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The proinflammatory chemokine interleukin-8 (IL-8) is undetectable in androgen-responsive prostate cancer cells (e.g., LNCaP and LAPC-4), but it is highly expressed in androgen-independent metastatic cells, such as PC-3. In this report, we show IL-8 functions in androgen independence, chemoresistance, tumor growth, and angiogenesis. We stably transfected LNCaP and LAPC-4 cells with IL-8 cDNA and selected IL-8–secreting (IL8-S) transfectants. The IL8-S transfectants that secreted IL-8 at levels similar to that secreted by PC-3 cells (100–170 ng/106 cells) were characterized. Continuous or transient exposure of LNCaP and LAPC-4 cells to IL-8 reduced their dependence on androgen for growth and decreased sensitivity (>3.5×) to an antiandrogen. IL-8–induced cell proliferation was mediated through CXCR1 and was independent of androgen receptor (AR). Quantitative PCR, immunoblotting, and transfection studies showed that IL8-S cells or IL-8–treated LAPC-4 cells exhibit a 2- to 3-fold reduction in PSA and AR levels, when compared with vector transfectants. IL8-S cells expressed 2- to 3-fold higher levels of phospho-EGFR, src, Akt, and nuclear factor κB (NF-κB) and showed increased survival when treated with docetaxel. This increase was blocked by NF-κB and src inhibitors, but not by an Akt inhibitor. IL8-S transfectants displayed a 3- to 5-fold increased motility, invasion, matrix metalloproteinase-9 and vascular endothelial growth factor production. LNCaP IL8-S cells grew rapidly as tumors, with increased microvessel density and abnormal tumor vasculature when compared with the tumors derived from their vector-transfected counterparts. Therefore, IL-8 is a molecular determinant of androgen-independent prostate cancer growth and progression. [Cancer Res 2007;67(14):6854–62]

Supplementary Table 1 from Interleukin-8 Is a Molecular Determinant of Androgen Independence and Progression in Prostate Cancer

Bioactive phosphate glasses incorporated with Zn2+ (predicted to be useful for bone regeneration applications) were synthesized. Characterization of the bioglasses were done using XRD, FTIR, SEM, and EDS techniques, both prior to and after soaking in simulated body fluid (SBF) solution. The bioactive performance of samples was evaluated by incubated in SBF for different days by means of the pH measuring and comparing the results of XRD and SEM studies. The obtained results show the formation of hydroxyapatite (HAP) layer on the surface of as-developed bioactive glasses. The degradation of the samples evaluated by weight loss and pH of the remnant solution measured as functions of ZnO concentration and immersion time revealed the enhanced formation of HAP layer on the sample surface. The results further indicated the rate of degradation can be monitored by tailoring the concentration of ZnO and immersion time. The studies were also extended to in vitro cytocompatibility and cell proliferation measurements on rMSC using CCK-8 for incubation periods of 24 h and 72 h. These studies have revealed the considerable levels of rMSC proliferation and improved viability within the limits of nontoxic levels. The measurements of antibacterial activity of ZnO-doped phosphate bioactive glasses against E. coli and S. aureus, carried out for 24 h and 48 h have confirmed their potential antibacterial activity. Finally, quantitative analysis of these results confirmed an enhanced in vitro biological and antibacterial activity of the samples due to the ZnO doping and subsequent controlled release of Zn2+ ions in the glass matrix.

Tailoring the surface of biomaterial scaffolds has been a key strategy to modulate the cellular interactions that are helpful for tissue healing process. In particular, nanotopological surfaces have been demonstrated to regulate diverse behaviors of stem cells, such as initial adhesion, spreading and lineage specification. Here, we tailor the surface of biopolymer nanofibers with carbon nanotubes (CNTs) to create a unique bi-modal nanoscale topography (500 nm nanofiber with 25 nm nanotubes) and report the performance in modulating diverse in vivo responses including inflammation, angiogenesis, and bone regeneration. When administered to a rat subcutaneous site, the CNT-coated nanofiber exhibited significantly reduced inflammatory signs (down-regulated pro-inflammatory cytokines and macrophages gathering). Moreover, the CNT-coated nanofibers showed substantially promoted angiogenic responses, with enhanced neoblood vessel formation and angiogenic marker expression. Such stimulated tissue healing events by the CNT interfacing were evidenced in a calvarium bone defect model. The in vivo bone regeneration of the CNT- coated nanofibers was significantly accelerated, with higher bone mineral density and up-regulated osteogenic signs (OPN, OCN, BMP2) of in vivo bone forming cells. The in vitro studies using MSCs could demonstrate accelerated adhesion and osteogenic differentiation and mineralization, supporting the osteo-promoting mechanism behind the in vivo bone forming event. These findings highlight that the CNTs interfacing of biopolymer nanofibers is highly effective in reducing inflammation, promoting angiogenesis, and driving adhesion and osteogenesis of MSCs, which eventually orchestrate to accelerate tissue healing and bone regeneration process. Statement of significance Here we demonstrate that the interfacing of biopolymer nanofibers with carbon nanotubes (CNTs) could modulate multiple interactions of cells and tissues that are ultimately helpful for the tissue healing and bone regeneration process. The CNT-coated scaffolds significantly reduced the pro-inflammatory signals while stimulating the angiogenic marker expressions. Furthermore, the CNT-coated scaffolds increased the bone matrix production of bone forming cells in vivo as well as accelerated the adhesion and osteogenic differentiation of MSCs in vitro. These collective findings highlight that the CNTs coated on the biopolymer nanofibers allow the creation of a promising platform for nanoscale engineering of biomaterial surface that can favor tissue healing and bone regeneration process, through a series of orchestrated events in anti-inflammation, pro-angiogenesis, and stem cell stimulation.

Nanomaterials combined with phototherapy and multimodal imaging are promising for cancer theranostics. Our aim is to develop fluorescent mesoporous bioglass nanoparticles (fBGn) based on carbon dots (CD) with delivery, triple-mode imaging, and photothermal (PTT) properties for cancer theranostics. A direct and label-free approach was used to prepare multicolor fluorescent fBGn with 3-aminopropyl triethoxysilane as the surface-functionalizing agent. The calcination at 400 °C provided fBGn with high fluorescence intensity originating from the CD. In particular, a triple-mode emission [fluorescence imaging, two-photon (TP), and Raman imaging] was observed which depended on CD nature and surface properties such as surface oxidation edge state, amorphous region, nitrogen passivation of surface state, and crystalline region. The fBGn also exhibited phototherapeutic properties such as photodynamic (PDT) and PTT effects. The antitumor effect of the combined PDT/PTT therapy was significantly higher than that of individual (PDT or PTT) therapy. The fBGn, due to the mesoporous structure, the anticancer drug doxorubicin could be loaded and released in a pH-dependent way to show chemotherapy effects on cancer cells. The in vivo imaging and biocompatibility of fBGn were also demonstrated in a nude mouse model. The fBGn, with the combined capacity of anticancer delivery, triple-mode imaging, and PTT/PDT therapy, are considered to be potentially useful for cancer theranostics.

Designing various transplantable biomaterials, especially nanoscale matrixes for bone regeneration, involves precise tuning of topographical features. The cellular fate on such engineered surfaces is highly influenced by many factors imparted by the surface modification (hydrophilicity, stiffness, porosity, roughness, ROS responsiveness). Herein, hybrid matrixes of gelatin methacryloyl (GelMA) decorated with uniform layers of nanoceria (nCe), called Ce@GelMA, were developed without direct incorporation of nCe into the scaffolds. The fabrication involves a simple base-mediated in situ deposition in which uniform nCe coatings were first made on GelMA hydrogels and then nCe layered GelMA scaffolds were made by cryodesiccation. In this hybrid platform, degradable GelMA biopolymer provides the porous microstructure and nCe provides the nanoscaled biointerface. The surface morphology and elemental composition of the matrixes analyzed by field emission scanning electron microscopy (FE-SEM) and energy-dispersive spectroscopy (EDS) show uniform nCe distribution. The surface nanoroughness and chemistry of the matrixes were also characterized using atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The presence of nCe on GelMA enhanced its mechanical properties as confirmed by compressive modulus analysis. Substantial bonelike nanoscale hydroxyapatite formation was observed on scaffolds after simulated body fluid (SBF) immersion, which was confirmed by SEM, X-ray diffraction (XRD), and Fourier transform infrared (FT-IR) spectroscopy. Moreover, the developed scaffolds could also be used as an antioxidant matrix owing to the reactive oxygen species (ROS) scavenging property of nCe as assessed by 3,3',5,5'-tetramethylbenzidine (TMB) assay. The enhanced proliferation and viability of rat bone marrow mesenchymal stem cells (rMSCs) on the scaffold surface after 3 days of culture ensures the biocompatibility of the proposed material. Considering all, it is proposed that the micro/nanoscaled matrix could mimic the composition and function of hard tissues and could be utilized as degradable scaffolds in engineering bones.

Regenerating defective bone in patients with diabetes mellitus remains a significant challenge due to high blood glucose level and oxidative stress. Here we aim to tackle this issue by means of a drug- and cell-free scaffolding approach. We found the nanoceria decorated on various types of scaffolds (fibrous or 3D-printed one; named nCe-scaffold) could render a therapeutic surface that can recapitulate the microenvironment: modulating oxidative stress while offering a nanotopological cue to regenerating cells. Mesenchymal stem cells (MSCs) recognized the nanoscale (tens of nm) topology of nCe-scaffolds, presenting highly upregulated curvature-sensing membrane protein, integrin set, and adhesion-related molecules. Osteogenic differentiation and mineralization were further significantly enhanced by the nCe-scaffolds. Of note, the stimulated osteogenic potential was identified to be through integrin-mediated TGF-β co-signaling activation. Such MSC-regulatory effects were proven in vivo by the accelerated bone formation in rat calvarium defect model. The nCe-scaffolds further exhibited profound enzymatic and catalytic potential, leading to effectively scavenging reactive oxygen species in vivo. When implanted in diabetic calvarium defect, nCe-scaffolds significantly enhanced early bone regeneration. We consider the currently-exploited nCe-scaffolds can be a promising drug- and cell-free therapeutic means to treat defective tissues like bone in diabetic conditions.

Providing appropriate biophysical and biochemical cues to the interface is a facile strategy to enhance the osteogenic ability of metallic implants. Here we exploited this through the incorporation of mesoporous bioactive glass nanoparticles (MBGN) at a high content (1:1 by weight) to a biopolymer chitosan in the electrodeposition process of titanium. The MGBN/chitosan layer thickness, tunable by electrodeposition parameters, exhibited an accelerated ability of apatite mineral induction in a body simulating medium. Of note, the involvement of MBGN could generate nanoscale roughness in a unique range of 10-25 nm. Moreover, the layer showed a slowly releasing profile of ions (calcium and silicate) over weeks at therapeutically relevant doses. The ion-releasing nanotopological surface was demonstrated to alter the preosteoblasts responses in a way favorable for osteogenic differentiation. The combinatory cues of nanotopology (25 nm roughness) and ion release enabled highly accelerated cellular anchorage with somewhat limited spreading area at initial periods. The subsequent osteoblastic differentiation behaviors on the engineered surface, as examined up to 21 days, showed significantly enhanced alkaline phosphate activity and up-regulated expression of bone-associated genes (ALP, Col I, OPN, and OCN). These results indicate that the combinatory cues provided by nanotopology (25 nm roughness) and ions released from MBGN are highly effective in stimulating osteoblastic differentiation and suggest that the MBGN/chitosan may serve as a potential composition for bone implant coatings.

Critical limb ischemia (CLI) is a serious form of peripheral arterial disease that involves severe blockage of blood flow in lower extremities, often leading to foot necrosis and limb loss. Lack of blood flow and high pro-inflammation with overproduced reactive oxygen species (ROS) in CLI aggravate the degenerative events. Among other therapies, cell delivery is considered potential for restoring regenerative capacity, and preservation of cell survival under high oxidative stress has been challenging and prerequisite to harness cellular functions. Here, we introduce a multicellular delivery system that is intercalated with nanoceria-decorated graphene oxide (CeGO), which is considered to have high ROS scavenging ability while providing cell-matrix interaction signals. The CeGO nano-microsheets (8-nm-nanoceria/0.9-μm-GO) incorporated in HUVEC/MSC (7/3) could form cell-material hybrid spheroids mediated by cellular contraction. Under in vitro oxidative-stress-challenge with H

A novel glass system 8ZnO–22Na2O–(24-x)CaO–46P2O5–xTiO2 (x = 0.2, 0.4, 0.6, 0.8 and 1 mol%) was fabricated and investigated in detail for the appropriateness in the use of bone repair and regeneration applications. In this context, we explored the structural, thermal, mechanical, degradation, pH evaluation along with antibacterial assay, cytocompatability and cell proliferation by various characterization techniques like X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), Energy dispersive spectrometry (EDS) and differential thermal analysis (DTA), Vickers hardness, cell counting kit (CCK8) method and agar plates method. The obtained results of density, thermal stability and Vickers hardness increase with the increasing content of TiO2 leads to the densification of glass structure dueto formation new linkages P–O–Ti and enters into the network in the form of either TiO4 or TiO5/6 structural units. The formation of a rich crystalline hydroxyl apatite (HAp) layer on the samples with incubation time (3, 7, 14 and 21days) and content of TiO2 up to 0.6 mol% in simulated body fluid (SBF) were confirmed by in vitro analysis. Interestingly, no inhibitory effects on HAp layer formation with the addition of titanium up to 1 mol% were noticed. Lower degradation rate and pH values endorsed to hydration resistant with Ti4+ inclusion, leads to controlled ion leaching. The rat mesenchymal stem cells (rMSCs) growth on glass samples showed the enhanced biocompatibility and proliferation without toxicity. In addition, all glasses possess good antimicrobial properties against bacterial species Escherichia coli (E.coli). Finally, the results revealed that the 0.6 mol% of TiO2 glass (T.6) showed abundant performance for bone generation applications.

Organic molecular monolayers (MoLs) have been used for improving the performance of various electronic device structures. In this work, the concept of organic molecular surface modification is applied for improving the performance of GaN-based metal-semiconductor-metal (MSM) ultraviolet (UV) photodetectors (PDs). Organic molecules of phenol-functionalized metallated porphyrin (hydroxyl-phenyl-zinc-tetra-phenyl-porphyrin (Zn-TPPOH)) were adsorbed on GaN, and Ni/Zn-TPPOH/GaN/Zn-TPPOH/Ni PD structures were fabricated. This process was beneficial in two ways: first, the reverse-bias dark current was reduced by 1000 times, and second, the photocurrent was enhanced by ∼100 times, in comparison to the dark and photocurrent values obtained for Ni/GaN/Ni MSM PDs, at high voltages of ±10 V. The responsivity of the devices was increased from 0.22 to 4.14 kA/W at 5 μW/cm

Natural inorganic/organic nanohybrids are a fascinating model in biomaterials design due to their ultra-microstructure and extraordinary properties. Here, we report unique-structured nanohybrids through self-assembly of biomedical inorganic/organic nanounits, composed of bioactive inorganic nanoparticle core (hydroxyapatite, bioactive glass, or mesoporous silica) and chitosan shell - namely Chit@IOC. The inorganic core thin-shelled with chitosan could constitute as high as 90%, strikingly contrasted with the conventional composites. The Chit@IOC nanohybrids were highly resilient under cyclic load and resisted external stress almost an order of magnitude effectively than the conventional composites. The nanohybrids, with the nano-roughened surface topography, could accelerate the cellular responses through stimulated integrin-mediated focal adhesions. The nanohybrids were also able to load multiple therapeutic molecules in the core and shell compartment and then release sequentially, demonstrating controlled delivery systems. The nanohybrids compartmentally-loaded with therapeutic molecules (dexamethasone, fibroblast growth factor 2, and phenamil) were shown to stimulate the anti-inflammatory, pro-angiogenic and osteogenic events of relevant cells. When implanted in the in vivo calvarium defect model with 3D-printed scaffold forms, the therapeutic nanohybrids were proven to accelerate new bone formation. Overall, the nanohybrids self-assembled from Chit@IOC nanounits, with their unique properties (ultrahigh inorganic content, nano-topography, high resilience, multiple-therapeutics delivery, and cellular activation), can be considered as promising 3D tissue regenerative platforms.

Carbon-based nanomaterials include fullerenes, carbon nanotubes, graphene and its derivatives, graphene oxide, nanodiamonds, and carbon-based quantum dots. Due to their unique structural dimensions and excellent mechanical, electrical, thermal, optical and chemical properties, these materials have attracted significant interest in diverse areas, including biomedical applications. Among them, there has been recent focus on the imaging of cells and tissues and the delivery of therapeutic molecules for disease treatment and tissue repair. The broad-range one-photon property of carbon based-nanomaterials together with their biocompatibility and ease of functionalization has made them candidate imaging agents for tumor diagnosis. In particular, the intrinsic two-photon fluorescence property of carbon based-nanomaterials in the long wavelength region (near-infrared II) allows deep-tissue optical imaging. This review highlights the recent development on carbon based-nanomaterials in the field of one-photon and two-photon imaging and discusses their possible and promising diagnostic and therapeutic applications for the treatment of various diseases including cancer.

Bioactive nanostructured coating has been a key strategy to improve the cell adhesion and osseointegration of metallic implants. This study presents the electrophoretic coatings of hydroxyapatite with tunable nanocrystal morphologies. The hydroxyapatite nanocrystals were prepared with three different elongated dimensions by the hydrothermal method (∼80 nm; SHA, ∼300 nm; MHA, and ∼900 nm; LHA), which were used in combination with a fugitive biopolymer chitosan for the electrophoretic deposition on titanium. All the HA coatings were densely and homogeneously deposited and had different and unique nanotopologies and corresponding surface areas. The coating parameter significantly altered the cell behaviors including anchorage, spreading and proliferation; the cell adhesion was better on the small- and middle-sized nanocrystals (SHA, MHA > LHA), which was interestingly opposite in cell spreading (LHA > SHA, MHA), and then the cell proliferation was again up-regulated on SHA and MHA. Although more studies are needed to elucidate the biological phenomenon, the sets of results imply the importance of tailored nanocrystal morphology in the initial (adhesion and growth) cellular events.

Tissue engineering provides great possibilities to manage tissue damages and injuries in modern medicine. The involvement of hard biocompatible materials in tissue engineering-based therapies for the healing of soft tissue defects has impressively increased over the last few years: in this regard, different types of bioceramics were developed, examined and applied either alone or in combination with polymers to produce composites. Bioactive glasses, carbon nanostructures, and hydroxyapatite nanoparticles are among the most widely-proposed hard materials for treating a broad range of soft tissue damages, from acute and chronic skin wounds to complex injuries of nervous and cardiopulmonary systems. Although being originally developed for use in contact with bone, these substances were also shown to offer excellent key features for repair and regeneration of wounds and "delicate" structures of the body, including improved cell proliferation and differentiation, enhanced angiogenesis, and antibacterial/anti-inflammatory activities. Furthermore, when embedded in a soft matrix, these hard materials can improve the mechanical properties of the implant. They could be applied in various forms and formulations such as fine powders, granules, and micro- or nanofibers. There are some pre-clinical trials in which bioceramics are being utilized for skin wounds; however, some crucial questions should still be addressed before the extensive and safe use of bioceramics in soft tissue healing. For example, defining optimal formulations, dosages, and administration routes remain to be fixed and summarized as standard guidelines in the clinic. This review paper aims at providing a comprehensive picture of the use and potential of bioceramics in treatment, reconstruction, and preservation of soft tissues (skin, cardiovascular and pulmonary systems, peripheral nervous system, gastrointestinal tract, skeletal muscles, and ophthalmic tissues) and critically discusses their pros and cons (e.g., the risk of calcification and ectopic bone formation as well as the local and systemic toxicity) in this regard. STATEMENT OF SIGNIFICANCE: Soft tissues form a big part of the human body and play vital roles in maintaining both structure and function of various organs; however, optimal repair and regeneration of injured soft tissues (e.g., skin, peripheral nerve) still remain a grand challenge in biomedicine. Although polymers were extensively applied to restore the lost or injured soft tissues, the use of bioceramics has the potential to provides new opportunities which are still partially unexplored or at the very beginning. This reviews summarizes the state of the art of bioceramics in this field, highlighting the latest evolutions and the new horizons that can be opened by their use in the context of soft tissue engineering. Existing results and future challenges are discussed in order to provide an up-to-date contribution that is useful to both experienced scientists and early-stage researchers of the biomaterials community.

Biocompatible and multifunctional nanocarriers significantly improve the therapeutic and diagnostic efficacy of the cargo molecules. Here we report a novel biocompatible apatite nanocrystal-based delivery system with in situ imaging capacity. A nanorod (40 nm × 10 nm) produced by a citrate-involved sol–gel process expressed a strong blue emission at 427 nm under fluorescence microscopy. The CO2˙− radical impurities present in the apatite crystal lattice account for the fluorescent behavior. The fluorescent nanorods exhibited excellent cell viability (over 90% up to ∼100 μg ml−1 concentration for both osteoblasts and osteoclasts). The nanorods loaded alendronate drug at a high efficiency (10%) and released over 3 days, while enabling in situ fluorescence imaging within the cells. The fluorescent apatite was further hybridized onto the surface of mesoporous nanospheres, aimed at improving the drug-delivery capacity. Small interfering RNA (siRNA) gene, encoding Plekho-1, was effectively loaded to the hybrid nanocarrier, and was sustainably released over 5 days. The siRNA-loaded nanocarrier exhibited excellent osteoblastic uptake (96% efficiency) and gene-silencing effect, suppressing Plekho-1 down to ∼18%, while preserving intracellular fluorescence signals. Taken as a whole, the self-fluorescent nature of apatite nanorods is believed to find potential and versatile applications as biocompatible drug-delivery and in situ imaging systems.

An effort was made to analyze the spatial and temporal variability of rainfall and temperature in 13 districts of the Uttarakhand, India over the period of 102 years (1901–2002). The main focus was to examine the rainfall variability and its future response during wheat crop period (November-April). Mann–Kendall test and Sen's slope estimator test used to detect monotonic trend direction and magnitude of change over time on annual and seasonal basis. The Pettit-Mann–Whitney test applied to detect the change points over the century. Mean annual precipitation varied from 821 mm (in Haridwar) to 1244 mm (in Pithoragarh) whereas it was 75 mm (in Udham Singh Nagar) to 178 mm (in Pithoragarh) during wheat growing period. During the wheat crop period, annual precipitation decrease was noticed in Udham Singh Nagar (-37.1%) which was maximum. Maximum decrease in minimum and maximum temperature during wheat growing period and annual period was observed for Uttarkashi district which was -39.4%, -28% and -25.1%, -21.1%, respectively. Similarly, Champawat was second after Udham Singh Nagar having highest temperature in both the periods. The most affected year of change was 1978 and 1940 in annual precipitation and maximum, minimum temperature, but during wheat growing period it was observed in 1945 and 1978, respectively. Mann Kendal trend test shows decrease in precipitation for all the stations during wheat growing period and annual period. In case of annual minimum temperature, average change was 0.0040C, though during wheat crop period it was 0.009 0C /year.

Biomedical cements are considered promising injectable materials for bone repair and regeneration . Calcium phosphate composition sized with tens of micrometers is currently one of the major powder forms. Here we report a unique cement form made from mesoporous bioactive glass nanoparticles (BGn). The nanopowder could harden in reaction with aqueous solution at powder-to-liquid ratios as low as 0.4–0.5 ( vs . 2.0–3.0 for conventional calcium phosphate cement CPC). The cementation mechanism investigated from TEM, XRD, FT-IR, XPS, and NMR analyses was demonstrated to be the ionic (Si and Ca) dissolution and then reprecipitation to form Si-Ca-(P) based amorphous nano-islands that could network the particles. The nanopowder-derived nanocement exhibited high surface area (78.7 m 2 /g); approximately 9 times higher than conventional CPC. The immersion of nanocement in simulated body fluid produced apatite nanocrystallites with ultrafine size of 10 nm ( vs. 55 nm in CPC). The ultrafine nanocement adsorbed protein molecules (particularly positive charged proteins) at substantial levels; approximately 160 times higher than CPC. The nanocement released Si and Ca ions continuously over the test period of 2 weeks; the Si release was unique in nanocement whereas the Ca release was in a similar range to that observed in CPC. The release of ions significantly stimulated the responses of cells studied (rMSCs and HUVECs). The viability and osteogenesis of rMSCs were significantly enhanced by the nanocement ionic extracts. Furthermore, the in vitro tubular networking of HUVECs was improved by the nanocement ionic extracts. The in vivo neo-blood vessel formation in CAM model was significantly higher by the nanocement implant when compared with the CPC counterpart, implying the Si ion release might play a significant role in pro-angiogenesis. Furthermore, the early bone forming response of the nanocement, based on the implantation in a rat calvarial bone defect, demonstrated a sign of osteoinductivity along with excellent osteocondution and bone matrix formation. Although more studies remain to confirm the potential of nanocement, some of the intriguing physico-chemical properties and the biological responses reported herein support the promise of the new ‘nanopowder-based nanocement’ for hard tissue repair and regeneration .

Osteoarthritis entails excessive ROS generation, severe inflammatory responses, and anatomical destruction of cartilage and subchondral bone. Nanoceria holds antioxidant activity, exerting therapeutic efficacy under high ROS conditions. Here we investigate if the nanoceria properly administered to an osteoarthritic joint would be effective in protecting the cartilage and bone against osteoarthritic degeneration. Three-days post-induction of osteoarthritis in a rat temporomandibular joint, nanoceria (~20 nm) at varying doses (100 ~ 2000 µg/mL) were locally administered once, and tissue samples were analyzed at 10 days post-treatment. The nanoceria-administered groups could preserve the cartilage and subchondral anatomical structure of joint; particularly at 500 µg/mL, the preservation of quantitated hypertrophic layer and cartilage proteoglycan was as high as ~ 80% (vs. ~ 30% in an osteoarthritic group), albeit higher doses gradually shielded the efficacy (~50–60%). The degeneration of subchondral bone was thus significantly prevented by the nanoceria treatment; ~70–80% of intact control with 500 µg/mL vs. ~ 50% in the osteoarthritic group. Moreover, the nanoceria treatment profoundly reduced the degenerative symptoms including cellular apoptosis and the secretion of catabolic proteins (COX2/PGE2) and pro-inflammatory cytokines (IL-1β/TNFα) while boosting regenerative events such as the polarization of M2 macrophages (CD206/163) and the production of anti-inflammatory cytokines (IL-10) and chondrogenic glycoproteins. The excessive ROS generated in the osteoarthritis joint was observed to be effectively scavenged by the nanoceria. Such therapeutic effects of nanoceria witnessed in vivo were further demonstrated in parallel with the in vitro experiments particularly involving the osteoarthritis-mimicking chondrocytes/macrophages co-culture models, where the anti-apoptotic and immunomodulatory roles of nanoceria were revealed to be major molecular mechanisms. The present findings may place the nanoceria a promising nanotherapeutic candidate for the treatment of degenerative joint diseases.

Theranostics based on nanoparticles (NPs) is a promising paradigm in nanomedicine. Mesoporous silica nanoparticle (MSN)-based systems offer unique characteristics to enable multimodal imaging or simultaneous diagnosis and therapy. They include large surface area and volume, tunable pore size, functionalizable surface, and acceptable biological safety. Hybridization with other NPs and chemical modification can further potentiate the multifunctionality of MSN-based systems toward translation. Here, we update the recent progress on MSN-based systems for theranostic purposes. We discuss various synthetic approaches used to construct the theranostic platforms either via intrinsic chemistry or extrinsic combination. These include defect generation in the silica structure, encapsulation of diagnostic NPs within silica, their assembly on the silica surface, and direct conjugation of dye chemicals. Collectively, in vitro and in vivo results demonstrate that multimodal imaging capacities can be integrated with the therapeutic functions of these MSN systems for therapy. With further improvement in bioimaging sensitivity and targeting specificity, the multifunctional MSN-based theranostic systems will find many clinical applications in the near future.

Cerium oxide nanomaterials (CeNMs), due to their excellent scavenging properties of reactive oxygen species (ROS), have gained great promise for therapeutic applications. A high level of ROS often degrades the potential of stem cells in terms of survivability, maintenance and lineage differentiation. Here we hypothesize the CeNMs may play an important role in protecting the capacity of stem cells against the oxidative insult, and the suppression mechanism of ROS level may depend on the internalization of CeNMs. We synthesized CeNMs with different directional shapes (aspect ratios) by a pH-controlled hydrothermal method, and treated them to stem cells derived from human dental pulp at various doses. The short CeNMs (nanoparticles and nanorods) were internalized rapidly to cells whereas long CeNMs (nanowires) were slowly internalized, which led to different distributions of CeNMs and suppressed the ROS levels either intracellularly or extracellularly under the H 2 O 2 -exposed conditions. Resultantly, the stem cells, when dosed with the CeNMs, were rescued to have excellent cell survivability; the damages in intracellular components including DNA fragmentation, lipid rupture and protein degradation were significantly alleviated. The findings imply that the ROS-scavenging events of CeNMs need special consideration of aspect ratio-dependent cellular internalization, and also suggest the promising use of CeNMs to protect stem cells from the ROS-insult environments, which can ultimately improve the stem cell potential for tissue engineering and regenerative medicine uses. Statement of Significance Oxidative stress governs many stem cell functions like self-renewal and lineage differentiation, and the biological conditions involving tissue repair and disease cure where stem cell therapy is often needed. Here we demonstrate the unique role of cerium oxide nanomaterials (CeNMs) in rescuing stem cell survivability, migration ability, and intracellular components from oxidative stress. In particular, we deliver a novel finding that nano-morphologically varied CeNMs show different mechanisms in their scavenging reactive oxygen species either intracellularly or extracellularly, and this is related with their different cellular internalizations. We used human dental pulp stem cells for the model study and proved the CeNMs were effective in controlling ROS level by means of scavenging intracellularly or extracellularly, which ultimately led to improving the intact therapeutic potential of stem cells. This work touches an important biological issue of nanomaterial interactions with stem cells under the conditions related with oxidative stress and the resultant damage. The correlation of shape factor in therapeutic nanomaterials with stem cell interaction and the oxidative stress-related functions will provide informative ideas in the design of CeNMs for cellular therapy.

Silica-based nanomaterials (SiNMs) with different forms, including nanoparticles, nanorods and nanofibers either with a dense, porous or hollow structure, have been demonstrated as fascinating platforms for the delivery of therapeutic molecules in the inorganic nanocarrier regime. This is primarily due to their unique physicochemical properties, which are effective and tunable for the uptake of different cargo molecules, as well as to their biological responses favorable for cells and tissues. Over the last decade, a substantial number of studies have exploited SiNMs with different shapes, sizes, mesopore structures and surface charges for use in cancer therapy, imaging and bioseparation. In particular, their surface can be functionalized with candidate molecules from dyes to drugs for theranostic purposes. Moreover, providing the carriers with intelligent modes, such as stimuli-responsiveness, and with multifunctionality through combining them with imaging particles (magnetic nanoparticles, quantum dots and carbon dots) improves their therapeutic and diagnostic potential. While many pioneering works in the SiNM systems have focused on cancer therapy, there is growing demand for using SiNMs in the area of regenerative medicine, for stem cell therapy and tracking, and for the repair of dysfunctional tissues. Here we review the most recent advances in SiMNs that are available for regenerative therapies. For this, we first give an overview of the general nanostructure forms and characteristics of the SiNMs from a physicochemical and biological point of view, and then deal with the intracellular uptake mechanism and toxicity issues. Finally, advanced designs of SiNMs to provide multifunctional and intelligent actions of loading and delivery of drugs and molecules are detailed, and then perspectives for their potential uses in regenerative medicine are provided.

Objective Magnetic biomaterials have recently gained great attention due to their some intriguing cell and tissue responses. However, little attention has been given to the fields of dental tissue regeneration. In this sense, we aim to investigate the effects of magnetic nanofiber scaffolds on the human dental pulp cell (HDPC) behaviors and to elucidate the underlying signaling mechanisms in the events. Methods Magnetic nanofiber scaffolds incorporating magnetic nanoparticles at varying contents were prepared into nanofibrous matrices to cultivate cells. Cell growth by MTS assay, odontoblastic differentiation by alkaline phosphatase (ALP) activity, mineralization, and the mRNA expression of differentiation-related genes of HDPCs, in vitro angiogenesis by migration and capillary tube formation in endothelial cells on the conditioned medium obtained from HDPSCs in the presence or absence of scaffolds. Western blot analysis and confocal immunofluorescene were used to asses signaling pathways. Results The growth of HDPCs was significantly enhanced on the magnetic scaffolds with respect to the non-magnetic counterpart. The odontogenic differentiation of cells was significantly up-regulated by the culture with magnetic scaffolds. Furthermore, the magnetic scaffolds promoted the HDPC-induced angiogenesis of endothelial cells. The expression of signaling molecules, Wnt3a, phosphorylated GSK-3β and nuclear β-catenin, was substantially stimulated by the magnetic scaffolds; in parallel, the MAPK and NF-κB were highly activated when cultured on the magnetic nanofiber scaffolds. Significance This study is the first to demonstrate that magnetic nanofiber scaffolds stimulate HDPCs in the events of growth, odontogenic differentiation, and pro-angiogenesis, and the findings imply the novel scaffolds can be potentially useful as dentin-pulp regenerative matrices.

Providing an osteogenic stimulatory environment is a key strategy to construct stem cell-based bone-equivalent tissues. Here we design a stem cell delivering gel matrix made of collagen (Col) with bioactive glass nanocarriers (BGn) that incorporate osteogenic signaling molecule, fibroblast growth factor 18 (FGF18), a reservoir considered to cultivate and promote osteogenesis of mesenchymal stem cells (MSCs). The presence of BGn in the gel was shown to enhance the osteogenic differentiation of MSCs, possibly due to the therapeutic role of ions released. The mesoporous nature of BGn was effective in loading FGF18 at large quantity, and the FGF18 release from the BGn-Col gel matrix was highly sustainable with almost a zero-order kinetics, over 4 weeks as confirmed by the green fluorescence protein signal change. The released FGF18 was effective in accelerating osteogenesis (alkaline phosphatase activity and bone related gene expressions) and bone matrix formation (osteopontin, bone sialoprotein, and osteocalcin production) of MSCs. This was attributed to the bone morphogenetic protein (BMP) signaling pathway, where the FGF18 release stimulated the endogenous secretion of BMP2 and the downstream signal Smad1/5/8. Taken together, the FGF18-BGn/Col gel is considered an excellent osteopromoting depot to support and signal MSCs for bone tissue engineering.

Coatings of metallic implants facilitate a new bioactive interface that favors osteogenic responses and bone formation. Providing a therapeutic capacity to the coatings, involving with a sustainable and controllable delivery of drug molecules, significantly improves the bone regenerative potential. Here we design a novel nanocomposite coating, made of mesoporous silica-shelled hydroxyapatite (MS-HA) nanoparticles and chitosan (Chi), incorporating osteogenic drug dexamethasone phosphate (Dex(P)) within the MS-HA, by the process of an electrophoretic deposition (EPD). MS-HA, produced by a sol–gel reaction of silica onto an HA nanorod, exhibited mono-dispersed core–shell nanoparticles with a size of ∼40 nm and a shell thickness of ∼25 nm. The highly mesoporous structure enabled an effective loading of Dex(P) onto the nanocarriers, showing a loading capacity as high as 15% by weight. The Dex(P) loaded MS-HA were homogenized with Chi in acidic ethanol/water to allow for the EPD process. Nanocomposite coatings were produced well, forming thicknesses a few micrometers largely tunable with EPD parameters and exhibiting MS-HA nanoparticles evenly distributed within Chi matrix. While Dex(P) release from the bare MS-HA nanocarrier was very abrupt, showing a complete release within 24 h, the Dex(P) release from the nanocomposite coatings profiled a highly sustainable pattern over a month. Rat mesenchymal stem cells cultured on the Dex(P)-releasing coatings were substantially stimulated to an osteoblastic lineage, presenting enhanced alkaline phosphate activity and higher levels of osteogenic genes, with respect to coatings free of Dex(P). An indirect culture test also confirmed the long-term release effects of Dex(P) from the coatings over 4 weeks. The currently-developed nanocomposite EPD coatings, with a capacity to load osteogenic drug at large quantity and to deliver for a long-term period, are considered as a promising therapeutic coating platform for metallic bone implants.

Biocompatible nanomaterials that allow for labeling cells and tissues with the capacity to load and deliver drug molecules hold great promise for the therapeutic-diagnostic purposes in tissue repair and disease cure. Here a novel nanoplatform, called C-dot bioactive organosilica nanosphere (C-BON), is introduced to have excellent theranostic potential, such as controlled drug delivery, visible-light imaging, and NIR photothermal activity. C-dots with a few nanometers were in situ generated in the Ca-containing organosilica mesoporous nanospheres through the sol-gel and thermal-treatment processes. The C-BON exhibited multicolor luminescence over a wide visible-light range with strong emissions and high photostability over time and against acidity and the possible in vivo optical imaging capacity when injected in rat subcutaneous tissues. Moreover, the C-BON showed a photothermal heating effect upon the irradiation of near-infrared. The C-BON, thanks to the high mesoporosity and existence of Ca(2+) ions, demonstrated excellent loading capacity of anticancer drug doxorubicin (as high as 90% of carrier weight) and long-term (over a couple of weeks) and pH/NIR-dependent release ability. The C-BON preserved the compositional merit of Ca-Si glass, having excellent bioactivity and cell compatibility in vitro. Taken all, the multifunctional properties of C-BON-multicolor luminescence, photothermal activity, and high drug loading and controlled release-together with its excellent bioactivity and cell compatibility potentiate the future applications in theranostics (chemotherapy and photothermal therapy with optical imaging).

Nanocarriers are one of the key elements to improve the therapeutic potential of signaling molecules, including genes for the disease treatment and tissue repair. Here, a nanocarrier system is reported that delivers genetic molecule small interference RNA (siRNA) for osteoblastic stimulation. For this, a hollow form of mesoporous silica nanoshell (MSns) is designed to load and release siRNA to silence Plekho-1 gene. In particular, a pressure-induced loading method is effective in enhancing the incorporation of siRNA within a hollow space; a loading level attained ≈30% is almost three times higher than that of a non-hollow form. Furthermore, the release of siRNA from the nanocarriers is highly sustainable; continued over 18 d in a diffusion-controlled manner, in striking contrast to the rapid release (3 d) from a non-hollow form. The nanocarriers exhibit excellent cell viability, and the siRNA-nanocarrier complexes are efficiently internalized to osteoblastic cells (uptake level over 90%). The intracellular delivery suppresses the target gene Plekho-1 expression down to 20%, which in turn up-regulates the expression of osteoblast transcriptional factors (Runx2 and Smad2), demonstrating an effective gene delivery system for bone repair.

Bulk (Mn1-xCox)2VAl (x = 0, 0.25, 0.50) alloys in highly ordered L21 structure with a very small amount of B2 disorder have been prepared and their magnetic properties have been measured. The value of saturation magnetizations of the alloys with x = 0, 0.25 and 0.50 are 1.88 μB, 0.84 μB and 0.07 μB, respectively, being consistent with 2.00 μB, 1.00 μB and 0 μB, respectively, predicted by the Slater–Pauling rule. This indicates that the stoichiometric MnCoVAl alloy is a fully compensated ferrimagnet (FCF). Spin polarization measurements using point contact Andreev reflection technique showed that the quaternary alloys exhibited higher intrinsic spin polarization than the parent ternary composition. The spin polarization of 0.60 deduced for the MnCoVAl alloy suggests that spin-polarized current can be extracted from FCF. Curie temperature (TC) and the effective anisotropy constant of (Mn1-xCox)2VAl alloys decrease with increase in Co content.

In critical limb ischemia (CLI), overproduction of reactive oxygen species (ROS) and impairment of neovascularization contribute to muscle damage and limb loss. Cerium oxide nanoparticles (CNP, or ‘nanoceria’) possess oxygen-modulating properties which have shown therapeutic utility in various disease models. Here we show that CNP exhibit pro-angiogenic activity in a mouse hindlimb ischemia model, and investigate the molecular mechanism underlying the pro-angiogenic effect. CNP were injected into a ligated region of a femoral artery, and tissue reperfusion and hindlimb salvage were monitored for 3 weeks. Tissue analysis revealed stimulation of pro-angiogenic markers, maturation of blood vessels, and remodeling of muscle tissue following CNP administration. At a dose of 0.6 mg CNP, mice showed reperfusion of blood vessels in the hindlimb and a high rate of limb salvage (71%, n = 7), while all untreated mice (n = 7) suffered foot necrosis or limb loss. In vitro, CNP promoted endothelial cell tubule formation via the Ref-1/APE1 signaling pathway, and the involvement of this pathway in the CNP response was confirmed in vivo using immunocompetent and immunodeficient mice and by siRNA knockdown of APE1. These results demonstrate that CNP provide an effective treatment of CLI with excessive ROS by scavenging ROS to improve endothelial survival and by inducing Ref-1/APE1-dependent angiogenesis to revascularize an ischemic limb.

In the field of nanomedicine, drug-loaded nanocarriers that integrate nanotechnology and chemotherapeutics are widely used to achieve synergistic therapeutic effects. Here, we prepared mesoporous silica nanoparticles capped with cerium oxide nanoparticles (COP@MSN) wherein a pH trigger-responsive mechanism was used to control drug release and intracellular drug delivery. We blocked the mesopores of the carboxyl-functionalized MSN with aminated COP. These pores could be opened in acidic conditions to release the loaded drug, thus establishing a pH-responsive drug release system. We loaded doxorubicin (DOX) as anticancer biomolecule into the pores of MSN and capped with COP. The COP@DOX-MSN system showed a typical drug release profile in an acidic medium, which, however, was not observed in a neutral medium. In vitro studies using cancer cell line (HeLa) proved that the COP@DOX-MSN entered efficiently into HeLa cells and released DOX to the level sufficient for cytotoxicity. The cytotoxic effect of COP in cancer cells was facilitated by the pro-oxidant property of COPs, which considerably raised the reactive oxygen species (ROS) level, thereby leading to cellular apoptosis. The combination of DOX with COP (COP@DOX-MSN) showed even higher ROS level, demonstrating a cytotoxic synergism of drug and nanoparticle in terms of ROS generation. Collectively, the COP@DOX-MSN is considered useful for cancer treatment with the combined capacity of pH-controlled drug delivery, chemotherapeutics, and redox activity.

Biocompatible nanostructured surfaces control the cell behaviors and tissue integration process of medical devices and implants. Here we develop a novel biocompatible nanostructured surface based on mesoporous silica nanotube (MSNT) by means of an electrodeposition. MSNTs, replicated from carbon nanotubes of 25 nm × 1200 nm size, were interfaced in combination with fugitive biopolymers (chitosan or collagen) onto a Ti metallic substrate. The MSNT-biopolymer deposits uniformly covered the substrate with weight gains controllable by the electrodeposition conditions. Random nanotubular networks were generated successfully, which alongside the high mesoporosity provided unique nanotopological properties for the cell responses and the loading/delivery of biomolecules. Of note, the adhesion and spreading behaviors of mesenchymal stem cells (MSCs) were significantly altered, revealing more rapid cell anchorage and extensive nanofilopodia development along the nanotubular networks. Furthermore, the nanotubular surface improved the loading capacity of biomolecules (dexamethasone and bovine serum albumin) up to 5-7 times. The release of the biomolecules was highly sustained, exhibiting a diffusion-controlled pattern over 15 days. The therapeutic efficacy of the delivered biomolecules was also confirmed in the osteogenic differentiation of MSCs. While in vivo performance and applicability studies are needed further, the current biocompatible nanostructured surface may be considered as a novel biointerfacing platform to control cellular behaviors and biomolecular delivery.