The repair of large bone defects remains a major clinical orthopaedic challenge. Bone is a highly vascularised tissue reliant on the close spatial and temporal connection between blood vessels and bone cells to maintain skeletal integrity. Angiogenesis thus plays a pivotal role in skeletal development and bone fracture repair. Current procedures to repair bone defects and to provide structural and mechanical support include the use of grafts (autologous, allogeneic) or implants (polymeric or metallic). These approaches face significant limitations due to insufficient supply, potential disease transmission, rejection, cost and the inability to integrate with the surrounding host tissue.

The sorptive properties of clay are harnessed to provide niches for tissue regeneration. Synthetic smectite clays self‐organize into gels under physiological conditions to allow encapsulation of cells and demonstrate remarkable capacity for the localization of biological molecules without the need for complex chemical modifications.

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Medical advances have led to a welcome increase in life expectancy. However, accompanying longevity introduces new challenges: increases in age-related diseases and associated reductions in quality of life. The loss of skeletal tissue that can accompany trauma, injury, disease or advancing years can result in significant morbidity and significant socio-economic cost and emphasise the need for new, more reliable skeletal regeneration strategies. To address the unmet need for bone augmentation, tissue engineering and regenerative medicine have come to the fore in recent years with new approaches for de novo skeletal tissue formation. Typically, these approaches seek to harness stem cells, innovative scaffolds and biological factors that promise enhanced and more reliable bone formation strategies to improve the quality of life for many. This review provides an overview of recent developments in bone tissue engineering focusing on skeletal stem cells, vascular development, bone formation and the translation from preclinical in vivo models to clinical delivery.

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Skeletal stem cells confer to bone its innate capacity for regeneration and repair. Bone regeneration strategies seek to harness and enhance this regenerative capacity for the replacement of tissue damaged or lost through congenital defects, trauma, functional/esthetic problems, and a broad range of diseases associated with an increasingly aged population. This review describes the state of the field and current steps to translate and apply skeletal stem cell biology in the clinic and the problems therein. Challenges are described along with key strategies including the isolation and ex vivo expansion of multipotential populations, the targeting/delivery of regenerative populations to sites of repair, and their differentiation toward bone lineages. Finally, preclinical models of bone repair are discussed along with their implications for clinical translation and the opportunities to harness that knowledge for musculoskeletal regeneration.

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