Successful bone healing depends significantly on the structure of blood clots and the functional responses of blood cells. Despite the importance of blood clots in osteogenesis, few studies have investigated the effects of blood clots during material-mediated bone regeneration. In this study, we implanted the bone graft substitute hydroxyapatite/tricalcium phosphate (HA/TCP) subcutaneously, with or without blood prefabrication, to evaluate the effects of blood clots on material-mediated bone formation. We observed that blood prefabricated HA/TCP induced ectopic vascularized bone-like structures, implying that blood prefabrication can induce a microenvironment sufficient for HA/TCP-mediated bone formation. The possible mechanisms were related to (1) modification of the fibrin network, which facilitates MSCs recruitment and differentiation, (2) modulation of the early osteoimmune environment with the upregulation of osteogenic factor BMP2, and (3) improved expression of VEGF and the enhancement of angiogenesis. These results demonstrate the multifaceted effects of blood clots in regulating osteogenesis, osteoclastogenesis, immune responses, and angiogenesis. Therefore, blood prefabrication can serve as a valuable strategy to improve the osteogenic capacity of materials, and prefabricating materials with blood clots prior to implantation should be encouraged. New generation bone substitute materials could target the modulation of a favorable blood clot response for improved bone regeneration.

中文翻译：

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血液预制的羟基磷灰石/磷酸三钙可通过调节骨免疫环境来诱导异位血管化骨形成†

骨的成功愈合在很大程度上取决于血凝块的结构和血细胞的功能性反应。尽管血块在成骨中很重要，但很少有研究调查血块在材料介导的骨再生过程中的作用。在这项研究中，我们在有或没有血液预制的情况下，将骨移植替代物羟基磷灰石/磷酸三钙（HA / TCP）皮下植入，以评估血凝块对材料介导的骨形成的影响。我们观察到血液预制的HA / TCP诱导了异位血管化的骨样结构，这意味着血液预制可以诱导足以用于HA / TCP介导的骨形成的微环境。可能的机制与（1）纤维蛋白网络的修饰有关，这有助于MSC的募集和分化，（2）借助成骨因子BMP2的上调来调节早期的骨免疫环境，以及（3）改善VEGF的表达并增强血管生成。这些结果证明了血凝块在调节成骨，破骨细胞生成，免疫反应和血管生成中的多方面作用。因此，血液预制可作为提高材料成骨能力的有价值的策略，应鼓励在植入前用血块预制材料。新一代的骨替代材料可以针对有利的血凝块反应的调节，以改善骨再生。这些结果证明了血凝块在调节成骨，破骨细胞生成，免疫反应和血管生成中的多方面作用。因此，血液预制可作为提高材料成骨能力的有价值的策略，应鼓励在植入前用血块预制材料。新一代的骨替代材料可以针对有利的血凝块反应的调节，以改善骨再生。这些结果证明了血凝块在调节成骨，破骨细胞生成，免疫反应和血管生成中的多方面作用。因此，血液预制可作为提高材料成骨能力的有价值的策略，应鼓励在植入前用血块预制材料。新一代的骨替代材料可以针对有利的血凝块反应的调节，以改善骨再生。