Electrospun Nanofiber Meshes for the Functional Repair of Bone Defects

Bone defects caused by trauma, tumor resection or disease present a significant clinical problem. Failures in ‘high risk’ fractures and large bone defects have been reported to be as high as 30-50%. The drawbacks associated with current bone grafting procedures have stimulated the search for improved techniques for bone repair. Tissue engineering/regenerative medicine approaches promote tissue repair by providing a combination of physical and biological cues through structural scaffolds and bioactive agents. Though they have demonstrated significant promise for bone regeneration, very little has been translated to clinical practice.

The goal of this thesis was to investigate the potential of electrospun nanofiber mesh scaffolds for bone regeneration. Nanofiber meshes were utilized in a three-pronged approach. First, we validated their ability to robustly support osteogenic cell functions, including proliferation and matrix mineralization. We also demonstrated their efficacy as a cell delivery vehicle. Second, we investigated the effects of modulating nanofiber bioactivity and orientation on stem cell programming. Our results indicate that functionalization of nanofiber meshes with a collagen-mimetic peptide enhanced the migration, proliferation and osteogenic differentiation of cells. Fiber alignment improved cell migration along the direction of fiber orientation. Finally, a nanofiber mesh based hybrid system for growth factor delivery was developed for bone repair and tested in a challenging animal model. The delivery of bone morphogenetic protein (BMP) via this system resulted in the functional restoration of limb function, and in fact proved more efficacious than the current clinical standard for BMP delivery.

The studies performed in this thesis have suggested novel techniques for improving the repair of clinically challenging bone defects. They indicate that delivery of BMP via the hybrid system may reduce the dose and side effects of BMP, thereby broadening the use of BMP based bone augmentation procedures. Therefore, this nanofiber mesh based system has the potential to become the standard of care for clinically challenging bone defects, including large bone defects, open tibial fractures, and nonunions.

Year	Entry
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Year

Entry

1999

Rowley JA, Madlambayan G, Mooney DJ. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials. January 1999;20(1):45-53.

1998

Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. October 1998;355(suppl):S7-S21.

2007

Rai B, Oest ME, Dupont KM, Ho KH, Teoh SH, Guldberg RE. Combination of platelet‐rich plasma with polycaprolactone‐tricalcium phosphate scaffolds for segmental bone defect repair. J Biomed Mater Res. June 15, 2007;A81(4):888-899.

2004

Simmons CA, Alsberg E, Hsiong S, Kim WJ, Mooney DJ. Dual growth factor delivery and controlled scaffold degradation enhance in vivo bone formation by transplanted bone marrow stromal cells. Bone. August 2004;35(2):562-569.

2003

Lutolf MP, Lauer-Fields JL, Schmoekel HG, Metters AT, Weber FE, Fields GB, Hubbell JA. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc Natl Acad Sci USA. April 29, 2003;100(9):5413-5418.