An Effective Alternative to Autogenous Bone Grafts in Critically Sized Defects
Autogenous bone grafts remain the gold standard for bone regeneration although their limitations include donor site morbidity, insufficient volume, and restrictions in graft shape and contour. The use of bone morphogenetic protein 2 combined with a scaffold, remains an alternative to autogenous bone grafting. However, in higher doses, it has been associated with significant heterotopic bone formation and increased inflammation1. Recognition of this problem has lead to developing advanced spatiotemporal delivery strategies that effectively regenerate bone using lower and therefore potentially safer doses of BMP2. Our objective is to compare the healing of critically sized segmental bone defects treated with 5ug rhBMP2 delivered in a hybrid alginate-nanofiber mesh delivery system with autogenous grafts.
Materials and Methods
Bilateral 8mm mid-diaphyseal femoral segmental defects in 13-week old female rats were treated with either 150ul alginate + 5ug rhBMP2 (Alginate) or autogenous bone grafts. For the autogenous bone graft, the resected bone segments from both legs were crushed into smaller pieces and packed into a nanofiber mesh tube to volumetrically fill the defect. Bone regeneration was longitudinally tracked by radiography and micro-CT at 2, 4, 8, and 12 weeks post-op. A density threshold of >50% of the density of native cortical bone was used for image segmentation. Torsional tests were performed at 12 weeks to estimate the extent of functional regeneration. Routine histology was used at all time points to characterize regeneration. Non-decalcified tissue sections were used to identify temporal mineralization patterns with vital bone stains.
Results
Radiographs of defects treated with alginate appear radiolucent at earlier time points compared to autogenous graft. Longitudinal micro-CT showed a significantly higher bone volume for autogenous graft at 2 and 4 weeks. At 8 weeks, no significant differences in volumes were apparent and by 12 weeks the alginate group showed significantly higher bone volume (p<0.001). The bone density remained higher for the autogenous graft compared to the alginate group at all time points. Biomechanical testing revealed significantly higher maximum torque (p=0.02) and stiffness (p=0.037) for the alginate group at 12 weeks.
On histology, the alginate group showed diffuse mineral deposition in the defect at 4 weeks with evidence of some further activity at 8 weeks. The autogenous graft showed more localized mineral deposition at the graft edges and focal areas within the graft at 4 weeks and predominantly edge deposition at 8 weeks.
Conclusions
These results demonstrate that the alginate-rhBMP2 hybrid delivery system produced greater bone formation and restoration of biomechanical function than autologous bone grafts. Superior mechanical properties of the alginate group despite overall lower bone density compared to autogenous graft might suggest a positive influence of architecture on the healing of bone defects, or a limitation of the slower integration of autografts by remodeling.
References
1. T. G. Carter, P. S. Brar, A. Tolas, and O. R. Beirne 2008 Off-label use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for reconstruction of mandibular bone defects in humans. J Oral Maxillofac Surg 66(7):1417-25.
2. Kolambkar YM, Dupont KM, Boerckel JD, Huebsch N, Mooney DJ, Hutmacher DW, Guldberg RE 2011 An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects. Biomaterials 32(1):65-74.