Single level posterolateral spinal fusion in rabbits is the accepted preclinical model for evaluating bone graft substitutes or treatments to enhance/augment healing. This study aimed to improve preclinical testing by developing a multi-level unilateral fusion model that could be used as a screening tool prior to larger scale preclinical experiments. A four level unilateral posterolateral fusion was performed in nine animals. The materials were randomly allocated and placed between the decorticated surfaces of the transverse processes and vertebral bodies. Animals were euthanised at three, six and 12 weeks. The materials were (1) 25 kGy y-irradiated rabbit allograft chips (RAC), (2) SCF RAC, (3) 60% tri-calcium phosphate, 40% hydroxyapatite formagraft (BiOstetic) (4) Autograft (1.5 cc morsellised to 1-2.5 mm granules). The autograft was harvested from the iliac crest using the L5-L6 incision. Endpoints included x-ray, CT, micro CT and histology. The animals tolerated the surgery well. Radiographic data provided a useful method to differentiate between groups. Micro CT however was extremely valuable demonstrating new bone formation as early as three weeks across the groups. Gamma irradiated samples demonstrated an initial inflammatory reaction while the autograft, SCF allograft and synthetic TCP did not show this response. As expected, time was an important factor demonstrating the maturity in the fusions. These materials responded in a similar fashion in this model as observed in a single level fusion. A unilateral multi-level fusion can be performed in rabbits to provide a useful screening for different materials. Gamma irradiated allograft has an initial inflammatory reaction that may be related to the presence of residual cellular material whereas SCF and synthetic materials do not

Background. Identification of novel therapeutics to accelerate acute fracture healing remains critical. A prostaglandin EP-2 receptor agonist (CP-533,536) has demonstrated acceleration of fracture healing in preclinical models. The objective of this study is to assess the efficacy of a single dose of CP-533,536 in subjects with a closed fracture of the tibial shaft using radiographic measurements compared to placebo treatment. Methods. In a phase II randomised, blinded, placebo-controlled trial, the efficacy of a single local injection of three doses of CP-533,536 (0.5mg, 1.5mg and 15mg) was compared to a placebo and a standard of care arm in patients with closed tibial shaft fractures. The tibial fractures were treated with reamed inter-locked intramedullary nails. Patients were followed at two week intervals to six months with a final evaluation at one year. Fracture healing was independently adjudicated by a radiologist panel and an orthopaedic surgeon panel. Results. Ninety-nine patients were enrolled ranging from 17-76 years in age. Baseline characteristics were comparable across treatment groups. No statistically significant differences in median healing time between any of the CP-533,536 treatment groups and placebo were observed based on the radiology panel assessment; however, significant differences were demonstrated by an orthopaedic panel. At weeks 8, 10, 12, 14 and 16 a higher percentage of subjects in the CP-533,536-1.5 and 0.5 mg groups were considered healed compared to the placebo and the 15 mg groups by the orthopaedic panel assessment. Moreover, the CP-533,536- 0.5 mg group showed a statistically higher (p=0.05) mean radiographic healing score than placebo treated group at weeks 8, 14, 16, 18, and 24. Conclusion. CP-533,536 demonstrated accelerated healing in patients with acute tibia fractures by an orthopaedic panel. Confirmatory trials are required to assure validity of the observed treatment effects