Substantial and innovative developments in the field of bone tissue engineering have prompted increased demand for suitable pre-clinical large animal models. The pig has several advantages over other non-primate species, including availability, rapid growth, large litters, and similar anatomy and physiology to humans. These characteristics make them ideal models for research in diverse applications such as cardiovascular disease, pharmacological activity testing, and organ transplantation. There has been an increased interest in the use of swine as a model for bone healing and grafting techniques. Maxillofacial surgeons strive to develop the best therapy for large bone defects in the face resulting from tumour resection, congenital abnormalities, and traumatic injuries. Creating a model to study a critical-sized bone defect in the mandible, which does not spontaneously heal without clinical intervention, would be a method to test growth factors and synthetic bone graft therapies. However, the size of bone defect required to create this condition has not been ascertained. In the current study, we examined the in vivo healing response for 4, 8, and 16 weeks of surgically created bone defects in the posterior region of the pig mandible. Yorkshire barrows (n = 12) 6–7 months of age were used for the study. All animal experiments conformed to the University of Illinois Institutional Animal Care and Use Committee (IACUC) guidelines. Animals were maintained under general anaesthesia and transcortical, circular defects with diameters of 6, 10, 16, or 25 mm were created on both sides of the mandible. The presence and amount of calcified tissue was assessed using radiographs and dual energy x-ray absorptiometry (DEXA). Tissue morphology was examined using hard-tissue histological methods and a light microscope. Defect diameters of 6, 10, and 16 mm had completed healing or were in the process of healing within the 16-week timeframe of the study. Compared to controls, average percent differences in bone mineral density, in order of increasing defect size, were 0.62%, 28.1%, and 54.5%, respectively. In contrast, 25 mm diameter defects displayed limited collagenous tissue ingrowth, and the presence of calcified tissue was not detected, as indicated by radiographs and histological staining. As the defect size increased, the time required to heal was prolonged until a critical size was determined and normal bone was not completely regenerated. In conclusion, circular defects in the posterior region of the pig mandible with diameters equal or greater than 25 mm will result in limited healing without additional medical intervention and can be termed critical-sized defects. This porcine model will allow for the rapid development and testing of new approaches for the repair of damaged bone, which is especially prevalent in the craniofacial area.
This work was partially supported by the Carle Foundation Hospital (#2007-04072) and the Illinois Regenerative Medicine Institute (IDPH #63080017).
The Annals of Biomedical Engineering on Critical Size Bone Defect: A Review
