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3D printed porous titanium (Ti) holds enormous potential for load-bearing orthopedic applications. Although the 3D printing technique has good control over the macro-sturctures of porous Ti, the surface properties that affect tissue response are beyond its control, adding the need for tailored surface treatment to improve its osseointegration capacity. Here, the one step microarc oxidation (MAO) process was applied to a 3D printed porous Ti6Al4V (Ti64) scaffold to endow the scaffold with a homogeneous layer of microporous TiO2 and significant amounts of amorphous calcium-phosphate. Following the treatment, the porous Ti64 scaffolds exhibited a drastically improved apatite forming ability, cyto-compatibility, and alkaline phosphatase activity. In vivo test in a rabbit model showed that the bone in-growth at the untreated scaffold was in a pattern of distance osteogenesis by which bone formed only at the periphery of the scaffold. In contrast, the bone in-growth at the MAO-treated scaffold exhibited a pattern of contact osteogenesis by which bone formed in situ on the entire surface of the scaffold. This pattern of bone in-growth significantly increased bone formation both in and around the scaffold possibly through enhancement of bone formation and disruption of bone remodeling. Moreover, the implant surface of the MAO-treated scaffold interlocked with the bone tissues through the fabricated microporous topographies to generate a stronger bone/implant interface. The increased osteoinetegration strength was further proven by a push out test. MAO exhibits a high efficiency in the enhancement of osteointegration of porous Ti64 via optimizing the patterns of bone in-growth and bone/implant interlocking. Therefore, post-treatment of 3D printed porous Ti64 with MAO technology might open up several possibilities for the development of bioactive customized implants in orthopedic applications.

Bringing multifunctional graphene out of solution through facile self-assembly to form 2D surface nanostructures, with control over the lateral size and surface properties, would be an intriguing accomplishment, especially in biomedical fields where biointerfaces with functional diversity are in high demand. Guided by this goal, in this work, we built such graphene-based self-assemblies on orthopedic titanium, attempting to selectively regulate bacterial activities and osteoblastic functions, which are both crucial in bone regeneration. Briefly, large-area graphene oxide (GO) sheets and functionalized reduced GO (rGO) micro-/nanosheets were self-assembled spontaneously and controllably onto solid Ti, through an evaporation-assisted electrostatic assembly process and a mussel-inspired one-pot assembly process, respectively. The resultant layers were characterized in terms of topological structure, chemical composition, hydrophilicity, and protein adsorption properties. The antibacterial efficacies of the assemblies were examined by challenging them with pathogenic Staphylococcus aureus (S. aureus) bacteria that produce biofilms, whereby around 50% antiadhesion effects and considerable antibiofilm activities were observed for both layer types but through dissimilar modes of action. Their cytocompatibility and osteogenic potential were also investigated. Interfaced with MC3T3-E1 cells, the functionalized rGO sheets evoked better cell adhesion and growth than GO sheets, whereas the latter elicited higher osteodifferentiation activity throughout a 28-day in vitro culture. In this work, we showed that it is technically possible to construct graphene interface layers of varying lateral dimensions and surface properties and confirmed the concept of using the obtained assemblies to address the two major challenges facing orthopedic clinics. In addition, we determined fundamental implications for understanding the surface-biology relationship of graphene biomaterials, in efforts to better design and more safely use them for future biomedicine.

Restoring large-scale bone defects, where osteogenesis is slow while infections lurk, with biomaterials represents a formidable challenge in orthopedic clinics. Here, we propose a scaffold-based multipurpose anti-infection and bone repairing strategy to meet such restorative needs. To do this, personalized multifunctional titanium meshes were produced through an advanced additive manufacturing process and dual "TiO-poly(dopamine)/Ag (nano)" post modifications, yielding macroporous constructs with micro-/nanoporous walls and nanosilver bullets immobilized/embedded therein. Ultrahigh loading capacity and durable release of Ag were accomplished. The scaffolds were active against planktonic/adherent bacteria (Gram-negative and positive) for up to 12 weeks. Additionally, they not only defended themselves from biofilm colonization but also helped destroy existing biofilms, especially in combination with antibiotics. Further, the osteoblasts/bacteria coculture study displayed that the engineered surfaces aided MG-63 cells to combat bacterial invasion. Meanwhile, the scaffolds elicited generally acceptable biocompatibility (cell adhesion, proliferation, and viability) and hastened osteoblast differentiation and maturation (alkaline phosphatase production, matrix secretion, and calcification), by synergy of micro-/nanoscale topological cues and bioactive catecholamine chemistry. Although done ex vivo, these studies reveal that our three-in-one strategy (infection prophylaxis, infection fighting, and bone repair) has great potential to simultaneously prevent/combat infections and bridge defected bone. This work provides new thoughts to the use of enabling technologies to design biomaterials that resolve unmet clinical needs.

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With the progressively increasing demand for orthopedic Ti implants, the balance between two primary complications restricting implant applications is needed to be solved: the lack of bone tissue integration and biomedical device-associated infections (BAI), where emergence of multiresistance bacteria make it worse. Notably, a combination of silver nanoparticles (AgNPs) and a kind of antibiotic can synergistically inhibit bacterial growth, where a low concentration of AgNPs has been confirmed to promote the proliferation and osteogenesis of osteoblasts. In this work, we built AgNPs/gentamicin (Gen)-embedded silk fibroin (SF)-based biomimetic coatings on orthopedic titanium by a facile dipping-drying circular process and with the assistance of polydopamine (PD). Ag was reduced to AgNPs by SF under ultraviolet (UV) irradiation, and then they were detected by transmission electron microscope (TEM) images and UV-visible (UV-vis) analyses. Intriguingly, the addition of Gen highly improved the reduction efficiency of Ag. The antibacterial efficiency of SF-based coatings was examined by challenging them with pathogenic Staphylococcus aureus (S. aureus) bacteria which produced biofilms, and consequently, we found that low concentration loading, durable release of Ag (28 days), and 10-fold improvement of antibacterial efficiency were achieved for our novel AgNPs- and Gen-embeded silk fibroin coatings. In bacteria and a cells cocultured system, AgNPs/Gen-embedded coatings strongly inhibited adhesion and proliferation of S. aureus, simultaneously improving cell adhesion and growth. To investigate cytocompatibility and osteogenic potential, different coatings were cultured with MC3T3 cells; AgNPs/Gen-embedded coatings showed generally acceptable biocompatibility (cell adhesion, proliferation, and viability) and accelerated osteoblast maturation (alkaline phosphatase production, matrix secretion, and calcification). Expectantly, this novel biofunctional coating will have promising applications in orthopedic and dental titanium implants thanks to its excellently antibacterial, biocompatible, and osteogenic activities.

Electron beam melting (EBM)-fabricated porous titanium implants possessing low elastic moduli and tailored structures are promising biomaterials for orthopedic applications. However, the bio-inert nature of porous titanium makes reinforcement with growth factors (GFs) a promising method to enhance implant in vivo performance. Bone-morphogenic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) are key factors of angiogenesis and osteogenesis. Therefore, the present study is aimed at evaluating EBM-fabricated porous titanium implants incorporating GF-doped fibrin glue (FG) as composite scaffolds providing GFs for improvement of angiogenesis and osteogenesis in rabbit femoral condyle defects. BMP-2 and VEGF were added into the constituent compounds of FG, and then this GF-doped FG was subsequently injected into the porous scaffolds. In five groups of implants, angiogenesis and osteogenesis were evaluated at 4 weeks post-implantation using Microfil perfusion and histological analysis: eTi (empty scaffolds), cTi (containing undoped FG), BMP/cTi (containing 50 μg rhBMP-2), VEGF/cTi (containing 0.5 μg VEGF) and Dual/cTi (containing 50 μg rhBMP-2 and 0.5 μg VEGF). The results demonstrate that these composite implants are biocompatible and provide the desired gradual release of the bioactive growth factors. Incorporation of GF delivery, whether a single factor or dual factors, significantly enhanced both angiogenesis and osteogenesis inside the porous scaffolds. However, the synergistic effect of the dual factors combination was observable on angiogenesis but absent on osteogenesis. In conclusion, fibrin glue is a biocompatible material that could be employed as a delivery vehicle in EBM-fabricated porous titanium for controlled release of BMP-2 and VEGF. Application of this method for loading a porous titanium scaffold to incorporate growth factors is a convenient and promising strategy for improving osteogenesis of critical-sized bone defects.