Lalchandani Keshav B, Donneys Alexis, Nelson Noah S, Daniel Melissa, Urlaub Kevin M, Lynn Jeremy V, Cragg Kyle, Wessels Emma, Singh Navya, Forrest Laird, Cohen Mark, Buchman Steven R
From the Craniofacial Research Laboratory, Plastic Surgery Section, University of Michigan, Ann Arbor, MI.
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI.
Ann Plast Surg. 2025 Jul 1;95(1):93-99. doi: 10.1097/SAP.0000000000004355.
The purpose of this work is to therapeutically reverse the damaging effects of radiotherapy on bone graft incorporation to enable nonvascularized bone grafting (NVBG) in the irradiated mandible. While NVBG has lost favor as a surgical reconstructive method in irradiated bone, it offers advantages to the current gold standard free tissue transfer, as it is less invasive and avoids the need for complex microsurgery. Therapeutically, fortifying the NVBG technique with angiogenic stimulants may offer avenues for the reintroduction of this practical method of surgical reconstruction.Utilizing a rodent model of mandibular bone grafting and established standard outcome measures, we quantified metrics of diminished graft take and bone healing as a consequence of radiotherapy (XRT). We hypothesized that the addition of Ferroximend, a novel implantable formulation of angiogenic deferoxamine conjugated to hyaluronic acid, would demonstrate substantial, clinically relevant degrees of remediation on the process of bone graft incorporation in the aftermath of radiation injury.
Three groups of Lewis rats were investigated (n = 8/group): control, XRT, and Ferroximend (FER). The XRT and FER groups received a human equivalent dose of 70 gray (Gy) of radiotherapy to left hemi-mandibles. In all groups, a circular 6-mm critical sized defect was created and repaired with a bone graft. Mandibles were imaged at 15, 40, and 60 days with in vivo μCT and radiomorphometrics were analyzed. Upon harvest, bony union was assessed by 3 blinded reviewers prior to biomechanical testing.
Radiation impaired bone graft incorporation as evidenced by diminished radiomorphometrics and biomechanical metrics at 40 and 60 days. Ferroximend implantation after radiotherapy significantly improved radiomorphometrics and metrics of biomechanical strength when compared to irradiated, nonimplanted animals. Notably, the bony union percentage of the FER group demonstrated both statistical and clinically significant improvement when compared to the XRT group (89% vs 39%, respectively) and was not significantly different than control animals (94%).
Our results suggest that the implantation of Ferroximend during NVBG reconstruction can remediate the damaging effects of radiotherapy. Upon clinical translation, countless patients may benefit from the successful reintroduction of nonvascularized bone grafting as a reconstructive option in oncologic reconstruction after radiotherapy.
本研究的目的是通过治疗逆转放疗对骨移植融合的破坏作用，从而使在受照射的下颌骨中进行非血管化骨移植（NVBG）成为可能。虽然NVBG作为一种在受照射骨中的手术重建方法已不再受青睐，但它相对于当前的金标准游离组织移植具有优势，因为它侵入性较小且无需复杂的显微外科手术。在治疗方面，用血管生成刺激剂强化NVBG技术可能为重新引入这种实用的手术重建方法提供途径。利用下颌骨移植的啮齿动物模型和既定的标准结果测量方法，我们量化了放疗（XRT）导致的移植骨成活率降低和骨愈合的指标。我们假设，添加Ferroximend（一种与透明质酸偶联的血管生成去铁胺的新型可植入制剂）将在辐射损伤后的骨移植融合过程中显示出显著的、具有临床相关性的修复程度。
研究了三组Lewis大鼠（每组n = 8）：对照组、XRT组和Ferroximend（FER）组。XRT组和FER组接受相当于人类剂量70格雷（Gy）的放疗，照射左半下颌骨。在所有组中，创建一个6毫米的圆形临界尺寸缺损，并用骨移植进行修复。在第15、40和60天用体内微型计算机断层扫描（μCT）对下颌骨进行成像，并分析放射形态计量学。收获后，在进行生物力学测试之前，由3名盲法评审员评估骨愈合情况。
放疗损害了骨移植融合，这在第40天和第60天的放射形态计量学和生物力学指标降低中得到证明。与接受放疗但未植入的动物相比，放疗后植入Ferroximend显著改善了放射形态计量学和生物力学强度指标。值得注意的是，与XRT组相比，FER组的骨愈合百分比在统计学和临床上均有显著改善（分别为89%和39%），且与对照动物无显著差异（94%）。
我们的结果表明，在NVBG重建过程中植入Ferroximend可以修复放疗的破坏作用。在临床转化后，无数患者可能会受益于成功重新引入非血管化骨移植作为放疗后肿瘤重建中的一种重建选择。
