Department of Stomatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China.
Shanghai Key Laboratory of Multiphase Materials Chemical Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai, China.
Acta Biomater. 2019 Aug;94:253-267. doi: 10.1016/j.actbio.2019.05.066. Epub 2019 May 31.
Bone tissue engineering has substantial potential for the treatment of massive bone defects; however, efficient vascularization coupled with bone regeneration still remains a challenge in this field. In the current study, supercritical carbon dioxide (scCO) foaming technique was adopted to fabricate mesoporous bioactive glasses (MBGs) particle-poly (lactic-co-glycolic acid) (PLGA) composite scaffolds with appropriate mechanical and degradation properties as well as in vitro bioactivity. The MBG-PLGA scaffolds incorporating the bioactive lipid FTY720 (designated as FTY/MBG-PLGA) exhibited simultaneously sustained release of the bioactive lipid and ions. In addition to providing a favorable microenvironment for cellular adhesion and proliferation, FTY/MBG-PLGA scaffolds significantly facilitated the in vitro osteogenic differentiation of rBMSCs and also markedly stimulated the upregulation of Hif-1α expression via the activation of the Erk1/2 pathway, which mediated the osteogenic and pro-angiogenic effects on rBMSCs. Furthermore, FTY/MBG-PLGA extracts induced superior in vitro angiogenic performance of HUVECs. In vivo evaluation of critical-sized rat calvarial bone defects indicated that FTY/MBG-PLGA scaffolds potently promoted vascularized bone regeneration. Notably, the significantly enhanced formation of type H vessels (CD31Emcn neo-vessels) was observed in newly formed bone tissue in FTY/MBG-PLGA group, strongly suggesting that FTY720 and therapeutic ions released from the scaffolds synergistically induced more type H vessel formation, which indicated the coupling of angiogenesis and osteogenesis to achieve efficiently vascularized bone regeneration. Overall, the results indicated that the foamed porous MBG-PLGA scaffolds incorporating bioactive lipids achieved desirable vascularization-coupled bone formation and could be a promising strategy for bone regenerative medicine. STATEMENT OF SIGNIFICANCE: Efficacious coupling of vascularizationandbone formation is critical for the restoration of large bone defects. Anoveltechnique was used to fabricate composite scaffolds incorporating bioactive lipids which possessedsynergistic cues of bioactive lipids and therapeutic ions to potently promotebone regenerationas well as vascularization. The underlying molecular mechanism for the osteogenic and pro-angiogenic effects of the compositescaffolds was unveiled. Interestingly, the scaffolds were furtherfoundto enhance the formation oftype H capillarieswithin the bone healing microenvironment to couple angiogenesis to osteogenesis to achieve satisfyingvascularizedbone regeneration.These findings provide a novel strategy to develop efficiently vascularized engineering constructs to treat massive bone defects.
骨组织工程在治疗大体积骨缺损方面具有巨大的潜力；然而，在该领域中，高效的血管化与骨再生仍然是一个挑战。在本研究中，采用超临界二氧化碳（scCO2）发泡技术制备具有适当机械和降解性能以及体外生物活性的介孔生物活性玻璃（MBG）颗粒-聚（乳酸-共-羟基乙酸）（PLGA）复合支架。负载生物活性脂质 FTY720 的 MBG-PLGA 支架（命名为 FTY/MBG-PLGA）表现出生物活性脂质和离子的持续释放。除了为细胞黏附和增殖提供有利的微环境外，FTY/MBG-PLGA 支架还显著促进 rBMSCs 的体外成骨分化，并通过激活 Erk1/2 通路显著上调 Hif-1α 的表达，从而介导 rBMSCs 的成骨和促血管生成作用。此外，FTY/MBG-PLGA 提取物诱导 HUVECs 的体外血管生成性能得到显著提高。体内评价大鼠颅骨临界尺寸骨缺损表明，FTY/MBG-PLGA 支架可强力促进血管化骨再生。值得注意的是，在 FTY/MBG-PLGA 组的新形成骨组织中观察到显著增强的 H 型血管（CD31Emcn 新生血管）形成，强烈表明 FTY720 和支架释放的治疗离子协同诱导更多的 H 型血管形成，表明血管生成和骨生成的耦合以实现有效的血管化骨再生。总体而言，结果表明，负载生物活性脂质的发泡多孔 MBG-PLGA 支架实现了理想的血管化耦合骨形成，可能成为骨再生医学的一种有前途的策略。
