Angiogenesis plays a pivotal role in tissue development and regeneration, but few safe and efficient pro-angiogenic factors are available for long-term clinical therapy. Although stem cell-derived exosomes exhibit excellent biocompatibility and considerable pro-angiogenic capacity, their low yield extremely limits their clinical potential. Exosome-mimetics (EMs) employ similar features to exosomes and can be produced in a higher yield. In this study, the HY-EMs were produced to enhance and pro-angiogenic ability from hypoxia-preconditioned bone marrow mesenchymal stem cells (BMSCs) using a serial extrusion method. The yield of EMs was over 10 times greater than that of exosomes. Furthermore, compared with the EMs group, the tube number of human umbilical vein endothelial cells (HUVECs) doubled in the HY-EMs treated group, and the number of blood vessels increased by 186% in subcutaneously implanted scaffold with HY-EMs. More importantly, the HY-EMs effectively promoted vascularized osteogenesis in a critical-sized cranial defect model, with the new bone volume and vessel number in regenerated bone increased to 120% and 175%, respectively. Consequently, our current work provides a promising strategy to customize and mass-produce functional EMs for vascularized osteogenesis.

中文翻译：

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缺氧触发的外泌体模拟物加速血管化成骨

血管生成在组织发育和再生中发挥着关键作用，但可用于长期临床治疗的安全有效的促血管生成因子很少。尽管干细胞来源的外泌体表现出优异的生物相容性和相当大的促血管生成能力，但其低产量极大地限制了其临床潜力。外泌体模拟物（EM）具有与外泌体相似的特征，并且可以以更高的产量生产。在本研究中，使用连续挤出方法生产 HY-EM，以增强缺氧预处理的骨髓间充质干细胞 (BMSC) 的促血管生成能力。 EM 的产量比外泌体高 10 倍以上。此外，与EMs组相比，HY-EMs治疗组的人脐静脉内皮细胞（HUVEC）管数增加了一倍，皮下植入HY-EMs支架的血管数量增加了186%。更重要的是，HY-EMs在临界尺寸颅骨缺损模型中有效促进了血管化成骨，再生骨中的新骨体积和血管数量分别增加至120%和175%。因此，我们目前的工作为定制和批量生产用于血管化成骨的功能性 EM 提供了一种有前景的策略。