Room (IBB 1128)
Advisors: Robert Guldberg, PhD (Georgia Institute of Technology)
Todd McDevitt, PhD (Gladstone Institute of Cardiovascular Disease)
Committee Members:
Scott Boden, MD (Emory University)
Edward Botchwey, PhD (Georgia Institute of Technology)
Andrés García, PhD (Georgia Institute of Technology)
Johnna Temenoff, PhD (Georgia Institute of Technology)
Title: Heparin Microparticle-Mediated Delivery of BMP-2 and Pluripotent Stem Cell Morphogens for Bone Repair
Abstract:
Musculoskeletal injuries resulting in significant bone loss affect thousands of people each year. The delivery of osteoinductive growth factors, such as bone morphogenetic protein-2 (BMP-2), offers a promising means of stimulating endogenous repair mechanisms to heal injured bone. However, clinical application of growth factor therapy is hindered by the lack of adequate biomaterial delivery vehicles to promote repair without causing adverse events. Glycosaminoglycans (GAGs), such as heparin, have the capacity to strongly bind BMP-2 and other growth factors implicated in bone regeneration, and present the opportunity to locally deliver growth factors to injury sites. Moreover, pluripotent stem cells (PSCs) secrete many potent heparin-binding growth factors that have been implicated in tissue regeneration following cell transplantation and may provide cues for repair. Thus, heparin can also be used to concentrate and deliver PSC-derived morphogens to tissue injury sites, thereby overcoming challenges associated with stem cell transplantation.
The goal of this work was to improve growth factor delivery for bone repair by both (1) creating an effective biomaterial for BMP-2 delivery and (2) investigating stem cell morphogens as a novel source of therapeutic growth factors. We developed heparin-based microparticles to deliver growth factors to regenerate bone in a critically sized femoral defect, with the hypothesis that heparin microparticles would increase the retention of bioactive growth factors within the tissue injury site, leading to improved bone repair. We demonstrated that heparin microparticles could bind and retain large amounts of bioactive BMP-2 in vitro and improve BMP-2 retention in vivo, resulting in spatially localized bone formation in a femoral defect. Furthermore, heparin microparticles could also be used to sequester and concentrate complex mixtures of bioactive PSC-secreted
proteins and may be developed into cell-free therapies in the future. Overall, this work broadens current understanding of bone tissue engineering, biomaterial delivery vehicles, and stem cell-based therapeutics, and provides valuable information can be used to develop affinity-based biomaterials for other clinical applications.
