Novel Hydrogel Adjuvant of Chinese Medicine External Preparations for Accelerated Healing of Deep Soft Tissue Injuries.

Traditional Chinese medicine external prescriptions have displayed excellent clinical effects for treating deep soft tissue injuries. However, the effects cannot be fully utilized due to the limitations of their dosage forms and usage methods. It is still a challenge to develop a satisfactory adjuvant of traditional Chinese medicine external prescriptions. Herein, a hydrogel adjuvant was prepared based on gallic acid coupled ε-poly-l-lysine and partially oxidized hyaluronic acid. The resulting adjuvant shows great physicochemical properties, low hemolysis rate (still much less than 5% at 5 mg/mL), excellent antibacterial ability (about 95% at 2 mg/mL), strong antioxidant ability (1.687 ± 0.085 mmol FeSO4/(g hydrogel) at 1 mg/mL), as well as outstanding biocompatibility. A clinically used Chinese medicine external preparation was selected as an example to investigate the effectiveness of the adjuvant in treating deep soft tissue injuries. The results show that the prescription can be evenly dispersed in the adjuvant. Moreover, the introduction of the prescription has not significantly changed these advanced properties of the adjuvant. Importantly, the hydrogel adjuvant significantly improves the effectiveness of the prescription in treating deep soft tissue injuries. This work offers an alternative approach to the development of a new-type adjuvant of Chinese medicine external preparations and also provides a new strategy for the combination of traditional Chinese medicine and hydrogel to treat clinical diseases.

Antioxidative and antibacterial gallium (III)-phenolic coating for enhanced osseointegration of titanium implants via pro-osteogenesis and inhibiting osteoclastogenesis.

Improving the ability of implants to integrate with natural bone tissue at the initial stage of implantation remains a huge challenge because bone-to-implant interfaces are often accompanied by abnormal microenvironments with infection, reactive oxygen species (ROS) and unbalanced bone homeostasis. In this study, a multifunctional coating was fabricated on the basis of gallium (III)-phenolic networks. It is easily obtained by immersing the implants into a mixed solution of tannic acids (TAs) and gallium ions. The thickness of the coating can be precisely controlled by adjusting the number and time of immersion experiments. The resulting coating displays excellent near-infrared photothermal property. As the coating degrades, TAs and gallium ions with low concentration are released from the coating, which is more rapid in acidic and oxidative stress microenvironments. Photothermal performance as well as released TAs and gallium ions give the coating outstanding broad-spectrum antibacterial ability. Furthermore, the coating effectively reduces intracellular ROS of osteoblasts. In vitro and in vivo experiments demonstrate the capability of the coating enhancing implants' osseointegration via pro-osteogenesis and inhibiting osteoclastogenesis. The findings imply that gallium (III)-phenolic coating holds great promise to promote implant osseointegration by rescuing abnormal microenvironments of infection, oxidative stress and unbalanced bone homeostasis.

Osteogenesis regulation of mesenchymal stem cells via autophagy induced by silica-titanium composite surfaces with different mechanical moduli.

The high surface elastic modulus of the titanium (Ti) implant is one of the critical factors causing poor osteointegration between the implant surface and surrounding bone tissue. To address this challenge, spherical silica nanoparticles (SSNs) and spherical titania nanoparticles (STNs) with different sizes were synthesized and embedded into Ti surfaces via a micro-arc oxidation (MAO) technique. There were no significant changes in the surface roughness and protein adsorption behaviors before and after the embedding of spherical silica nanoparticles and titania nanoparticles into the Ti implant. However, the surface elastic modulus of Ti-SSNs decreased from 93 GPa to 6.7 GPa, while there was still no change in surface elastic modulus between Ti and Ti-STN groups. In vitro experiments showed that Ti-SSNs, especially Ti-SSN3, significantly stimulated the expression level and nuclear localization of the transcription factor YAP. YAP/TAZ could further inhibit the phosphorylation of AKT and mTOR proteins in MSCs, leading to higher LC3-II protein expression and osteogenic differentiation of MSCs. Ti-SSNs also showed a higher level of autophagosome formation, ALP activity and mineralization capability compared to the other groups. Our results showed that the surface elasticity modulus of an implant plays an important role in the regulation of MSC behaviors. Therefore, designing an implant with an optimal elastic modulus at the surface might have great clinical potential in the bone repair field.

Osteogenic differentiation of mesenchymal stem cells by silica/calcium micro-galvanic effects on the titanium surface.

Based on the sensitivity to the extracellular H+ concentration of proton-sensing receptors, we immobilized Si/CaCO3 nanoparticles on a titanium surface (TiMNPs) by using micro-arc oxidation (MAO) to produce micro-galvanic effects by Schottky contact, aiming to regulate the hydrogen evolution reaction of micro-galvanic couples and osteogenic response of mesenchymal stem cells (MSCs). The surface zeta potential measurement and dynamic potential polarization test confirmed that micro-galvanic effects were successfully produced on the titanium surface after the treatment of Si/CaCO3 nanoparticles. The Ti substrate with a Si/CaCO3 nanoparticle loading concentration of 100 mg mL-1 (TiMNPs 100) could lead to the highest level of hydrogen evolution reaction. In vitro experiments showed that TiMNPs 100 were significantly superior in their ability to down-regulate the expression level of proton-sensing receptors and key proteins in the PLC/Ca2+ signal pathway, which in turn promoted MSC osteogenesis differentiation. A higher level of ALP activity, mineralization capacity and collagen secretion on TiMNPs 100 was confirmed as compared to those of other groups. This study provides a new insight into designing novel biomaterials for bone generation.

Substance P-embedded multilayer on titanium substrates promotes local osseointegration via MSC recruitment.

In this study, the chemokine substance P (SP) was inserted into multilayered systems on titanium (Ti)-based substrates for endogenous mesenchymal stem cell (MSC) recruitment to facilitate bone healing. The multilayer was constructed with cationic chitosan (Chi), SP and anionic gelatin (Gel) via a spin-coater-assisted layer-by-layer (LBL) approach. The characterization results demonstrated that the multilayer system was successfully constructed and was capable of continuously releasing SP for almost 2 weeks. We further confirmed that MSCs grown on SP-modified Ti-based substrates showed improved migration capabilities as well as enhanced secretion of matrix metalloproteinases (MMP2, MMP9), rather than enhanced MSC proliferation and differentiation in vitro. In the CD29+/CD90+ double immunofluorescence assay, the Ti/LBL-SP group showed the highest number of MSCs migrating to the peri-implant area after implantation. Consistently, the Ti/LBL-SP implants also significantly enhanced new bone formation according to the results of micro-CT scanning analysis, H&E staining, Masson's trichrome staining and immunohistochemical staining. The obtained results reveal that SP-modified Ti-based substrates were beneficial for bone formation via recruiting endogenous MSCs.

Remote eradication of biofilm on titanium implant via near-infrared light triggered photothermal/photodynamic therapy strategy.

Biofilm formation is a main challenge in treatment of bone-implant-associated infections, resulting in tolerance to immune system and antibiotics. However, smart non-surgical or non-invasive treatment methods of combating established biofilm on an implant have been less reported. Herein, a therapeutic system consisting of mesoporous polydopamine nanoparticles (MPDA) to combat biofilm is reported for the first time. We develop a synergistic photothermal/photodynamic therapy (PTT/PDT) strategy aiming for biofilms eradication on titanium (Ti) implant, which is integrated with MPDA loading with photosensitizer Indocyanine Green (ICG) by π-π stacking. Specifically, MPDA is functionalized with RGD peptide to endow the modified Ti sample (Ti-M/I/RGD) with good cytocompatibility. More importantly, Ti-M/I/RGD implant remarkably kills Staphylococcus aureus (S. aureus) biofilm with an efficiency of 95.4% in vivo upon near infrared (NIR). After biofilm eradication, implant still displays great performance regarding osteogenesis and osseointegration. Overall, this study provides a PTT/PDT strtategy for the development of antibacterial Ti implants for potential orthpediac application.

Biocompatible MoS2/PDA-RGD coating on titanium implant with antibacterial property via intrinsic ROS-independent oxidative stress and NIR irradiation.

To inhibit bacterial infection in situ and improve osseointegration are essentially important for long-term survival of an orthopedic implant, in particular for infection-associating revision surgery. Herein, we fabricate a functional molybdenum disulfide (MoS2)/polydopamine (PDA)-arginine-glycine-aspartic acid (RGD) coating on titanium (Ti) implant to address above concerns simultaneously. The coating not only improved the osteogenesis of mesenchymal stem cells (MSCs), but also endowed Ti substrates with effective antibacterial ability when exposing to near-infrared (NIR) irradiation. It accelerated glutathione (GSH) oxidation via photothermal energy and induced intrinsic ROS-independent oxidative stress damage deriving from MoS2 nanosheets. The results displayed that RGD-decorated MoS2 nanosheets significantly increased the cellular osteogenic behaviors of MSCs via up-regulating osteogenesis-related genes (ALP, Runx2, Col I and OCN) in vitro. Moreover, the functionalized Ti substrates demonstrated great antibacterial efficiency of over 92.6% inhibition for S. aureus and E. coli under NIR-irradiation. Hyperthermia induced by photothermal effect accelerated the GSH consumption and ROS-independent oxidative stress destroyed the integrity of bacteria membranes, which synergistically led to protein leakage and ATP decrease. Furthermore, co-culture experiment showed that S. aureus contamination was efficiently cleaned from MoS2/PDA-RGD surface after NIR photothermal treatment, while MSCs adhered and proliferated on the MoS2/PDA-RGD surface. In an S. aureus infection model in vivo, MoS2/PDA-RGD modified Ti rods killed bacteria with an efficiency of 94.6% under NIR irradiation, without causing damage to normal tissue. More importantly, the MoS2/PDA-RGD modified Ti implants accelerated new bone formation in comparison with TNT implants in vivo.

Differentiation regulation of mesenchymal stem cells via autophagy induced by structurally-different silica based nanobiomaterials.

Autophagy is associated with the proliferation and differentiation of mesenchymal stem cells (MSCs). In this study, we investigated the biological impact of silica-based nanobiomateiral-induced autophagy on the differentiation of MSCs, in which the nanoparticulate cues include solid silica nanoparticles (SSN), mesoporous silica nanoparticles (MSN) and biodegradable mesoporous silica nanoparticles (DMSN). The treatment with SSN significantly up-regulated the LC3-II expression via ERK1/2 and AKT/mTOR signaling pathways compared to DMSN and MSN, leading to a higher autophagic activity in MSCs. The enhanced protein adsorption of DMSN and MSN could prevent the direct interaction between cells and nanoparticles, which consequently reduces the autophagic stimulation of MSCs. It should be noted that MSCs exhibited increased differentiation potential when the autophagic activity was enhanced by the treatment with different nanoparticles. In comparison, no difference in the cell differentiation potential was found when an autophagy inhibitor (chloroquine, CQ) was incorporated in all groups. The study may contribute to the development of silica-based nanobiomaterials in the future.

Regulation of osteoblast differentiation by osteocytes cultured on sclerostin antibody conjugated TiO2 nanotube array.

Sclerostin is a negative regulator of the Wnt signaling pathway for osteoblast differentiation. In this study, osteoblasts were co-cultured with osteocytes (MLO-Y4 cells) on the surface of sclerostin antibody-conjugated TiO2 nanotube arrays (TNTs-scl). Field emission scanning electron microscopy (SEM), contact angle measurement and confocal laser scanning microscope (CLSM) were employed to characterize the conjugation of sclerostin antibody onto the surface of TiO2 nanotube arrays. The cellular viability and morphology results displayed TNTs-scl (TNT30-scl and TNT70-scl) were beneficial to the growth of MLO-Y4 cells. There was no apparent change in sclerostin gene expression between MLO-Y4 cells grown on TNTs and TNTs-scl. However, TNTs-scl significantly reduced the amount of sclerostin in the medium. In comparison with the control groups, osteoblasts displayed higher differentiation capability when co-cultured with MLO-Y4 cells on the surface TNTs-scl, which was indicated by the ALP activity, mineralization capability as well as expression levels of key proteins in Wnt signaling. This study provides a simple strategy to engineer titanium surface for bone fracture recovery, especially in osteoporotic conditions.

Peptide LL-37 coating on micro-structured titanium implants to facilitate bone formation in vivo via mesenchymal stem cell recruitment.

Titanium (Ti) and Ti-alloys were widely used in clinic orthopedics, however, the insufficient bone formation surrounding Ti-based implants still limited their biological performances. Surface modification of Ti substrates is essential to improve their interactions with bone-forming cells and bone tissue. In this study, we modified Ti substrates by coating peptide LL-37 onto micro-structured Ti substrates and aimed to (i) induce mesenchymal stem cells (MSCs) migration both in vitro and in vivo, (ii) facilitate osteogenic differentiation of MSCs and new bone formation. The surface micro-structured Ti substrates with hydroxyapatite deposition were fabricated by a two-step method including micro-arc oxidation (MAO) and hydrothermal treatment. LL-37 was loaded on micro-structured Ti substrates with the assistance of polydopamine coating. We confirmed that surface-modified Ti substrates benefited viability, adhesion, migration and osteogenic differentiation of MSCs in vitro. In a femur-defect rat model, the surface-modified Ti implants effectively induced CD29+/CD90+ positive cells migration in one week after implantation. According to the results of H&E, Masson's trichrome staining and immunohistochemical staining of OCN, OPN and collagen I, the targeted Ti implants exhibited significant new bone formation after implantation for 4 weeks. These results indicate that the surface modification of Ti samples facilitated bone formation through MSCs recruitment. STATEMENT OF SIGNIFICANCE: The inherent surface bioinertness of titanium (Ti) and Ti-alloys still limits their biological performances in clinical applications. Recently, the strategy of mesenchymal stem cells (MSCs) recruitment has been proposed to improve the osteointegration of bone implants. Herein, we reports the surface modification of Ti implants from the point of MSCs recruitment. Peptide LL-37 was coated on micro-structured Ti substrates to (i) recruit MSCs, (ii) regulate bio-physiological performance of MSCs, and (iii) facilitate bone formation in vivo. Our results improve the understanding of the interaction between Ti implants and MSCs, and provide a promising strategy of MSCs recruitment in the design of bone repair related biomaterials.

Deferoxamine loaded titania nanotubes substrates regulate osteogenic and angiogenic differentiation of MSCs via activation of HIF-1α signaling.

To develop biomaterials for inducing osteogenic and angiogenic differentiation of mesenchymal stem cells (MSCs) is crucial for bone repair. In this study, we employed titania nanotubes (TNT) as drug nanoreservoirs to load deferoxamine (DFO), and then deposited chitosan (Chi) and gelatin (Gel) multilayer as coverage structure via layer-by-layer (LBL) assembly technique, resulting in TNT-DFO-LBL substrates. Scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and contact angle measurements were employed to characterize the physical and chemical properties of the substrates. The results proved the successful fabrication of multilayer coating on TNT array. DFO released from the TNT arrays in a sustained manner. The drug-device combination titanium (Ti) substrates positively improved the adhesion, proliferation, osteogenic/angiogenic differentiation of MSCs and mediated the growth behavior of human umbilical vein endothelial cells (HUVECs). Moreover, the TNT-DFO-LBL substrates up-regulated osteogenic and angiogenic differentiation related genes expression of MSCs by activating HIF-1α signaling pathway. The approach presents here has a potential impact on the development of high quality Ti-based orthopedic implants.

Regulation of osteogenesis by micro/nano hierarchical titanium surfaces through a Rock-Wnt5a feedback loop.

Titanium substrates with micro/nano hierarchical features could positively mediate the osteogenesis of a titanium implant; nevertheless, the underlying molecular mechanism needs to be further revealed. In this work, we fabricated a micro/nano hierarchically structured Ti (MNT) sample and attempted to evaluate its topography-mediated biological effects and potential molecular mechanisms in vitro. The results proved that MNT could not only affect cell morphology and osteogenic differentiation, but also regulate ROCK activity cell biological functions of osteoblasts involved in ROCK activation, ß-catenin accumulation, and high-Wnt5a expression in respect to topographical features. Moreover, blockade of ROCK activation resulted in significant inhibition of cell differentiation and Wnt5a expression. Furthermore, the anti-Wnt5a significantly down-regulated ROCK activity. In short, these results indicate the important role of ROCK-Wnt5a feedback loop in regulating cell differentiation by topographies.

Multilayered coating of titanium implants promotes coupled osteogenesis and angiogenesis in vitro and in vivo.

We used surface-modified titanium (Ti) substrates with a multilayered structure composed of chitosan-catechol (Chi-C), gelatin (Gel) and hydroxyapatite (HA) nanofibers, which were previously shown to improve osteogenesis, as a platform to investigate the interaction of osteogenesis and angiogenesis during bone healing. Combined techniques of Transwell co-culture, wound healing assay, enzyme linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical staining were used to evaluate adhesion, morphology and migration of adipose-derived mesenchymal stem cells (Ad-MSCs) and human umbilical vein endothelial cells (HUVECs) grown on different Ti substrates. We investigated the effect of substrates on the osteogenic differentiation of Ad-MSCs and reciprocal paracrine effects of Ad-MSCs on HUVECs or vice versa. The multilayered Ti substrates directly regulated the cellular functions of Ad-MSCs and angiogenic HUVECs and mediated communication between them by enhancing paracrine effects via cell-matrix interactions in vitro. The in vivo results showed that the change of microenvironment induced by surface-modified Ti implants promoted the adhesion, recruitment and proliferation of MSCs and facilitated coupled osteogenesis and angiogenesis in bone healing. The study proved that multilayer-film-coated Ti substrates positively mediated cellular biological function in vitro and improved bone healing in vivo. STATEMENT OF SIGNIFICANCE: Recent studies have revealed that osteogenesis and angiogenesis are coupled, and that communication between osteoblasts and endothelial cells is essential for bone healing and remodeling processes; however, these conclusions only result from in vitro studies or in vivo studies using transgenic murine models. Relatively little is known about the communication between osteoblasts and endothelial cells in peri-implants during bone healing processes. Our results revealed the cellular/molecular mechanism of how multilayered Ti substrates mediate reciprocal paracrine effects between adipose-derived mesenchymal stem cells and human umbilical vein endothelial cells; moreover, the interactions between the cell-matrix and peri-implant was proven in vivo with enhanced bone healing. This study contributes to our understanding of the fundamental mechanisms of angiogenesis and osteogenesis that affect peri-implantation, and thus, provides new insights into the design of future high-quality orthopedic implants.

Sustained raloxifene release from hyaluronan-alendronate-functionalized titanium nanotube arrays capable of enhancing osseointegration in osteoporotic rabbits.

To enhance the localized bone remodeling at titanium-based implants under osteoporotic conditions, TiO2 nanotube arrays (TNT) were used as nanoreserviors for raloxifene (Ral) and then covered with the hybrid multilayered coating of chitosan and alendronate grafted hyaluronic acid (HA-Aln) via a spin-assisted layer-by-layer technique. The fabrication of this system (TNT/Ral/LBL-Aln) was characterized by field emission scanning electron microscopy (SEM), atomic force microscope (AFM) and X-ray photoelectron spectroscopy (XPS), respectively. The release test showed that the composited multilayers onto Ral-loaded TiO2 nanotube substrate (TNT/Ral) could prevent the burst release of Ral from TiO2 nanotube arrays and maintain stable Ral concentration at the implant site even after 192h. The TNT/Ral/LBL-Aln system demonstrated higher alkaline phosphatase (ALP) activity, mineralization capability in osteoblasts as well as lower tartrate-resistant acid phosphatase (TRAP) activity in osteoclasts compared to both bare TiO2 nanotube and TNT/Ral substrate, respectively. Moreover, the in vivo tests of micro-CT, histological staining and push-out testing showed that TNT/Ral/LBL-Aln implant could efficiently enhance the formation of new bone around the implant and promote bone binding in osteoporotic rabbits. The study indicated the potential application of TNT/Ral/LBL-Aln system for bone remodeling under osteoporotic condition.

Strontium folic acid derivative functionalized titanium surfaces for enhanced osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo.

The introduction of the bioactive strontium (Sr) element has become an attractive method in the design of bio-functional layers on titanium surfaces. However, there are still no effective solutions to some of the associated problems including the toxicity of free Sr2+ ions and the rapid and irreversible loss of the strontium element from the bio-functional layers. In this study, we successfully fabricated a bioactive layer on Ti substrates with a strontium folic acid derivative (FASr). About 3.11 at% Sr was incorporated into the Ti surface. The characterization results showed that FASr was stable over a long period of time and minimal free Sr2+ ions were detected in simulated body fluid (SBF). In the in vitro experiment, the FASr could significantly promote the cell adhesion, proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) over a short period. Furthermore, it could dramatically accelerate the bone formation around the implant. In vivo, a total of 30 7-week old male Sprague Dawley (SD) rats were applied for implantation tests. The results showed that this positive stimulatory effect became more evident in the later stages of the in vivo observation. This study provides an effective strategy for designing and optimizing Ti-based implants.

Nanosheet-pore topographical titanium substrates: a biophysical regulator of the fate of mesenchymal stem cells.

Recent reports have demonstrated that nano- or micro-scale topography could enhance the cellular functions of stem cells. In this study, a sub-micrometer topography composed of nanosheet-pore structures was fabricated on the pure titanium surface by a simple vapor alkaline-treatment method to understand more profoundly sub-micrometer topography mediated stem cell behaviors. The topography was characterized by scanning electron microscopy, atomic force microscopy, X-ray photoelectron spectroscopy, X-ray diffraction and contact angle measurements, respectively. It specifically mediated cellular functions of rat bone marrow-derived mesenchymal stem cells (MSCs) on cellular and molecular levels under either normal medium or osteoinductive medium conditions. The experimental results indicated that the topography dramatically promoted the adhesion of MSCs grown on the surface, but the shape, morphology and spreading of cells were not significantly affected. In addition, the study demonstrated that the formation of focal adhesion complexes (FAs) were highly dependent on the topography, which in turn affects the subsequent biological functions of MSCs, especially accelerating osteogenic differentiation of MSCs under different conditions. Overall, the sub-micrometer topographical titanium substrate was an excellent biophysical regulator of the fate of mesenchymal stem cells, specifically inducing their differentiation into osteoblasts.

Alendronate-loaded hydroxyapatite-TiO2 nanotubes for improved bone formation in osteoporotic rabbits.

Early mechanical fixation between an implant and native bone is critically important for successful orthopedic implantation, especially for hosts suffering osteoporosis with reduced bone mass. To endow a titanium-based implant with a desirable local anti-osteoporosis property for enhancing its early osseointegration, alendronate-loaded hydroxyapatite-TiO2 nanotube (TNT-HA-Aln) substrates were fabricated and systematically characterized in this study. The results of Aln/Ca2+ release and Ca2+ concentration in an osteoclast medium verified that the release of Aln was significantly accelerated along with the acidity rise caused by osteoclast differentiation. Other in vitro tests, such as CCK-8, alkaline phosphatase (ALP), mineralization, gene expression (Runx2, Osterix, ALP, Col I, OPN, OC, OPG and RANKL), protein production (OPG and RANKL) and tartrate-resistant acid phosphatase (TRAP), proved that TNT-HA-Aln substrates have great potential for improving osteoblast proliferation/differentiation and inhibiting osteoclast differentiation. Moreover, in vivo tests, such as the push-out test, micro-CT and H&E staining proved that TNT-HA-Aln implants could efficiently improve local osseointegration after implantation for 3 months. The study provides an alternative to exploiting drug-device combinations to enhance early osseointegration in osteoporosis.

Influence of strontium ions incorporated into nanosheet-pore topographical titanium substrates on osteogenic differentiation of mesenchymal stem cells in vitro and on osseointegration in vivo.

Biophysical cues or biochemical cues were proved to efficiently regulate the fate of mesenchymal stem cells (MSCs), but their synergistic effects on the biological functions of MSCs remain to be further investigated. In this study, titanium (Ti) substrates were fabricated with distinct sub-micrometer nanosheet-pore topography via a vapor alkaline treatment method. Strontium (Sr) ions were then incorporated into the Ti substrates via ion exchange. Apart from the influence of biophysical cues from topography, MSCs were simultaneously affected by the biochemical cues from the continuously released Sr ions. The MSCs grown onto Ti substrates with Sr incorporated in them displayed higher (p < 0.05 or p < 0.01) cellular functions than those of pure Ti substrates, including proliferation, the genes and proteins expressions of osteogenic markers and mineralization potential when comparing them with the results of those MSCs grown onto pure Ti substrates. Furthermore, the in vivo investigations demonstrated that the Sr incorporated Ti implants promoted new bone formation. All the results indicated that the incorporated Sr ions and the nanosheet-pore topography of the Ti substrates synergistically enhanced the osteogenic differentiation of MSCs in vitro and osseointegration in vivo. This study advances the understanding of the synergistic influence of biophysical cues and biochemical cues on MSC osteogenic differentiation.

A pH-responsive nanocontainer based on hydrazone-bearing hollow silica nanoparticles for targeted tumor therapy.

A pH-responsive drug delivery system based on hollow mesoporous silica nanoparticles (HMSNs) was fabricated for targeted tumor therapy by using hydrazone bonds as pH-sensitive linkers and hyaluronic acid (HA) molecules as both blocking and targeting agents. HMSNs were synthesized with good dispersion and dimensions of around 88 nm. Detailed material characterisation suggested that the drug delivery system was successfully constructed. It displayed a fast pH stimulus response for controlled drug release in vitro. Besides, systematic biological investigations revealed that the drug delivery system had good biocompatibility, which could effectively target tumor cells and deliver therapeutic cargo to induce tumor cell apoptosis in vitro and suppression of tumor growth in vivo. This study reports a promising drug delivery system for potential clinical application against tumor therapy.

Regulation of local bone remodeling mediated by hybrid multilayer coating embedded with hyaluronan-alendronate/BMP-2 nanoparticles on Ti6Al7Nb implants.

Osteoporosis, a common bone disease, has been identified as a major obstacle for successful implantation. Therefore, the promotion of early mechanical fixation between implants and the surrounding bone can strongly increase the success rate of orthopedic operation in osteoporosis patients. In this study, functional hyaluronan-alendronate/BMP-2 (HA-Aln/BMP-2) nanoparticles were embedded into the Gel/Chi multilayers on Ti6Al7Nb surfaces (namely Ti6Al7Nb/LBL/NP) to endow the Ti6Al7Nb-based implant with local anti-osteoporosis properties. The release test showed that the loaded BMP-2 only slowly released along with the degradation of multilayers, and no burst release emerged at the early stage. In vitro cell experiments, including cell morphology, viability, alkaline phosphatase (ALP) activity, mineralization capacity and tartrate-resistant acid phosphatase (TRAP), demonstrated that the prepared Ti6Al7Nb/LBL/NP implants not only improved the proliferation and differentiation of osteoblasts but also inhibited the maturity of osteoclasts. Moreover, the in vivo tests of the push-out test, micro-CT and histological stains further verified that the Ti6Al7Nb/LBL/NP implant was more beneficial to promoting the local osseointegration between the natural bone and the implant when compared to those of the control groups after implantation for 3 months in osteoporotic rabbits. The study demonstrated a flexible method for effectively enhancing the early osseointegration between the implant and the native osteoporotic bone.