Osteoinductive biodegradable intramedullary implant accelerates bone healing and mitigates complications in a rat bone transport model. Osteoinductive biodegradable intramedullary implant accelerates bone healing and mitigates complications in a rat bone transport model

Bone transport distraction osteogenesis (DO) is one of the most successful surgery-driven endogenous tissue regeneration approaches for the treatment of large bone defects. However, prolonged consolidation, docking site nonunion, and pin tract infection remain challenging complications. Here, we engineered an osteoinductive, biodegradable intramedullary (IM) implant for sustained release of bone morphogenetic protein-2 (BMP-2) as an adjunctive therapy of bone transport to address the clinical challenges. A hybrid tissue engineering construct (HyTEC) technique was developed to enable sustained release of BMP-2 in a broad range. 100% bony fusion was achieved in the IM implants incorporating with 2 μg and 6 μg BMP-2 as early as 34 days after bone transport surgeries in the management of 8-mm femoral defect. Load bearing was restored 55 days after surgeries when the fixator was removed. Eluting BMP-2 from the IM implants accelerates bone formation and angiogenesis at early phase, and increase mineralization at late phase, especially at the docking sites, leading to early bony bridging. Moreover, no pin tract infection but seamless integration could be found in the 2 μg and 6 μg BMP-2 treated groups. Surgical control and IM implant showed high proportion of non-union and pin tract infections. 2 μg BMP-2 delivered by collagen sponge or 0.5 μg BMP-2-laden IM implant did not induce bone regeneration effectively, resulting in some non-unions and infections. A presence of bacteria of fecal origin in the infection sites was identified. In conclusion, this osteoinductive IM implant holds great promise in revolutionizing bone transport DO technique in the management of bone defect by accelerating bone regeneration and mitigating complications. Overall design: 8 mm bone defect and 4 mm segmental bone was created in rat femurs. Then rats were divided into three groups. For rats in control group, segmental bone was placed in the middle of defect site. Distraction osteogenesis and BMP2-eluting implant was not used for these rats. Rats in blank group received distraction ostegenesis without BMP2-eluting implant. Rats in BMP2 group received distraction osteogenesis with BMP-2 eluting implant.

骨运输型牵张成骨术（bone transport distraction osteogenesis, DO）是治疗大骨缺损最成功的手术驱动型内源性组织再生方法之一。然而，骨愈合延迟、对接部位骨不连及针道感染仍是颇具挑战性的临床并发症。本研究构建了一种具备骨诱导性、可降解的髓内（intramedullary, IM）植入物，用于持续释放骨形态发生蛋白-2（bone morphogenetic protein-2, BMP-2），作为骨搬运术的辅助治疗手段以解决上述临床难题。研究开发了复合组织工程支架（hybrid tissue engineering construct, HyTEC）技术，可实现宽剂量范围的BMP-2持续释放。在针对8mm股骨缺损的骨搬运手术中，植入负载2μg及6μg BMP-2的髓内植入物后，术后34天即可实现100%骨融合。术后55天拆除外固定架时，大鼠已恢复肢体承重功能。从髓内植入物中洗脱的BMP-2可在早期促进骨形成与血管生成，并在晚期提升矿化水平，尤其在对接部位，从而实现早期骨桥接。此外，在2μg及6μg BMP-2处理组中，未观察到针道感染，且植入物实现了无缝整合。而单纯手术处理组及髓内植入物组的骨不连与针道感染占比较高。采用胶原海绵递送2μg BMP-2或负载0.5μg BMP-2的髓内植入物均未能有效诱导骨再生，进而引发部分骨不连及感染病例。研究在感染部位检测到粪便来源的细菌。综上，这种骨诱导性髓内植入物通过加速骨再生、减轻并发症，有望革新骨搬运牵张成骨术在骨缺损治疗中的应用。实验总体设计：在大鼠股骨上制备8mm骨缺损及4mm节段性骨段。随后将大鼠分为三组：对照组大鼠将节段性骨段放置于缺损区域中央，不实施牵张成骨术及BMP-2缓释植入物治疗；空白组大鼠接受牵张成骨术，但未植入BMP-2缓释植入物；BMP-2组大鼠接受牵张成骨术联合BMP-2缓释植入物治疗。