Treatment of large calvarial defects with bone transport osteogenesis: a preclinical sheep model.

BACKGROUND: Bone transport osteogenesis (BTO), distraction of a free portion of bone across a defect, offers an autologous solution to large cranial defects that may allow treatment without permanent hardware implantation. This study establishes a sheep model to evaluate the feasibility and distraction kinetics of BTO. METHODS: Subtotal cranial defects (3.5 × 3.5 cm) were created in 10 young adult sheep and a transport segment (3.5 × 2 cm) traversed the defect at varying distraction rates (0, 0.5, 1.0, and 1.5 mm/day) using semi-buried cranial distractors. After a 6-week consolidation period, sheep were euthanized and the resultant bone was analyzed by CT, histology, and mechanical testing. RESULTS: Gross examination, histology, and 3D CT revealed that control animals had fibrous nonunion whereas distraction animals had ossified defects with fibrous nonunion at the distal docking site. There was one premature consolidation in the 0.5 mm/day group. The volume of bony regenerate in the 0.5, 1.0, and 1.5 mm/day distraction rate groups was statistically indistinct (P = 0.16). The mean flexural moduli (MPa) of non-decalcified samples from the control cranium, transport segment, and bone regenerate were found to be 4.50 ± 4.9, 6.17 ± 2.1, and 4.14 ± 4.8, respectively (P = 0.24). CONCLUSIONS: This experiment provides proof of concept for BTO for large calvarial defects in a sheep model. Distraction at a rate of 0.5 mm per day may place individuals at higher risk for premature consolidation, but distraction rates did not have significant effects on regenerate quantity or quality. Future work will include the use of curvilinear distraction devices for 3-dimensional contour.

Sustained delivery of rhBMP-2 by means of poly(lactic-co-glycolic acid) microspheres: cranial bone regeneration without heterotopic ossification or craniosynostosis.

BACKGROUND: Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. The authors used rhBMP2 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres placed in a rabbit cranial defect model to test whether low-dose, sustained delivery can effectively induce bone regeneration. METHODS: The rhBMP2 was encapsulated in 15% PLGA using a double-emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10 mm) were created in the calvaria of New Zealand white rabbits (5 to 7 months of age, male and female) and filled with a collagen scaffold containing either (1) no implant, (2) collagen scaffold only, (3) PLGA-rhBMP2 (0.1 µg per implant), or (4) free rhBMP2 (0.1 µg per implant). After 6 weeks, the rabbits were killed and defects were analyzed by micro-computed tomography, histology, and finite element analysis. RESULTS: The rhBMP2 delivered by means of bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by micro-computed tomography (p=0.025 and p=0.025). Finite element analysis indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p=0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation. CONCLUSIONS: Sustained delivery by means of PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reducing the risk for recently reported rhBMP2-related adverse effects.