SiO2 and ZnO dopants in three-dimensionally printed tricalcium phosphate bone tissue engineering scaffolds enhance osteogenesis and angiogenesis in vivo

Abstract

Calcium phosphate (CaP) scaffolds with three dimensionally (3D) interconnected pores play an important role in mechanical interlocking and biological fixation in bone implant applications. CaPs alone, however, are only osteoconductive (ability to guide bone growth). Much attention has been given to the incorporation of biologics and pharmacologics to add osteoinductive (ability to cause new bone growth) properties to CaP materials. Because biologics and pharmacologics are generally delicate compounds and also subject to increased regulatory scrutiny, there is a need to investigate alternative methods to introduce osteoinductivity to CaP materials. In this study silica (SiO2) and zinc oxide (ZnO) have been incorporated in to 3D printed β-tricalcium phosphate (TCP) scaffolds to investigate their potential to trigger osteoinduction in vivo. Silicon and zinc are trace elements that are common to bone and have also been shown to have many beneficial properties from increased bone regeneration to angiogenesis. Implants were placed in bicortical femur defects introduced to a murine model for up to 16 weeks. Addition of dopants into TCP increased the capacity for new early bone formation by modulating collagen I production and osteocalcin production. Neovascularization was found to be up to three times more than the pure TCP control group. The findings from this study indicate that the combination of SiO2 and ZnO dopants in TCP may be a viable alternative to introduce osteoinductive properties to CaPs.

Synthesized zinc peroxide nanoparticles (ZnO₂-NPs): a novel antimicrobial, anti-elastase, anti-keratinase, and anti-inflammatory approach toward polymicrobial burn wounds

“…[3][4][5][6] ZnO-NPs may be considered as bi-functional materials because of their ability to work as safe antimicrobial agents for dermatological and orthopedic applications in addition to the role of zinc as a vital trace element for building, stabilizing, and functioning of proteins and enzymes. 7,8 Moreover, most of the elements constituting the metal oxides are considered as trace elements that are vital to the human body. 9 Therefore, there is a great interest in incorporating antimicrobial metal oxide NPs within orthopedic, dental, and skin biomaterials.…”

Improving the bone forming ability of synthetic bone substitutes using trace element additions

“…Because these "side effects" provoked by the substitution of foreign ions are almost inevitable, there is thus a lack of direct evidence proving the essential role of trace elements in osteoinduction. Furthermore, considering osteoinduction can be triggered without trace elements (Chapter 3 and Chapter 4), while many positive results with trace elements have been obtained at bony sites or with the combination of BMP [128,147,148,318], the current data suggest that the added ions may not be the essential trigger responsible for the observed osteoinduction.…”

“…By incorporating various trace elements into calcium phosphate materials, we expected a release of the doped ion, in this way affecting the cellular responses surrounding the implants and subsequently promote the local osteogenesis. So far the introduction of ions in synthetic materials have been shown to improve their osteoconductivity [122,129,132,135,140,142,148,149,199,[318][319][320], but it is not clear whether osteoinduction may be achieved or whether trace elements may boost the osteoinductivity of the small group of inductive ceramics [42,98,321]. If osteoinduction is obtainable by trace element containing calcium phosphates, it needs to be determined to which extent the inductive bone formation can be attributed to the doped ions.…”

“…So far, atomic absorption spectroscopy (AAS) or inductively coupled plasma (ICP) have been employed to detect the ion concentration in urine [318], plasma [337,290,270,338] and bone mineral [290]. However, few methods could locally monitor the release of ions at the implant site.…”

“…This provides vast potential to use vary trace elements additions to meet diverse demands in clinic. The application of trace elements is thus not limited to bone, but also in other fields such as instructing vascularisation [318,329,[348][349][350] and anti-infection [331,351,352]. For example, the antimicrobial silver (Ag) could suppress inflammatory responses [330,353,354] and the doping of Ag in calcium phosphates has shown to reduce the risk of implant-associated infections [331,351,352,355].…”