Gene-activated titanium implants for gene delivery to enhance osseointegration

Osseointegration is the direct and intimate contact between mineralized tissue and titanium implant at the bone-implant interface. Early establishment and stable maintenance of osseointegration is the key to long-term implant success. However, in patients with compromised conditions such as osteoporosis and patients beginning early load-bearing activities such as walking, lower osseointegration around titanium implants is often observed, which might result in implant early failure. Gene-activated implants show an exciting prospect of combining gene delivery and biomedical implants to solve the problems of poor osseointegration formation, overcoming the shortcomings of protein therapy, including rapid degradation and overdose adverse effects. The conception of gene-activated titanium implants is based on "gene-activated matrix" (GAM), which means scaffolds using non-viral vectors for in situ gene delivery to achieve a long-term and efficient transfection of target cells. Current preclinical studies in animal models have shown that plasmid DNA (pDNA), microRNA (miRNA), and small interference RNA (siRNA) functionalized titanium implants can enhance osseointegration with safety and efficiency, leading to the expectation of applying this technique in dental and orthopedic clinical scenarios. This review aims to comprehensively summarize fabrication strategies, current applications, and futural outlooks of gene-activated implants, emphasizing nucleic acid targets, non-viral vectors, implant surface modification techniques, nucleic acid/vector complexes loading strategies.