1 Division of Orthopaedics, McGill University Health Center , Montreal, Canada .
2 Bone Engineering Labs, Research Institute-McGill University Health Centre , Montreal, Canada .
Tissue Eng Part A. 2017 Dec;23(23-24):1372-1381. doi: 10.1089/ten.TEA.2016.0526. Epub 2017 Jul 19.
Tissue hypoxia is a critical driving force for angiogenic and osteogenic responses in bone regeneration and is, at least partly, under the control of the Hypoxia Inducible Factor-1α (HIF-1α) pathway. Recently, the widely used iron chelator deferoxamine (DFO) has been found to elevate HIF-1α levels independent of oxygen concentrations, thereby, creating an otherwise normal environment that mimics the hypoxic state. This has the potential to augment the biological properties of inorganic scaffolds without the need of recombinant growth factors. This pilot study investigates the effect of local delivery of DFO on bone formation and osseointegration of an anatomically matched bone graft substitute, in the treatment of segmental bone defects. Three-dimensional printing was used to create monetite grafts, which were implanted into 10 mm midshaft ulnar defects in eight rabbits. Starting postoperative day 4, one graft site in each animal was injected with 600 μL (200 μM) of DFO every 48 h for six doses. Saline was injected in the contralateral limb as a control. At 8 weeks, micro-CT and histology were used to determine new bone growth, vascularity, and assess osseointegration. Six animals completed the protocol. Bone metric analysis using micro-CT showed a significantly greater amount of new bone formed (19.5% vs. 13.65% p = 0.042) and an increase in bone-implant contact area (63.1 mm vs. 33.2 mm p = 0.03) in the DFO group compared with control. Vascular channel volume was significantly greater in the DFO group (20.9% vs. 16.2% p = 0.004). Histology showed increased bone formation within the osteotomy gap, more bone integrated with the graft surface as well as more matured soft tissue callus in the DFO group. This study demonstrates a significant increase in new bone formation after delivery of DFO in a rabbit long bone defect bridged by a 3D-printed bioresorbable bone graft substitute. Given the safety, ease of handling, and low expense of this medication, the results of this study support further investigation into the use of iron chelators in creating a biomimetic environment for bone healing in segmental bone loss.
组织缺氧是骨再生中血管生成和成骨反应的关键驱动力，至少部分受到缺氧诱导因子-1α（HIF-1α）途径的控制。最近，广泛使用的铁螯合剂去铁胺（DFO）已被发现可独立于氧浓度升高 HIF-1α 水平，从而创造出一种正常的环境，模拟缺氧状态。这有可能增强无机支架的生物学特性，而无需使用重组生长因子。这项初步研究调查了局部递送 DFO 对解剖匹配骨移植物替代物的骨形成和骨整合的影响，以治疗节段性骨缺损。使用三维打印技术创建了磷灰石移植物，将其植入 8 只兔子的 10mm 尺骨干缺损中。从术后第 4 天开始，每只动物的一个移植物部位每 48 小时注射 600μL（200μM）DFO，共 6 次。对侧肢体注射盐水作为对照。8 周时，使用 micro-CT 和组织学来确定新骨生长、血管生成并评估骨整合。6 只动物完成了方案。使用 micro-CT 进行的骨计量分析显示，DFO 组形成的新骨量明显更多（19.5%比 13.65%，p=0.042），骨-植入物接触面积增加（63.1mm 比 33.2mm，p=0.03）。DFO 组的血管通道体积明显更大（20.9%比 16.2%，p=0.004）。组织学显示，DFO 组骨切间隙内骨形成增加，与移植物表面结合的骨更多，成熟的软组织骨痂也更多。这项研究表明，在 3D 打印可吸收骨移植物替代物桥接的兔长骨缺损中递送 DFO 后，新骨形成显著增加。鉴于这种药物的安全性、易于处理和低费用，本研究结果支持进一步研究铁螯合剂在创建节段性骨丢失中骨愈合的仿生环境中的应用。
