Regulation of Angiogenesis and Bone Regeneration with Natural and Synthetic Small Molecules

Abstract

Regeneration of bone requires the coordinated processes of angiogenesis and osteogenesis. These repair mechanisms are closely linked through both direct cell-cell contact and indirect paracrine signaling among osteoblasts, endothelial cells, and other cell types. The vasculature provides a source of nutrients, oxygen, metabolic substrates, and access for circulating cells that help to support new bone formation. The complexity of the endogenous signaling axis that promotes angiogenesis provides numerous opportunities for therapeutic intervention ranging from progenitor cell mobilization to endothelial proliferation and sprouting. Small molecules are particularly appealing for regenerative medicine applications because many exhibit extended in vivo stability, low cost, and scalable production. Innovative techniques for developing small molecules such as high throughput functional assays and broad-spectrum database analysis techniques have led to the development of new compounds and the identification of novel applications of existing drugs. In addition, rapid advances in biomaterials design and synthesis provide platforms to deliver therapeutic small molecules to sites of bone injury. This review presents an overview of current strategies for harnessing endogenous healing mechanisms using small molecules by targeting angiogenesis, osteogenesis, or both.

Synergistic effects of dimethyloxalylglycine and butyrate incorporated into α-calcium sulfate on bone regeneration

“…Small molecules are appealing for regenerative medicine applications because many exhibit extended in vivo stability, a limited period of action, low cost, and scalable production [5,7]. A number of small molecules have been investigated for bone regeneration.…”

“…The small molecules that regulate the cellular signaling pathways involving BMPs, Wnts, Hedgehog, sphingolipids, and HIF-1 showed to promote osteogenesis and/or angiogenesis, which led to accelerated bone regeneration [5,8,31e36]. For these applications, biomaterials can provide platforms to deliver therapeutic small molecules to injury sites in a controlled manner to minimize the systemic side effect [5,8]. In this study, we evaluated the combined delivery of small molecules that stimulate angiogenic and osteogenic responses in bone defects using aCS as a delivery vehicle and as a bone void filler.…”

“…Nevertheless, growth factor approaches have been hampered by several complications, including high dose requirements, lower half-life, protein instability, higher costs and undesired side effects [5,7]. Recently, various small molecules have been explored as alternatives to growth factors for tissue regeneration applications.…”

“…Small molecules are simple biochemical components that elicit specific cellular responses through signaling cascades. It is proposed that small molecule-based strategies can reduce various side effects of high dosage growth factors, maintain bioactivity in a biological environment, and minimize cost issues associated with complex biological growth factors [5,7,8].…”

“…It has been suggested that small molecules be delivered directly to the target site by drug delivery vehicles. Successful delivery of drugs can be achieved through biomaterial vehicles [5,8]. It is possible that small molecules-containing aCS would consistently release the molecules during aCS resorption, given that aCS has excellent releasing characteristics [26].…”