The effect of Iron chelators on bioceramic bone graft remodelling

摘要

Purpose:. Local delivery of the widely available iron chelator, Deferoxamine (DFO) has recently been shown to augment angiogenesis and osteogenesis in fracture models through activation of the Hypoxia Inducible Factor (HIF) signaling pathway. Add Reference 1HIF activation is also thought to induce osteoclast differentiation and resorptive function, however mimicking this effect with iron chelators has shown contradicting in vitro resultsAdd Reference 3Add Reference 4. Few studies have examined the effect of these commonly used medications on bioceramic bone graft remodeling. We aimed to determine the effect of the local delivery of DFO on new bone ingrowth in a rabbit ulnar defect bridged by 3D-printed monetite (CaHPO_4) grafts. Secondly we aimed to accurately quantify the effect of iron chelator delivery on osteoclast mediated graft resorption using a monetite graft cranial onlay model. Methods: In 6 rabbits, 3D-printed Monetite (CaHPO_4) grafts were implanted into bilateral 10mm ulnar defects. Starting on day 4 post-op, DFO (600ul/200uM) was injected into one graft every 48hrs × 6 doses, with the contralateral receiving saline. In 8 rabbits, 2 circular grafts (9mm f / 4mm thick) were fixed subperiosteally onto the cranium. Three rabbits had DFO injected into both grafts and three received saline. Two rabbits were injected with another chelator, 1,10-Phenanthroline (PHT). At 8 weeks, micro-CT and histology were used to assess bone growth and graft resorption. TRAP stain identified osteoclast density at the bone-graft interface. Results: Ulnar defect: New bone growth was significantly higher in the DFO group compared to the saline group (Bv/Tv: 19.6% vs 13.5% (P＜0.05).Add Figure 1 Histological analysis showed increased bone within the osteotomy gap and more bone integrated at the graft surface in the DFO group. Cranial Model: A marked decrease in graft resorption and vertical bone growth was evident in the DFO and PHT group as compared to saline controls.Add Figure 2 TRAP stain quantification showed a 3-fold significant decrease in osteoclast density in the chelation groups compared to controls. Conclusion: In the long-bone model, where cellular resorption of the graft is not required for bone formation since graft dissolution predominates, bone growth was enhanced by DFO. In the static cranial onlay model, bone growth was actually decreased by iron chelators and this was correlated to a reduction in osteoclast number and graft remodeling. This previously unreported in vivo finding has a number of exciting potential applications in surgery such as augmenting graft integration and temporizing resorption during reconstructive procedures.