Ti Implants Research Articles

Research progress on antibacterial activity of medical titanium alloy implant materials.

Titanium and its alloys are the preferred materials for medical implants. However, easy infection is a fatal shortcoming of Ti implants. Fortunately, the ongoing development of antibacterial implant materials is a promising solution, and Ti alloys with antibacterial properties hold immense potential for medical applications. In this review, we briefly outline the mechanisms of bacterial colonization and biofilm formation on implants; discuss and classify the major antimicrobials currently in use and development, including inorganic and organic antimicrobials; and describe the important role of antimicrobials in the development of implant materials for clinical applications. Strategies and challenges related to improving the antimicrobial properties of implant materials as well as the prospects of antibacterial Ti alloys in the medical field are also discussed.

Nanoscale Morphologies on the Surface of 3D-Printed Titanium Implants for Improved Osseointegration: A Systematic Review of the Literature.

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.

Histologic Osseointegration Level Comparing Titanium and Zirconia Dental Implants: Meta-analysis of Preclinical Studies.

Purpose: To assess the literature comparing histologic levels of osseointegration for titanium vs zirconia dental implants. Materials and Methods: This systematic review was conducted following the PRISMA guidelines and was registered in PROSPERO (CRD42021236781). Electronic and manual searches were carried out through the PubMed/MEDLINE, PubMed Central, and Embase databases with a platform-specific search strategy combining controlled terms (MeSH and Emtree) and text words. The articles were selected by two independent investigators who evaluated the articles based on the criteria for eligibility. Results: A total of 17 articles were included. All were preclinical studies. The populations included dogs (27.55%), minipigs (14.28%), rats (14.28%), and rabbits (43.89%); and the implantation site varied among the mandible (36.82%), maxilla (9.04%), tibia (17.64%), skull (10.70%), and femur (25.80%). A total of 370 titanium (Ti) implants and 537 zirconia (Zr) implants were evaluated. The average osseointegration (% bone-to-implant contact) for Zr was 55.51% (17.6% to 89.09%), and for Ti was 58.50% (23.2% to 87.85%). There was no statistical difference between studies at the 2-month follow-up (P = .672), but this difference was significant at 1 and 3 months (P < .001). Conclusions: Within the limitations of this review, Zr implants had a similar level of osseointegration compared to Ti implants. Nonetheless, because these findings are based on preclinical research, all data must be carefully examined.

Visible-light-induced antibacterial activity of carbon and nitrogen co-doped rutile TiO2 films

The visible-light-responsive photocatalytic activity of TiO2 coatings offers a promising route for the antibacterial functionalization of Ti implants. In this study, carbon and nitrogen co-doped single-phase rutile TiO2 films were fabricated on Ti substrates via a two-step thermal oxidation process involving subsequent treatments with N2–1% CO and N2–1% O2. Under optimized treatment conditions, the single-phase rutile TiO2 films exhibited antibacterial activity against Escherichia coli under visible-light irradiation (λ > 400 nm) at 15 mW∙cm–2 for 15 min. The TiO2 films exhibited a double-layered structure comprising an inner layer (containing carbon and nitrogen) on the Ti substrate side and an outer layer (without carbon or nitrogen) on the topmost surface. The excitation of electrons and holes generated by dissolved carbon and nitrogen in the inner layer of the TiO2 films contributed to visible-light responsiveness. The bonding strength between the TiO2 film and Ti substrate exceeded 60 MPa. The cytotoxicity against the mouse osteoblast-like cell (MC3T3-E1) of the TiO2 film was comparable to that of well plates, under visible light and in the dark. This study demonstrates the visible-light-responsive antibacterial activity of a single-phase rutile TiO2 film on Ti. Further, the TiO2 film exhibited excellent bonding strength with the Ti substrate, indicating its high potential as an antibacterial active coating in combination with visible-light irradiation for Ti implants.

Titanium implants with antiaging effect to repair senile osteoporosis fracture

Accelerated population ageing has brought a great burden to the development of society. Repairing senile osteoporosis fractures is a great challenge, but a desirable way to address this issue is by developing multifunctional titanium(Ti) implants with antiaging and pro-osteogenic effects. Herein, to endow TI substrate with an antiaging effect for enhanced bone formation, an exercise-induced myokine(irisin) was loaded on titanium dioxide nanotubes(TNTs) and then a multilayered structure composed of chitosan(Chi) and gelatin(Gel) was constructed on the substrates via a layer-by-layer-assembly technique(TNT-IR-LBL). The surface topography of TNT-IR-LBL was characterized by scanning electron microscopy (SEM), atomic force microscopy(AFM), X-ray photoelectron spectroscopy(XPS) and water contact angle measurements, respectively. As an exercise-induced myokine, the irisin secreted from skeletal muscle exhibits strong activity for against the chronic diseases. The implants synthesized here displayed good biocompatibility towards osteoblasts. Moreover, irisin was sustainably released from TNT-IR-LBL for more than 3 weeks. In vitro studies indicated the TNT-IR-LBL substrates promoted osteoblast differentiation. In addition, compared to bare titanium, TNT-IR-LBL significantly promoted new bone formation around the implant interface in senile osteoporosis rats 4 weeks after implantation. Overall, this study provides a promising candidate to develop Ti-based orthopaedic implants to repair senile osteoporosis fractures.

Guiding Fibroblast Activation Using an RGD-Mutated Heparin Binding II Fragment of Fibronectin for Gingival Titanium Integration.

The formation of a biological seal around the neck of titanium (Ti) implants is critical for ensuring integration at the gingival site and for preventing bacterial colonization that may lead to periimplantitis. This process is guided by activated fibroblasts, named myofibroblasts, which secrete extracellular matrix (ECM) proteins and ECM-degrading enzymes resolving the wound. However, in some cases, Ti is not able to attract and activate fibroblasts to a sufficient extent, which may compromise the success of the implant. Fibronectin (FN) is an ECM component found in wounds that is able to guide soft tissue healing through the adhesion of cells and attraction of growth factors (GFs). However, clinical use of FN functionalized Ti implants is problematic because FN is difficult to obtain, and is sensitive to degradation. Herein, functionalizing Ti with a modified recombinant heparin binding II (HBII) domain of FN, mutated to include an Arg-Gly-Asp (RGD) sequence for promoting both fibroblast adhesion and GF attraction, is aimed at. The HBII-RGD domain is able to stimulate fibroblast adhesion, spreading, proliferation, migration, and activation to a greater extent than the native HBII, reaching values closer to those of full-length FN suggesting that it might induce the formation of a biological sealing.

Elimination of methicillin-resistant Staphylococcus aureus biofilms on titanium implants via photothermally-triggered nitric oxide and immunotherapy for enhanced osseointegration

BackgroundTreatment of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium (Ti) implants. There is a need to explore more effective approaches for the treatment of MRSA biofilm infections.MethodsHerein, an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles (PDA), nitric oxide (NO) release donor sodium nitroprusside (SNP) and osteogenic growth peptide (OGP) onto Ti implants, denoted as Ti-PDA@SNP-OGP. The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy, X-ray photoelectron spectroscope, water contact angle, photothermal property and NO release behavior. The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2′,7′-dichlorofluorescein diacetate probe, 1-N-phenylnaphthylamine assay, adenosine triphosphate intensity, o-nitrophenyl-β-d-galactopyranoside hydrolysis activity, bicinchoninic acid leakage. Fluorescence staining, assays for alkaline phosphatase activity, collagen secretion and extracellular matrix mineralization, quantitative real‑time reverse transcription‑polymerase chain reaction, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells (MSCs), RAW264.7 cells and their co-culture system. Giemsa staining, ELISA, micro-CT, hematoxylin and eosin, Masson’s trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms, inhibition of inflammatory response, and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo.ResultsTi-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light irradiation, and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species (ROS)-mediated oxidative stress, destroying bacterial membrane integrity and causing leakage of intracellular components (P < 0.01). In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs, but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype (P < 0.05 or P < 0.01). The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways (P < 0.01). In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model (P < 0.01).ConclusionsThese findings suggest that Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.

Construction of a Localized and Long-Acting CCN2 Delivery System on Percutaneous Ti Implant Surfaces for Enhanced Soft-Tissue Integration

Soft-tissue integration (STI) plays an essential role in the long-term success of percutaneous Ti implants since it acts as a biological barrier that protects the soft and hard tissue around implants. Surface modification of Ti implants with drug-release properties to achieve soft-tissue regeneration has been proven to be effective in STI. However, the short-acting effect caused by the uncontrolled drug release of the topical delivery system limits long-term STI enhancement. Herein, a long-acting protein delivery system for Ti implants that involved micro-arc oxidation of Ti surfaces (MAO-Ti) and localized immobilization of cellular communication network factor 2 (CCN2) bearing mesoporous silica nanoparticles (MSNs) on MAO-Ti was prepared, namely, CCN2@MSNs-Ti. The CCN2 release study of CCN2@MSNs-Ti demonstrated a sustained-release profile for 21 days, which was able to maintain long-term stable STI. In addition, in vitro cell behavior evaluation results indicated that CCN2@MSNs-Ti could promote the STI-related biological response of human dermal fibroblasts via the FAK-MAPK pathway. More importantly, the system could effectively enhance STI after 4 weeks and proinflammatory factors in the soft tissue decreased significantly in a rat model of implantation. These results denote that CCN2@MSNs-Ti showed an appealing application prospect for enhanced STI around transcutaneous Ti implants, which would ultimately result in an increased success rate of percutaneous Ti implants.

Bacteriostatic coatings formed on titanium dental implants for veterinary applications

Titanium (Ti) dental implants were anodized in calcium hypophosphite solution to obtain a porous, bioactive layer. The anodized implant surface was covered by a poly(sebacic anhydride) (PSBA) layer with amoxicillin. SEM analysis showed an irregular distribution of the antibiotic on the surface. However, confocal microscopy images revealed the formation of a uniform polymer layer. The thickness of the oxide and polymer layers was similar, between 6 and 9 μm. PSBA is an easy, hydrolysable polymer. After the polymer with amoxicillin was immersed in phosphate buffered solution (PBS) for 1 h, >53 % of hydrolysis products were detected by 1H NMR spectroscopy. After 9 days of polymer immersion, the hydrolysis product content was >67 %. Drug release was analyzed using high-performance liquid chromatography (HPLC). After 1 h of implant immersion in PBS an average of 6.0 μg/mL of amoxicillin was released. Importantly, the released concentration of amoxicillin was enough to inhibit S. aureus and S. epidermidis growth, minimal inhibitory concentration (inhibition zones between 27 mm and 30 mm) and decrease bacteria adhesion to the implant surface were achieved. This paper presents the cytocompatibility results of PSBA, amoxicillin, and extracts collected from the implants exposed to mouse fibroblast L929 and osteoblast-like MG-63 cells. PSBA concentrations up to 1 % did not significantly affect cell viability. Amoxicillin concentrations up to 150 μL/mL were cytocompatible with both cell lines. Cell viability was >70 % for both cell lines after 24 h of treatment with extracts from modified implants that were immersed in PBS for 72 h prior to viability experiments. This work presents a simple method to obtain a hybrid, bacteriostatic and biocompatible layer on long-term implant surfaces. These techniques may find application in the surface treatment of various Ti implants with a variety of shapes and sizes for veterinary applications.

Piezoelectric Nanostructured Surface for Ultrasound‐Driven Immunoregulation to Rescue Titanium Implant Infection

AbstractTreating bacterial biofilm infections on implanted materials remains challenging in clinical practice, as bacteria can be resistant by weakening the host defense from immune cells like macrophages. Herein, a metal‐piezoelectric hetero‐nanostructure with mechanical energy‐driven antimicrobial property is in situ constructed on the Ti implant. Under ultrasonic irradiation, the formed piezotronic Ti (piezoTi) can promote the generation of reactive oxygen species (ROS) by facilitating local charge transfer at the surface, thus leading to piezodynamic killing of Staphylococcus aureus (S. aureus) while downregulating biofilm‐forming genes. In addition, the stimulated macrophages on piezoTi display potent phagocytosis and anti‐bacterial activity through the activation of PI3K‐AKT and MAPK pathway. As a demonstration, one‐time ultrasound irradiation of piezoTi pillar implanted in an osteomyelitis model efficiently eliminates the S. aureus biofilm infection and rescues the implant with enhanced osteointegration. By the synergistic effect of ultrasound‐driven piezodynamic therapy and immuno‐regulation, the proposed piezoelectric nanostructured surface can endow Ti implants with highly efficient antibacterial performance in an antibiotic‐free, noninvasive, and on‐demand manner.

Fracture strength of screw-retained zirconia crowns assembled on zirconia and titanium implants.

This in vitro study evaluated the fracture strength of screw-retained zirconia crowns connected to zirconia (Zr) and titanium (Ti) implants after undergoing a simulation of 5 years of clinical use. Forty-eight screw-retained zirconia crowns were fabricated and assembled on four implant systems, with 12 in each group: (1) Zr implant (pure ceramic; Straumann AG) (PZr); (2) Zr implant (NobelPearl; Nobel Biocare) (NPZr); (3) Ti-Zr implant (Bone Level Roxolid; Straumann AG) (RSTiZr); (4) Ti implant (Conical Connection PMC; Nobel Biocare) (NRTi). Crowns were luted to their associated abutments using resin cement and then torqued to their assigned implants at the recommended torque value. Specimens were subjected to dynamic loading for 1,200,000 loading cycles. Fracture strength, measured in Newtons (N), was tested under static compression load using a universal testing machine at an angle of 30°. One-way ANOVA and Tukey's multiple comparisons post hoc test were used to compare the mean fracture values between the groups at a significance level of 0.05. The average fracture strengths for the RSTiZr and NRTi groups were 1207±202 and 1073±217N, respectively, which was significantly (p<0.0001) higher than the PZr and NPZr groups (712±76 and 571.6±167N, respectively). However, no significant difference was found between the fracture strength value of RSTiZr and NRTi (p=0.260) or PZr and NPZr (p=0.256) groups. Zirconia crowns connected to Zr implants have the potential to withstand the average physiological occlusal forces which occur in the anterior and premolar regions.

Combined photothermal and sonodynamic therapy using a 2D black phosphorus nanosheets loaded coating for efficient bacterial inhibition and bone-implant integration

Surgical site infection (SSI) remains a major threat for implant failure in orthopedics. Herein, we report a dual-functional coating on Ti implants (named Ti/PDA/BP) with the integration of two-dimensional (2D) photo-sono sensitive black phosphorus nanosheets (BPNSs) and polydopamine (PDA) for efficient bacterial inhibition and bone-implant integration. For the first time, we employ BPNSs as generators of reactive radicals (ROS) under ultrasound (US) stimuli for implant associated infection. Additionally, the application of PDA improves the stability of BPNSs, the biocompatibility and photothermal performance of this hybrid coating. The as-prepared Ti/PDA/BP coating exhibits superior biocompatibility, bioactivity, photothermal and sonodynamic conversion abilities. Owing to the synergistic effect of hyperthermia and ·OH, Ti/PDA/BP damages the membrane and antioxidant system of Staphylococcus aureus, reaching a high antibacterial activity of 96.6% in vitro and 97.3% in vivo with rapid 10 min NIR irradiation and 20 min US treatment. In addition, we firstly unveil the significant effect of Ti/PDA/BP-based sonodynamic therapy (SDT) on bacterial membrane and oxidative stress at the transcriptome level. Moreover, the Ti/PDA/BP coating remarkably promotes osteogenesis in vitro and bone-implant osseointegration in vivo. Overall, development of Ti/PDA/BP bioactive coating provides a new strategy for combating the implant associated infection.

CELLULAR RESPONSE OF HEALTHY AND OSTEOPOROTIC BONE CELLS TOWARDS TITANIUM SCAFFOLDS CREATED BY NOVEL LASER TEXTURING COMPARED WITH CLINICAL STANDARD SLA IMPLANTS

The goal was to analyze the cellular response, specifically the osteogenic capacity, of titanium (Ti) implants harbouring a novel laserbased-surface-structure with the overall aim: augmented osteointegration. Surface micro-/nanoproperties greatly influence cell behaviour at the tissue-implant-interface and subsequent osteointegration. We investigated Ti-materials subjected to a specially developed shifted-Laser-Surface-Texturing (sLST) technology and compared them to a standard roughening-technique (sand-blasting-acid-etching, SLA). The biological response was evaluated with hMSCs, which are naturally available at the bone-implant-interface. We hypothesized: the novel surface is beneficial for our three different (young/healthy-YH; aged/healthy-AH;aged/osteoporotic-OP) cohorts.The sLST was performed using a SPI-G3-series laser (beam-wavelength=1064nm, pulse-duration=200ns). For the SLA surface, Ti was sandblasted, afterwards acid-etched (HCl/H2SO4). Three different hMSC cohorts were studied: YH: n=6,29±6; AH: n=5,79±5; OP: n=5,76±5 years (osteoporosis confirmed via DEXA-scan). OP hMSCs show e.g. ColI-deficient-matrix and decreased mineralization. Cells were examined for survival, cell proliferation and cytoskeleton arrangement. Osteogenic differentiation was carried out over 21 days, matrix mineralization was validated with Alizarin-Red-S-staining and quantification.Laser-texturing generated precisely the desired microgeometry. On nanostructural level, differently-sized Ti-droplets were formed stochastically by laser-induced-Ti-plasma. Live/dead-/Actin-stainings showed comparable results for all cohorts and surfaces in terms of survival and cell shape. On Ti-materials, cell growth showed no significant difference between the 3 cohorts. Alizarin quantification revealed the highest levels on laser-textured-surfaces; highest value for YH, followed by AH, lastly OP; no significance between AH/YH, but between OP/YH (p&lt;0.0001). However, mineralization of all cohorts cultured on laser-textured-surfaces increased significantly (p&lt;0.0001) compared to respective SLA-group, with &gt;20fold higher value in the OP-cohort (AH:11fold, YH:6fold).The data proves the biocompatibility of the laser-structured-Ti for young+aged cohorts. Osteogenic differentiation was significantly augmented on laser-treated-Ti. Most intriguingly, OP-donors could reach manifold increased mineralization, suggesting the novel laser texturing can counteract the osteoporotic phenotype. As osteogenesis-enhancing capacities may be related to mechanisms controlling cellular shape/fate, further investigations referring to this are currently ongoing. In conclusion, our laser-textured-Ti-materials are safe, can have a demand-oriented designer-surface-topography and represent a great potential for development into next-generation-implants suitable for different patient-cohorts, especially osteoporosis patients.

Effect of zinc or copper doping on corrosion resistance and anti-oxidative stress of strontium-based micro-arc oxidation coatings on titanium

In osteoporosis, the osteogenic microenvironment maintains a high level of oxidative stress (OS) due to the overaccumulation of reactive oxygen species (ROS). It not only significantly destroys the bioactivity of titanium (Ti) implants, but also enhances Ti implant corrosion, which has a significant impact on the early osteointegration of Ti implants. In this study, using microarc oxidation (MAO) technology, we constructed strontium/zinc (Sr/Zn)- and strontium/copper (Sr/Cu)-doped MAO coatings on the surface of the Ti implant and studied their corrosion resistance and osteoinductive properties under normal and OS conditions. Apart from their chemical compositions, their physical and chemical properties (roughness, hydrophilicity, morphology, and crystal structure) were similar. In the anti-corrosion test, the MAO-Sr/Zn groups (especially MAO-Sr/Zn3) exhibited perfect performance in both normal and OS microenvironments, whereas MAO-Sr/Cu showed poor corrosion resistance. In terms of biological behavior, based on the perfect osteogenesis and anti-OS properties of Sr and Zn, MAO-Sr/Zn3 exhibited the best performance in terms of cell viability, mineralization, and anti-OS ability, followed by MAO-Sr/Cu2, due to a suitable proportion of Sr/Cu. Therefore the excellent comprehensive performance of MAO-Sr/Zn3 showed that it has broad potential for implant repair in patients with osteoporosis.

Micro-nano porous structured tantalum-coated dental implants promote osteogenic activity in vitro and enhance osseointegration in vivo.

Due to its excellent biocompatibility and corrosion resistance, tantalum demonstrates versatility as an implant material. However, limited studies investigated the role of tantalum coated titanium-based dental implants. This study aimed to investigate the potential application of micro-nano porous structured tantalum coating on the surface of titanium dental implant. In the present study, micro-nano porous structured tantalum coating was prepared by vacuum plasma spraying (VPS) under selected optimum parameters, various characteristics of tantalum coating (Ta/Ti), including the morphology, potential, constituent, and hydrophilia, were investigated in comparison with its respective control groups, sandblasted titanium (Ti) and titanium coating (Ti/Ti). The adhesion, proliferation, and osteogenic differentiation ability of rat bone marrow mesenchymal cells (BMSCs) on different materials were assessed in vitro. Then the osseointegration capacity of Ti, Ti/Ti, Ta/Ti, and Straumann implants in canine mandible was evaluated with micro-CT, histological sections, and energy dispersive X-ray spectroscopy. These results demonstrated that micro-nanostructured, uneven, and granular tantalum coating was successfully prepared on titanium substrate by VPS with pore size ranging from 50 nm to 5μm and thickness ranging from 80 to 100 μm. Tantalum coating revealed the highest surface potential, best hydrophilia, and most protein adsorption among Ta/Ti, Ti/Ti, and Ti. Furthermore, Ta/Ti surfaces significantly promoted the adhesion, proliferation, and osteogenic differentiation of BMSCs. In vivo, Ta/Ti implants displayed positive osseointegration capability associated with increased bone mineral density and formation of new bone around implants without tantalum particles released. Together, these findings indicate that tantalum-coated titanium dental implants may serve as a new type of dental implant.

Surface modification of titanium implant for repairing/improving microenvironment of bone injury and promoting osseointegration

• A coating consist of MnO 2 nanoenzyme and Sr ions was fabricated on Ti implant. • MnO 2 nanoenzyme alleviated OA and O 2 deficiency at the injury site. • Sr ions released from the surface of implant promoted the growth of MSCs. • The modified Ti implant significantly accelerate bone regeneration in vivo . Bone injury and implantation operation are often accompanied by microenvironment damage of bone tissue, which seriously affects the process of osseointegration of implants, especially for titanium (Ti)-based bioinert materials. Thus, repairing or improving the microenvironment of damaged bone tissue is of great significance for bone rescue, reconstruction, and regeneration still a major medical challenge. Oxidative stress (OS) and oxygen (O 2 ) deficiency are considered to be specific physiological signals of the bone-injury microenvironment. From the above background, a coating consisting of manganese dioxide (MnO 2 ) nanoenzyme and strontium (Sr) ions was fabricated on the surface of the Ti implant via a one-step hydrothermal treatment. MnO 2 nanoenzyme presented in the coating alleviated OS and O 2 deficiency at the injury site by catalyzing the decomposition of abundant endogenous H 2 O 2 around the modified Ti implants into O 2 . In addition, Sr ions were released from the surface of the implant at a certain rate in a body-fluid environment, further promoting the adhesion, growth, and osteogenic differentiation of mesenchymal stem cells. More importantly, a Sprague Dawley rat femur model demonstrated that the modified Ti implant showed significant potential to accelerate bone tissue reconstruction in vivo . In summary, the present system provides a new idea for the treatment of bone injury and the development of new orthopedic implants.

3D printed porous titanium filled with mineralized UV-responsive chitosan hydrogel promotes cell proliferation and osteogenesis in vitro

The modification of 3D printed porous titanium (Ti), especially for the internal pore structure, is critical and has received more attention to promoting its osteogenesis for clinical use. Ultra-violet (UV) responsive chitosan (CSMA), as an injectable filling material, was firstly incorporated into porous Ti, and then CSMA was in-situ mineralized by carbon oxide (CO2) diffusion (CSMA/CaCO3). Their physical-chemical and biological properties were investigated in vitro. CaCO3 crystals within CSMA hydrogels were successfully deposited into pores of porous Ti, which exhibited favorable biocompatibility. Ti implants filled with CSMA/CaCO3 promoted adhesion and proliferation of bone mesenchymal stem cells (BMSCs). Moreover, Ti implant filled CSMA/CaCO3 hydrogels could increase alkaline phosphatase (ALP) activities, up-regulate osteopontin (OPN) and osteocalcin (OCN) expression levels, and enhance extracellular mineralization. 3D printed porous Ti filled with mineralized UV-responsive chitosan hydrogel could promote proliferation and osteogenesis of BMSCs, and have great potential for the modification of porous Ti implants in bone tissue engineering.

A HAase/NIR responsive surface on titanium implants for treating bacterial infection and improving osseointegration

• A mild antibacterial system for S. aureus and MRSA was constructed based on the synergistic effect of photothermal and antibiotic. • Antibiotic in MPDA can be sealed with HAc, which can avoid the damage to normal tissue caused by the burst release CIP and inhibit the early adhesion of bacteria. • Bacteria can secrete bacterial hyaluronidase to accelerate the degradation of HAc, realizing the smart enzyme-triggered release of antimicrobials at the site of infection on demand. • NIR light irradiation can not only accelerate the CIP release but also activate the photothermotherapy of MPDA nanoparticles. Bacterial infection and insufficient osseointegration are critical factors affecting the long-term success of titanium-based implants. Unfortunately, the direct application of antibiotic on Ti implants easily leads to poor cytocompatibility, as well as the production of drug-resistant bacteria. So, in this work, we designed a prospective antibacterial strategy by combining photothermal and ciprofloxacin (CIP). The synergistic effect of photothermal and antibiotic may provide an effective bacteriostatic efficacy without sacrificing osteogenesis at a mild condition of moderate temperature and less antibiotic. Herein, CIP was loaded into mesoporous polydopamine (MPDA) nanoparticles (MPDA@CIP), which were anchored on the surface of titanium and finally covered with sodium hyaluronate-catechol (HAc) coating. The hydrophilic HAc layer could inhibit the early adhesion of bacteria, and some bacteria could secrete bacterial hyaluronidase to accelerate the degradation of HAc. This enabled smart enzyme-triggered release of antimicrobials at the site of infection on-demand and avoided unwanted side effects on normal tissues. In addition, NIR light irradiation had a positive influence on both CIP release and MPDA nanoparticle's photothermal effect. Moreover, before anchoring MPDA@CIP, by the construction of hydroxyapatite microstructure on Ti surface with micro-arc oxidation and alkali heat treatment, the ability of bone formation of Ti could be promoted also. Both in vitro as well as in vivo assays demonstrated that functional Ti has an excellent antibacterial effect and osteogenic ability.

Novel Strategy for Surface Modification of Titanium Implants towards the Improvement of Osseointegration Property and Antibiotic Local Delivery

The topography and chemical composition modification of titanium (Ti) implants play a decisive role in improving biocompatibility and bioactivity, accelerating osseointegration, and, thus, determining clinical success. In spite of the development of surface modification strategies, bacterial contamination is a common cause of failure. The use of systemic antibiotic therapy does not guarantee action at the contaminated site. In this work, we proposed a surface treatment for Ti implants that aim to improve their osseointegration and reduce bacterial colonization in surgery sites due to the local release of antibiotic. The Ti discs were hydrothermally treated with 3M NaOH solution to form a nanostructured layer of titanate on the Ti surface. Metronidazole was impregnated on these nanostructured surfaces to enable its local release. The samples were coated with poly(vinyl alcohol)-PVA films with different thickness to evaluate a possible control of drug release. Gamma irradiation was used to crosslink the polymer chains to achieve hydrogel layer formation and to sterilize the samples. The samples were characterized by XRD, SEM, FTIR, contact angle measurements, "in vitro" bioactivity, and drug release analysis. The alkaline hydrothermal treatment successfully produced intertwined, web-like nanostructures on the Ti surface, providing wettability and bioactivity to the Ti samples (Ti + TTNT samples). Metronidazole was successfully loaded and released from the Ti + TTNT samples coated or not with PVA. Although the polymeric film acted as a physical barrier to drug delivery, all groups reached the minimum inhibitory concentration for anaerobic bacteria. Thus, the surface modification method presented is a potential approach to improve the osseointegration of Ti implants and to associate local drug delivery with dental implants, preventing early infections and bone failure.

Functional Titanium Substrates Synergetic Photothermal Therapy for Enhanced Antibacterial and Osteogenic Performance via Immunity Regulation.

Implant-associated infections (IAIs) significantly impair the integration between titanium (Ti) implants and bone tissues. Bacteria colonized on the surface of the implant can induce innate immune suppression of the host to resist clearance. Herein, an interfacial functionalization strategy is employed to introduce FeIII TA nanoparticles (NPs) and acetyl Bletilla striata polysaccharide (acBSP) on the Ti substrate to obtain the Ti-TF-acBSP system. Under near-infrared (NIR) irradiation, the hyperthermal effect induced by FeIII TA NPs directly killed bacteria. Meanwhile, macrophages are induced by acBSP to polarize into pro-inflammatory M1 phenotype, which enhanced the phagocytosis ability of macrophages and activated host innate immunity. Moreover, the asBSP instructed macrophages to secrete pro-osteogenic cytokine, which promoted osteogenic differentiation of MSCs. The results of the animal experiment in vivo confirmed that the Ti-TF-acBSP implant effectively eliminated bacterial infection under NIR irradiation, enhanced the expression of pro-inflammatory cytokine, and induced the production of bone-forming related factors. In a word, the functionalized Ti implant not only have a direct bactericidal effect but also regulate macrophage polarization as well as macrophage-mediated bactericidal and osteogenic effect. The strategy of combining photothermal therapy with immunoregulation will present a potential candidate for the development of novel antibacterial orthopedic devices.