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    Fabrication of chitosan/heparinized graphene oxide multilayer coating to improve corrosion resistance and biocompatibility of magnesium alloys. Gao Fan,Hu Youdong,Gong Zhihao,Liu Tao,Gong Tao,Liu Sen,Zhang Chao,Quan Li,Kaveendran B,Pan Changjiang Materials science & engineering. C, Materials for biological applications Due to its good biodegradability and mechanical properties, magnesium alloys are considered as the ideal candidate for the cardiovascular stents. However, the rapid degradation in human physiological environment and the poor biocompatibility seriously limit its application for biomaterials. In the present study, a chitosan/heparinized graphene oxide (Chi/HGO) multilayer coating was constructed on the AZ31B magnesium alloy surface using layer-by-layer (LBL) method to improve the corrosion resistance and biocompatibility. The results of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), Raman spectrum (RAMAN), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) showed that a dense and compact Chi/HGO multilayer coating was fabricated on the magnesium alloy surface. The results of potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), pH value changes and magnesium ion release suggested that the multilayer coating can significantly enhance the corrosion resistance of the magnesium alloy. Moreover, the Chi/HGO multilayer coating could not only significantly reduce the hemolysis rate and platelet adhesion, but also promote the adhesion and proliferation of endothelial cells. Therefore, the Chi/HGO multilayer coating can simultaneously improve the corrosion resistance and biocompatibility of the magnesium alloys. 10.1016/j.msec.2019.109947
    Innovative coating based on graphene and their decorated nanoparticles for medical stent applications. ElSawy Amr M,Attia Nour F,Mohamed Hadeer I,Mohsen M,Talaat M H Materials science & engineering. C, Materials for biological applications Novel coating for stainless steel stent was developed. Graphene sheets were exfoliated directly in chitosan solution as biopolymer and then decorated with TiO nanoparticles of an average size of 21 nm. Coating solutions of chitosan, graphene sheets and graphene sheets decorated TiONPs were coated on stainless steel stent in uniform form. The average thickness of the coated layer was found to be 6 and 10.6 μm for graphene and TiONPs decorated graphene coatings, respectively. The mechanical properties and hematological properties of the developed coated and uncoated stents were studied. The graphene sheets based coated stent showed good mechanical properties compared to chitosan and decorated coated stents. Furthermore, the mechanical properties of the coating layer based graphene on stent surface were investigated reflecting very good mechanical properties compared to graphene nanoparticles decorated coating layer. Also, the coated stent based on graphene sheets reflects very good behaviour regarding no platelets adhesion in healthy and diabetic human blood compared to uncoated, chitosan and TiONPs decorated graphene coated stents. The graphene sheets and their decorated composites with TiONPs were characterized using transmission electron microscopy. Also, the uncoated and coated stents morphologies were evaluated using scanning electron microscopy. This study presents new approach for developing and engineering medical stent using green and cost-effective graphene sheets for enhancing its performance. 10.1016/j.msec.2018.11.084
    Preparation of an antibacterial, hydrophilic and photocatalytically active polyacrylic coating using TiO nanoparticles sensitized by graphene oxide. Nosrati Rahimeh,Olad Ali,Shakoori Sahar Materials science & engineering. C, Materials for biological applications In recent years more attentions have been paid for preparation of coatings with self-cleaning and antibacterial properties. These properties allow the surface to maintain clean and health over long times without any need to cleaning or disinfection. Acrylic coatings are widely used on various surfaces such as automotive, structural and furniture which their self-cleaning and antibacterial ability is very important. The aim of this work is the preparation of a polyacrylic based self-cleaning and antibacterial coating by the modification of TiO as a coating additive. TiO nanoparticles were sensitized to the visible light irradiation using graphene oxide through the preparation of TiO/graphene oxide nanocomposite. Graphene oxide was prepared via a modified Hummers method. TiO/graphene oxide nanocomposite was used as additive in a polyacrylic coating formulation. Hydrophilicity, photocatalytic and antibacterial activities as well as coating stability were evaluated for TiO/graphene oxide modified polyacrylic coating and compared with that of pristine TiO modified and unmodified polyacrylic coatings. TiO/graphene oxide nanocomposite and polyacrylic coating modified by TiO/graphene oxide additive were characterized using FT-IR, UV-Vis, XRD, and FESEM techniques. The effect of TiO/graphene oxide composition and its percent in the coating formulation was evaluated on the polyacrylic coating properties. Results showed that polyacrylic coating having 3% W TiO/graphene oxide nanocomposite additive with TiO to graphene oxide ratio of 100:20 is the best coating considering most of beneficial features such as high photodecolorization efficiency of organic dye contaminants, high hydrophilicity, and stability in water. According to the results, TiO is effectively sensitized by graphene oxide and the polyacrylic coating modified by TiO/graphene oxide nanocomposite shows good photocatalytic activity under visible light irradiation. 10.1016/j.msec.2017.07.004
    Magnetically Controlled Growth-Factor-Immobilized Multilayer Cell Sheets for Complex Tissue Regeneration. Zhang Wenjie,Yang Guangzheng,Wang Xiansong,Jiang Liting,Jiang Fei,Li Guanglong,Zhang Zhiyuan,Jiang Xinquan Advanced materials (Deerfield Beach, Fla.) The scaffold-free cell-sheet technique plays a significant role in stem-cell-based regeneration. Furthermore, growth factors are known to direct stem cell differentiation and enhance tissue regeneration. However, the absence of an effective means to incorporate growth factors into the cell sheets hinders further optimization of the regeneration efficiency. Here, a novel design of magnetically controlled "growth-factor-immobilized cell sheets" is reported. A new Fe O magnetic nanoparticle (MNP) coated with nanoscale graphene oxide (nGO@Fe O ) is developed to label stem cells and deliver growth factors. First, the nGO@Fe O MNPs can be easily swallowed by dental-pulp stem cells (DPSCs) and have no influence on cell viability. Thus, the MNP-labeled cells can be organized via magnetic force to form multilayered cell sheets in different patterns. Second, compared to traditional Fe O nanoparticles, the graphene oxide coating provides plenty of carboxyl groups to bind and deliver growth factors. Therefore, with these nGO@Fe O MNPs, bone-morphogenetic-protein-2 (BMP2) is successfully incorporated into the DPSCs sheets to induce more bone formation. Furthermore, an integrated osteochondral complex is also constructed using a combination of DPSCs/TGFβ3 and DPSCs/BMP2. All these results demonstrate that the new cell-sheet tissue-engineering approach exhibits promising potential for future use in regenerative medicine. 10.1002/adma.201703795
    In situ synthesis and biocompatibility of nano hydroxyapatite on pristine and chitosan functionalized graphene oxide. Li Ming,Wang Yanbo,Liu Qian,Li Qiuhong,Cheng Yan,Zheng Yufeng,Xi Tingfei,Wei Shicheng Journal of materials chemistry. B Motivated by the success of using graphene oxide (GO) as a nanofiller of composites, there is a drive to search for this new kind of carbon material as a reinforcing phase in biocomposites. In the present work, graphene oxide and chitosan (CS) functionalized graphene oxide were introduced as templates to fabricate hydroxyapatite (HA) using a facile solution-based in situ synthesis method, and GO-HA and CS-GO-HA nanocomposites were successfully prepared for the first time. It was found that the spindle like HA nanoparticles with a diameter of about 27 ± 7 nm and a length around 150 ± 25 nm were decorated randomly and strongly on the surface or aggregated at the edges of the pristine and chitosan functionalized GO matrix. Compared with HA, the prepared GO-based HA nanocomposites displayed an increased elastic modulus and hardness. The in vitro cytotoxicity of the prepared nanocomposites was investigated using CCK-8 assay on murine fibroblast L-929 cell line and human osteoblast-like MG-63 cell line, respectively. Both of the nanocomposites exhibited a high cell proliferation rate for L-929 and MG-63, and the CS-GO-HA could provide significantly higher cell viability and alkaline phosphatase activity compared to the GO-HA composite. These findings may provide new prospects for utilizing the GO-based hydroxyapatite biocomposites in bone repair, bone augmentation, as well as coating of biomedical implants and broaden the application of GO sheets in biological areas. 10.1039/c2tb00053a
    Development of a Highly Proliferated Bilayer Coating on 316L Stainless Steel Implants. Khosravi Fatemeh,Nouri Khorasani Saied,Khalili Shahla,Esmaeely Neisiany Rasoul,Rezvani Ghomi Erfan,Ejeian Fatemeh,Das Oisik,Nasr-Esfahani Mohammad Hossein Polymers In this research, a bilayer coating has been applied on the surface of 316 L stainless steel (316LSS) to provide highly proliferated metallic implants for bone regeneration. The first layer was prepared using electrophoretic deposition of graphene oxide (GO), while the top layer was coated utilizing electrospinning of poly (ε-caprolactone) (PCL)/gelatin (Ge)/forsterite solutions. The morphology, porosity, wettability, biodegradability, bioactivity, cell attachment and cell viability of the prepared coatings were evaluated. The Field Emission Scanning Electron Microscopy (FESEM) results revealed the formation of uniform, continuous, and bead-free nanofibers. The Energy Dispersive X-ray (EDS) results confirmed well-distributed forsterite nanoparticles in the structure of the top coating. The porosity of the electrospun nanofibers was found to be above 70%. The water contact angle measurements indicated an improvement in the wettability of the coating by increasing the amount of nanoparticles. Furthermore, the electrospun nanofibers containing 1 and 3 wt.% of forsterite nanoparticles showed significant bioactivity after soaking in the simulated body fluid (SBF) solution for 21 days. In addition, to investigate the in vitro analysis, the MG-63 cells were cultured on the PCL/Ge/forsterite and GO-PCL/Ge/forsterite coatings. The results confirmed an excellent cell adhesion along with considerable cell growth and proliferation. It should be also noted that the existence of the forsterite nanoparticles and the GO layer substantially enhanced the cell proliferation of the coatings. 10.3390/polym12051022
    Delivery of Interleukin 4 from a Titanium Substrate Coated with Graphene Oxide for Enhanced Osseointegration by Regulating Macrophage Polarization. Li Qingfan,Liang Beilei,Wang Fei,Wang Zuolin ACS biomaterials science & engineering Macrophage-related inflammation has been identified as a possible predictor of the success or failure of implants based on their polarization of the pro-inflammatory/anti-inflammatory (M1/M2) phenotype. The purpose of this study was to deliver interleukin 4 (IL-4, a cytokine that triggers M2 polarization of macrophages) from a titanium substrate by a graphene oxide (GO) coating to regulate the macrophage-related inflammatory response and improve the implant performance. The GO/IL-4 coating showed good biocompatibility and promoted macrophages polarization to the M2 phenotype . Conditioned media from macrophages cultured on a GO/IL-4 surface promoted the proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). As the inflammatory response at the interface of GO/IL-4 weakened, the percentage of M2-polarized macrophages increased and the best stability, bone-implant contact, and osteogenesis were observed . These results demonstrate that the macrophage-related inflammatory response plays a crucial role in osteogenesis around implants and that this GO/IL-4 coating provides an effective strategy for promoting implant osseointegration by regulating immune function. 10.1021/acsbiomaterials.0c01011
    Taking Hydroxyapatite-Coated Titanium Implants Two Steps Forward: Surface Modification Using Graphene Mesolayers and a Hydroxyapatite-Reinforced Polymeric Scaffold. Fathi A M,Ahmed M K,Afifi M,Menazea A A,Uskoković Vuk ACS biomaterials science & engineering Coating with hydroxyapatite (HAP) presents a mainstream strategy for rendering bioinert titanium implants bioactive. However, the low porosity of pure HAP coatings does not allow for the infiltration of the surface of the metallic implant with the host cells. Polymeric scaffolds do enable this osseointegration effect, but their bonding onto titanium presents a challenge because of the disparity in hydrophilicity. Here, we demonstrate the inability of a composite scaffold composed of carbonated HAP (CHAP) nanoparticles interspersed within electrospun ε-polycaprolactone (PCL) nanofibers to bind onto titanium. To solve this challenge, an intermediate layer of graphene nanosheets was deposited in a pulsed laser deposition process, which facilitated the bonding of the scaffold. The duration of the deposition of graphene (0, 5, 10, 15, and 20 min) and the thickness of its mesolayer affected numerous physical and chemical properties of the material, including the surface atomic proportion of carbon bonds, the orientation and interlinking of the polymeric nanofibers, and the surface roughness, which increased in direct proportion with the thickness of the graphene mesolayer. Because the polymeric scaffold did not adhere onto the surface of pure titanium, no cells were detected growing on it . In contrast, human fibroblasts adhered, spread, and proliferated well on all the substrates sputtered with both graphene and the composite scaffold. The orientations of cytoskeletal filopodia and lamellipodia were largely determined by the topographic orientation of the nanofibers and the geometry of the surface pores, attesting to the important effects that the presence of a scaffold has on the cellular behavior. The protection of titanium from corrosion in the simulated body fluid (SBF) was enhanced by coating with graphene and the composite scaffold, with the most superior resistance to the attack of the corrosive ions being exhibited by the substrate subjected to the shortest duration of the graphene deposition because of the highest atomic ratio of C-C to C-O bonds detected in it. Overall, some properties of titanium, such as roughness and wettability, were improved monotonously with an increase in the thickness of the graphene mesolayer, while others, such as cell viability and resistance to corrosion, required optimization, given that they were diminished at higher graphene mesolayer thicknesses. Nevertheless, every physical and chemical property of titanium analyzed was significantly improved by coating with graphene and the composite scaffold. This type of multilayer design evidently holds a great promise in the design of biomaterials for implants in orthopedics and tissue engineering. 10.1021/acsbiomaterials.0c01105
    Tea Polyphenol-Reduced Graphene Oxide Deposition on Titanium Surface Enhances Osteoblast Bioactivity. Liu Mengting,Hao Liying,Huang Qian,Zhao Dan,Li Qianshun,Cai Xiaoxiao Journal of nanoscience and nanotechnology Graphene, a novel carbon-based material, has been widely used as osteogenic agent for the potential effect on the promotion of osteoblast proliferation. Tea polyphenol-reduced graphene oxide (TPG) is a simple and environmental-friendly raw material to obtain graphene. In this study, TPG was deposited on the Ti substrate to promote the bone regeneration. We prepared a honeycomb-like structure by acid and alkali pretreatment and immobilized the TPG layer (Ti-TPG) on the surface via electrochemical deposition. Scanning electron microscopy (SEM), atomic force microscopy (AFM) and X-ray diffraction (XRD) were used to identify the immobilization of TPG on the titanium (Ti) successfully. Furthermore, the biological response of the Ti-TPG surface to rat osteoblast was evaluated. We also studied the cell adhesion, proliferation and expression of ossification genes on the sample. The results revealed that Ti-TPG had an advantage over Ti alloys in modulating cellular activity and Ti-TPG may be a promising coating for biological materials. 10.1166/jnn.2018.14649
    Nanoscale Hybrid Coating Enables Multifunctional Tissue Scaffold for Potential Multimodal Therapeutic Applications. Guo Zhijun,Jiang Nan,Moore Jessica,McCoy Colin P,Ziminska Monika,Rafferty Cormac,Sarri Gianluca,Hamilton Andrew R,Li Yubao,Zhang Li,Zhu Songsong,Sun Dan ACS applied materials & interfaces Through a nature-inspired layer-by-layer assembly process, we developed a unique multifunctional tissue scaffold that consists of porous polyurethane substrate and nanoscale chitosan/graphene oxide hybrid coating. Alternative layers of drug-laden chitosan and graphene oxide nanosheets were held together through strong electrostatic interaction, giving rise to a robust multilayer architecture with control over structural element orientation and chemical composition at nanoscale. Combined pH-controlled co-delivery of multiple therapeutic agents and photothermal therapy has been achieved by our scaffold system. The new platform technology can be generalized to produce other tissue scaffold systems and may enable potential multimodal therapeutic applications such as bone cancer managements. 10.1021/acsami.9b04278
    Graphene-Modified Titanium Surface Enhances Local Growth Factor Adsorption and Promotes Osteogenic Differentiation of Bone Marrow Stromal Cells. Lu Jiayu,Sun Jiayue,Zou Derong,Song Jinlin,Yang Sheng Frontiers in bioengineering and biotechnology Graphene coating exhibits excellent abilities of protein adsorption and cell adhesion, which might expand the osteogenic activity of titanium implant surface to adapt to the environment of low bone mass and poor bone quality. In this paper, we designed and explored the graphene-coated titanium sheet, through the surface modification of oxygen-containing functional groups, to optimize the adsorption capacity of material by improving the electrostatic interactions, and successfully adsorbed and sustained-released a variety of osteogenic related growth factors in the autologous concentrated growth factors. Compared with the pure titanium, we observed that the bone marrow stromal cells (BMSCs) on the graphene-coated titanium with concentrated growth factors showed a flat shape and expressed osteogenic related genes and proteins, while the coating surfaces promoted and accelerated the osteogenic differentiation ability of BMSCs. The results suggested that it might be a feasible alternative to improve the osteogenesis of dental implant in the early stage. 10.3389/fbioe.2020.621788
    Evaluation of the osteogenesis and osseointegration of titanium alloys coated with graphene: an in vivo study. Li Kewen,Wang Chunhui,Yan Jinhong,Zhang Qi,Dang Baoping,Wang Zhuo,Yao Yun,Lin Kaifeng,Guo Zhongshang,Bi Long,Han Yisheng Scientific reports The aim of this study was to investigate whether a surface coating with graphene could enhance the surface bioactivation of titanium alloys (TiAlV) to further accelerate in vivo osteogenesis and osseointegration at the implant surface. In this study, a New Zealand white rabbit femoral condyle defect model was established. After 4, 12 and 24 weeks, biomechanical testing, micro-computed tomography (Micro-CT) analyses and histological observations were performed. At the highest push-out forces during the test, microstructure parameters, such as the bone volume/total volume fraction (BV/TV) and mineral apposition rate (MAR), of the new bone were significantly higher in the graphene-coated TiAlV group (G-TiAlV) than in the TiAlV group (P < 0.05). Van Gieson (VG) staining showed that the G-TiAlV group had more new bone formation than the TiAlV group, and the G-TiAlV group showed a closer fit between the bone and implant. In conclusion, graphene might be a novel type of nano-coating material for enhancing the surface biological activity of Ti-based alloy materials and may further promote in vivo osteogenesis and osseointegration. 10.1038/s41598-018-19742-y
    Reduced graphene oxide coating enhances osteogenic differentiation of human mesenchymal stem cells on Ti surfaces. Kang Moon Sung,Jeong Seung Jo,Lee Seok Hyun,Kim Bongju,Hong Suck Won,Lee Jong Ho,Han Dong-Wook Biomaterials research BACKGROUND:Titanium (Ti) has been utilized as hard tissue replacement owing to its superior mechanical and bioinert property, however, lack in tissue compatibility and biofunctionality has limited its clinical use. Reduced graphene oxide (rGO) is one of the graphene derivatives that possess extraordinary biofunctionality and are known to induce osseointegration in vitro and in vivo. In this study, rGO was uniformly coated by meniscus-dragging deposition (MDD) technique to fabricate rGO-Ti substrate for orthopedic and dental implant application. METHODS:The physicochemical characteristics of rGO-coated Ti (rGO-Ti) substrates were evaluated by atomic force microscopy, water contact angle, and Raman spectroscopy. Furthermore, human mesenchymal stem cells (hMSCs) were cultured on the rGO-Ti substrate, and then their cellular behaviors such as growth and osteogenic differentiation were determined by a cell counting kit-8 assay, alkaline phosphatase (ALP) activity assay, and alizarin red S staining. RESULTS:rGO was coated uniformly on Ti substrates by MDD process, which allowed a decrease in the surface roughness and contact angle of Ti substrates. While rGO-Ti substrates significantly increased cell proliferation after 7 days of incubation, they significantly promoted ALP activity and matrix mineralization, which are early and late differentiation markers, respectively. CONCLUSION:It is suggested that rGO-Ti substrates can be effectively utilized as dental and orthopedic bone substitutes since these graphene derivatives have potent effects on stimulating the osteogenic differentiation of hMSCs and showed superior bioactivity and osteogenic potential. 10.1186/s40824-021-00205-x
    Delivery of a therapeutic protein for bone regeneration from a substrate coated with graphene oxide. La Wan-Geun,Park Saibom,Yoon Hee-Hun,Jeong Gun-Jae,Lee Tae-Jin,Bhang Suk Ho,Han Jeong Yeon,Char Kookheon,Kim Byung-Soo Small (Weinheim an der Bergstrasse, Germany) The therapeutic efficacy of drugs often depends on the drug delivery carrier. For efficient delivery of therapeutic proteins, delivery carriers should enable the loading of large doses, sustained release, and retention of the bioactivity of the therapeutic proteins. Here, it is demonstrated that graphene oxide (GO) is an efficient carrier for delivery of therapeutic proteins. Titanium (Ti) substrates are coated with GO through layer-by-layer assembly of positively (GO-NH₃⁺) and negatively (GO-COO⁻) charged GO sheets. Subsequently, a therapeutic protein (bone morphogenetic protein-2, BMP-2) is loaded on the GO-coated Ti substrate with the outermost coating layer of GO-COO⁻ (Ti/GO⁻). The GO coating on Ti substrate enables loading of large doses and the sustained release of BMP-2 with preservation of the structure and bioactivity of the drug. The extent of in vitro osteogenic differentiation of human bone marrow-derived mesenchymal stem cells is higher when they are cultured on Ti/GO- carrying BMP-2 than when they are cultured on Ti with BMP-2. Eight weeks after implantation in mouse models of calvarial defects, the Ti/GO-/BMP-2 implants show more robust new bone formation compared with Ti, Ti/GO-, or Ti/BMP-2 implants. Therefore, GO is an effective carrier for the controlled delivery of therapeutic proteins, such as BMP-2, which promotes osteointegration of orthopedic or dental Ti implants. 10.1002/smll.201300571
    Delivery of bone morphogenetic protein-2 and substance P using graphene oxide for bone regeneration. La Wan-Geun,Jin Min,Park Saibom,Yoon Hee-Hun,Jeong Gun-Jae,Bhang Suk Ho,Park Hoyoung,Char Kookheon,Kim Byung-Soo International journal of nanomedicine In this study, we demonstrate that graphene oxide (GO) can be used for the delivery of bone morphogenetic protein-2 (BMP-2) and substance P (SP), and that this delivery promotes bone formation on titanium (Ti) implants that are coated with GO. GO coating on Ti substrate enabled a sustained release of BMP-2. BMP-2 delivery using GO-coated Ti exhibited a higher alkaline phosphatase activity in bone-forming cells in vitro compared with bare Ti. SP, which is known to recruit mesenchymal stem cells (MSCs), was co-delivered using Ti or GO-coated Ti to further promote bone formation. SP induced the migration of MSCs in vitro. The dual delivery of BMP-2 and SP using GO-coated Ti showed the greatest new bone formation on Ti implanted in the mouse calvaria compared with other groups. This approach may be useful to improve osteointegration of Ti in dental or orthopedic implants. 10.2147/IJN.S50742
    Graphene-Oxide-Decorated Microporous Polyetheretherketone with Superior Antibacterial Capability and In Vitro Osteogenesis for Orthopedic Implant. Ouyang Ling,Deng Yi,Yang Lei,Shi Xiuyuan,Dong Taosheng,Tai Youyi,Yang Weizhong,Chen Zhi-Gang Macromolecular bioscience Due to its similar elastic modulus of human bones, polyetheretherketone (PEEK) has been considered as an excellent cytocompatible material. However, the bioinertness, poor osteoconduction, and weak antibacterial activity of PEEK limit its wide applications in clinics. In this study, a facile strategy is developed to prepare graphene oxide (GO) modified sulfonated polyetheretherketone (SPEEK) (GO-SPEEK) through a simple dip-coating method. After detailed characterization, it is found that the GO closely deposits on the surface of PEEK, which is attributed to the π-π stacking interaction between PEEK and GO. Antibacterial tests reveal that the GO-SPEEK exhibits excellent suppression toward Escherichia coli. In vitro cell attachment, growth, differentiation, alkaline phosphatase activity, quantitative real-time polymerase chain reaction analyses, and calcium mineral deposition all illustrate that the GO-SPEEK substrate can significantly accelerate the proliferation and osteogenic differentiation of osteoblast-like MG-63 cells compared with those on PEEK and SPEEK groups. These results suggest that the GO-SPEEK has an improved antibacterial activity and cytocompatibility in vitro, showing that the developed GO-SPEEK has a great potential as the bioactive implant material in bone tissue engineering. 10.1002/mabi.201800036
    Electrophoretic deposition of chitosan reinforced graphene oxide-hydroxyapatite on the anodized titanium to improve biological and electrochemical characteristics. Karimi N,Kharaziha M,Raeissi K Materials science & engineering. C, Materials for biological applications Chitosan reinforced hydroxyapatite-graphene oxide (CS-GO-HA) nanocomposite coatings were developed using electrophoretic deposition process in order to improve the biological and electrochemical properties of Ti surface. Moreover, the role of anodized layer on the physical and electrochemical properties of the CS-GO-HA nanocomposite coating was evaluated. After synthesize of HA-GO nanopowder using a sol-gel process, nanocomposite coatings with various concentrations of chitosan (0.5, 1 and 1.5 mg/ml) were produced. Increasing the chitosan content lowered the deposition rate of HA-GO nanoparticles, reduced the coating thickness and diminished apatite-formation ability and biocompatibility. Noticeably, MG63 cell viability significantly reduced form 119.3 ± 5.1 (% control) to 51.9 ± 14.8 (% control), when the chitosan concentration increased from 0.5 to 1.5 mg/ml. In addition, the CS-GO-HA coating containing 0.5 mg/ml chitosan revealed the best barrier property owing to the less crack formation. Furthermore, anodizing of titanium substrate and formation of TiO nanotube (TiNT) resulted in the formation of crack-free and homogeneous CS-GO-HA coatings without any observable defect. Moreover, the TiNT formation noticeably improved barrier resistance of the coating (6.7 times) due to better adhesion governed between coating and substrate. Our results confirmed that the surface modification using both anodizing of Ti substrate and electrophoretic deposition of ternary CS-GO-HA nanocomposite coating with 0.5 mg/ml chitosan successfully improves electrochemical properties, bioactivity and cell function, which makes it promising for bone implant applications. 10.1016/j.msec.2018.12.136
    The promising application of graphene oxide as coating materials in orthopedic implants: preparation, characterization and cell behavior. Zhao Changhong,Lu Xiuzhen,Zanden Carl,Liu Johan Biomedical materials (Bristol, England) To investigate the potential application of graphene oxide (GO) in bone repair, this study is focused on the preparation, characterization and cell behavior of graphene oxide coatings on quartz substrata. GO coatings were prepared on the substrata using a modified dip-coating procedure. Atomic force microscopy (AFM), scanning electron microscopy (SEM) and Raman spectroscopy results demonstrated that the as-prepared coatings in this study were homogeneous and had an average thickness of ~67 nm. The rapid formation of a hydroxyapatite (HA) layer in the simulated body fluid (SBF) on GO coated substrata at day 14, as proved by SEM and x-ray diffraction (XRD), strongly indicated the bioactivity of coated substrata. In addition, MC3T3-E1 cells were cultured on the coated substrata to evaluate cellular activities. Compared with the non-coated substrata and tissue culture plates, no significant difference was observed on the coated substrata in terms of cytotoxicity, viability, proliferation and apoptosis. However, interestingly, higher levels of alkaline phosphatase (ALP) activity and osteocalcin (OC) secretion were observed on the coated substrata, indicating that GO coatings enhanced cell differentiation compared with non-coated substrata and tissue culture plates. This study suggests that GO coatings had excellent biocompatibility and more importantly promoted MC3T3-E1 cell differentiation and might be a good candidate as a coating material for orthopedic implants. 10.1088/1748-6041/10/1/015019
    Graphene modified titanium alloy promote the adhesion, proliferation and osteogenic differentiation of bone marrow stromal cells. Li Kewen,Yan Jinhong,Wang Chunhui,Bi Long,Zhang Qi,Han Yisheng Biochemical and biophysical research communications We studied the effects of graphene coating on improving the biological activity of a titanium alloy (TiAlV) widely used in hip and knee joint replacements. The experiments included immunofluorescence staining for observing cellular adhesion, Cell Counting Kit-8 (CCK-8) for evaluating cellular proliferation and reverse transcription-polymerase chain reaction (RT-PCR) for detecting the differentiation of bone marrow stromal cells on different scaffolds. The results showed that G-TiAlV exhibited a higher mean integrated optical density (IOD) for vinculin and resulted in a higher cell proliferation rate and higher osteoblast-specific gene transcription levels. In summary, graphene could be used as a new nanocoating material for TiAlV scaffolds to enhance their surface bioactivity. 10.1016/j.bbrc.2017.05.124
    Involvement of FAK/P38 Signaling Pathways in Mediating the Enhanced Osteogenesis Induced by Nano-Graphene Oxide Modification on Titanium Implant Surface. Li Qingfan,Wang Zuolin International journal of nanomedicine Background:Titanium implants are widely used in dental and orthopedic medicine. Nevertheless, there is limited osteoinductive capability of titanium leading to a poor or delayed osseointegration, which might cause the failure of the implant therapy. Therefore, appropriate modification on the titanium surface for promoting osseointegration of existing implants is still pursued. Purpose:Graphene oxide (GO) is a promising candidate to perform implant surface biofunctionalization for modulating the interactions between implant surface and cells. So the objective of this study was to fabricate a bioactive GO-modified titanium implant surface with excellent osteoinductive potential and further investigate the underlying biological mechanisms. Materials and Methods:The large particle sandblasting and acid etching (SLA, commonly used in clinical practice) surface as a control group was first developed and then the nano-GO was deposited on the SLA surface via an ultrasonic atomization spraying technique to create the SLA/GO group. Their effects on rat bone marrow mesenchymal stem cells (BMSCs) responsive behaviors were assessed in vitro, and the underlying biological mechanisms were further systematically investigated. Moreover, the osteogenesis performance in vivo was also evaluated. Results:The results showed that GO coating was fabricated on the titanium substrates successfully, which endowed SLA surface with the improved hydrophilicity and protein adsorption capacity. Compared with the SLA surface, the GO-modified surface favored cell adhesion and spreading, and significantly improved cell proliferation and osteogenic differentiation of BMSCs in vitro. Furthermore, the FAK/P38 signaling pathways were proven to be involved in the enhanced osteogenic differentiation of BMSCs, accompanied by the upregulated expression of focal adhesion (vinculin) on the GO coated surface. The enhanced bone regeneration ability of GO-modified implants when inserted into rat femurs was also observed and confirmed that the GO coating induced accelerated osseointegration and osteogenesis in vivo. Conclusion:GO modification on titanium implant surface has potential applications for achieving rapid bone-implant integration through the mediation of FAK/P38 signaling pathways. 10.2147/IJN.S245608
    Novel Reduced Graphene Oxide/Zinc Silicate/Calcium Silicate Electroconductive Biocomposite for Stimulating Osteoporotic Bone Regeneration. Xiong Kun,Wu Tingting,Fan Qingbo,Chen Lin,Yan Minhao ACS applied materials & interfaces In the absence of external assistance, autogenous healing of bone fracture is difficult due to impaired regeneration ability under osteoporosis pathological conditions. In this study, a reduced graphene oxide/zinc silicate/calcium silicate (RGO/ZS/CS) conductive biocomposite with an optimal surface electroconductivity of 5625 S/m was prepared by a two-step spin-coating method. The presence of lamellar apatite nanocrystals on the surfaces of the biocomposite suggests that it has good in vitro biomineralization ability. The silicon and zinc released from the biocomposite induced a significant increase in the osteogenesis of mouse bone mesenchymal stem cells (mBMSCs). Furthermore, alkaline phosphatase activities were further promoted when 3 μA direct current was applied to stimulate the mBMSCs that were cultured on the RGO/ZS/CS surface. However, electrical stimulation failed to further upregulate the osteogenesis-related gene expression. Moreover, RGO/ZS/CS extracts were found to suppress the receptor activator of nuclear factor-κB ligand-induced osteoclastic differentiation of mouse leukemic monocyte macrophages (RAW264.7 cells). Although the zinc ions in the RGO/ZS/CS extracts showed an inhibitory role in human umbilical vein endothelial cell (HUVEC) proliferation, dilutions of the RGO/ZS/CS extracts (1/16, 1/32, and 1/64) promoted HUVEC proliferation, and their angiogenesis-related gene expression was also upregulated. On the basis of the results of the in vitro angiogenesis model, more interconnected tubes formed when the above dilutions of RGO/ZS/CS extracts were added to ECMatrix. The new RGO/ZS/CS electroconductive biocomposite has potential to be used for stimulating osteoporotic bone regeneration. 10.1021/acsami.7b16206
    Graphene Oxide-Copper Nanocomposite-Coated Porous CaP Scaffold for Vascularized Bone Regeneration via Activation of Hif-1α. Zhang Wenjie,Chang Qing,Xu Ling,Li Guanglong,Yang Guangzheng,Ding Xun,Wang Xiansong,Cui Daxiang,Jiang Xinquan Advanced healthcare materials Graphene has been studied for its in vitro osteoinductive capacity. However, the in vivo bone repair effects of graphene-based scaffolds remain unknown. The aqueous soluble graphene oxide-copper nanocomposites (GO-Cu) are fabricated, which are used to coat porous calcium phosphate (CaP) scaffolds for vascularized bone regeneration. The GO-Cu nanocomposites, containing crystallized CuO/Cu2 O nanoparticles of ≈30 nm diameters, distribute uniformly on the surfaces of the porous scaffolds and maintain a long-term release of Cu ions. In vitro, the GO-Cu coating enhances the adhesion and osteogenic differentiation of rat bone marrow stem cells (BMSCs). It is also found that by activating the Erk1/2 signaling pathway, the GO-Cu nanocomposites upregulate the expression of Hif-1α in BMSCs, resulting in the secretion of VEGF and BMP-2 proteins. When transplanted into rat with critical-sized calvarial defects, the GO-Cu-coated calcium phosphate cement (CPC) scaffolds (CPC/GO-Cu) significantly promote angiogenesis and osteogenesis. Moreover, it is observed via histological sections that the GO-Cu nanocomposites are phagocytosed by multinucleated giant cells. The results suggest that GO-Cu nanocomposite coatings can be utilized as an attractive strategy for vascularized bone regeneration. 10.1002/adhm.201500824
    Coating of ß-tricalcium phosphate scaffolds-a comparison between graphene oxide and poly-lactic-co-glycolic acid. Ardjomandi N,Henrich A,Huth J,Klein C,Schweizer E,Scheideler L,Rupp F,Reinert S,Alexander D Biomedical materials (Bristol, England) Bone regeneration in critical size defects is a major challenge in oral and maxillofacial surgery, and the gold standard for bone reconstruction still requires the use of autologous tissue. To overcome the need for a second intervention and to minimize morbidity, the development of new biomaterials with osteoinductive features is the focus of current research. As a scaffolding material, ß-tricalcium phosphate (ß-TCP) is suitable for bone regeneration purposes, although it does not carry any functional groups for the covalent immobilization of molecules. The aim of the present study was to establish effective coating variants for ß-TCP constructs to enable the biofunctionalization of anorganic blocks with different osteogenic molecules in future studies. We established working protocols for thin surface coatings consisting of polylactic-co-glycolic acid (PLGA) and graphene oxide (GO) by varying parameters. Surface properties such as the angularity and topography of the developed scaffolds were analyzed. To examine biological functionality, the adhesion and proliferation behavior of jaw periosteal cells (JPCs) were tested on the coated constructs. Our results suggest that PLGA is the superior material for surface coating of ß-TCP matrices, leading to higher JPC proliferation rates and providing a more suitable basis for further biofunctionalization in the field of bone tissue engineering. 10.1088/1748-6041/10/4/045018
    Antibacterial graphene-based hydroxyapatite/chitosan coating with gentamicin for potential applications in bone tissue engineering. Stevanović Milena,Djošić Marija,Janković Ana,Kojić Vesna,Vukašinović-Sekulić Maja,Stojanović Jovica,Odović Jadranka,Crevar Sakač Milkica,Kyong Yop Rhee,Mišković-Stanković Vesna Journal of biomedical materials research. Part A Electrophoretic deposition process (EPD) was successfully used for obtaining graphene (Gr)-reinforced composite coating based on hydroxyapatite (HAP), chitosan (CS), and antibiotic gentamicin (Gent), from aqueous suspension. The deposition process was performed as a single step process at a constant voltage (5 V, deposition time 12 min) on pure titanium foils. The influence of graphene was examined through detailed physicochemical and biological characterization. Fourier transform infrared spectroscopy, field emission scanning electron microscopy, thermogravimetric analysis, X-ray diffraction, Raman, and X-ray photoelectron analyses confirmed the formation of composite HAP/CS/Gr and HAP/CS/Gr/Gent coatings on Ti. Obtained coatings had porous, uniform, fracture-free surfaces, suggesting strong interfacial interaction between HAP, CS, and Gr. Large specific area of graphene enabled strong bonding with chitosan, acting as nanofiller throughout the polymer matrix. Gentamicin addition strongly improved the antibacterial activity of HAP/CS/Gr/Gent coating that was confirmed by antibacterial activity kinetics in suspension and agar diffusion testing, while results indicated more pronounced antibacterial effect against Staphylococcus aureus (bactericidal, viable cells number reduction >3 logarithmic units) compared to Escherichia coli (bacteriostatic, <3 logarithmic units). MTT assay indicated low cytotoxicity (75% cell viability) against MRC-5 and L929 (70% cell viability) tested cell lines, indicating good biocompatibility of HAP/CS/Gr/Gent coating. Therefore, electrodeposited HAP/CS/Gr/Gent coating on Ti can be considered as a prospective material for bone tissue engineering as a hard tissue implant. 10.1002/jbm.a.36974
    Effects of aspirin-loaded graphene oxide coating of a titanium surface on proliferation and osteogenic differentiation of MC3T3-E1 cells. Ren Liping,Pan Shuang,Li Haiqing,Li Yanping,He Lina,Zhang Shuang,Che Jingyi,Niu Yumei Scientific reports Graphene oxide (GO) has attracted considerable attention for biomedical applications such as drug delivery because of its two-dimensional structure, which provides a large surface area on both sides of the nanosheet. Here, a new method for titanium (Ti) surface modification involving a GO coating and aspirin (A) loading (A/Ti-GO) was developed, and the bioactive effects on mouse osteoblastic MC3T3-E1 cells were preliminarily studied. The X-ray photoelectron spectrometry indicated new C-O-N, C-Si-O-C, and C-N=C bond formation upon GO coating. Remarkably, the torsion test results showed stable bonding between the GO coating and Ti under a torsional shear force found in clinical settings, in that, there was no tearing or falling off of GO coating from the sample surface. More importantly, through π-π stacking interactions, the release of aspirin loaded on the surface of Ti-GO could sustain for 3 days. Furthermore, the A/Ti-GO surface displayed a significantly higher proliferation rate and differentiation of MC3T3-E1 cells into osteoblasts, which was confirmed by a water-soluble tetrazolium salt-8 (WST-8) assay and alkaline phosphatase activity test. Consequently, Ti surface modification involving GO coating and aspirin loading might be a useful contribution to improve the success rate of Ti implants in patients, especially in bone conditions. 10.1038/s41598-018-33353-7
    Collagen Functionalized With Graphene Oxide Enhanced Biomimetic Mineralization and in Situ Bone Defect Repair. Zhou Chuchao,Liu Shaokai,Li Jialun,Guo Ke,Yuan Quan,Zhong Aimei,Yang Jie,Wang Jiecong,Sun Jiaming,Wang Zhenxing ACS applied materials & interfaces Biomimetic mineralization using simulated body fluid (SBF) can form a bonelike apatite (Ap) on the natural polymers and enhance osteoconductivity and biocompatibility, and reduce immunological rejection. Nevertheless, the coating efficiency of the bonelike apatite layer on natural polymers still needs to be improved. Graphene oxide (GO) is rich in functional groups, such as carbonyls (-COOH) and hydroxyls (-OH), which can provide more active sites for biomimetic mineralization and improve the proliferation of the rat bone marrow stromal cells (r-BMSCs). In this study, we introduced 0%, 0.05%, 0.1%, and 0.2% w/v concentrations of GO into collagen (Col) scaffolds and immersed the fabricated scaffolds into SBF for 1, 7, and 14 days. In vitro environment scanning electron microscopy (ESEM), energy-dispersive spectrometry (EDS), thermogravimetric analysis (TGA), micro-CT, calcium quantitative analysis, and cellular analysis were used to evaluate the formation of bonelike apatite on the scaffolds. In vivo implantation of the scaffolds into the rat cranial defect was used to analyze the bone regeneration ability. The resulting GO-Col-Ap scaffolds exhibited a porous and interconnected structure coated with a homogeneous distribution of bonelike apatite on their surfaces. The Ca/P ratio of 0.1% GO-Col-Ap group was equal to that of natural bone tissue on the basis of EDS analysis. More apatites were observed in the 0.1% GO-Col-Ap group through TGA analysis, micro-CT evaluation, and calcium quantitative analysis. Furthermore, the 0.1% GO-Col-Ap group showed significantly higher r-BMSCs adhesion and proliferation in vitro and more than 2-fold higher bone formation than the Col-Ap group in vivo. Our study provides a new approach of introducing graphene oxide into bone tissue engineering scaffolds to enhance biomimetic mineralization. 10.1021/acsami.8b17636
    Bilayered BMP2 Eluting Coatings on Graphene Foam by Electrophoretic Deposition: Electroresponsive BMP2 Release and Enhancement of Osteogenic Differentiation. Yao Qingqing,Jing Jiajia,Zeng Qingyan,Lu T L,Liu Yu,Zheng Xiao,Chen Qiang ACS applied materials & interfaces Recent development of three-dimensional graphene foam (GF) with conductive and interconnected macroporous structure is attracting particular attention as platforms for tissue engineering. However, widespread application of GF as bone scaffolds is restricted due to its poor mechanical property and inert surface character. To overcome these drawbacks, in this study, a bilayered biopolymer coating was designed and successfully deposited covering the entire surface area of GF skeleton. A poly(lactic-co-glycolic acid) layer was first dip-coated to strengthen the GF substrate, followed by the electrophoretic codeposition of a hybrid layer, consisting of chitosan and BMP2, to functionalize GF with the ability to recruit and induce osteogenic differentiation of hMSC. Our data indicated that the mechanical property of GF was significantly increased without compromising the macroporous structure. Importantly, the immobilized BMP2 exhibited sustained and electroresponsive release profiles with rapid response to the electric field exerted on GF, which is beneficial to balancing BMP2 dose in a physiological environment. Moreover, the osteogenic differentiation of hMSC was significantly improved on the functionalized GF. Taking advantage of the unique macrostructure from GF as well as the superior mechanical properties and BMP2 release profile supported by the deposited coatings, it is therefore expected that the developed GF could be a promising alternative as innovative bone-forming favorable scaffolds. 10.1021/acsami.7b10180
    The enhancement of osseointegration using a graphene oxide/chitosan/hydroxyapatite composite coating on titanium fabricated by electrophoretic deposition. Suo Lai,Jiang Nan,Wang Yan,Wang Puyu,Chen Junyu,Pei Xibo,Wang Jian,Wan Qianbing Journal of biomedical materials research. Part B, Applied biomaterials Titanium (Ti) has been commonly used as an implant material in dentistry and bone surgery for several decades. Meanwhile, surface modification of titanium can enhance the osseointegration of implants. In this study, a graphene oxide/chitosan/hydroxyapatite (GO/CS/HA) composite coating was fabricated by electrophoretic deposition on Ti substrates. Subsequently, the surface morphology, phase composition, wettability, and bonding strength of this composite coating were researched. Additionally, in vitro cytological examination was performed, including evaluations of cell adhesion, cell viability, cell differentiation, cell mineralization, and osteogenetic factor expression. Finally, the in vivo osteogenetic properties were evaluated through an animal study, including a histological analysis, a microcomputed tomography, and biomechanical tests. The results showed that a homogeneous and crack-free GO/CS/HA composite coating was coated on Ti, and the wettability and bonding strength of the GO/CS/HA composite coating were enhanced compared with HA, GO/HA, and CS/HA coatings. Furthermore, the GO/CS/HA coating greatly heightened the cell-material interactions in vitro. Additionally, this GO/CS/HA-Ti implant could enhance osseointegration in vivo. Consequently, GO/CS/HA-Ti may have potential applications in the field of dental implants. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 635-645, 2019. 10.1002/jbm.b.34156
    Enhanced Osseointegration of Titanium Alloy Implants with Laser Microgrooved Surfaces and Graphene Oxide Coating. Wang Chenchen,Hu Hongxing,Li Zhipeng,Shen Yifan,Xu Yong,Zhang Gangqiang,Zeng Xiangqiong,Deng Jun,Zhao Shichang,Ren Tianhui,Zhang Yadong ACS applied materials & interfaces Rapid and effective osseointegration, as a critical factor in affecting the success rate of titanium (Ti) implants in orthopedic applications, is significantly affected by their surface microstructure and chemical composition. In this work, surface microgrooved Ti-6Al-4V alloys with graphene oxide coating (Ti-G-GO) were fabricated by a combination of laser processing and chemical assembly techniques. The osteogenic capability in vitro and new bone formation in vivo of the implants were systematically investigated, and biomechanical pull-out tests of the screws were also performed. First, in vitro studies indicated that the optimal microgroove width of the titanium alloy surface was 45 μm (Ti-G), and the optimum GO concentration was 1 mg/mL. Furthermore, the effects of the surface microstructure and GO coating on the in vitro bioactivity were investigated through culturing bone marrow mesenchymal stem cells (BMSCs) on the surface of titanium alloy plates. The results showed that the BMSCs cultured on the Ti-G-GO group exhibited the best adhesion, proliferation, and differentiation, compared with that on the Ti-G and Ti groups. Micro-computed tomography evaluation, histological analysis, and pull-out testing demonstrated that both Ti-G and Ti-G-GO implants had the higher osseointegration than the untreated Ti implant. Moreover, the osteogenic capability of the Ti-G-GO group appeared to be superior to that of the Ti-G group, which could be attributed to the improvement of surface wettability and apatite formation by the GO coatings. These results suggest that the combination of the microgroove structure and GO coatings exhibits considerable potential for enhancing the surface bioactivation of materials, and the combination modification is expected to be used on engineered titanium alloy surfaces to enhance osseointegration for orthopedic applications. 10.1021/acsami.9b12733
    Novel hydroxyapatite/graphene oxide/collagen bioactive composite coating on Ti16Nb alloys by electrodeposition. Yılmaz Eren,Çakıroğlu Bekir,Gökçe Azim,Findik Fehim,Gulsoy H Ozkan,Gulsoy Nagihan,Mutlu Özal,Özacar Mahmut Materials science & engineering. C, Materials for biological applications A novel implant coating material containing graphene oxide (GO) and collagen (COL), and hydroxyapatite (HA) was fabricated with the aid of tannic acid by electrodeposition. The surface of Ti16Nb alloy was subjected to anodic oxidation, and then HA-GO coating was applied to Ti16Nb surface by cathodic method. Then, COL was deposited on the surface of the HA-GO coating by the biomimetic method. HA, HA-GO, HA-GO-COL coatings on the surface of the Ti16Nb alloy have increased the corrosion resistance by the formation of a barrier layer on the surface. For HA-GO-COL coating, the highest corrosion resistance is obtained due to the compactness and homogeneity of the coating structure. The contact angle of the bare Ti16Nb is approximately 65°, while the contact angle of the coated samples is close to 0°. Herein, the increased surface wettability is important for cell adhesion. The surface roughness of the uncoated Ti16Nb alloy was between 1 and 3 μm, while the surface roughness of the coated surfaces was measured between 20 and 110 μm. The contact between the bone and the implant has been improved. Graphene oxide-containing coatings have improved the antibacterial properties compared to the GO-free coating using S. aureus. The hardness and elastic modulus of the coatings were measured by the nanoindentation test, and the addition of GO and collagen to the HA coating resulted in an increase in strength. The addition of GO to the HA coating reduced the viability of 3 T3 fibroblast cells, whereas the addition of collagen to HA-GO coat increased the cell adhesion and viability. 10.1016/j.msec.2019.03.078
    Carbon nanotube, graphene and boron nitride nanotube reinforced bioactive ceramics for bone repair. Gao Chengde,Feng Pei,Peng Shuping,Shuai Cijun Acta biomaterialia The high brittleness and low strength of bioactive ceramics have severely restricted their application in bone repair despite the fact that they have been regarded as one of the most promising biomaterials. In the last few years, low-dimensional nanomaterials (LDNs), including carbon nanotubes, graphene and boron nitride nanotubes, have gained increasing attention owing to their favorable biocompatibility, large surface specific area and super mechanical properties. These qualities make LDNs potential nanofillers in reinforcing bioactive ceramics. In this review, the types, characteristics and applications of the commonly used LDNs in ceramic composites are summarized. In addition, the fabrication methods for LDNs/ceramic composites, such as hot pressing, spark plasma sintering and selective laser sintering, are systematically reviewed and compared. Emphases are placed on how to obtain the uniform dispersion of LDNs in a ceramic matrix and maintain the structural stability of LDNs during the high-temperature fabrication process of ceramics. The reinforcing mechanisms of LDNs in ceramic composites are then discussed in-depth. The in vitro and in vivo studies of LDNs/ceramic in bone repair are also summarized and discussed. Finally, new developments and potential applications of LDNs/ceramic composites are further discussed with reference to experimental and theoretical studies. STATEMENT OF SIGNIFICANCE:Despite bioactive ceramics having been regarded as promising biomaterials, their high brittleness and low strength severely restrict their application in bone scaffolds. In recent years, low-dimensional nanomaterials (LDNs), including carbon nanotubes, graphene and boron nitride nanotubes, have shown great potential in reinforcing bioactive ceramics owing to their unique structures and properties. However, so far it has been difficult to maintain the structural stability of LDNs during fabrication of LDNs/ceramic composites, due to the lengthy, high-temperature process involved. This review presents a comprehensive overview of the developments and applications of LDNs in bioactive ceramics. The newly-developed fabrication methods for LDNs/ceramic composites, the reinforcing mechanisms and the in vitro and in vivo performance of LDNs are also summarized and discussed in detail. 10.1016/j.actbio.2017.05.020
    Promoting tendon to bone integration using graphene oxide-doped electrospun poly(lactic-co-glycolic acid) nanofibrous membrane. Su Wei,Wang Zhiying,Jiang Jia,Liu Xiaoyun,Zhao Jinzhong,Zhang Zhijun International journal of nanomedicine Background:These normal entheses are not reestablished after repair despite significant advances in surgical techniques. There is a significant need to develop integrative biomaterials, facilitating functional tendon-to-bone integration. Materials and methods:We fabricated a highly interconnective graphene oxide-doped electrospun poly(lactide-co-glycolide acid) (GO-PLGA) nanofibrous membrane by electrospinning technique and evaluated them using in vitro cell assays. Then, we established rabbit models, the PLGA and GO-PLGA nanofibrous membranes were used to augment the rotator cuff repairs. The animals were killed postoperatively, which was followed by micro-computed tomography, histological and biomechanical evaluation. Results:GO was easily mixed into PLGA filament without changing the three dimensional microstructure. An in vitro evaluation demonstrated that the PLGA membranes incorporated with GO accelerated the proliferation of BMSCs and furthered the Osteogenic differentiation of BMSCs. In addition, an in vivo assessment further revealed that the local application of GO-PLGA membrane to the gap between the tendon and the bone in a rabbit model promoted the healing enthesis, increased new bone and cartilage generation, and improved collagen arrangement and biomechanical properties in comparison with repair with PLGA only. Conclusion:The electrospun GO-PLGA fibrous membrane provides an effective approach for the regeneration of tendon to bone enthesis. 10.2147/IJN.S183842
    Hierarchically Porous Hydroxyapatite Hybrid Scaffold Incorporated with Reduced Graphene Oxide for Rapid Bone Ingrowth and Repair. Zhou Kai,Yu Peng,Shi Xiaojun,Ling Tingxian,Zeng Weinan,Chen Anjing,Yang Wei,Zhou Zongke ACS nano Hydroxyapatite (HA), the traditional bone tissue replacement material was widely used in the clinical treatment of bone defects because of its excellent biocompatibility. However, the processing difficulty and poor osteoinductive ability greatly limit the application of HA. Although many strategies have been reported to improve the machinability and osteointegration ability, the performance including mechanical strength, porosity, cell adhesion, of material still can not meet the requirements. In this work, a soft template method was developed and a porous scaffold with hierarchical pore structure, nano surface morphology, suitable porosity and pore size, and good biomechanical strength was successfully prepared. The hierarchical pore structure is beneficial for cell adhesion, fluid transfer, and cell ingrowth. Moreover, the loaded reduced graphene oxide (rGO) can improve the adhesion and promote the proliferation and spontaneous osteogenic differentiation bone marrow mesenchymal stem cells. The scaffold is then crushed, degraded and wrapped by the newly formed bone and the newly formed bone gradually replaces the scaffold. The degradation rate of the scaffold well matches the rate of the new bone formation. The hierarchical porous HA/rGO composite scaffolds can greatly accelerate the bone ingrowth in the scaffold and bone repair in critical bone defects, thus providing a clinical potential candidate for large segment bone tissue engineering. 10.1021/acsnano.9b04723
    In vitro effect of graphene structures as an osteoinductive factor in bone tissue engineering: A systematic review. Mohammadrezaei Dorsa,Golzar Hossein,Rezai Rad Maryam,Omidi Meisam,Rashedi Hamid,Yazdian Fatemeh,Khojasteh Arash,Tayebi Lobat Journal of biomedical materials research. Part A Graphene and its derivatives have been well-known as influential factors in differentiating stem/progenitor cells toward the osteoblastic lineage. However, there have been many controversies in the literature regarding the parameters effect on bone regeneration, including graphene concentration, size, type, dimension, hydrophilicity, functionalization, and composition. This study attempts to produce a comprehensive review regarding the given parameters and their effects on stimulating cell behaviors such as proliferation, viability, attachment and osteogenic differentiation. In this study, a systematic search of MEDLINE database was conducted for in vitro studies on the use of graphene and its derivatives for bone tissue engineering from January 2000 to February 2018, organized according to the PRISMA statement. According to reviewed articles, different graphene derivative, including graphene, graphene oxide (GO) and reduced graphene oxide (RGO) with mass ratio ≤1.5 wt % for all and concentration up to 50 μg/mL for graphene and GO, and 60 μg/mL for RGO, are considered to be safe for most cell types. However, these concentrations highly depend on the types of cells. It was discovered that graphene with lateral size less than 5 µm, along with GO and RGO with lateral dimension less than 1 µm decrease cell viability. In addition, the three-dimensional structure of graphene can promote cell-cell interaction, migration and proliferation. When graphene and its derivatives are incorporated with metals, polymers, and minerals, they frequently show promoted mechanical properties and bioactivity. Last, graphene and its derivatives have been found to increase the surface roughness and porosity, which can highly enhance cell adhesion and differentiation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2284-2343, 2018. 10.1002/jbm.a.36422
    Nanocomposite chitosan film containing graphene oxide/hydroxyapatite/gold for bone tissue engineering. Prakash J,Prema D,Venkataprasanna K S,Balagangadharan K,Selvamurugan N,Venkatasubbu G Devanand International journal of biological macromolecules Recently, polymer based biomaterials are utilized in medical fields including surgical sutures, drug delivery devices, tissue supports and implants for interior bone fixation. However, polymer based implants leads to the formation of bio-films that are highly susceptible to microbial adhesion. In this study, we have fabricated Chitosan/Polyvinyl alcohol/Graphene oxide/Hydroxyapatite/gold films for potential orthopedic application. Graphene oxide/Hydroxyapatite/gold nanocomposite (GO/HAP/Au) was synthesized by simple hydrothermal method and GO/HAP/Au nanocomposite incorporated polymeric film was fabricated using gel casting method. The morphology, phase composition, crystalline structure and chemical state of the nanocomposite were characterized using as XRD, HR-TEM, FE-SEM and FT-IR. The bio-films were found to be biocompatible with mouse mesenchymal cells and it enhanced osteoblast differentiation as evidenced by more alkaline phosphatase activity at the cellular level. Hence, these results suggested that the developed nanocomposites films are osteogenic potential for treating bone and bone-related diseases. Antibacterial analysis of the films shows high inhibition zones against Gram positive and Gram Negative bacteria (Escherichia coli, streptococcus mutans, Staphylococcus aureus and Pseudomonas aeruginosa). Thus, the obtained nanocomposites bio-films are highly biocompatible and it can be used for bone regeneration application. 10.1016/j.ijbiomac.2020.03.095
    Ultrasonicated graphene oxide enhances bone and skin wound regeneration. Hussein Kamal Hany,Abdelhamid Hani Nasser,Zou Xiaodong,Woo Heung-Myong Materials science & engineering. C, Materials for biological applications In the present study, we investigated the applications of ultrasonicated graphene oxide (UGO) for bone regeneration and skin wound healing. Ultrasonication of a GO suspension increased the dispersion and stability (by increasing the zeta potential) of the GO suspension. UGO has fewer oxygen-containing groups but still displays excellent water dispersion. The UGO supension showed high biocompatibility for human fetal osteoblast (hFOB cells), human endothelial cells (EA.hy 926 cells), and mouse embryonic fibroblasts. Importantly, UGO could support cell attachment and proliferation, in addition to promoting the osteogenesis of seeded cells and the promotion of new bone formation. In addition, a 1% UGO supension enhanced cell migration in an in vitro skin scratch assay and promoted wound closure in an in vivo rat excisional skin defect model. These results showed that UGO offers a good environment for cells involved in bone and skin healing, suggesting its potential application in tissue regeneration. 10.1016/j.msec.2018.09.051