Functional Approaches in Promoting Vascularization and Angiogenesis in Bone Critical-Sized Defects via Delivery of Cells, Growth Factors, Drugs, and Particles.

Critical-sized bone defects, or CSDs, are defined as bone defects that cannot be regenerated by themselves and require surgical intervention via employing specific biomaterials and a certain regenerative strategy. Although a variety of approaches can be used to treat CSDs, poor angiogenesis and vascularization remain an obstacle in these methods. The complex biological healing of bone defects depends directly on the function of blood flow to provide sufficient oxygen and nutrients and the removal of waste products from the defect site. The absence of vascularization can lead to non-union and delayed-union defect development. To overcome this challenge, angiogenic agents can be delivered to the site of injury to stimulate vessel formation. This review begins by introducing the treatment methods for CSDs. The importance of vascularization in CSDs is subsequently highlighted. Delivering angiogenesis agents, including relevant growth factors, cells, drugs, particles, cell secretion substances, their combination, and co-delivery to CSDs are fully explored. Moreover, the effects of such agents on new bone formation, followed by vessel formation in defect areas, are evaluated.