Bone defects combined with tumors, infections, or other bone diseases are challenging in clinical practice. Autologous and allogeneic grafts are two main traditional remedies, but they can cause a series of complications. To address this problem, researchers have constructed various implantable biomaterials. However, the original pathological microenvironment of bone defects, such as residual tumors, severe infection, or other bone diseases, could further affect bone regeneration. Thus, the rational design of versatile biomaterials with integrated bone therapy and regeneration functions is in great demand. Many strategies have been applied to fabricate smart stimuli-responsive materials for bone therapy and regeneration, with stimuli related to external physical triggers or endogenous disease microenvironments or involving multiple integrated strategies. Typical external physical triggers include light irradiation, electric and magnetic fields, ultrasound, and mechanical stimuli. These stimuli can transform the internal atomic packing arrangements of materials and affect cell fate, thus enhancing bone tissue therapy and regeneration. In addition to the external stimuli-responsive strategy, some specific pathological microenvironments, such as excess reactive oxygen species and mild acidity in tumors, specific pH reduction and enzymes secreted by bacteria in severe infection, and electronegative potential in bone defect sites, could be used as biochemical triggers to activate bone disease therapy and bone regeneration. Herein, we summarize and discuss the rational construction of versatile biomaterials with bone therapeutic and regenerative functions. The specific mechanisms, clinical applications, and existing limitations of the newly designed biomaterials are also clarified.

Bone is consisted of bone matrix, cells and bioactive factors, and bone matrix is the combination of inorganic minerals and organic polymers. Type I collagen fibril made of five triple-helical collagen chains is the main organic polymer in bone matrix. It plays an important role in the bone formation and remodeling process. Moreover, collagen is one of the most commonly used scaffold materials for bone tissue engineering due to its excellent biocompatibility and biodegradability. However, the low mechanical strength and osteoinductivity of collagen limit its wider applications in bone regeneration field. By incorporating different biomaterials, the properties such as porosity, structural stability, osteoinductivity, osteogenicity of collagen matrixes can be largely improved. This review summarizes and categorizes different kinds of biomaterials including bioceramic, carbon and polymer materials used as components to fabricate collagen based composite scaffolds for bone regeneration. Moreover, the possible directions of future research and development in this field are also proposed.