Titanium and titanium alloys are widely favored materials for orthopedic implants due to their exceptional mechanical properties and biological inertness. The additional benefit of sustained local release of bioactive substances further promotes bone tissue formation, thereby augmenting the osseointegration capacity of titanium implants and attracting increasing attention in bone tissue engineering. Among these bioactive substances, growth factors have shown remarkable osteogenic and angiogenic induction capabilities. Consequently, researchers have developed various physical, chemical, and biological loading techniques to incorporate growth factors into titanium implants, ensuring controlled release kinetics. In contrast to conventional treatment modalities, the localized release of growth factors from functionalized titanium implants not only enhances osseointegration but also reduces the risk of complications. This review provides a comprehensive examination of the types and mechanisms of growth factors, along with a detailed exploration of the methodologies used to load growth factors onto the surface of titanium implants. Moreover, it highlights recent advancements in the application of growth factors to the surface of titanium implants (Scheme 1). Finally, the review discusses current limitations and future prospects for growth factor-functionalized titanium implants. In summary, this paper presents cutting-edge design strategies aimed at enhancing the bone regenerative capacity of growth factor-functionalized titanium implants-a significant advancement in the field of enhanced bone regeneration.

Three-dimensional (3D) printing is serving as the most promising approach to fabricate personalized titanium (Ti) implants for the precise treatment of complex bone defects. However, the bio-inert nature of Ti material limits its capability for rapid osseointegration and thus influences the implant lifetime in vivo. Despite the macroscale porosity for promoting osseointegration, 3D-printed Ti implant surface morphologies at the nanoscale have gained considerable attention for their potential to improve specific outcomes. To evaluate the influence of nanoscale surface morphologies on osseointegration outcomes of 3D-printed Ti implants and discuss the available strategies, we systematically searched evidence according to the PRISMA on PubMed, Embase, Web of Science, and Cochrane (until June 2022). The inclusion criteria were in vivo (animal) studies reporting the osseointegration outcomes of nanoscale morphologies on the surface of 3D-printed Ti implants. The risk of bias (RoB) was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE\'s) tool. The quality of the studies was evaluated using the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. (PROSPERO: CRD42022334222). Out of 119 retrieved articles, 9 studies met the inclusion criteria. The evidence suggests that irregular nano-texture, nanodots and nanotubes with a diameter of 40-105nm on the surface of porous/solid 3D-printed Ti implants result in better osseointegration and vertical bone ingrowth compared to the untreated/polished ones by significantly promoting cell adhesion, matrix mineralization, and osteogenic differentiation through increasing integrin expression. The RoB was low in 41.1% of items, unclear in 53.3%, and high in 5.6%. The quality of the studies achieved a mean score of 17.67. Our study demonstrates that nanostructures with specific controlled properties on the surface of 3D-printed Ti implants improve their osseointegration. However, given the small number of studies, the variability in experimental designs, and lack of reporting across studies, the results should be interpreted with caution.

BACKGROUND: Bionic surface nanopatterns of titanium (Ti) materials have excellent antibacterial effects in vitro for infection prevention. To date, there is a lack of knowledge about the in vivo bactericidal outcomes of the nanostructures on the Ti implant surfaces.
METHODS: A systematic review was performed using the PubMed, Embase, and Cochrane databases to better understand surface nanoscale patterns\' in vivo antibacterial efficacy. The inclusion criteria were preclinical studies (in vivo) reporting the antibacterial activity of nanopatterns on Ti implant surface. Ex vivo studies, studies not evaluating the antibacterial activity of nanopatterns or surfaces not modified with nanopatterns were excluded.
RESULTS: A total of five peer-reviewed articles met the inclusion criteria. The included studies suggest that the in vivo antibacterial efficacy of the nanopatterns on Ti implants\' surfaces seems poor.
CONCLUSIONS: Given the small number of literature results, the variability in experimental designs, and the lack of reporting across studies, concluding the in vivo antibacterial effectiveness of nanopatterns on Ti substrates\' surfaces remains a big challenge. Surface coatings using metallic or antibiotic elements are still practical approaches for this purpose. High-quality preclinical data are still needed to investigate the in vivo antibacterial effects of the nanopatterns on the implant surface.

Titanium particles as a product of degradation have been detected in periimplant oral tissues and it has been assumed that implants were the source of these particles. Periimplantitis sites had higher concentrations of particles in comparison to healthy implant sites. Several factors have been identified in the degradation of dental implant surface, such as mechanical wear, contact with chemical agents, and the effects of biofilm adhesion. Titanium particles silently prompt the immune-system activation and generate a pro-inflammatory response in macrophages, T lymphocytes and monocytes. During the activation, inflammatory cytokines are released including, granulocyte-macrophage colony-stimulating factor (GM-CSF), prostaglandin, and TNF-α, IL-1β, IL-6. The nanoparticles depict unique features such as high level of biological reactivity and potentially harmful compared to microparticles since they have a relatively greater surface area to volume ratio. Allergic response to titanium as a cause of implant failure has not been well documented. Evidence demonstrating biological complication due to titanium particles release includes peri-implant tissue inflammation that lead terminally to implant loss. There is a biological probability for a relation between the presence of titanium particles and ions, biological complication, and corrosion, but there is no justifiable evidence for unidirectional series of causative actions.

Chitosan is a natural polysaccharide extracted from the shells of crustaceans that has been proposed as a scaffold in tissue engineering. Certain studies have proven a greater osseointegration of titanium surfaces that are functionalized with chitosan. The MEDLINE, CENTRAL, PubMed, and Web of Science databases were electronically searched for in vivo studies. Seven studies met the inclusion criteria. Animal models, implant site, chitosan incorporation methods, and methods of analysis were emphasized. The selected studies were individually discussed regarding the coatings, osseointegration potential, and suitability of the experimental models used, analyzing their limitations. We concluded that chitosan-biofunctionalized titanium surfaces have greater osseointegration capacity that uncoated control titanium alloys.

The aim of the present review was to evaluate the clinical and radiographic performance of one-piece zirconia implants (O-PZI). This review followed the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines that addressed the following focused question: What is the overall clinical and radiographic performance of O-PZI? The MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Oral Health Group Trials Register databases were searched. Six clinical studies were included. For studies evaluating O-PZI compared with one-piece titanium implants, zirconia implants showed higher crestal bone loss (CBL) in both the studies. However, one study demonstrated a high failure rate compared to titanium dental implants, while one study demonstrated comparable survival rates between zirconia and titanium dental implants. For studies evaluating O-PZI for the restoration of single crown and fixed dental prostheses, O-PZI showed comparable bone loss and survival rates for single crowns and fixed dental prostheses. Two studies were included that compared O-PZI with two-piece zirconia (T-PZI). One study showed a higher CBL and low survival rate for O-PZI compared to T-PZI, whereas the other study demonstrated comparable CBL and survival rates between O-PZI and T-PZI. It is still debatable whether O-PZI demonstrate better clinical performance when compared with titanium implants or two-piece design.

Hip osteoarthritis is the most common joint disorder, and is represented by a degenerative process, resulting in pain and functional impairment. If conservative treatment for hip osteoarthritis fails, the only remaining option is hip arthroplasty. Despite good survival of implants, loosening of components is the most common complication. This leads to revision surgeries, which are technically demanding, expensive, and result in a low satisfaction rate. Uncemented hip replacements require proper osseointegration for increased survival. Physical characteristics of implants include biocompatibility, Young\'s modulus of elasticity, strength, and corrosion resistance, and each influence fixation of implants. Moreover, implant surface treatments, pore size, pore density, and femoral stem design should be appropriately selected. Patients\' optimization of obesity, osteoporosis, cardiovascular disease, psychotic disorders, and smoking cessation are associated with a higher survival of implants. Surgical factors, such as approach, drilling and rasping, acetabular bone coverage, acetabular cup positioning, and implant size, also affect survival of implants. Avoiding drugs, which may impair osseointegration of implants, and having an appropriate rehabilitation protocol are important. Future directions include anabolic and anti-catabolic bone-acting drugs to enhance osseointegration of implants. Comprehensive knowledge of the factors mentioned above is important for preventing aseptic loosening, with important socioeconomic consequences.

Recent research data have suggested that the beneficial action of statins in bone tissue could improve osseointegration around titanium implants by increasing the bone implant contact (BIC), the expression of bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF). The aim of this systematic review was to evaluate the influence of statins on osseointegration of titanium implants in animal studies. Two reviewers searched independently four databases (MEDLINE, SCOPUS, WEB OF SCIENCE and the Cochrane Library), until March 15, 2016. The Cochrane Collaboration\'s Tool for Assessing Risk of Bias was used to assess the quality of the included studies. Papers that reported outcome data considering bone implant contact (BIC), mechanical tests or other histological evaluation were eligible for inclusion. 312 references were eletronically retrieved, 21 full-text papers were screened and 17 studies were included. Thirteen trials presented histomorphometry data on bone implant contact measures. All of them showed a significant improved BIC when using statins. Despite data from included studies point to beneficial effects, standardized studies and with less risk of bias, are needed to clarify the role of statins on osseointegration.

OBJECTIVE: The purpose of this article is to review the mechanical requirements of the tissue-implant interface and analyze related theories.
METHODS: The osseointegration capacity of titanium implants has been investigated over the past 50 years. We considered the ultimate goal of osseointegration to which form a desirable interfacial layer and a bone matrix with adequate biomechanical properties.
RESULTS: Occasionally, the interface comprises porous titanium and bone ingrowth that enables a functionally graded Young\'s modulus, thereby allowing reduction of stress shielding. However, the optimal biomechanical connection at the interface has not yet been fully clarified. There have been publications supporting several universal mechanical testing technologies in terms of bone-titanium bonding ability, although the separation of newly formed bone quality is unlikely.
CONCLUSIONS: The understanding of complex mechanical bone behavior and size-dependent properties ranging from a nano- to a macroscopic level are essential in the biomechanical optimization of implants. The requirements of regenerated tissue at the interface include high strength, fracture toughness related to ductility, and time-dependent energy dissipation and/or elastic-plastic stress distribution. Moreover, a strong relationship between strain signals and peri-implant tissue turnover could be expected, so that ideal implant biomechanics may enable longevity via adaptive bone remodeling.

OBJECTIVE: Titanium is a primary metallic biomaterial used in load-bearing orthopedic or dental implants because of its favorable mechanical properties and osseointegration capability. This article reviews the current status of surface optimization techniques for titanium implants, whether such concepts are in the form of sufficiently evidence-based, and highlights the related experimental tools.
METHODS: A strong emphasis was placed on the enhanced biological responses to titanium implants by modifying the surface finishing process. On this basis, a clear partition of surface chemistry and topography was critical.
RESULTS: The intrinsic host tissue response to titanium implants is facilitated by the chemistry or topography of a passive oxide film, although the extent to which the surface characteristics enable rapid osseointegration is still uncertain.
CONCLUSIONS: Besides the fundamental requirements, such as the promotion of osteogenic differentiation, the titanium implant surface should accelerate wound-healing phenomena prior to bone ingrowth toward the surface. Moreover, because initial bacterial attachment to the implant surface is unavoidable, infection control by surface modification is also an important determinant in reducing surgical failure. A desirable surface-biological relationship often needs to be characterized at the nanoscale by means of advanced technologies.