The supply of vascularized bone grafts for the therapeutic regeneration of large, non-healing bone defects remains a huge unmet clinical need affecting more than one million people in the US every year. Tissue engineering solutions have the potential to significantly advance currently available treatment methods. The data from this study will be utilized to significantly improve approaches to engineer functional vascularized bone grafts for regenerative medicine. Results from this CAREER project will be integrated into the educational curricula taught by the PI, providing students with the tools needed to perform cutting-edge research and improve fundamental understanding of cell and developmental biology as it pertains to tissue engineering. The educational benefit will be extended to international students who will be exposed to world-class research environments through intensive summer internships. The award will also benefit 'at-risk' minority high school students through the establishment of a transformative internship program.
The overall objective of this CAREER proposal is to develop a fundamental understanding of how the decision of stem cells to commit to a particular lineage during tissue formation impacts the structure and morphology of engineered tissue constructs. During vascularized bone formation in cell culture models, mesenchymal stem cells differentiate into pericytes (to stabilize the nascent vasculature) and osteoblasts (to deposit mineral). This decision to become pericyte or osteoblasts varies as a function of both space and time in culture. Both cell types are critical for the formation and maintenance of the appropriate tissue organization yet it remains unclear how the perivascular microenvironment impacts the lineage specification of stem cells into either of these particular phenotypes. By combining tissue engineering cell-culture models with molecular biology techniques it is possible to explore the intricate cell-fate decisions that regulate complex tissue formation. This proposal tests the hypothesis that regulating the pericyte/osteoblast lineage commitment of mesenchymal stem cells as a function of space (proximity to vascular structures) and time underlies the potential to form integrated vascular networks and mineralized bone deposits. There are three primary research objectives: (i) Determine the effect of cell composition and growth factor delivery on the structure and organization of tissue engineered vascularized bone. (ii) Evaluate effect of growth factor concentration and spatial gradients on tissue structure. (iii) Investigate the role of pericyte and osteoblast plasticity in mediating vascularized bone development.
This CAREER award by the Biotechnology, Biochemical, and Biomass Engineering Program of the CBET Division is co-funded by the Biomaterials Program of the Division of Materials Research and by the Mathematical Biology Program of the Division of Mathematical Sciences.
