Guangzhou Key Laboratory of Spine Disease Prevention and Treatment, The Third Affiliated Hospital, Guangzhou Medical University, 63 Duobao Road, Guangzhou 510150, China; Department of Orthopaedic Surgery, The Third Affiliated Hospital, Guangzhou Medical University, 63 Duobao Road, Guangzhou 510150, China.
Department of Rheumatology, Liwan Central Hospital of Guangzhou, 35 Liwan Road, Guangzhou 510030, China.
Acta Biomater. 2022 Nov;153:108-123. doi: 10.1016/j.actbio.2022.09.018. Epub 2022 Sep 14.
Insufficient vascularization is a major challenge in the repair of critical-sized bone defects. Deferoxamine (DFO) has been reported to play a potential role in promoting the formation of H-type blood vessels, a specialized vascular subtype with coupled angiogenesis and osteogenesis. However, whether DFO promotes the expression of H-type vessels in critical femoral defects with complete periosteal damage remains unknown. Moreover, stable drug loading systems need to be designed owing to the short half-life and high-dose toxic effects of DFO. In this study, we developed an injectable DFO-gelatin microspheres (GMs) hydrogel complex as a stable drug loading system for the treatment of critical femoral defects in rats. Our results showed that sustained release of DFO in critical femoral defects stimulated the generation of functional H-type vessels. The DFO-GMs hydrogel complex effectively promoted proliferation, formation, and migration of human umbilical vein endothelial cells in vitro. In vivo, the application of the DFO-GMs hydrogel complex expanded the distribution range and prolonged the expression time of H-type vessels in the defect area and was positively correlated with the number of osterix+ cells and new bone tissue. Topical application of the HIF-1α inhibitor PX-478 partially blocked the stimulation of H-type vessels by DFO, whereas the osteogenic potential of the latter was also weakened. Our results extended the local application of DFO and provided a theoretical basis for targeting H-type vessels to treat large femoral defects. STATEMENT OF SIGNIFICANCE: Abundant functional blood vessels are essential for bone repair. The H-type blood vessel is a functional subtype with angiogenesis and osteogenesis coupling potential. A drug loading system with long-term controlled release was first used to investigate the formation of H-type blood vessels in critical femoral defects and promotion of bone repair. Our results showed that the application of DFO-GMs hydrogel complex expanded the distribution range and expression time of H-type vessels, and was positively correlated with the number of osteoblasts and volume of new bone tissue. These results expanded the local application approach of DFO and provide a theoretical basis for targeting H-type vessels to treat large femoral defects.
血管生成不足是修复临界尺寸骨缺损的主要挑战。去铁胺（DFO）已被报道在促进 H 型血管形成中发挥潜在作用，H 型血管是一种具有血管生成和成骨耦联潜力的特殊血管亚型。然而，DFO 是否促进具有完整骨膜损伤的临界股骨缺损中 H 型血管的表达尚不清楚。此外，由于 DFO 的半衰期短和高剂量毒性作用，需要设计稳定的药物加载系统。在这项研究中，我们开发了一种可注射的 DFO-明胶微球（GMs）水凝胶复合物，作为治疗大鼠临界股骨缺损的稳定药物加载系统。我们的结果表明，在临界股骨缺损中持续释放 DFO 刺激功能性 H 型血管的生成。DFO-GMs 水凝胶复合物在体外有效促进人脐静脉内皮细胞的增殖、形成和迁移。在体内，DFO-GMs 水凝胶复合物的应用扩大了 H 型血管在缺陷区域的分布范围并延长了其表达时间，与骨钙素+细胞和新骨组织的数量呈正相关。局部应用 HIF-1α抑制剂 PX-478 部分阻断了 DFO 对 H 型血管的刺激，而后者的成骨潜力也减弱。我们的结果扩展了 DFO 的局部应用，并为靶向 H 型血管治疗大股骨缺损提供了理论依据。
丰富的功能性血管对于骨修复至关重要。H 型血管是一种具有血管生成和成骨耦联潜力的功能性亚型。本研究首次使用载药系统，研究了临界股骨缺损中 H 型血管的形成及其对骨修复的促进作用。结果表明，DFO-GMs 水凝胶复合物的应用扩大了 H 型血管的分布范围和表达时间，与成骨细胞的数量和新骨组织的体积呈正相关。这些结果扩展了 DFO 的局部应用方法，并为靶向 H 型血管治疗大股骨缺损提供了理论依据。
