Stem cell-based approaches to engineering vascularized bone

•Stem cells can self-assemble into complex tissues.•Heterogenous populations of autologous cells can form vascularized bone tissues.•Strategic combinations of stem cells with biomaterials can regenerate bony non-unions.

The treatment of large, non-healing bone defects remains a clinical challenge, and has driven efforts toward the development of new approaches to engineer vascularized bone grafts. Despite great advances in bone tissue engineering over the past decade, clinical translation of stem cell-based strategies has been limited. This article discusses the hurdles blocking the effective application of stem cell-based regeneration of mature bone with perfusable vascular networks as well as avenues for potentially overcoming those hurdles. Particular focus is placed on the combination of autologous heterogeneous cell sources with key regenerative growth factors to mimic the complex cellular and biochemical environments that occur during normal bone healing. Understanding how to guide the intrinsic self-assembly mechanisms of these cells may increase their regenerative efficacy and enable in situ tissue morphogenesis. The development of more effective, safer, and simpler approaches to engineer vascularized bone grafts may bring stem cell-based approaches closer to wider clinical application.