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Loay A. Al-Zube
Biomedical Engineering Program
B.S., 2000, Jordan University of Science & Technology, Irbid, Jordan
M.S., 2004, New Jersey Institute of Technology
Thesis Advisor: J. Patrick OíConnor, Ph.D.
Department of Biochemistry and Molecular Biology
Tuesday, April 29, 2008
Fracture healing is a complex process that involves the sequential recruitment of cells and the specific temporal expression of genes essential for bone repair. While the process by which fracture repair occurs is well describe, relatively little is understood about the coordinate regulation of events leading to successful repair. Furthermore, even less is understood about how the process can fail, leading to cases of delayed union, nonunion, and pseudoarthrosis. Local growth factors are believed to play an integral role in the regulation of bone formation, resorption and remodeling and are expressed at different times during fracture healing.
Almost 20 factors have been reported to impair bone healing including hormonal deficiency, pathological factors, aging, illicit drugs, smoking, alcohol abuse, non-steroid anti-inflammatory agents and systemic diseases such as diabetes mellitus (DM).
Clinical and experimental studies have demonstrated that diabetes mellitus impairs fracture healing. The specific mechanism through which diabetes impairs bone healing is currently unknown. One possible mechanism of diabetic-impaired fracture healing is the decreased or uncoordinated release of local growth factors at the fracture site. Cellularity in the callus during the proliferative phase of healing is reduced by 40 percent in poorly controlled diabetic animals; the decreased callus cellularity is belived to be secondary to decreased levels of mitogenic or chemotactic growth factors.
Exogenous growth factors have been proposed as potential therapeutic agents to ameliorate the deleterious effects of impaired bone repair, as well as to accelerate the normal repair process.
The hypothesis that mitogenic growth factors can accelerate bone fracture healing as well as ameliorate the deleterious effect of impaired fracture repair was investigated. In this thesis, novel local delivery systems were used in normal and diabetic BB Wistar rats to investigate the potential direct effects of recombinant human platelet derived growth factor (rhPDGF-BB) or insulin on femur fracture healing.
Data obtained from the diabetic BB Wistar rat model suggest that the decreased local release of mitogenic growth factors directly impairs diabetic fracture healing. The reduction in PDGF release leads to impaired callus cellular proliferation resulting in impaired late parameters of fracture healing. Conversely, Local rh-PDGF treatment ameliorated the deleterious effect of DM on bone healing.
Recombinant human platelet derived growth factor delivered at the fracture site via ‚ tri-calcium phosphate/collagen matrix resulted in a dose-dependent effect on cellular proliferation 4 days after fracture and enhanced later (mineralized tissue and mechanical strength) parameters of diabetic fracture healing.
Previous studies indicated that local insulin delivery ameliorates the effect of DM on bone fracture healing. In a normal (non-DM) BB Wistar femoral fracture model, two vehicles for local insulin delivery were examined; ‚ tri-calcium phosphate (TCP) and calcium sulfate (CaSO4). Insulin delivery at the fracture site via CaSO4 enhanced the early (cellular proliferation and chondrogenesis) and late (mineralized tissue, cartilage content and mechanical strength) parameters of fracture healing without a significant effect on the systemic parameters of blood glucose homeostasis.
The data obtained from the normal (non-DM) BB Wistar rat model suggest that local insulin treatment directly mediated the fracture healing process via the insulin or insulin like growth factor-I (IGF-I) signaling pathways. An analysis of insulin release kinetics from CaSO4 and TCP indicated that sustained release of insulin for 7 days from the CaSO4 carrier produced significantly better healing outcomes.
Based on these findings a mathematical model was suggested to investigate the effect of local growth factors on impaired fracture healing.