Investigation of Mg-xLi-Zn alloys for potential application of biodegradable bone implant materials.

Implant therapy after osteosarcoma surgery is a major clinical challenge currently, especially the requirements for mechanical properties, degradability of the implants, and their inhibition of residual tumor cells. Biodegradable magnesium (Mg) alloy as medical bone implant material has full advantages and huge potential development space. Wherein, Mg-lithium (Li) based alloy, as an ultra-light alloy, has good properties for implants under certain conditions, and both Mg and Li have inhibitory effects on tumor cells. Therefore, Mg-Li alloy is expected to be applied in bone implant materials for mechanical supporting and inhibiting tumor cells simultaneously. In this contribution, the Mg-xLi-Zinc (Zn) series alloys (x = 3 wt%, 6 wt%, 9 wt%) were prepared to study the influence of different elements and contents on the structure and properties of the alloy, and the biosafety of the alloy was also evaluated. Our data showed that the yield strength, tensile strength, and elongation of as-cast Mg-xLi-Zn alloy were higher than those of as-cast Mg-Zn alloy; Mg-xLi-Zn alloy can kill osteosarcoma cells (MG-63) in a concentration-dependent manner, wherein Mg-3Li-Zn alloy (x = 3 wt%) and Mg-6Li-Zn alloy (x = 6 wt%) promoted the proliferation of osteoblasts (MC3T3) at a certain concentration of Li. In summary, our study demonstrated that the Mg-6Li-Zn alloy could be potentially applied as a material of orthopedic implant for its excellent multi-functions.

A DFT study of the adsorption of short peptides on Mg and Mg-based alloy surfaces.

Adsorption of short peptides, including three dipeptides: arginine-glycine (Arg-Gly), glycine-aspartic acid (Gly-Asp), arginine-aspartic acid (Arg-Asp), and one tripeptide arginine-glycine-aspartic acid (RGD), on the surfaces of Mg and Mg alloys (Mg-Zn, Mg-Y, and Mg-Nd), was studied using the first-principles calculations based on density functional theory (DFT), considering van der Waals (vdW) correction. The calculated adsorption energies (Eads) of short peptides on the clean Mg(0001) surface are in the range of -1.73 to -2.80 eV per dipeptide, and -3.24 eV for RGD. The short peptides prefer to bond to Mg atoms at the surface by the O and N anions in their functional groups. For the clean Mg(0001) surface, the Eads of the short peptides are exclusively dominated by the number of functional groups binding to the surface. However, for the surface of the Mg-Zn alloy (1% Zn), the adsorption of the peptides is clearly enhanced (by about 0.3 eV per peptide) due to the enhanced N-Mg bond and the electrostatic interactions between the doped Zn at the surface and the backbone chains of the peptides. Furthermore, the attractive interactions are increased with the increase of doped Zn contents (up to 3%). In contrast, for the surfaces of Mg-Y (1% Y) and Mg-Nd (1% Nd) alloys, the adsorption of the peptides is slightly weakened compared to that on the clean Mg(0001) surfaces. Our results provide useful guidance in understanding the interactions between peptides and the Mg-based biomedical alloy surfaces at the atomic scale in the biomimetic coating fields.

Investigation on the in vitro cytocompatibility of Mg-Zn-Y-Nd-Zr alloys as degradable orthopaedic implant materials.

Mg-Zn-Y-Nd-Zr alloy has been developed as a new type of biodegradable orthopaedic implant material by the authors' research group with its excellent mechanical properties and controllable degradation rate. In this study, the cytocompatibility of Mg-Zn-Y-Nd-Zr alloy was systematically evaluated through in vitro cell culture method. MTT assay was applied to evaluate the cytotoxicity of Mg-Zn-Y-Nd-Zr alloy and no toxic effect was observed on L929 and MC3T3-E1 cells followed the protocol of ISO 10993 standard. Considering the potential ion accumulation in the bony environment, this study further investigated the cytotoxic effect of accumulated metallic ions during the alloy degradation by extending the extract preparation time. When the extract preparation time was prolonged to 1440 h, the accumulated metallic ions leaded to severe cell apoptosis, of which the combined ion concentration was determined as 39.5-65.8 µM of Mg2+, 3.5-5.9 µM of Zn2+, 0.44-0.74 µM of Y3+, 0.3-0.52 µM of Nd3+ and 0.11-0.18 µM of Zr4+ for L929, and 65.8-92.2 µM of Mg2+, 5.9-8.3 µM of Zn2+, 0.74-1.04 µM of Y3+, 0.52-0.73 µM of Nd3+ and 0.18-0.25 µM of Zr4+ for MC3T3-E1 cells. Besides the cell viability assessment, high expression of ALP activity and calcified nodules implied that metal elements in Mg-Zn-Y-Nd-Zr alloys can promote the osteogenic differentiation. Hence, excellent cytocompatibility has equipped Mg-Zn-Y-Nd-Zr alloy as a promising candidate for orthopaedic implant application, which can remarkably guide the magnesium-based alloy design and provide scientific evidence for clinical practice in future.

A Cu(â ¡)-eluting coating through silk fibroin film on ZE21B alloy designed for in situ endotheliazation biofunction.

In the cardiovascular field, coating containing copper used to catalyze NO (nitric oxide) production on non-degradable metal surfaces have shown unparalleled expected performance, but there are few studies on biodegradable metal surfaces. Magnesium-based biodegradable metals have been applied in cardiovascular field in large-scale because of their excellent properties. In this study, the coating of copper loaded in silk fibroin is fabricated on biodegradable ZE21B alloy. Importantly, the different content of copper is set to investigate the effects of on the degradation performance and cell behavior of magnesium alloy. Through electrochemical and immersion experiments, it is found that high content of copper will accelerate the corrosion of magnesium alloy. The reason is the spontaneous micro-batteries between copper and magnesium with the different standard electrode potentials, that is, the galvanic corrosion accelerates the corrosion of magnesium alloy. Moreover, the coating formed through silk fibroin by the right amount copper not only have a protective effect on the ZE21B alloy substrate, but also promotes the adhesion and proliferation of endothelial cells in blood vessel micro-environment. The production of NO catalyzed by copper ions makes this trend more significant, and inhibits the excessive proliferation of smooth muscle cells. These findings can provide guidance for the amount of copper in the coating on the surface of biodegradable magnesium alloy used for cardiovascular stent purpose.

The enhanced antibacterial effect of BNNS_Van@CS/MAO coating on Mg alloy for orthopedic applications.

The development of multifunctional Mg-based active implants with controllable degradation and antibacterial capabilities has become a hotspot in the research field of biodegradable metallic materials. To this end, a BN nanosheets (BNNS) _vancomycin (Van) @chitosan (CS) nanocomposite coating containing two antibacterial components (BNNS and Van) was prepared on Mg alloys via a micro-arc oxidation (MAO) pre-treatment combined with following electrodeposition. The related characterizations of the coating show that the composite coating has a high roughness, hydrophobicity and fair corrosion resistance. In vitro antibacterial experiments show that the BNNS_Van@CS/MAO composite coating have obvious inhibitory effect on the growth of both E. coli and S. aureus. The antibacterial effect of the BNNS_Van@CS/MAO composite coating was attributed to the synergistic effect of CS, BNNS and Van. This study provides a valuable surface modification strategy for developing multifunctional Mg-based implants with good corrosion resistance and antibacterial properties.

Skin-friendly and antibacterial monodomain liquid crystal elastomer actuator.

Monodomain liquid crystal elastomers (mLCEs) are flexible and biocompatible smart materials that show unique behaviors of soft elasticity, anisotropy, and reversible shape changes above the nematic-isotropic transition temperature. Therefore, it has great potential for application in wearable devices and biologically. However, most of the reported mLCEs have nematic-isotropic transition temperature (TNI) higher than 60 °C; and above this TNI, the tensile strength of the mLCEs decreases by orders of magnitude. These issues have received little attention, limiting their application in humans. Herein, the TNI of mLCEs was reduced from 78.4 °C to 23.5 °C by substituting part of the rigid LC mesogens with a flexible backbone. The physical entanglement of hydrogen bonds between molecular chains alleviated the molecular chain slip caused by the long flexible backbone. The tensile strength remained constant during the phase transformation. Furthermore, dynamic disulfide bonds were used to modify the LC polymer network, imparting it with excellent antimicrobial, programmable, and self-healing properties. To realize its application in the closure of skin wounds, a porous PHG-mLCE/hydrogel patch that was breathable and waterproof was designed to increase skin adhesion (262 N/m).

A biodegradable magnesium alloy vascular stent structure: Design, optimisation and evaluation.

The existing biodegradable magnesium alloy stent (BMgS) structure is prone to problems, such as insufficient support capacity and early fracture at areas of concentrated stress. Herein, a stent structural design, which reduced the cross section of the traditional sin-wave stent by nearly 30% and introduces a regular arc structure in the middle of the support ring. The influence of the dual-parameter design of bending radius (r) and ring length (L) on plastic deformation, expansion and compression resistance performances are discussed. The non-dominated sorting genetic algorithm II (NSGA-II) was used to search for the optimal solution. It was found that the introduction of parameter r effectively improved the plastic deformation and expansion performance, and the reduction of L improved stent compression resistance. Finally, an optimized stent configuration was obtained. In vitro mechanical tests, including balloon inflation, radial strength and flexibility, verified the simulation results. The radial strength for the optimised stent increases by approximately 40% compared with that for the sinusoidal stent. Microarea X-ray diffraction result shows that the circumferential residual stress for the optimised stent decreases by half compared with that for the sinusoidal stent, thus effectively reducing the stress concentration phenomenon. STATEMENT OF SIGNIFICANCE: Despite current progress in BMgS research, the optimal design of the structure is limited. We present a new type of structurally designed stent. The performance of this stent was analysed by a finite element method and experimentally verified. The structural design positively influenced stent performance.

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.

Sol-gel coating loaded with inhibitor on ZE21B Mg alloy for improving corrosion resistance and endothelialization aiming at potential cardiovascular application.

To improve the service performance of vascular stents, we designed/selected a series of organic compounds from commercial drugs, natural plants, and marine life as the potential corrosion inhibitors for ZE21B alloy. Paeonol condensation tyrosine (PCTyr) Schiff base was found to be the most efficient inhibitor among them. The biocompatible, self-healing, anti-corrosive sol-gel coating loaded with corrosion inhibitor was fabricated on the Mg substrate through a convenient dip-coating tactic. The corrosion resistance, self-healing ability, cytotoxicity, and hemocompatibility of the coated sample were evaluated. These results suggested the potentiality of Schiff base inhibitor-loaded sol-gel coating for enhanced corrosion protection and desired biocompatibility of bioabsorbable cardiovascular implants.

Application of 3D Printing Technology in Bone Tissue Engineering: A Review.

Clinically, the treatment of bone defects remains a significant challenge, as it requires autogenous bone grafts or bone graft substitutes. However, the existing biomaterials often fail to meet the clinical requirements in terms of structural support, bone induction, and controllable biodegradability. In the treatment of bone defects, 3D porous scaffolds have attracted much attention in the orthopedic field. In terms of appearance and microstructure, complex bone scaffolds created by 3D printing technology are similar to human bone. On this basis, the combination of active substances, including cells and growth factors, is more conducive to bone tissue reconstruction, which is of great significance for the personalized treatment of bone defects. With the continuous development of 3D printing technology, it has been widely used in bone defect repair as well as diagnosis and rehabilitation, creating an emerging industry with excellent market potential. Meanwhile, the diverse combination of 3D printing technology with multi-disciplinary fields, such as tissue engineering, digital medicine, and materials science, has made 3D printing products with good biocompatibility, excellent osteoinductive capacity, and stable mechanical properties. In the clinical application of the repair of bone defects, various biological materials and 3D printing methods have emerged to make patient-specific bioactive scaffolds. The microstructure of 3D printed scaffolds can meet the complex needs of bone defect repair and support the personalized treatment of patients. Some of the new materials and technologies that emerged from the 3D printing industry's advent in the past decade successfully translated into clinical practice. In this article, we first introduced the development and application of different types of materials that were used in 3D bioprinting, including metal, ceramic materials, polymer materials, composite materials, and cell tissue. The combined application of 3D bioprinting and other manufacturing methods used for bone tissue engineering are also discussed in this article. Finally, we discussed the bottleneck of 3D bioprinting technique and forecasted its research orientation and prospect.

Influence of the second phase on protein adsorption on biodegradable Mg alloys' surfaces: Comparative experimental and molecular dynamics simulation studies.

The effect of the second phase on the mechanical properties and corrosion resistance of Mg alloys has been systematically studied. However, there is limited information on the effect of the second phase on protein adsorption behavior. In the present study, the effect of the second phase on protein adsorption on the surfaces of biodegradable Mg alloys was investigated using experimental methods and molecular dynamics (MD) simulations. The experimental results showed that the effect of the second phase on fibrinogen adsorption was type-dependent. Fibrinogen preferentially adsorbed on Y-, Ce-, or Nd-involved second phases, while the second phase containing Zn inhibited its adsorption. MD simulations revealed the mechanism of the second phase that influenced protein adsorption in terms of charge distribution, surface-protein interaction energy, and water molecule distribution. Our studies proposed a deep understanding of the design of Mg-based biomaterials with superior biocompatibility. STATEMENT OF SIGNIFICANCE: Mechanical properties, uniform degradation, and biocompatibility must be considered while designing biomedical Mg alloys. To improve the mechanical properties and corrosion resistance of Mg alloys, the second phase is usually required. However, the effects of the second phase on biocompatibility of Mg alloys have been rarely reported. Here, the influence of the second phase on protein adsorption was experimentally studied by designing Mg alloys with different types of second phase. The first principle calculation and MD simulation were used to reveal the mechanism by which the second phase influences protein adsorption. This work could be used to better elucidate the protein adsorption mechanisms and design principles to improve the biocompatibility of Mg alloys.

Microstructure and corrosion properties of as sub-rapid solidification Mg-Zn-Y-Nd alloy in dynamic simulated body fluid for vascular stent application.

Magnesium alloy stent has been employed in animal and clinical experiment in recent years. It has been verified to be biocompatible and degradable due to corrosion after being implanted into blood vessel. Mg-Y-Gd-Nd alloy is usually used to construct an absorbable magnesium alloy stent. However, the corrosion resistant of as cast Mg-Y-Gd-Nd alloy is poor relatively and the control of corrosion rate is difficult. Aiming at the requirement of endovascular stent in clinic, a new biomedical Mg-Zn-Y-Nd alloy with low Zn and Y content (Zn/Y atom ratio 6) was designed, which exists quasicrystals to improve its corrosion resistance. Additionally, sub-rapid solidification processing was applied for preparation of corrosion-resisting Mg-Zn-Y-Nd and Mg-Y-Gd-Nd alloys. Compared with the as cast sample, the corrosion behavior of alloys in dynamic simulated body fluid (SBF) (the speed of body fluid: 16 ml/800 ml min(-1)) was investigated. The results show that as sub-rapid solidification Mg-Zn-Y-Nd alloy has the better corrosion resistance in dynamic SBF due to grain refinement and fine dispersion distribution of the quasicrystals and intermetallic compounds in alpha-Mg matrix. In the as cast sample, both Mg-Zn-Y-Nd and Mg-Y-Gd-Nd alloys exhibit poor corrosion resistance. Mg-Zn-Y-Nd alloy by sub-rapid solidification processing provides excellent corrosion resistance in dynamic SBF, which open a new window for biomedical materials design, especially for vascular stent application.

Preparing a novel magnesium-doped hyaluronan/polyethyleneimine nanoparticle to improve endothelial functionalisation.

Nowadays, tissue engineering vascularisation has become an important means of organ repair and treatment of major traumatic diseases. Vascular endothelial layer regeneration and endothelial functionalisation are prerequisites and important components of tissue engineering vascularisation. The present researches of endothelial functionalisation mainly focus on tissue engineering scaffold preparation and implant surface modification. Few studies have reported the interaction of endothelial functionalisation and scaled materials, especially the nanomaterials. Magnesium (Mg), as an essential cytotropic active element in the human body, should promote the growth of endothelial cells. However, the authors' previous work found that the Mg in the alloys had a defect of delayed endothelialisation, which may be attributed to the non-uniform scales of the degradation products from Mg alloys. To validate this hypothesis and fabricate a novel nanomaterial for tissue engineering vascularisation, the authors prepared Mg-doped hyaluronan (HA)/polyethyleneimine (PEI) nanoparticles for endothelial cells testing. Their data showed that the Mg-doped HA/PEI nanoparticle with small scales (diameter <150 nm) presented better ability on improving endothelial cells growth, functionalisation and nitric oxide release.

Tailoring of cardiovascular stent material surface by immobilizing exosomes for better pro-endothelialization function.

Stent intervention as available method in clinic has been widely applied for cardiovascular disease treatment for decades. However, the restenosis caused by late thrombosis and hyperplasia still limits the stents long-term application, and the essential cause is usually recognized as endothelial functionalization insufficiency of the stent material surface. Here, we address this limitation by developing a pro-endothelial-functionalization surface that immobilized a natural factors-loaded nanoparticle, exosome, onto the poly-dopamine (PDA) coated materials via electrostatic binding. This PDA/Exosome surface not only increased the endothelial cells number on the materials, but also improved their endothelial function, including platelet endothelial cell adhesion molecule-1 (CD31) expression, cell migration and nitric oxide release. The pro-inflammation macrophage (M1 phenotype) attachment and synthetic smooth muscle cell proliferation as the interference factors for the endothelialization were not only inhibited by the PDA/Exosome coating, while the cells were also regulated to anti-inflammation macrophage (M2 phenotype) and contractile smooth muscle cell, which may contribute to endothelialization. Thus, it can be summarized this method has potential application on surface modification of cardiovascular biomaterials.

Effects of degradation products of biomedical magnesium alloys on nitric oxide release from vascular endothelial cells.

Nitric oxide (NO) released by vascular endothelial cells (VECs), as a functional factor and signal pathway molecule, plays an important role in regulating vasodilation, inhibiting thrombosis, proliferation and inflammation. Therefore, numerous researches have reported the relationship between the NO level in VECs and the cardiovascular biomaterials' structure/functions. In recent years, biomedical magnesium (Mg) alloys have been widely studied and rapidly developed in the cardiovascular stent field for their biodegradable absorption property. However, influence of the Mg alloys' degradation products on VEC NO release is still unclear. In this work, Mg-Zn-Y-Nd, an Mg alloy widely applied on the biodegradable stent research, was investigated on the influence of the degradation time, the concentration and reaction time of degradation products on VEC NO release. The data showed that the degradation product concentration and the reaction time of degradation products had positive correlation with NO release, and the degradation time had negative correlation with NO release. All these influencing factors were controlled by the Mg alloy degradation behaviors. It was anticipated that it might make sense for the cardiovascular Mg alloy design aiming at VEC NO release and therapy.

Processing and properties of magnesium alloy micro-tubes for biodegradable vascular stents.

Magnesium alloys are considered to be one of the most promising stent materials due to their good biological compatibility and biodegradable properties. However, the poor workability at room temperature restricts the processing of high-precision micro-tubes for the application as stent materials. In this study, Mg-Zn-Y-Nd alloy tube blank was firstly produced through hot extrusion. By multi-pass cold drawing combining with interpass annealing, the extruded tube blank can be processed into high-precision micro-tube with an outer diameter of about 2.0 mm and a wall thickness of about 0.15 mm. The drawn micro-tube after annealing exhibits improved mechanical properties with an ultimate tensile strength of about 298 MPa and a large breaking elongation of up to 20%. Meanwhile, the micro-tube shows good corrosion resistance with a trend of uniform corrosion in simulated body fluid solution. The investigation revealed that a significant improvement in the mechanical properties is mainly attributed to grain refinement and texture weaken, while the good biodegradable properties is related with the low density of crystallographic defects as well as fine and homogeneous microstructure. As a result, the successful processing of magnesium alloy micro-tube provides the precursor for laser engraving stents.

The microstructure and properties of cyclic extrusion compression treated Mg-Zn-Y-Nd alloy for vascular stent application.

Magnesium alloys are promising candidate materials for cardiovascular stents due to their good biocompatibility and degradation properties in the human body. However, in vivo tests also show that improvement in their mechanical properties and corrosion resistance is necessary before wide application. In this study, cyclic extrusion compression (CEC) was used to enhance the mechanical properties and corrosion resistance of Mg-Zn-Y-Nd alloy. The results show that the grain size was greatly refined to 1 µm after CEC treatment. The second phase distributed along the grain boundaries with grid shape and nano-sized particles uniformly distributed in grains. The elongation (δ), ultimate tensile strength (UTS) and yield strength (YS) of the CEC treatment samples were 30.2%, 303 MPa and 185 MPa respectively. The CEC treated samples showed homogeneous corrosion because of the grain refinement and the homogeneous distribution of nano-sized second phase. The corrosion current density of the alloy decreased from 2.8×10(-4) A/cm(2) to 6.6×10(-5) A/cm(2) after CEC treatment. Therefore, improved mechanical properties, uniform corrosion and reduced corrosion rate could be achieved by CEC.

In vivo degradation behavior of Ca-deficient hydroxyapatite coated Mg-Zn-Ca alloy for bone implant application.

In present paper, an in vivo study was carried out on uncoated and calcium-deficient hydroxyapatite (Ca-def HA) coated Mg-Zn-Ca alloy to investigate the effect of Ca-def HA coating on the degradation behavior and bone response of magnesium substrate. Magnesium alloy rods were implanted into rabbit femora and evaluated during 24 weeks implantation. The characterization of both implants indicates that in vivo degradation of the Ca-def HA coating and magnesium substrate occurs almost simultaneously, and in vivo valid life of the coating is about 8 weeks, after that the degradation rate of the coated implants increases obviously. The main reasons for the Ca-def HA coating degradation can be attributed to its reaction with body fluid and the substitution of Mg(2+) ions in Ca-def HA. Histopathological examinations show that the Ca-def HA coating has good osteoconductivity and is in favor of the formation of more new bone on the surface of magnesium alloy. So the Ca-def HA coating could not only slow down in vivo degradation of magnesium alloy but also improve its bone response.