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Bone injuries and fractures are often associated with post-surgical failures, extended healing times, infection, a lack of return to a normal active lifestyle, and corrosion associated allergies. In this regard, this review presents a comprehensive report on advances in nanotechnology driven solutions for bone tissue engineering. The fabrication of metals such as copper, gold, platinum, palladium, silver, strontium, titanium, zinc oxide, and magnetic nanoparticles with tunable physico-chemical and opto-electronic properties for osteogenic scaffolds is discussed here in detail. Furthermore, the rational selection of a polymeric base such as chitosan, collagen, poly (L-lactide), hydroxyl-propyl-methyl cellulose, poly-lactic-co-glycolic acid, polyglucose-sorbitol-carboxymethy ether, polycaprolactone, natural rubber latex, and silk fibroin for scaffold preparation is also discussed. These advanced materials and fabrication strategies not only provide for appropriate mechanical strength but also render integrity, making them appealing for orthopedic applications. Further, such scaffolds can be functionalized with ligands or biomolecules such as hydroxyapatite, polypyrrole (PPy), magnesium, zinc dopants, and growth factors to stimulate osteogenic differentiation, mineralization, and neovascularization to aid in rapid healing. Future directions to co-incorporate bioceramics, biogenic nanoparticles, and fourth generation biomaterials to enhance biocompatibility, mechanical properties, and rapid recovery are also included in this review. Hence, the further development of such biomimetic metal-based nano-scaffolds at a lower cost with reduced risks and greater efficacy at regrowing bone can revolutionize the future of orthopedics.

Herein, we report the design of electrospun ultrathin fibers based on the combination of three different polymers polycaprolactone (PCL), polyethylene glycol (PEG), and gelatin methacryloyl (GelMA), and their potential bactericidal activity against three different bacteria Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the morphology, chemical structure and wettability before and after UV photocrosslinking of the produced scaffolds. Results showed that the developed scaffolds presented hydrophilic properties after PEG and GelMA incorporation. Moreover, they were able to significantly reduce gram-positive, negative, and MRSA bacteria mainly after UV photocrosslinking (PCL:PEG:GelMa-UV). Furthermore, we performed a series of study for gaining a better mechanistic understanding of the scaffolds bactericidal activity through protein adsorption study and analysis of the reactive oxygen species (ROS) levels. Furthermore, the in vivo subcutaneous implantation performed in rats confirmed the biocompatibility of our designed scaffolds.

Here, electrospun fibers based on a blend of polycaprolactone (PCL), poly(ethylene glycol) (PEG), and gelatin methacryloyl (GelMA) were developed. The careful choice of this polymer combination allowed for the preparation of a biomaterial that preserved the mechanical strength of PCL, while at the same time improving the hydrophilicity of the blended material and human osteoblast maturation. The morphology, chemical structure, wettability, and mechanical properties before and after UV photocrosslinking were evaluated. Furthermore, human osteoblasts (hFOB) were cultivated for up to 21 days on the scaffolds, and their potential to upregulate cell proliferation, alkaline phosphatase (ALP) activity, and calcium deposition were investigated. Contact angle measurement results showed that the developed scaffolds presented hydrophilic properties after PEG and GelMA incorporation before (25°) and after UV photocross-linking (69°) compared to pure PCL (149°). PCL:PEG:GelMA-UV displayed a slight increase in mechanical strength (elastic modulus ~37 MPa) over PCL alone (~33 MPa). Normally, an increase in strength of fibers leads to a decrease in elongation at break, due to the material becoming less deformable and stiffer, thus leading to breaks at low strain. This behavior was observed by comparing PCL (elongation at break ~106%) and PCL:PEG:GelMA-UV (~50%). Moreover, increases in ALP activity (10-fold at day 14) and calcium deposition (1.3-fold at day 21) by hFOBs were detected after PEG and GelMA incorporation after UV photocross-linking compared to pure PCL. Ultrathin and hydrophilic fibers were obtained after PEG and GelMA incorporation after UV photocrosslinking, but the strength of PCL was maintained. Interestingly, those ultrathin fiber characteristics improved hFOB functions. These findings appear promising for the use of these electrospun scaffolds, based on the combination of polymers used here for numerous orthopedic applications.

Lobo AO, Afewerki S, de Paula MM, et al. Int J Nanomedicine. 2018;13:7891-7903. The authors have advised that due to an error at the time of figure assembly, Figure 2 on page 7894 is incorrect. Images in Figures 2G-I were inserted incorrectly due to mislabeling of the image files. A revised Figure 2G-I have been inserted to address this issue. The correct Figure 2 is as follows. Figure 2 (A-I) Morphology of electrospun fibers from the SEM analysis: (A-C) PCL-PEG, (D-F) PCL-PEG-GelMA, and (G-I) PCL-PEG-GelMA-UV fibers. (J-L) The distribution of the fiber diameters for (J) PCL-PEG, (K) PCL-PEG-GelMA, and (L) PCL:PEG:GelMA-UV fibers.Abbreviations: GelMA, gelatin methacryloyl; PCL, polycaprolactone; PEG, poly(ethylene glycol); SEM, scanning electron microscopy. The authors apologize for this error.

In vitro and in vivo studies have shown that metallic implants coated with nano hydroxyapatite (HA) reduce the time needed for complete osseointegration compared to metallic implants coated with conventional or micron-sized HA. Moreover, due to their biologically inspired nanometer dimensions, amphiphilic peptide nanoparticles (APNPs) can also promote osteoblast attachment and enhance other cell functions if used as a coating material. Coatings made of HA and APNPs could improve osteoblast functions, but have never been tested. The objective of this study was to prepare coatings of nanocrystalline HA and APNPs on poly(2-hydroxyethyl methacrylate) (pHEMA) coatings in order to improve osteoblast (bone-forming cells) adhesion and cell density. HA was synthesized by a wet chemical process. Coatings were synthesized with different conditions and components. X-ray diffraction infrared spectroscopy, transmission electron microscopy, and electron diffraction showed that nanocrystalline HA was synthesized with an expected nano size and shape distribution but with low impurities. pHEMA hydrogels with HA and APNPs increased osteoblast densities after 3 days compared to controls. Since cell proliferation is a prerequisite function for bone formation, these results imply that the current materials should be tested for a wide range of orthopedic applications.

Bacterial cellulose (BC), a nano fibrous hydrogel synthesized from non-pathogenic bacteria, is an excellent candidate scaffold for bone tissue engineering applications due to its biocompatibility, high purity and mechanical strength. However, BC is not biodegradable and possesses small pore sizes, which hinders the ingrowth of cells and thereby limits its potential as a bone tissue engineering scaffold. In this study, microporous BC (termed Porous BC) scaffolds with well-defined honeycomb pore arrays were prepared using a laser patterning technique. The BC scaffolds were modified using periodate oxidation to yield biodegradable oxidized BC scaffolds. In a unique manner, the BC scaffolds were then mineralized with nano hydroxyapatite (nano HA) to mimic the inorganic component of native bone tissue, improve bone cell compatibility, enhance mechanical properties, and control degradation. Results confirmed that sodium periodate oxidation successfully oxidized BC and Porous BC honeycomb pore arrays with 300 μm pore sizes with irregularly shaped 77 ± 15 nm nano HA and aggregated 200–500 nm nano HA were formed. BC and its composites displayed suitable mechanical properties for bone tissue engineering applications. The in vitro degradation study showed a significant 13–25 % loss of their dry mass in the oxidized BC composites thus confirming that the oxidized cellulose can biodegrade. Most importantly, the results also demonstrated that human-derived bone marrow mesenchymal stem cells (hMSCs) adhered to and were viable on the BC and its composites, thus, confirming their potential to serve as improved bone tissue engineering scaffolds. The novelty of the present study includes the precipitation of nano HA onto cellulose to promote hMSCs functions for improving orthopedic applications.

Boussoufi F, Navarro Gallón SM, Chang R, Webster TJ. Int J Nanomedicine. 2018;13:6199-6205. The authors have advised Figure 3 on page is incorrect. The authors inadvertently duplicated the image for Figure 3B (PEP-AuNPs immediately after the synthesis) and Figure 3D (PEP-AuNPs after centrifugation). The correct Figure 3 is shown below. The authors advise this does not change the conclusions of the paper. Read the original article

In nanomedicine, gold nanoparticles (AuNPs) have demonstrated versatile therapeutic efficiencies and, in particular, have been developed for the treatment of various cancers due to their high selectivity in killing cancer, not healthy, cells. In this study, AuNPs were conjugated with the cell-penetrating peptide Cys-(Arg) -Asp-Ser (CRRRRRRRRGDS) by direct cross-linking of the cysteine's thiol group to the gold surface and a fibronectin-derived RGD group was also used due to its efficacy toward cancer cell targeting and possible promotion of healthy fibroblast functions. Ultraviolet-visible absorbance spectrum and transmission electron microscope images of the synthesized peptide-capped AuNPs (PEP-AuNPs) validated the formation of AuNP aggregates. The presence of peptides on AuNPs was confirmed by Fourier transform infrared spectroscopy and quantified by a bicinchoninic acid assay. After being modified with the arginine-rich peptide, the AuNPs possessed a positive charge, as their zeta potential increased from -23.81±8.43 mV to 8 mV on average. In this manner, an easy method to conjugate AuNPs was shown here. Further, MTS assays were performed using healthy human dermal fibroblasts. After 24 hours of treatment with PEP-AuNPs, the cell density increased dramatically to around 25,000 cells/cm . Results further showed a very high half-maximal inhibitory concentration of 69.2 µM for the PEP-AuNPs (indicating low toxicity). The results showed for the first time the ability of PEP-AuNPs to promote human dermal fibroblast cell viability, which after further investigation, may show an ability to replace cancerous tissue with healthy soft tissue.

Background: In nanomedicine, gold nanoparticles (AuNPs) have demonstrated versatile therapeutic efficiencies and, in particular, have been developed for the treatment of various cancers due to their high selectivity in killing cancer, not healthy, cells. Methods: In this study, AuNPs were conjugated with the cell-penetrating peptide Cys-[(Arg).sub.8]Asp-Ser (CRRRRRRRRGDS) by direct cross-linking of the cysteine's thiol group to the gold surface and a fibronectin-derived RGD group was also used due to its efficacy toward cancer cell targeting and possible promotion of healthy fibroblast functions. Results: Ultraviolet-visible absorbance spectrum and transmission electron microscope images of the synthesized peptide-capped AuNPs (PEP-AuNPs) validated the formation of AuNP aggregates. The presence of peptides on AuNPs was confirmed by Fourier transform infrared spectroscopy and quantified by a bicinchoninic acid assay. After being modified with the arginine-rich peptide, the AuNPs possessed a positive charge, as their zeta potential increased from -23.81[+ or -]8.43 mV to 8 mV on average. In this manner, an easy method to conjugate AuNPs was shown here. Further, MTS assays were performed using healthy human dermal fibroblasts. After 24 hours of treatment with PEP-AuNPs, the cell density increased dramatically to around 25,000 cells/[cm.sup.2]. Results further showed a very high half-maximal inhibitory concentration of 69.2 [micro]M for the PEP-AuNPs (indicating low toxicity). Conclusion: The results showed for the first time the ability of PEP-AuNPs to promote human dermal fibroblast cell viability, which after further investigation, may show an ability to replace cancerous tissue with healthy soft tissue. Keywords: gold nanoparticles, cell-penetrating peptide, cysteine, fibroblast

Purpose of ReviewTo identify the use of carbon nanomaterials in bone regeneration and present new data on the regenerative capacity of bone tissue in osteopenic rats treated with graphene nanoribbons (GNRs).Recent FindingsThe results show that the physical and chemical properties of the nanomaterials are suitable for the fabrication of scaffolds intended for bone regeneration. The in vitro tests suggested a non-toxicity of the GNRs as well as improved biocompatibility and bone mineralization activity.SummaryHere, for the first time, we evaluated the potential of GNRs in remodeling and repairing bone defects in osteoporotic animal models in vivo. Interestingly, bone mineralization and the initiation of the remodeling cycle by osteoclasts/osteoblasts were observed after the implantation of GNRs, thus implying healthy bone remodeling when using GNRs. This study, therefore, has opened our perspectives and certainly calls for more attention to the use of carbon nanomaterials for a wide range of osteoporosis applications.