Our long-term goal is to achieve rapid healing, integration and sustained fixation of dental and orthopaedic implants, particularly for injured elderly patients that heal more slowly and with less consistency. There are many reasons why the bones of older adults heal more slowly than their younger counterparts, including the reduced number and function of osteoprogenitor stem cells. Our group is studying the combined use of fibroblast growth factor-2 (FGF-2) and bone morphogenetic protein-2 (BMP-2) as a means of increasing and rejuvenating aged osteoprogenitors. Local administration of low doses of FGF-2 recruits and stimulates proliferation of aged progenitor cells and works synergistically with BMP-2 to increase new bone formation. High doses of FGF-2 inhibit new bone formation and high doses of BMP-2 causes unwanted calcification, thus growth factor delivery systems are needed that can modulate the delivery of a combination of low doses. Our in vitro studies with osteoprogenitors from young and old mice and our in vivo studies led us to appreciate the age-dependent responses of progenitors to FGF-2/BMP-2 administration. Simple two-phase delivery systems such as the one we used for our preliminary studies are not able to release fully active molecules or meet the age-dependent multi-factor delivery profile needs, therefore we propose to use polyelectrolyte multi-layer (PEM) technology because it is one of the most sophisticated delivery systems capable of any dose and delivery profile. PEM coatings will be applied to a clinically used biomaterial scaffold and tailored through layered nano-architectures to achieve temporal control of the release of multiple growth factors. We hypothesize that controlled delivery of low doses of FGF-2 and BMP-2 delivered via PEM/growth factor scaffolds will restore youthful proliferation and activity of osteoprogenitors in a bone defect site leading to more complete and consistent bone healing in elderly mice. We will refine the PEM architectures for maximal effectiveness through in vitro studies with a novel and efficient osteoblast lineage reporter assay as well as studies in young and old mice. In two animal models we will characterize the proliferative and differentiation effects of the PEM/FGF- 2/BMP-2 coated 3-D scaffolds using flow cytometry of cells retrieved at early time points from implanted scaffolds, as well as immunohistochemistry, H+E histology and microCT up to five weeks after implantation. We will demonstrate the specificity of the PEM/FGF-2/BMP-2 coated 3-D scaffolds to rejuvenate the healing of elderly osteoprogenitors through studies in FGF-2 knockout mice. This delivery system can be rapidly translated to the clinic and will be invaluable for the future development of dental and orthopaedic implants that stimulate robust, consistent healing and a return of injured or edentulous elderly patients to a highly- functioning and active lifestyle essential for their health.
Our long-term goal is to achieve rapid healing, integration and sustained fixation of dental and orthopaedic implants, particularly for injured elderly patients that heal more slowly and with less consistency. Towards this goal we propose to study the combined delivery of fibroblast growth factor-2 (FGF-2) and bone morphogenetic protein-2 (BMP-2) as a means of rejuvenating aged osteoprogenitors. We will develop a 3-D polyelectrolyte multi-layer coated biomaterials growth factor delivery system that can modulate release of multiple growth factors and overcome problems with existing systems.
|Kuhn, Liisa T; Ou, Guomin; Charles, Lyndon et al. (2013) Fibroblast growth factor-2 and bone morphogenetic protein-2 have a synergistic stimulatory effect on bone formation in cell cultures from elderly mouse and human bone. J Gerontol A Biol Sci Med Sci 68:1170-80|