Inadequate vascularization of engineered tissue constructs is a main challenge in developing a clinically impactful therapy for large, complex, and recalcitrant bone defects. It is well established that bone and blood vessels form concomitantly during development, as well as during repair after injury. Endothelial cells (ECs) and mesenchymal stromal cells (MSCs) are known to be key players in orthopedic tissue regeneration and vascularization, and these cell types have been used widely in tissue engineering strategies to create vascularized bone. Coculture studies have demonstrated that there is crosstalk between ECs and MSCs that can lead to synergistic effects on tissue regeneration. At the same time, the complexity in fabricating, culturing, and characterizing engineered tissue constructs containing multiple cell types presents a challenge in creating multifunctional tissues. In particular, the timing, spatial distribution, and cell phenotypes that are most conducive to promoting concurrent bone and vessel formation are not well understood. This review describes the processes of bone and vascular development, and how these have been harnessed in tissue engineering strategies to create vascularized bone. There is an emphasis on interactions between ECs and MSCs, and the culture systems that can be used to understand and control these interactions within a single engineered construct. Developmental engineering strategies to mimic endochondral ossification are discussed as a means of generating vascularized orthopedic tissues. The field of tissue engineering has made impressive progress in creating tissue replacements. However, the development of larger, more complex, and multifunctional engineered orthopedic tissues will require a better understanding of how osteogenesis and vasculogenesis are coupled in tissue regeneration.

中文翻译：

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工程骨科组织中成骨和血管生成的耦合

工程组织结构的血管化不足是开发针对大型、复杂和顽固性骨缺损的临床有效疗法的主要挑战。众所周知，骨骼和血管在发育过程中以及损伤后的修复过程中同时形成。众所周知，内皮细胞（EC）和间充质基质细胞（MSC）是骨科组织再生和血管化的关键参与者，这些细胞类型已广泛用于组织工程策略中以创建血管化骨。共培养研究表明，EC 和 MSC 之间存在串扰，可以对组织再生产生协同效应。与此同时，包含多种细胞类型的工程组织构建体的制造、培养和表征的复杂性对创建多功能组织提出了挑战。特别是，最有利于促进骨和血管同时形成的时间、空间分布和细胞表型尚不清楚。这篇综述描述了骨骼和血管发育的过程，以及如何在组织工程策略中利用这些过程来创建血管化骨骼。重点关注 EC 和 MSC 之间的相互作用，以及可用于理解和控制单个工程构建体中这些相互作用的培养系统。讨论了模拟软骨内骨化的发育工程策略，作为生成血管化骨科组织的一种手段。组织工程领域在创造组织替代品方面取得了令人瞩目的进展。然而，开发更大、更复杂和多功能的工程骨科组织将需要更好地了解成骨和血管生成在组织再生中如何耦合。