Craniofacial bone defects of critical size, caused by trauma, tumors, infections, or congenital maldevelopment, represent a major challenge in plastic and reconstructive surgery. Autologous bone grafting is considered the gold standard, but limitations such as donor site morbidity and limited availability have prompted the development of artificial bone tissue engineering scaffolds. In recent years, bioactive scaffolds have been increasingly utilized in favor of inert biomaterials due to their immunomodulation and osteoinduction capabilities. This review methodically summarizes loading strategies for the functionalization of scaffolds with bioactive components, including cell regulatory factors, drugs, ions, stem cells, exosomes, and components derived from human tissues or cells to promote bone regeneration. The following mechanisms are involved: (1) the polarization of macrophages (M1-M2 transition), (2) the dynamic regulation of bone metabolism, and (3) the coupling of osteogenesis and angiogenesis. This review focuses on innovative delivery systems, such as 3D-printed scaffolds, nanocomposites and so on, that enable spatiotemporal control of bioactive cargo release. These address key challenges, such as infection resistance, vascularization, and mechanical stability in the process of bone regeneration. In addition, the article discusses emerging technologies, including stem cells and exosome-based acellular therapies, which demonstrate potential for personalized bone regeneration. This review integrates immunology, materials science, and clinical needs, providing a roadmap for the design of next-generation bone tissue engineering scaffolds to overcome critical-sized bone defects.
Luo et al. (2025) studied this question.