Inorganic Agents for Enhanced Angiogenesis of Orthopedic Biomaterials

Abstract

Aseptic loosening of a permanent prosthesis remains one of the most common reasons for bone implant failure. To improve the fixation between implant and bone tissue as well as enhance blood vessel formation, bioactive agents are incorporated into the surface of the biomaterial. This study reviews and compares five bioactive elements (copper, magnesium, silicon, strontium, and zinc) with respect to their effect on the angiogenic behavior of endothelial cells (ECs) when incorporated on the surface of biomaterials. Moreover, it provides an overview of the state-of-the-art methodologies used for the in vitro assessment of the angiogenic properties of these elements. Two databases are searched using keywords containing ECs and copper, magnesium, silicon, strontium, and zinc. After applying the defined inclusion and exclusion criteria, 59 articles are retained for the final assessment. An overview of the angiogenic properties of five bioactive elements and the methods used for assessment of their in vitro angiogenic potential is presented. The findings show that silicon and strontium can effectively enhance osseointegration through the simultaneous promotion of both angiogenesis and osteogenesis. Therefore, their integration onto the surface of biomaterials can ultimately decrease the incidence of implant failure due to aseptic loosening.

Keywords: angiogenesis; bone regeneration; orthopedic implants; trace elements.

Figure 1

An illustration depicting the stages of fracture healing: 1) In the initial inflammatory phase (lasting up to 7 days after injury), the increased blood delivery to the affected site results in the formation of hematoma with a high content of cytokines; 2) cells attracted by cytokines and environmental factors (hypoxia, low pH, HIF1‐alpha, and VEGF) are responsible for the repair of damaged vessels and formation of provisional fibrous tissue called callus (7–10 days after injury); 3) at around two weeks after injury, MSCs undergo differentiation into osteoblasts and chondrocytes governed by Wnt and BMP signaling and provisional woven bone is generated; 4) in the final phase starting 3–4 weeks after injury and lasting up to several years, the woven bone is replaced by lamellar bone.

Figure 2

An illustration of sprouting angiogenesis. The presence of different factors (hypoxia, HIF1‐alpha, VEGF) can initiate angiogenesis, which is divided into 4 stages: 1) In the first stage, the membrane degrades resulting in the liberation of ECs; 2) the cells proliferate and migrate, thereby establishing new branches of the vascular network; 3) the new branches are initially formed without a lumen and are hollowed in a subsequent stage; 4) the new endothelium matures, and blood flow is established through the new vessels.