Collaborative Design of MgO/FeOx Nanosheets on Titanium: Combining Therapy with Regeneration.

The repair of bone defects caused by osteosarcoma resection remains a clinical challenge because of the tumor recurrence and bacterial infection. Combining tumor and bacterial therapy with bone regeneration properties in bone implants is a promising strategy for the treatment of osteosarcoma. Here, a layer of MgO/FeOx nanosheet is constructed on the Ti implant to prevent tumor recurrence and bacterial infection, while simultaneously accelerating bone formation. This MgO/FeOx double metal oxide demonstrates good peroxidase activity to catalyze H2 O2 , which is rich in tumor microenvironment, to form reactive oxygen species (ROS), and shows good photothermal conversion capacity to produce photothermal effect, thus synergistically killing tumor cells and eliminating tumor tissue. In addition, it generates a local alkaline surface microenvironment to inhibit the energy metabolism of bacteria to enhance the photothermal antibacterial effect. Furthermore, benefiting from the generation of a Mg ion-containing alkaline microenvironment, this MgO/FeOx film can promote the osteogenic differentiation of osteoblast and angiogenesis of vascular endothelial cells in vitro as well as accelerated bone formation in vivo. This study proposes a multifunctional platform for integrating tumor and bacterial therapy and bone regeneration, which has good application prospects for the treatment of osteosarcoma.

Complementary and Synergistic Design of Bi-Layered Double Hydroxides Modified Magnesium Alloy toward Multifunctional Orthopedic Implants.

Magnesium (Mg)-based alloys have been regarded as promising implants for future clinic orthopedics, however, how to endow them with good anti-corrosion and biofunctions still remains a great challenge, especially for complicated bone diseases. Herein, three transition metals (M = Mn, Fe, and Co)-containing layered double hydroxides (LDH) (LDH-Mn, LDH-Fe, and LDH-Co) with similar M content are prepared on Mg alloy via a novel two-step method, then systematic characterizations and comparisons are conducted in detail. Results showed that LDH-Mn exhibited the best corrosion resistance, LDH-Mn and LDH-Co possessed excellent photothermal and enzymatic activities, LDH-Fe revealed better cytocompatibility and antibacterial properties, while LDH-Co demonstrated high cytotoxicity. Based on these results, an optimized bilayer LDH coating enriched with Fe and Mn (LDH-MnFe) from top to bottom have been designed for further in vitro and in vivo analysis. The top Fe-riched layer provided biocompatibility and antibacterial properties, while the bottom Mn-riced layer provided excellent anti-corrosion, photothermal and enzymatic effects. In addition, the released Mg, Fe, and Mn ions have a positive influence on angiogenesis and osteogenesis. Thus, the LDH-MnFe showed complementary and synergistic effects on anti-corrosion and multibiofunctions (antibacteria, antitumor, and osteogenesis). The present work offers a novel multifunctional Mg-based implant for treating bone diseases.

Molecular Mechanism Underlying the Action of a Celastrol-Loaded Layered Double Hydroxide-Coated Magnesium Alloy in Osteosarcoma Inhibition and Bone Regeneration.

Osteosarcoma (OS) is a malignant bone tumor that threatens human health. Surgical removal of the tumor and followed by implantation with a graft is the golden standard for its clinical treatment. However, avoiding recurrence by enhancing the antitumor properties of the implants and improving osteogenesis around the implants remain a challenge. Here, we developed a layered double hydroxide (LDH)-coated magnesium (Mg) alloy and loaded it with celastrol. The celastrol-loaded Mg alloy exhibited enhanced corrosion resistance and sustained release of celastrol. In vitro cell culture suggested that the modified Mg alloy loaded with an appropriate amount of celastrol significantly inhibited the proliferation and migration of bone tumor cells while having little influence on normal cells. A mechanistic study revealed that the celastrol-loaded Mg alloy upregulated reactive oxygen species (ROS) generation in bone tumor cells, resulting in mitochondrial dysfunction due to reduced membrane potential, thereby inducing bone tumor cell apoptosis. Furthermore, it was found that celastrol-induced autophagy in tumor cells inhibited cell apoptosis in the initial 6 h. After ≥12 h of culture, inhibition of the PI3K-Akt-mTOR signaling pathway was noted, resulting in excessive autophagy in tumor cells, finally causing cell apoptosis. The celatsrol-loaded Mg alloy also exhibited effective antitumor properties in a subcutaneous tumor model. In vitro tartrate-resistant acid phosphatase (TRAP) staining and gene expression results revealed that the modified Mg alloy reduced the viability of osteoclasts, inducing a potential pathway for the increased bone regeneration around the modified Mg alloy seen in vivo. Together, the results of our study show that the celatsrol-loaded Mg alloy might be a promising implant for treating OS.

A copper-metal organic framework enhances the photothermal and chemodynamic properties of polydopamine for melanoma therapy.

The combination of photothermal treatment and chemodynamic therapy has attracted extensive attention for improving therapeutic effects and compensating the insufficiency of monotherapy. In this work, a copper-metal organic framework (Cu-BTC) was used to augment the photothermal effect of polydopamine (PDA) and endow it with a chemodynamic ability by constructing a Cu-BTC@PDA nanocomposite. Density functional theory calculations revealed that the plasmonic vibrations formed by the d-d transition of Cu at the Fermi level in Cu-BTC@PDA could enhance the photothermal performance of PDA. In addition, more Cu2+ released from Cu-BTC@PDA in the acidic microenvironment of the tumor was then reduced to Cu+ by glutathione (GSH) and further catalyzed H2O2 to generate more toxic hydroxyl radical (•OH), which synergized with photothermal treatment for melanoma therapy. Furthermore, Cu-BTC@PDA could quickly and effectively kill bacteria under the action of PTT, and the sustained release of Cu ions could contribute to the long-term and stable bacteriostatic ability of the material. This sustained release of Cu ions could also promote the cell migration and angiogenesis, and upregulate the expression of COL-, TGF-, and VEGF-related genes to accelerate wound healing. This multifunctional nanomaterial has potential application in the treatment of melanoma and repair of wounds. STATEMENT OF SIGNIFICANCE: We constructed a multifunctional nanoplatform (Cu-BTC@PDA) by two steps. This nanoplatform can not only perform cascade catalysis in the tumor microenvironment to generate more toxic hydroxyl radical (•OH), but also synergize with photothermal treatment for melanoma therapy. Additionally, Cu-BTC@PDA possesses enhanced photothermal performance through the plasmonic vibrations formed by the d-d transition of Cu at the Fermi level in Cu-BTC@PDA, which is revealed by DFT calculations. And Cu-BTC@PDA shows good antitumor, antibacterial, and wound healing properties in vivo and in vitro. Such a multifunctional nanomaterial has potential application in the treatment of melanoma and repair of wounds.

Shifting focus from bacteria to host neutrophil extracellular traps of biodegradable pure Zn to combat implant centered infection.

The widespread use of orthopedic implants to support or replace bones is increasingly threatened by the risk of incurable bacterial infections, impenetrable microbial biofilms, and irreversible antibiotic resistance. In the past, the development of anti-infective biomaterials focused solely on direct antibacterial properties while ignoring the host's immune response. Inspired by the clearance of infection by the innate neutrophil response and participation in anti-infectious immunity of Zn ions, we report an innovative neutrophil extracellular traps (NETs) strategy, induced by biodegradable pure Zn, which achieved therapeutic efficacy toward biomaterial-related infections. Our in vitro and in vivo data showed that pure Zn was favorable for NETs formation by promoting the release of DNA fibers and granule proteins in a reactive oxygen species (ROS)-dependent manner, thereby retraining and degrading bacteria with an efficiency of up to 99.5%. Transcriptome analysis revealed that cytoskeletal rearrangement and toll-like receptor (TLR) signaling pathway were also involved in Zn-induced NETs formation. Furthermore, the in vivo results of a Staphylococcus aureus (S. aureus)-infected rat model verified that pure Zn potentiated the bactericidal capability of neutrophils around implants, and promoted osseointegration in S. aureus-infected rat femurs. This antibacterial immunity concept lays a foundation for the development of other antibacterial biomaterials and holds great promise for treating orthopedic infections.

External validation of the SORG machine learning algorithms for predicting 90-day and 1-year survival of patients with lung cancer-derived spine metastases: a recent bi-center cohort from China.

BACKGROUND CONTEXT: The survival prediction of lung cancer-derived spinal metastases is often underestimated by several scores. The SORG machine learning (ML) algorithm is considered a promising tool to predict the risk of 90-day and 1-year mortality in patients with spinal metastases, but not been externally validated for lung cancer. PURPOSE: This study aimed to externally validate the SORG ML algorithms on lung cancer-derived spinal metastases patients from two large-volume, tertiary medical centers between 2018 and 2021. STUDY DESIGN/SETTING: Retrospective, cohort study. PATIENT SAMPLE: Patients aged 18 years or older at two tertiary medical centers in China are treated surgically for spinal metastasis. OUTCOME MEASURES: Mortality within 90 days of surgery, mortality within 1 year of surgery. METHODS: The baseline characteristics were compared between the development cohort and our validation cohort. Discrimination (receiver operating curve), calibration (calibration plot, intercept, and slope), the overall performance (Brier score), and decision curve analysis was used to assess the overall performance of the SORG ML algorithms. RESULTS: This study included 150 patients with lung cancer-derived spinal metastases from two medical centers in China. Ninety-day and 1-year mortality rates were 12.9% (19/147) and 51.3% (60/117), respectively. Lung Cancer with targeted therapies had the lowest Hazard Ratio (HR=0.490), showing an optimal protecting factor. The AUC of the SORG ML algorithm for 90-day mortality prediction in lung cancer-derived spinal metastases is 0.714. While the AUC for 1-year mortality prediction is 0.832 (95CI%, 0.758-0.906). The algorithm for 1-year mortality was well-calibrated with an intercept of 0.13 and a calibration slope of 1.00. However, the 90-day mortality prediction was underestimated with an intercept of 0.60 and a slope of 0.37. The SORG ML algorithms for 1-year mortality showed a greater net benefit than the "treats all or no patients" strategies. CONCLUSIONS: In the latest cohort of lung cancer-derived spinal metastases in China, the SORG algorithms for predicting 1-year mortality performed well on external validation. However, 90-day mortality was underestimated. The algorithm should be further validated by single primary tumor-derived metastasis treated with the latest comprehensive treatment in diverse populations.

Light-Programmable Nanocomposite Hydrogel for State-Switchable Wound Healing Promotion and Bacterial Infection Elimination.

Developing an ideal wound dressing that not only accelerates wound healing but also eliminates potential bacterial infections remains a difficult balancing act. This work reports the design of a light-programmable sodium alginate nanocomposite hydrogel loaded with BiOCl/polypyrrole (BOC/PPy) nanosheets for state-switchable wound healing promotion and bacterial infection elimination remotely. The nanocomposite hydrogel possesses programmable photoelectric or photothermal conversion due to the expanded light absorption range, optimized electron transmission interface, promoted photo-generated charge separation, and transfer of the BOC/PPy nanosheets. Under white light irradiation state, the nanocomposite hydrogel induces human umbilical vein endothelial cells migration and angiogenesis, and accelerates the healing efficiency of mouse skin in vivo. Under near-infrared light irradiation state, the nanocomposite hydrogel presents superior antibacterial capability in vitro, and reaches an antibacterial rate of 99.1% for Staphylococcus aureus infected skin wound in vivo. This light-programmable nanocomposite hydrogel provides an on-demand resolution of biological state-switching to balance wound healing and elimination of bacterial infection.

Oxyhydroxide-Coated PEO-Treated Mg Alloy for Enhanced Corrosion Resistance and Bone Regeneration.

Plasma electrolytic oxidation (PEO) is widely used as a surface modification method to enhance the corrosion resistance of Mg alloy, the most likely applied biodegradable material used in orthopedic implants. However, the pores and cracks easily formed on the PEO surface are unfavorable for long-term corrosion resistance. In this study, to solve this problem, we used simple immersion processes to construct Mn and Fe oxyhydroxide duplex layers on the PEO-treated AZ31 (PEO-Mn/Fe). As control groups, single Mn and Fe oxyhydroxide layers were also fabricated on PEO (denoted as PEO-Mn and PEO-Fe, respectively). PEO-Mn showed a similar porous morphology to the PEO sample. However, the PEO-Fe and PEO-Mn/Fe films completely sealed the pores on the PEO surfaces, and no cracks were observed even after the samples were immersed in water for 7 days. Compared with PEO, PEO-Mn, and PEO-Fe, PEO-Mn/Fe exhibited a significantly lower self-corrosion current, suggesting better corrosion resistance. In vitro C3H10T1/2 cell culture showed that PEO-Fe/Mn promoted the best cell growth, alkaline phosphatase activity, and bone-related gene expression. Furthermore, the rat femur implantation experiment showed that PEO-Fe/Mn-coated Mg showed the best bone regeneration and osteointegration abilities. Owing to enhanced corrosion resistance and osteogenesis, the PEO-Fe/Mn film on Mg alloy is promising for orthopedic applications.

Li-Doped Ti Surface for the Improvement of Osteointegration.

Aseptic loosening is the main factor that leads to the failure of orthopedic implants. Enhancing the early osteointegration of a bone implant can lower the risk of aseptic loosening. Here, a Li-doped surface was constructed on a Ti surface via plasma electrolytic oxidation (PEO) to improve osteointegration. The prepared Li-doped PEO coating showed a porous morphology and the sustained release of Li ions. In vitro results of rat bone marrow mesenchymal stem cell (rBMSC) culture studies suggested that the Li-doped Ti surface significantly favored cell adhesion. Moreover, it was found that the Li-doped surface enhanced alkaline phosphatase activity and extracellular matrix mineralization of rBMSCs. In addition, the surface improved the expression of osteogenesis-related genes. Furthermore, a bone implantation model indicated that the Li-doped Ti surface showed improved osteointegration. The incorporation of Li into a Ti surface is a promising method for orthopedic applications.

Porous thermosensitive coating with water-locking ability for enhanced osteogenic and antibacterial abilities.

Preferable antibacterial property and osteogenesis are the permanent pursuit for metallic implants. However, it is difficult to satisfy both the properties. In fact, implants may be contaminated with bacteria during storage and surgery, leading to inflammation. Therefore, the antibacterial property of biomaterial surfaces is required not only in the human environment but also at room temperature. In this study, porous structures loaded with a thermosensitive poly (N-isopropylacrylamide) (PNIPAM) hydrogel on a nitinol (NiTi) substrate were constructed. When the temperature is 25 â€‹°C, almost all bacteria cannot adhere to the sample surface due to the abundant hydration layer of the PNIPAM hydrogel. Meanwhile, when the temperature is 37 â€‹°C, the structure of the PNIPAM hydrogel collapses and the hydration layer disappears due to the temperature change. However, the porous structures lock water in the pores, which results in a high-hydration-rate sample surface. This surface has few bacterial adhesion sites; nevertheless, the adhesion of larger cells to the surface is not impeded by the porous structure. In addition, the PNIPAM hydrogel is soft and biocompatible, so the sample can have better cell adhesion and proliferation than a bare NiTi alloy. Based on these results, it can be concluded that the porous NiTi sample loaded with the thermosensitive PNIPAM hydrogel has the antibacterial property before implantation and the dual function of inhibiting bacterial adhesion and promoting cell adhesion and proliferation after implantation, which shows promising applications in the biomedical field such as orthopedic implantation.

Mg(OH)2 nanosheets on Ti with immunomodulatory function for orthopedic applications.

Macrophages play a vital role for guiding the fate of osteogenesis- related cells. It is well known that nano-topography and bioactive ions can directly enhance osteogenic behavior. However, the effects of nano-structure combined with bioactive ions release on macrophage polarization and the following osteogenesis and angiogenesis are rarely reported. Herein, Mg(OH)2 films with nano-sheet structures were constructed on the surface of Ti using hydrothermal treatment. The film presented nano-sheet topography and sustained release of Mg ions. The results of in vitro culture of bone marrow-derived macrophages (BMDMs), including PCR, western blot and flow cytometry suggested that the nano-Mg(OH)2 films were more favorable for macrophages polarizing to tissue healing M2 phenotype. Moreover, air-pouch model confirmed that the nano-Mg(OH)2 film coated Ti would induce milder inflammation and thinner fibrous layer in vivo, compared with untreated Ti. Furthermore, macrophages-conditioned culture mediums were collected from nano-Mg(OH)2 coated Ti group was superior for the osteogenic behaviors of mice bone marrow stem cells and the angiogenic behaviors of human umbilical vein endothelial cells. With harmonious early inflammatory response and subsequently improved osteogenesis and angiogenesis, the nano-Mg(OH)2 coated Ti is promising for orthopedic applications.

Strontium-Containing Barium Titanate-Modified Titanium for Enhancement of Osteointegration.

One of the major challenges for Ti-based implants is insufficient osteointegration, which might result in the loosening of the implant. In this study, we fabricated strontium (Sr)-containing barium titanate (BST) on the surface of Ti to improve the bioactivity for osteointegration enhancement. The introduction of Sr significantly reduced the crystallization time and improved crystallinity, which was proved by X-ray diffraction, X-ray photoelectron spectroscopy, and transmission electron microscopy. Compared with Ti, the BST film showed greater wettability surface and lower elastic modulus and hardness. Furthermore, in synergy with the release of Sr ions, the BST film improved early adhesion and followed osteogenic differentiation of rat bone mesenchymal stem cells. Furthermore, the bone implantation experiment suggested that the BST film could significantly improve the in vivo osteogenesis and osteointegration capabilities of Ti implants. In summary, this study revealed that BST-modified Ti has potential application in bone repair.

Black Mn-containing layered double hydroxide coated magnesium alloy for osteosarcoma therapy, bacteria killing, and bone regeneration.

Osteosarcoma (OS) tissue resection with distinctive bactericidal activity, followed by regeneration of bone defects, is a highly demanded clinical treatment. Biodegradable Mg-based implants with desirable osteopromotive and superior mechanical properties to polymers and ceramics are promising new platforms for treating bone-related diseases. Integration of biodegradation control, osteosarcoma destruction, anti-bacteria, and bone defect regeneration abilities on Mg-based implants by applying biosafe and facile strategy is a promising and challenging topic. Here, a black Mn-containing layered double hydroxide (LDH) nanosheet-modified Mg-based implants was developed. Benefiting from the distinctive capabilities of the constructed black LDH film, including near-infrared optical absorption and reactive oxygen species (ROS) generation in a tumor-specific microenvironment, the tumor cells and tissue could be effectively eliminated. Concomitant bacteria could be killed by localized hyperthermia. Furthermore, the enhanced corrosion resistance and synergistic biofunctions of Mn and Mg ions of the constructed black LDH-modified Mg implants significantly facilitated cell adhesion, spreading and proliferation and osteogenic differentiation in vitro, and accelerated bone regeneration in vivo. This work offers a new platform and feasible strategy for OS therapeutics and bone defect regeneration, which broadens the biomedical application of Mg-based alloys.

Zinc-doped ferric oxyhydroxide nano-layer enhances the bactericidal activity and osseointegration of a magnesium alloy through augmenting the formation of neutrophil extracellular traps.

Implant-associated infections (IAI) and osseointegration disorders are the most common complications in orthopedics. Studies have shown that neutrophils surrounding implants play a vital role in regulating these complications. Although magnesium (Mg) and its alloys are considered promising biodegradable bone implants, their role in neutrophil-mediated antibacteria has not yet been examined. Considering the rapid corrosion of Mg, it is necessary to develop methods to inhibit its corrosion. To solve these issues, a zinc-doped ferric oxyhydroxide nano-layer modified plasma electrolytic oxidation (PEO)-coated Mg alloy (PEO-FeZn) was developed in this study, and its antibacterial, immune anti-infective, and osteogenic ability were systematically evaluated. The results showed that PEO-FeZn nano-layer enhanced the corrosion resistance, biocompatibility, bactericidal activity, and osteoblastic differentiation activity of the Mg alloy. Moreover, PEO-FeZn nano-layer inhibited immune evasion-related gene expression and contributed to the formation of neutrophil extracellular traps (NETs) by activating the extracellular release of DNA fibers and granule proteins, and thereby suppressing bacterial invasion and promoting osseointegration in vivo in Staphylococcus aureus (S. aureus)-infected rat femurs. Overall, the findings of this study could serve as a reference for the fabrication of highly biocompatible and corrosion resistant Mg alloys to address the challenges of IAI and osseointegration disorders. STATEMENT OF SIGNIFICANCE: The widely used metallic biomaterials usually come with the risk of IAI. As the first responder around the biomaterials, neutrophils could form NETs to defense against microorganism and promote tissue remodeling. Therefore, biomaterials addressing antibacterial and neutrophils-modulatory strategies are highly necessary in reducing IAI. To solve these issues, we grew PEO-FeZn nano-layers in situ on Mg alloy using a simple and green technique. The nano-layer not only enhanced the corrosion resistance and biocompatibility of Mg alloy, but also elevated the antibacterial and osteogenesis capability. Moreover, nano-layer contributed to NETs formation, thereby suppressing bacterial invasion and even promoting osseointegration in S.aureus-infected femurs. Accordingly, this functionalized multilayer coating with antibacterial immunity represents a novel therapeutic strategy for IAI and weak osseointegration.