Key components of engineering vascularized 3-dimensional bioprinted bone constructs.

Vascularization has a pivotal role in engineering successful tissue constructs. However, it remains a major hurdle of bone tissue engineering, especially in clinical applications for the treatment of large bone defects. Development of vascularized and clinically-relevant engineered bone substitutes with sufficient blood supply capable of maintaining implant viability and supporting subsequent host tissue integration remains a major challenge. Since only cells that are 100-200 µm from blood vessels can receive oxygen through diffusion, engineered constructs that are thicker than 400 µm face a challenging oxygenation problem. Following implantation in vivo, spontaneous ingrowth of capillaries in thick engineered constructs is too slow. Thus, it is critical to provide optimal conditions to support vascularization in engineered bone constructs. To achieve this, an in-depth understanding of the mechanisms of angiogenesis and bone development is required. In addition, it is also important to mimic the physiological milieu of native bone to fabricate more successful vascularized bone constructs. Numerous applications of engineered vascularization with cell-and/or microfabrication-based approaches seek to meet these aims. Three-dimensional (3D) printing promises to create patient-specific bone constructs in the future. In this review, we discuss the major components of fabricating vascularized 3D bioprinted bone constructs, analyze their related challenges, and highlight promising future trends.