State-of-the-Art Functional Biomaterials in China.

In recent years, rapid advancements in multidisciplinary fields (materials, biology, chemical physics, etc [...].

Manganese-Implanted Titanium Modulates the Crosstalk between Bone Marrow Mesenchymal Stem Cells and Macrophages to Improve Osteogenesis.

Manganese (Mn) is an essential micronutrient in various physiological processes, but its functions in bone metabolism remain undefined. This is partly due to the interplay between immune and bone cells because Mn plays a central role in the immune system. In this study, we utilized the plasma immersion ion implantation and deposition (PIII&D) technique to introduce Mn onto the titanium surface. The results demonstrated that Mn-implanted surfaces stimulated the shift of macrophages toward the M1 phenotype and had minimal effects on the osteogenic differentiation of mouse bone marrow mesenchymal stem cells (mBMSCs) under mono-culture conditions. However, they promoted the M2 polarization of macrophages and improved the osteogenic activities of mBMSCs under co-culture conditions, indicating the importance of the crosstalk between mBMSCs and macrophages mediated by Mn in osteogenic activities. This study provides a positive incentive for the application of Mn in the field of osteoimmunology.

Atomic Layer Deposition of Tantalum Oxide Films on 3D-Printed Ti6Al4V Scaffolds with Enhanced Osteogenic Property for Orthopedic Implants.

There is an evident advantage in personalized customization of orthopedic implants by 3D-printed titanium (Ti) and its alloys. However, 3D-printed Ti alloys have a rough surface structure caused by adhesion powders and a relatively bioinert surface. Therefore, surface modification techniques are needed to improve the biocompatibility of 3D-printed Ti alloy implants. In the present study, porous Ti6Al4V scaffolds were manufactured by a selective laser melting 3D printer, followed by sandblasting and acid-etching treatment and atomic layer deposition (ALD) of tantalum oxide films. SEM morphology and surface roughness tests confirmed that the unmelted powders adhered on the scaffolds were removed by sandblasting and acid-etching. Accordingly, the porosity of the scaffold increased by about 7%. Benefiting from the self-limitation and three-dimensional conformance of ALD, uniform tantalum oxide films were formed on the inner and outer surfaces of the scaffolds. Zeta potential decreased by 19.5 mV after depositing tantalum oxide films. The in vitro results showed that the adhesion, proliferation, and osteogenic differentiation of rat bone marrow mesenchymal stem cells on modified Ti6Al4V scaffolds were significantly enhanced, which may be ascribed to surface structure optimization and the compatibility of tantalum oxide. This study provides a strategy to improve the cytocompatibility and osteogenic differentiation of porous Ti6Al4V scaffolds for orthopedic implants.

Microenvironment-responsive electrocution of tumor and bacteria by implants modified with degenerate semiconductor film.

Implantable biomaterials are widely used in the curative resection and palliative treatment of various types of cancers. However, cancer residue around the implants usually leads to treatment failure with cancer reoccurrence. Postoperation chemotherapy and radiation therapy are widely applied to clear the residual cancer cells but induce serious side effects. It is urgent to develop advanced therapy to minimize systemic toxicity while maintaining efficient cancer-killing ability. Herein, we report a degenerate layered double hydroxide (LDH) film modified implant, which realizes microenvironment-responsive electrotherapy. The film can gradually transform into a nondegenerate state and release holes. When in contact with tumor cells or bacteria, the film quickly transforms into a nondegenerate state and releases holes at a high rate, rendering the "electrocution" of tumor cells and bacteria. However, when placed in normal tissue, the hole release rate of the film is much slower, thus, causing little harm to normal cells. Therefore, the constructed film can intelligently identify and meet the physiological requirements promptly. In addition, the transformation between degenerate and nondegenerate states of LDH films can be cycled by electrical charging, so their selective and dynamic physiological functions can be artificially adjusted according to demand.

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.

AMPK/mTOR Pathway Is Involved in Autophagy Induced by Magnesium-Incorporated TiO2 Surface to Promote BMSC Osteogenic Differentiation.

Magnesium has been extensively utilized to modify titanium implant surfaces based on its important function in promoting osteogenic differentiation. Autophagy has been proven to play a vital role in bone metabolism. Whether there is an association between autophagy and magnesium in promoting osteogenic differentiation remains unclear. In the present study, we focused on investigating the role of magnesium ions in early osteogenic activity and the underlying mechanism related to autophagy. Different concentrations of magnesium were embedded in micro-structured titanium surface layers using the micro-arc oxidation (MAO) technique. The incorporation of magnesium benefited cell adhesion, spreading, and viability; attenuated intracellular ATP concentrations and p-mTOR levels; and upregulated p-AMPK levels. This indicates the vital role of the ATP-related AMPK/mTOR signaling pathway in the autophagy process associated with osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) induced by magnesium modification on titanium surfaces. The enhanced osteogenic differentiation and improved cellular autophagy activity of BMSCs in their extraction medium further confirmed the function of magnesium ions. The results of the present study advance our understanding of the mechanism by which magnesium regulates BMSC osteogenic differentiation through autophagy regulation. Moreover, endowing implants with the ability to activate autophagy may be a promising strategy for enhancing osseointegration in the translational medicine field in the future.

A multifunctional cascade bioreactor based on a layered double oxides composite hydrogel for synergetic tumor chemodynamic/starvation/photothermal therapy.

The field of nanomedicine-catalyzed tumor therapy has achieved a lot of progress; however, overcoming the limitations of the tumor microenvironment (TME) to achieve the desired therapeutic effect remains a major challenge. In this study, a nanocomposite hydrogel (GH@LDO) platform combining the nanozyme CoMnFe-layered double oxides (CoMnFe-LDO) and natural enzyme glucose oxidase (GOX) was engineered to remodel the TME to enhance tumor catalytic therapy. The CoMnFe-LDO is a nanozyme that can convert endogenous H2O2 into reactive oxygen species (ROS) and O2 to achieve chemodynamic therapy (CDT) and alleviate the hypoxic microenvironment. Meanwhile, GOX can catalyze the conversion of glucose and O2 to gluconic acid and H2O2, which not only represses the ATP production of tumor cells to achieve starvation therapy (ST), but also decreases the pH value of TME and supplies extra H2O2 to enhance the CDT effect. Furthermore, this well-designed CoMnFe-LDO possessed a high photothermal conversion efficiency of GH@LDO (66.63%), which could promote the generation of ROS to enhance the CDT effect and achieve photothermal therapy (PTT) under near-infrared light irradiation. The GH@LDO hydrogel performes cascade reaction which overcomes the limitation of the TME and achieves satisfactory CDT/ST/PTT synergetic effects in vitro and in vivo. This work provides a new strategy for remodeling the TME using nanomedicine to achieve precise tumor cascaded catalytic therapy. STATEMENT OF SIGNIFICANCE: At present, the focus of tumor therapy has begun to shift from monotherapy to combination therapy for improving the overall therapeutic effect. In this study, we synthesized a CoMnFe-LDO nanozyme composed of multiple transition metal oxides, which demonstrated improved peroxidase and oxidase activities as well as favorable photothermal conversion capability. The CoMnFe-LDO nanozyme was compounded with an injectable GH hydrogel crosslinked by GOX and horseradish peroxidase (HRP). This nanocomposite hydrogel overcame the limitations of weak acidity, H2O2, and O2 levels in the TME and achieved synergetic CDT, ST, and PTT effects based on the cascaded catalytic actions of CoMnFe-LDO and GOX to H2O2 and glucose.

Layered Double Hydroxide-Based Micro "Chemical Factory" with Arsenic Processing and Screening Functions on Nitinol for Gallbladder Cancer Treatment.

Gallbladder cancer is a common malignant tumor of the biliary system with a high fatality rate. Nitinol (Ni-Ti) stents, a standard treatment for prolonging patients' lives, are susceptible to reocclusion and cannot inhibit tumor recurrence because they lack antitumor and antibacterial activity. Herein, an arsenic-loaded layered double-hydroxide film is constructed on Ni-Ti, forming a micro "chemical factory." The LDH plays the role of a "processer" which absorbs highly toxic trivalent arsenic (As(III)) and processes it into lowly toxic pentavalent arsenic (As(V)). It also acts as a "quality-inspector," confining As(III) in the interlayer and releasing only As(V) (the finished product) to the outside. This control mechanism minimizes the toxicity during contact with normal tissue. The acidic microenvironment and overexpression of glutathione in tumor tissues not only accelerates the release of arsenic from the platform but also triggers the in situ transformation of arsenic from lowly toxic As(V) to highly toxic As(III), exerting a strong arsenic-mediated antineoplastic effect. Such a microenvironment-responsive "chemical factory" with arsenic processing and screening functions is expected to prevent tumor overgrowth, metastasis, and bacterial infection and provide new insights into the design of Ni-Ti drug-eluting stents for gallbladder cancer treatment.

Constructing fluorine-doped Zr-MOF films on titanium for antibacteria, anti-inflammation, and osteogenesis.

Implant infection, undesirable inflammation, and poor osseointegration are the primary reasons for implant failure, so it is pivotal to endow bone implants with antibacterial, anti-inflammatory, and osteogenic properties. Here, a multifunctional fluorine-doped zirconium-metal organic framework (Zr-MOF) film was constructed on the titanium to modify its biological performances. The fumaric acid, a common antioxidant, was selected as the ligand of Zr-MOF, and the hydrofluoric acid was used as the modulator to control the growth of Zr-MOF film. The obtained fluorine-doped Zr-MOF film possessed good biocompatibility and osteogenic ability, and it showed good antibacterial effects against both gram-positive S. aureus and gram-negative E. coli due to the release of fluoride ions. In addition, the doping of fluorine could reduce the stability of Zr-MOF by substituting fumaric acid, and stimulating the releases of fumaric acid. Furthermore, the fumaric acid released from Zr-MOF could down-regulate the expression of pro-inflammatory genes (NF-κB and IL-6), but up-regulate the expression of anti-inflammatory gene of IL-4 of macrophage, showing good anti-inflammatory ability. This study provided a reference for the modulation synthesis of MOF film, and proposed a promising strategy of designing Zr-MOF film to endow bone implants with antibacterial, anti-inflammatory, and osteogenic abilities.

Mechanical Force Induced Self-Assembly of Chinese Herbal Hydrogel with Synergistic Effects of Antibacterial Activity and Immune Regulation for Wound Healing.

Skin wounds, especially infected chronic wounds, have attracted worldwide attention due to the high prevalence and poor treatment outcomes. Hydrogel dressings with antibacterial ability and immune regulation property are urgently required. Herein, inspired by the grinding treatment of traditional Chinese medicine, mechanical force is introduced to promote the effective molecular collision and accelerate the self-assembly of chitosan (CS) and puerarin (PUE) for fabricating Chinese-herb-based hydrogels. The antibacterial rate of CS@PUE (C@P) hydrogel is more than 95%, and the wound closed rate is twice that of the control group. Interestingly, the rational design of C@P hydrogels with different PUE ratios enables a refined control over hydrogel formation, nanofiber appearance, viscoelastic, physicochemical, and biological properties. The extraordinary antibacterial ability of C@P hydrogels may originate from the nanofiber structure and the improved zeta potential on account of the orientation of amino groups in CS . Thus, the synergistically antibacterial and immune regulation properties of C@P hydrogels kill bacteria and relieve inflammation in the wound bed, ensuring the anti-infection effect, and boosting wound healing. In addition to providing a universal mechanosynthesis of PUE-based hydrogel for wound healing, this finding is expected to increase the attention paid to Chinese herbal medicines in the construction of biomaterials.

Hydroxyapatite composited PEEK with 3D porous surface enhances osteoblast differentiation through mediating NO by macrophage.

The adverse immune response mediated by macrophages is one of the main factors that are prone to lead poor osseointegration of polyetheretherketone (PEEK) implants in clinic. Hence, endowing PEEK with immunomodulatory ability to avoid the adverse immune response becomes a promising strategy to promote bone repair. In this work, sulfonation and hydrothermal treatment were used to fabricate a 3D porous surface on PEEK and hydroxyapatite (HA) composited PEEK. The HA composited PEEK with 3D porous surface inhibited macrophages polarizing to M1 phenotype and downregulated inducible nitric oxide synthase protein expression, which led to a nitric oxide concentration reduction in culture medium of mouse bone marrow mesenchymal stem cells (mBMSCs) under co-culture condition. The decrease of nitric oxide concentration could help to increase bone formation-related OSX and ALP genes expressions and decrease bone resorption-related MMP-9 and MMP-13 genes expressions via cAMP-PKA-RUNX2 pathway in mBMSCs. In summary, the HA composited PEEK with 3D porous surface has the potential to promote osteogenesis of PEEK through immunomodulation, which provides a promising strategy to improve the bone repair ability of PEEK.

A Novel Stimuli-Responsive Injectable Antibacterial Hydrogel to Achieve Synergetic Photothermal/Gene-Targeted Therapy towards Uveal Melanoma.

Uveal melanoma (UM) is the most prevalent primary intraocular malignant tumor with a high lethal rate. Patients who undergo conventional enucleation treatments consistently suffer permanent blindness, facial defects, and mental disorders, therefore, novel therapeutic modalities are urgently required. Herein, an injectable and stimuli-responsive drug delivery antibacterial hydrogel (CP@Au@DC_AC50) is constructed via a facile grinding method that is inspired by the preparation process of traditional Chinese medicine. The incorporation of gold nanorods can enhance the mechanical strength of the hydrogel and realize photothermal therapy (PTT) and thermosensitive gel-sol transformation to release the gene-targeted drug DC_AC50 on demand in response to low-density near-infrared (NIR) light. The orthotopic model of UM is built successfully and indicates the excellent efficiency of CP@Au@DC_AC50 in killing tumors without damage to normal tissue because of its synergistic mild temperature PTT and gene-targeted therapy. Moreover, the eyeball infection model reveals the remarkable antibacterial properties of the hydrogel which can prevent endophthalmitis in the eyeball. There is negligible difference between the CP@Au@DC_AC50+NIR group and normal group. This NIR light-triggered gene-targeted therapy/PTT/antibacterial treatment pattern provides a promising strategy for building multifunctional therapeutic platform against intraocular tumors and exhibits great potential for the clinical treatment of UM.

Synergistic effects of immunoregulation and osteoinduction of ds-block elements on titanium surface.

Ds-block elements have been gaining increasing attention in the field of biomaterials modification, owing to their excellent biological properties, such as antibiosis, osteogenesis, etc. However, their function mechanisms are not well understood and conflicting conclusions were drawn by previous studies on this issue, which are mainly resulted from the inconsistent experimental conditions. In this work, three most widely used ds-block elements, copper, zinc, and silver were introduced on titanium substrate by plasma immersion ion implantation method to investigate the rule of ds-block elements in the immune responses. Results showed that the implanted samples could decrease the inflammatory responses compared with Ti sample. The trend of anti-inflammatory effects of macrophages on samples was in correlation with cellular ROS levels, which was induced by the implanted biomaterials and positively correlated with the number of valence electrons of ds-block elements. The co-culture experiments of macrophages and bone marrow mesenchymal stem cells showed that these two kinds of cells could enhance the anti-inflammation and osteogenesis of samples by the paracrine manner of PGE2. In general, in their steady states on titanium substrate (Cu2+, Zn2+, Ag), the ds-block elements with more valence electrons exhibit better anti-inflammatory and osteogenic effects. Moreover, molecular biology experiments indicate that the PGE2-related signaling pathway may contribute to the desired immunoregulation and osteoinduction capability of ds-block elements. These findings suggest a correlation between the number of valence electrons of ds-block elements and the relevant biological responses, which provides new insight into the selection of implanted ions and surface design of biomaterials.

Enhanced physicochemical and biological properties of C/Cu dual ions implanted medical titanium.

It is increasingly popular for titanium and its alloys to be utilized as the medical implants. However, their bio-inert nature and lack of antibacterial ability limit their applications. In this work, by utilizing plasma immersion ion implantation and deposition (PIII&D) technology, the titanium surface was modified by C/Cu co-implantation. The mechanical property, corrosion resistance, antibacterial ability and cytocompatibility of modified samples were studied. Results indicate that after C/Cu co-implantation, copper nanoparticles were observed on the surface of titanium, and titanium carbide existed on the near surface region of titanium. The modified surface displayed good mechanical property and corrosion resistance. The Cu/C galvanic corrosion existed on the titanium surface implanted by C/Cu dual ions, and release of copper ions can be effectively controlled by the galvanic corrosion effect. Moreover, improved antibacterial performance of titanium surface can be achieved without cytotoxicity.

Dose-response relationships between copper and its biocompatibility/antibacterial activities.

BACKGROUND: Copper has already been widely used in the modification of biomaterials because it possesses multifunctional biological effects like osteogenic, angiogenic and antibacterial activities. However, it is still not clear how different cell lines and bacteria will respond to different concentrations of Cu2+, which is very critical to the application of copper-doped implants. METHODS: This study aimed to explore the dose-response relationships of Cu2+ and its biological effects in vitro. Rat bone marrow mesenchymal stem cell (rBMSCs), mouse osteoblastic cell line (MC3T3-E1), and human umbilical vein endothelial cells (HUVECs) were used to evaluate cellular behaviors. Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) were used to evaluate bacterial behaviors. RESULTS: Results showed that the HUVECs exhibited significantly higher tolerance to copper ions than MC3T3-E1 and rBMSCs. The IC50 values of copper for HUVECs, MC3T3-E1 and HUVECs were approximated to 327.9 µM, 134.6 µM, and 0.7 µM, respectively. Besides, the threshold concentration of copper for effective inhibition against bacteria growth is 37 µM. When the concentration exceeded the threshold value, antibacterial activity could increase dramatically. CONCLUSIONS: These results altogether establish a technological foundation for the application of copper-doped biomaterials in bone growth and remodeling.