Localized deferoxamine injection augments vascularity and improves bony union in pathologic fracture healing after radiotherapy.
Localized deferoxamine injection augments vascularity and improves bony union in pathologic fracture healing after radiotherapy.
复制标题
DOI：
10.1016/j.bone.2012.10.014
复制
发表时间：
2013-01
期刊：
影响因子：
4.1
通讯作者：
Buchman, Steven R.
中科院分区：
文献类型：
--
作者：
Donneys, Alexis;Weiss, Daniela M.;Deshpande, Sagar S.;Ahsan, Salman;Tchanque-Fossuo, Catherine N.;Sarhaddi, Deniz;Levi, Benjamin;Goldstein, Steven A.;Buchman, Steven R.
以医学为基础的预防或补救放射治疗对病理性骨折愈合的腐蚀作用的努力和替代治疗策略未能产生明确和令人信服的成功证据。在这种情况下，建立一种有效的药物选择来预防或治疗骨不连的发展可能具有巨大的治疗潜力。实验研究表明，去铁胺(DFO)是一种铁络合剂，当局部注射到长骨动物模型的骨折骨痂中时，可以增强血管，从而促进正常的骨折愈合。由于放射治疗会阻碍血管生成，我们假设DFO的药理作用有助于减轻放射治疗对体外和体内新血管形成的影响。利用Matrigel中的HUVEC细胞进行血管生成的体外研究。内皮小管形成实验分为4组：对照组、照射组、照射+低剂量DFO组和照射+高剂量DFO组。在实验过程中，对四组的肾小管形成进行了定量的显微镜观察和录像。在体内，三组SD大鼠接受了外固定器置入和左侧下颌骨骨折截骨术。两组均行术前分割放射治疗，其中一组骨折修复后给予DFO治疗。40天后灌流，用Micro-CT成像，计算血管放射形态计量学指标。在体外，内皮小管形成分析表明，DFO减轻了辐射对血管生成的有害影响。此外，高剂量DFO培养似乎在孵化2小时内组织起来，并实现了一个强大的网络，在加速方式上明显优于所有其他试验组。在活体实验中，接受等量人类放射治疗和左侧下颌骨骨折的动物显示血管密度的μCT指标显著降低，相关骨不连的发生率为75%。如3D血管造影术所示，DFO的加入显著改善了血管。此外，我们观察到，与未经治疗的放射骨折相比，DFO治疗组的骨性愈合发生率更高(分别为67%和25%)。我们的数据表明，选择性地通过局部注射DFO来靶向血管生成足以补救HEDR导致的相关严重血管减少。也许最重要和临床相关的发现是，在骨折愈合没有常规观察的模型中，能够减少骨不连的发生率。
Medically based efforts and alternative treatment strategies to prevent or remediate the corrosive effects of radiotherapy on pathologic fracture healing have failed to produce clear and convincing evidence of success. Establishing an effective pharmacologic option to prevent or treat the development of non-unions in this setting could have immense therapeutic potential. Experimental studies have shown that Deferoxamine (DFO), an iron- chelating agent, bolsters vascularity and subsequently enhances normal fracture healing when injected locally into a fracture callus in long bone animal models. Since radiotherapy is known to impede angiogenesis, we hypothesized that the pharmacologic addition of DFO would serve to mitigate the effects of radiotherapy on new vessel formation in vitro and in vivo. In vitro investigation of angiogenesis was conducted utilizing HUVEC cells in Matrigel. Endothelial tubule formation assays were divided into four groups: Control, Radiated, Radiated + Low Dose DFO and Radiated + High Dose DFO. Tubule formation was quantified microscopically and video recorded for the four groups simultaneously during the experiment. In vivo, three groups of Sprague–Dawley rats underwent external fixator placement and fracture osteotomy of the left mandible. Two groups received pre-operative fractionated radiotherapy, and one of these groups was treated with DFO after fracture repair. After 40 days, the animals were perfused and imaged with micro-CT to calculate vascular radiomorphometrics. In vitro, endothelial tubule formation assays demonstrated that DFO mitigated the deleterious effects of radiation on angiogenesis. Further, high-dose DFO cultures appeared to organize within 2 hours of incubation and achieved a robust network that was visibly superior to all other experimental groups in an accelerated fashion. In vivo, animals subjected to a human equivalent dose of radiotherapy (HEDR) and left mandibular fracture demonstrated quantifiably diminished μCT metrics of vascular density, as well as a 75% incidence of associated non-unions. The addition of DFO in this setting markedly improved vascularity as demonstrated with 3D angiographic modeling. In addition, we observed an increased incidence of bony unions in the DFO treated group when compared to radiated fractures without treatment (67% vs. 25% respectively). Our data suggest that selectively targeting angiogenesis with localized DFO injections is sufficient to remediate the associated severe vascular diminution resulting from a HEDR. Perhaps the most consequential and clinically relevant finding was the ability to reduce the incidence of non-unions in a model where fracture healing was not routinely observed.
登录
查看更多内容
影响因子：
4.1
作者：
Farberg, Aaron S.;Jing, Xi L.;Monson, Laura A.;Donneys, Alexis;Tchanque-Fossuo, Catherine N.;Deshpande, Sagar S.;Buchman, Steven R.
通讯作者：
Buchman, Steven R.
影响因子：
3.6
作者：
Tchanque-Fossuo CN;Monson LA;Farberg AS;Donneys A;Deshpande SS;Razdolsky ER;Halonen NR;Goldstein SA;Buchman SR
通讯作者：
Buchman SR
DOI：
10.1056/nejmct1004810
发表时间：
2011-01-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brittenham GM
通讯作者：
Brittenham GM
脯氨酰羟化酶抑制剂可增加小鼠股骨骨折后的新血管生成和愈伤组织形成。
影响因子：
2.8
作者：
Shen, Xing;Wan, Chao;Ramaswamy, Girish;Mavalli, Mahendra;Wang, Ying;Duvall, Craig L.;Deng, Lian Fu;Guldberg, Robert E.;Eberhart, Alan;Clemens, Thomas L.;Gilbert, Shawn R.
通讯作者：
Gilbert, Shawn R.
影响因子：
3.6
作者：
Fregene, Alero;Jing, Xi Lin;Buchman, Steven R.
通讯作者：
Buchman, Steven R.