Targeted delivery as key for the success of small osteoinductive molecules.

Molecules such as growth factors, peptides and small molecules can guide cellular behavior and are thus important for tissue engineering. They are rapidly emerging as promising compounds for the regeneration of tissues of the musculoskeletal system. Growth factors have disadvantages such as high cost, short half-life, supraphysiological amounts needed, etc. Therefore, small molecules may be an alternative. These molecules have been discovered using high throughput screening. Small osteoinductive molecules exhibit several advantages over growth factors owing to their small sizes, such as high stability and non-immunogenicity. These molecules may stimulate directly signaling pathways that are important for osteogenesis. However, systemic application doesn't induce osteogenesis in most cases. Therefore, local administration is needed. This may be achieved by using a bone graft material providing additional osteoconductive properties. These graft materials can also act by themselves as a delivery matrix for targeted and local delivery. Furthermore, vascularization is necessary in the process of osteogenesis. Many of the small molecules are also capable of promoting vascularization of the tissue to be regenerated. Thus, in this review, special attention is given to molecules that are capable of inducing both angiogenesis and osteogenesis simultaneously. Finally, more recent preclinical and clinical uses in bone regeneration of those molecules are described, highlighting the needs for the clinical translation of these promising compounds.