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.骨搬运牵张成骨术（Bone transport distraction osteogenesis, DO）是目前治疗大段骨缺损最成功的手术介导内源性组织再生策略之一。然而，骨愈合周期延长、对接点骨不连以及针道感染仍是亟待攻克的挑战性并发症。本研究开发了一种具备成骨诱导性、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方案以应对上述临床难题。研究团队开发了复合组织工程支架（hybrid tissue engineering construct, HyTEC）技术，可实现BMP-2的宽范围持续释放。在针对8mm股骨缺损的骨搬运手术中，植入搭载2μg和6μg BMP-2的髓内植入物的受试对象，最早在术后34天即实现100%骨融合。术后55天拆除外固定架时，受试对象已恢复负重功能。从髓内植入物中持续释放的BMP-2可在早期促进骨形成与血管生成，晚期提升矿化水平，尤其在对接位点，进而实现早期骨桥接。此外，在2μg和6μg BMP-2处理组中，未观察到针道感染，且实现了植入物与骨组织的无缝整合。而手术对照组与未负载有效剂量BMP-2的髓内植入物组，则存在较高比例的骨不连与针道感染问题。通过胶原海绵递送2μg BMP-2，或搭载0.5μg BMP-2的髓内植入物，均未能有效诱导骨再生，进而导致部分病例出现骨不连与感染。研究还在感染位点鉴定出粪便来源的细菌。综上，这种具备成骨诱导性的髓内植入物可通过加速骨再生、缓解并发症，有望革新骨搬运DO技术在骨缺损治疗中的应用前景。