Therapeutic metallic ions in bone tissue engineering: A systematic review of the literature

An important field of bone tissue engineering (BTE) concerns the design and fabrication of smart scaffolds capable of inducing cellular interactions and differentiation of osteo-progenitor cells. One of these additives that has gained growing attention is metallic ions as therapeutic agents (MITAs). The specific biological advantage that these ions bring to scaffolds as well as other potential mechanical, and antimicrobial enhancements may vary depending on the ion entity, fabrication method, and biomaterials used. Therefore, this article provides an overview on current status of in-vivo application of MITAs in BTE and the remaining challenges in the field. Electronic databases, including PubMed, Scopus, Science direct and Cochrane library were searched for studies on MITAs treatments for BTE. We searched for articles in English from January-2000 to October-2019. Abstracts, letters, conference papers and reviews, In-vitro studies, studies on alloys and studies investigating effects other than enhancement of new bone formation (NBF) were excluded. A detailed summary of relevant metallic ions with specific scaffold material and design, cell type, animal model and defect type, implantation period, measured parameters and obtained qualitative and quantitative results is presented. No ideal material or fabrication method suited to deliver MITAs can yet be agreed upon, but an investigation into various systems and their drawbacks or potential advantages can lead the future research. A tendency to enhance NBF with MITAs can be observed in the studies. However, this needs to be validated with further studies comparing various ions with each other in the same animal model using critical-sized defects.