George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Division of Biomaterials and Biomechanics, Department of Restorative Dentistry, Oregon Health and Science University (OHSU), Portland, OR 97201, USA.
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Acta Biomater. 2021 Jun;127:180-192. doi: 10.1016/j.actbio.2021.03.066. Epub 2021 Apr 3.
Successful bone healing in severe trauma depends on early revascularization to restore oxygen, nutrient, growth factor, and progenitor cell supply to the injury. Therapeutic angiogenesis strategies have therefore been investigated to promote revascularization following severe bone injuries; however, results have been inconsistent. This is the first study investigating the effects of dual angiogenic growth factors (VEGF and PDGF) with low-dose bone morphogenetic protein-2 (BMP-2; 2.5 µg) on bone healing in a clinically challenging composite bone-muscle injury model. Our hydrogel-based delivery systems demonstrated a more than 90% protein entrapment efficiency and a controlled simultaneous release of three growth factors over 28 days. Co-stimulation of microvascular fragment constructs with VEGF and PDGF promoted vascular network formation in vitro compared to VEGF or PDGF alone. In an in vivo model of segmental bone and volumetric muscle loss injury, combined VEGF (5 µg) and PDGF (7.5 µg or 15 µg) delivery with a low dose of BMP-2 significantly enhanced regeneration of vascularized bone compared to BMP-2 treatment alone. Notably, the regenerated bone mechanics reached ~60% of intact bone, a value that was previously only achieved by delivery of high-dose BMP-2 (10 µg) in this injury model. Overall, sustained delivery of VEGF, PDFG, and BMP-2 is a promising strategy to promote functional vascularized bone tissue regeneration following severe composite musculoskeletal injury. Although this study is conducted in a clinically relevant composite injury model in rats using a simultaneous release strategy, future studies are necessary to test the regenerative potential of spatiotemporally controlled delivery of triple growth factors on bone healing using large animal models. STATEMENT OF SIGNIFICANCE: Volumetric muscle loss combined with delayed union or non-union bone defect causes deleterious effects on bone regeneration even with the supplementation of bone morphogenetic protein-2 (BMP-2). In this study, the controlled delivery of dual angiogenic growth factors (vascular endothelial growth factor [VEGF] + Platelet-derived growth factor [PDGF]) increases vascular growth in vitro. Co-delivering VEGF+PDGF significantly increase the bone formation efficacy of low-dose BMP-2 and improves the mechanics of regenerated bone in a challenging composite bone-muscle injury model.
严重创伤中的骨愈合取决于早期再血管化，以恢复氧气、营养物质、生长因子和祖细胞供应到损伤部位。因此，已经研究了治疗性血管生成策略以促进严重骨损伤后的再血管化;然而，结果并不一致。这是第一项研究，探讨了低剂量骨形态发生蛋白-2（BMP-2；2.5μg）与双血管生成生长因子（VEGF 和 PDGF）联合应用对临床上具有挑战性的骨-肌复合损伤模型中骨愈合的影响。我们的水凝胶递送系统显示，超过 90%的蛋白质包封效率和超过 28 天的三种生长因子的受控同时释放。与 VEGF 或 PDGF 单独刺激相比，微脉管片段构建物与 VEGF 和 PDGF 的共同刺激促进了体外血管网络形成。在节段性骨和体积性肌肉缺失损伤的体内模型中，与单独使用 BMP-2 相比，联合使用 VEGF（5μg）和 PDGF（7.5μg 或 15μg）递送低剂量 BMP-2 可显著增强血管化骨的再生。值得注意的是，再生骨力学达到~60%的完整骨，这是以前在该损伤模型中仅通过递送高剂量 BMP-2（10μg）才能达到的值。总之，VEGF、PDFG 和 BMP-2 的持续递送是促进严重复合肌肉骨骼损伤后功能性血管化骨组织再生的有前途的策略。尽管这项研究是在大鼠中使用同时释放策略进行的具有临床相关性的复合损伤模型中进行的，但未来的研究有必要使用大动物模型测试三重生长因子时空控制释放对骨愈合的再生潜力。
体积性肌肉缺失与延迟愈合或非愈合性骨缺损结合会对骨再生产生有害影响，即使补充骨形态发生蛋白-2（BMP-2）也是如此。在这项研究中，双血管生成生长因子（血管内皮生长因子[VEGF]+血小板衍生生长因子[PDGF]）的控制递送增加了体外血管生长。共递送 VEGF+PDGF 可显著提高低剂量 BMP-2 的成骨效果，并改善具有挑战性的骨-肌复合损伤模型中再生骨的力学性能。
