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Title: Upregulation of early inflammation to enhance fracture repair
Author: Chan, James
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Fractures of bone are very common, affecting 2% of the population per annum. Whilst the majority heal uneventfully, 10-15% exhibit delayed or non-union. These complications tend to occur in patients who have sustained high-energy open fractures, which are limb-threatening injuries, or low-energy osteoporotic fractures, which are associated with high morbidity and mortality rates. Enhancement or acceleration of fracture repair would confer significant benefit to these patients as well as reduce the public health burden. Inflammation represents the earliest response following trauma and initiates a cascade of downstream events crucial for wound healing. However, the mechanism by which this occurs remains poorly defined. A detailed understanding of how these upstream events initiate fracture healing is a necessary step in the development of therapeutics to enhance this process. Our group previously reported that addition of low dose recombinant human TNF (rhTNF) at the fracture site accelerated fracture repair in a murine tibial fracture model. Here I show that local rhTNF treatment is only effective when administered within 24 hours of injury, when neutrophils represent the major inflammatory cell infiltrate. Endogenous TNF was expressed at the fracture site initially by neutrophils and after 3 days by monocytes/macrophages. Systemic administration of anti-TNF resulted in impaired fracture healing. The addition of rhTNF to the fracture environment in an air pouch model enhanced neutrophil recruitment, and promoted the recruitment of monocytes through CCL2 production. Conversely, inhibition of either neutrophils or the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility fractures represent a major unmet medical need and they are associated with permanent disability and premature death. Using a murine model of fragility fractures, rhTNF treatment improved fracture healing during the early phase of repair. Translated clinically, accelerated healing would permit earlier load bearing and reduce the morbidity and mortality associated with delayed patient mobilisation.
Supervisor: Nanchahal, Jagdeep; Horwood, Nicole; Mahoney, David Sponsor: Wellcome Trust ; Royal College of Surgeons of England ; Royal College of Surgeons of Edinburgh
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biology (medical sciences) ; Orthopaedics ; Rheumotology ; inflammation ; innate immunity ; fracture ; healing