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Interconnectivity is the key characteristic of bone tissue engineering scaffold modulating cell migration, blood vessels invasion and transport of nutrient and waste. However, efforts and understanding of the interconnectivity of porous Mg is limited due to the diverse architectures of pore struts and pore size distribution of Mg scaffold systems. In this work, biomimetic hierarchical porous Mg scaffolds with tailored interconnectivity as well as pore size distribution were prepared by template replication of infiltration casting. Mg scaffold with better interconnectivity showed lower mechanical strength. Enlarging interconnected pores would enhance the interconnectivity of the whole scaffold and reduce the change of ion concentration, pH value and osmolality of the degradation microenvironment due to the lower specific surface area. Nevertheless, the degradation rates of five tested Mg scaffolds were no different because of the same geometry of strut unit. Direct cell culture and evaluation of cell density at both sides of four typical Mg scaffolds indicated that cell migration through hierarchical porous Mg scaffolds could be enhanced by not only bigger interconnected pore size but also larger main pore size. In summary, design of interconnectivity in terms of pore size distribution could regulate mechanical strength, microenvironment in cell culture condition and cell migration potential, and beyond that it shows great potential for personalized therapy which could facilitate the regeneration process.

Yinhua pinggan granule (YHPGKL), a traditional Chinese medical compound, could treat pneumonia. Although previous studies demonstrated the protective and therapeutic effects of YHPGKL on pneumonia, its potential molecular mechanisms and its effective components are still elusive. Herein, we performed a network pharmacology analysis to determine the possible signaling pathways involved in the protective effects of components of YHPGKL. A total of 119 components and 257 target proteins of YHPGKL were identified, among which 117 effective components interacted with 113 proteins related to pneumonia. Then, a compound-effective component-target protein network was established to screen the effective hub components. The top three effective components, namely luteolin, kaempferol, and quercetin, were selected. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of 113 proteins revealed a significant enrichment term associated with host immune and anti-infectious responses. Furthermore, by constructing a protein-protein interaction network between common proteins, ten hub proteins were identified, among which three hub components hit eight proteins. A further molecular docking analysis confirmed that the three effective hub components had a good affinity with six hub proteins. Eventually, the interactions were further visualized and screened on account of an infectious macrophage model in vitro. The results noted that three components could inhibit proinflammatory related hub genes but had no effect on survival-related hub genes. Thus, the three effective hub components and corresponding hub genes may play essential roles in the treatment of YHPGKL on pneumonia.

The grain size of Mg foams was innovatively refined without alteration of pore structure and relative density by subjecting multi-axial forging (MAF) process to Ti-Mg composite, an intermediary product of the fabrication process of Mg foams where the spherical Ti particles were utilized as the replication material. The feasibility of the MAF process and the grain size effect on the mechanical properties of Mg foams were discussed. The results showed that, with the appropriate strain of 0.24 applied in the MAF process, Ti-Mg composites returned to original physical appearance without generating micro-cracks. And complete recrystallization was achieved after heat treatment, with the grain size of the MAF-processed Mg foams two to three orders of magnitude smaller than that of as-cast foam. The mechanical properties of Mg foams were enhanced extensively after grain refinement with the yield strength and the plastic collapse strength increased by 147% and 50.7%, respectively. A revised model integrated by the Hall-Petch law and Gibson-Ashby model was proposed, which gave a good estimation of the yield strength and the plastic collapse strength of Mg foams from the compressive behavior of the corresponding parent material, though a knockdown factor of 0.45 was introduced for the yield strength.

Biodegradable magnesium alloys are promising candidates for use in biomedical applications. However, degradable particles (DPs) derived from Mg-based alloys have been observed in tissue in proximity to sites of implantation, which might result in unexpected effects. Although previous in vitro studies have found that macrophages can take up DPs, little is known about the potential phagocytic pathway and the mechanism that processes DPs in cells. Additionally, it is necessary to estimate the potential bioeffects of DPs on macrophages. Thus, in this study, DPs were generated from a Mg-2.1Nd-0.2Zn-0.5Zr alloy (JDBM) by an electrochemical method, and then macrophages were incubated with the DPs to reveal the potential impact. The results showed that the cell viability of macrophages decreased in a concentration-dependent manner in the presence of DPs due to effects of an apoptotic pathway. However, the DPs were phagocytosed into the cytoplasm of macrophages and further degraded in phagolysosomes, which comprised lysosomes and phagosomes, by heterophagy instead of autophagy. Furthermore, several pro-inflammatory cytokines in macrophages were upregulated by DPs through the induction of reactive oxygen species (ROS) production. To the best of our knowledge, this is the first study to show that DPs derived from a Mg-based alloy are consistently degraded in phagolysosomes after phagocytosis by macrophages via heterophagy, which results in an inflammatory response owing to ROS overproduction. Thus, our research has increased the knowledge of the metabolism of biodegradable Mg metal, which will contribute to an understanding of the health effects of biodegradable magnesium metal implants used for tissue repair. STATEMENT OF SIGNIFICANCE: Biomedical degradable Mg-based alloys have great promise in applied medicine. Although previous studies have found that macrophages can uptake degradable particles (DPs) in vitro and observed in the sites of implantation in vivoin vivo, few studies have been carried out on the potential bioeffects relationship between DPs and macrophages. In this study, we analyzed the bioeffects of DPs derived from a Mg-based alloy on the macrophages. We illustrated that the DPs were size-dependently engulfed by macrophages via heterophagy and further degraded in the phagolysosome rather than autophagosome. Furthermore, DPs were able to induce a slight inflammatory response in macrophages by inducing ROS production. Thus, our research enhances the knowledge of the interaction between DPs of Mg-based alloy and cells, and offers a new perspective regarding the use of biodegradable alloys.

Degradability of bone tissue engineering scaffold that matching the regeneration rate could allow a complete replacement of host tissue. However, the porous structure of biodegradable Mg scaffolds certainly generated high specific surface area, and the three-dimensional interconnected pores provided fast pervasive invasion entrance for the corrosive medium, rising concern of the structural integrity during the degradation. To clarify the structural evolution of the three-dimensional (3D) porous structure, semi-static immersion tests were carried out to evaluate the degradation performance in our previous study. Nevertheless, dynamic immersion tests mimicking the in vivo circulatory fluid through the interconnected porous structure have yet been investigated. Moreover, the effects of dynamic flow rates on the degradation deposition behavior of 3D porous Mg scaffolds were rarely reported. In this study, Mg scaffolds degraded at three flow rates exhibited different degradation rates and deposition process. A flow rate of 0.5 mL/min introduced maximum drop of porosity by accumulated deposition products. The deposition products provided limited protection against the degradation process at a flow rate of 1.0 mL/min. The three-dimensional interconnected porous structure of Mg scaffold degraded at 2.0 mL/min well retained after 14 days showing the best interconnectivity resistance to the degradation deposition process. The dynamic immersion tests disclosed the reason for the different degradation rates on account of flow rates, which may bring insight into understanding of varied in vivo degradation rates related to implantation sites.

Additive manufacturing (AM) has enabled the fabrication of biodegradable porous metals to satisfy the desired characteristics for orthopedic applications. The geometrical design on AM biodegradable metallic scaffolds has been found to offer a favorable opportunity to regulate their mechanical and degradation performance in previous studies, however mostly confined to static responses. In this study, we presented the effect of the geometrical design on the dynamic responses of AM Mg scaffolds for the first time. Three different types of porous structures, based on various unit cells (i.e., biomimetic, diamond, and sheet-based gyroid), were established and then subjected to selective laser melting (SLM) process using group-developed Mg-Nd-Zn-Zr alloy (JDBM) powders. The topology after dynamic electropolishing, dynamic compressive properties, and dynamic biodegradation behavior of the AM Mg scaffolds were comprehensively evaluated. It was found that dynamic electropolishing effectively removed the excessive adhered powders on the surfaces and resulted in similar geometrical deviations amongst the AM Mg scaffolds, independent of their porous structures. The geometrical design significantly affected the compressive fatigue properties of the AM Mg scaffolds, of which the sheeted-based gyroid structure demonstrated a superior fatigue endurance limit of 0.85 at 106 cycles. Furthermore, in vitro dynamic immersion behaviors of the AM Mg scaffolds revealed a decent dependence on local architectures, where the sheeted-based gyroid scaffold experienced the lowest structural loss with a relatively uniform degradation mode. The obtained results indicate that the geometrical design could provide a promising strategy to develop desirable bone substitutes for the treatment of critical-size load-bearing defects. Statement of significance Additive manufacturing (AM) has provided unprecedented opportunities to fabricate geometrically complex biodegradable scaffolds where the topological design becomes a key determinant on comprehensive performance. In this paper, we fabricate 3 AM biodegradable Mg scaffolds (i.e., biomimetic, diamond, and sheet-based gyroid) and report the effect of the geometrical design on the dynamic responses of AM Mg scaffolds for the first time. The results revealed that the sheeted-based gyroid scaffold exhibited the best combination of superior compressive fatigue properties and relatively uniform dynamic biodegradation mode, suggesting that the regulation of the porous structures could be an effective approach for the optimization of AM Mg scaffolds as to satisfy clinical requirements in orthopedic applications

Bone tissue engineering is considered as a promising pathway for bone regeneration and defect reconstruction, in which scaffolds play an important role. Zn alloy, which is a biodegradable metal material that has advantages of metallic and biodegradable characteristics, has its special features, especially the ideal degradation rate and acceptable biocompatibility, which make it worthy to be further investigated for medical applications. In this study, new biodegradable porous Zn alloy scaffolds with Ca-P coating were attempted to repair cranial bone defect, and in vitro and in vivo assays were conducted to evaluate its biocompatibility, osteo-inductivity, and osteo-conductivity. The results indicated that coated Zn alloy possessed good biocompatibility, with no cytotoxicity. It could also promote osteogenic differentiation and calcium deposition of rabbit BMSCs in vitro, and new bone formation around the scaffold in vivo. The biodegradable porous Zn alloy scaffold with Ca-P coating is considered to be promising in cranial bone defect repair.

BACKGROUND: The removal of permanent internal fixation devices by secondary surgery could be avoided if these devices were made of degradable magnesium and magnesium alloys. Before such implants can be used clinically, however, the biological effect of magnesium exposure on surrounding bone must be evaluated. Previous studies have focused on bone formation; few have examined the effects of magnesium on the bone quality that affect many biomechanical properties. METHODS: Using bone quality parameters, we analyzed in vivo changes in bone properties and biomechanics after exposure to locally high levels of magnesium. RESULTS: Local bone mineralization was significantly disrupted following exposure to a porous rod of pure magnesium. Normal crystal formation and crystallinity were inhibited and the mineral-to-matrix ratio decreased. These results were consistent with those of in vitro experiments, in which high levels of magnesium inhibited mineral deposition by mesenchymal stem cells (MSCs) but increased alkaline phosphatase (ALP) expression. The same mineralization inhibition was observed around magnesium implants via micro-computerized tomography (micro-CT) and von Kossa staining. Such reduced bone quality around degrading magnesium rods could negatively impact bone biomechanics. CONCLUSIONS: This study showed that exposure to the local high magnesium levels that arise from rapidly degrading magnesium devices may significantly disrupt bone mineralization and negatively impact bone biomechanics.

Inspired by the process of bone reconstruction, porous scaffolds with robust osteogenesis and biodegradability would provide an ideal bone substitute for clinical practice. In this study, a novel porous Mg–Nd–Zn–Zr (JDBM) alloy scaffold coated with brushite (i.e., DCPD), denoted as JDBM-DCPD, is fabricated using a special patent template technique, which forms the main spherical pores (400–450 μm) and smaller pores (150–250 μm) interconnected between the adjacent main pores, facilitating nutrient penetration and cell in-growth, exhibiting sufficient mechanical properties. In vitro results demonstrate that JDBM-DCPD scaffolds promote cell in-growth and osteogenic differentiation, which significantly enhance mineralization, osteogenesis and angiogenesis-related genes expression when cultured with bone marrow mesenchymal stem cells. After implanting in vivo, JDBM-DCPD scaffolds effectively stimulate angiogenesis, osteogenesis, and remodeling with the degradation of JDBM-DCPD, and perfectly repair large bone defect in rat and rabbit models. Results from the present study provide the solid evidence that porous biodegradable Mg-based scaffolds whose pore structure can be precisely regulated by a spacer-selection technique may be a promising tissue engineering scaffolds for large bone defect repair clinically, free from any extra growth factors and live cells, such advances will make scaffold-based bone tissue repair safer, more convenient and more cost-effective. Keywords: Biodegradable Mg–Nd–Zn–Zr alloy scaffold, DCPD coating, Osteogenesis, Angiogenesis, Bone tissue engineering

The degradation behavior in consideration of the pore strut and the interconnectivity of two Mg scaffolds with different three-dimensional interconnected porous structures were evaluated. The interconnectivity of the two scaffolds gradually decreased along with the clogged interconnected pores due to the deposition formation on the pore wall. Mg scaffold with spherical pores and cambered pore strut degraded faster but exhibited better resistance to the deterioration of the interconnectivity compared with Mg scaffold with irregular pores and polygonal pore struts. Direct cell culture of MC3T3-E1 osteoblasts on the two scaffolds indicated a promising potential for bone tissue engineering.

Recently, Zn-based alloys are attracting intensive interest as biodegradable biomaterials. Their moderate degradation rate makes them a better potential candidate for porous scaffolds than Mg-based alloys. In this study, hot press sintering (HPS) was employed to enhance the stacking density of NaCl templates. And then, pure Zn and Zn-3 wt%Cu scaffolds with different porosities were achieved by replicating the architecture of NaCl templates. The pore structure, compressive properties and degradation behavior of the scaffolds were investigated. The scaffolds with a higher porosity of about 75% showed enhanced interconnectivity and reduced surface area due to the formation of more interconnected pores and the enlarged size of them. The scaffolds with a lower porosity of about 68% exhibited higher yield strength on account of the earlier closure of the smaller interconnected pores during deformation. The corrosion rate was decreased with the increase of the porosity due to the reduction of specific surface area. The compressive properties (including yield strength and modulus) and corrosion rate of the Zn scaffolds were significantly enhanced by the addition of 3 wt% Cu because of the solution of Cu in Zn matrix and the precipitation of CuZn5 secondary phase. Moreover, the effect of porosity on corrosion was more distinguishable for Zn-3 wt%Cu scaffolds than pure Zn scaffolds due to the acceleration of galvanic corrosion effect.

Mg-based scaffolds have great potential of application for bone defect repair due to their biodegradability and the excellent osteoinductivity, yet currently the fabrication of Mg-based porous materials is still a challenge. In this study, a new fabrication method was proposed to produce porous Mg scaffolds, which could be achieved by three steps: (1) defectless NaCl open porous template with enhanced relative density was prepared with NaCl particles by hot press sintering (HPS) process; (2) green compact of Mg and the NaCl template was produced by infiltration casting; (3) open porous Mg scaffold was achieved after leaching out the template. By using spherical NaCl particles and irregular polyhedral NaCl particles, respectively, two different types of templates were prepared, and correspondingly Mg scaffolds with spherical and irregular pores were respectively fabricated. The irregular-pore scaffold (I-scaffold) exhibited higher yield strength, while the spherical-pore scaffold (S-scaffold) showed superior interconnectivity and more stable compressive deformability due to the uniform spatial structure. Keywords: Mg scaffold, Infiltration casting, NaCl template, Interconnectivity, Mechanical properties, Microstructural evolution

Biomedical Mg alloy is promising for its widespread use clinically. In vitro and in vivo studies showed that the degradation products of biomedical Mg alloy were composed of O, P, Ca, Mg and other alloying elements. However, little is known about the metabolism of the degradation products. In this study, the in vitro macrophage phagocytosis of the degradation products of a biomedical Mg-Nd-Zn-Zr alloy was directly observed. This result affirms the necessity to investigate the long-term fate of Mg alloy degradation products in physiological environments. Besides, an electrochemical method was proposed to prepare enough amount of degradation products in vitro efficiently.

Development of bone graft substitutes with appropriate integration of mechanical, biodegradable, and biofunctional properties, which promote bone formation while simultaneously preventing implant-associated infections, remains a great challenge. Herein we designed and synthesized a brushite/Ag

Background The removal of permanent internal fixation devices by secondary surgery could be avoided if these devices were made of degradable magnesium and magnesium alloys. Before such implants can be used clinically, however, the biological effect of magnesium exposure on surrounding bone must be evaluated. Previous studies have focused on bone formation; few have examined the effects of magnesium on the bone quality that affect many biomechanical properties. Methods Using bone quality parameters, we analyzed in vivo changes in bone properties and biomechanics after exposure to locally high levels of magnesium. Results Local bone mineralization was significantly disrupted following exposure to a porous rod of pure magnesium. Normal crystal formation and crystallinity were inhibited and the mineral-to-matrix ratio decreased. These results were consistent with those of in vitro experiments, in which high levels of magnesium inhibited mineral deposition by mesenchymal stem cells (MSCs) but increased alkaline phosphatase (ALP) expression. The same mineralization inhibition was observed around magnesium implants via micro-computerized tomography (micro-CT) and von Kossa staining. Such reduced bone quality around degrading magnesium rods could negatively impact bone biomechanics. Conclusions This study showed that exposure to the local high magnesium levels that arise from rapidly degrading magnesium devices may significantly disrupt bone mineralization and negatively impact bone biomechanics.

Development of bone graft substitutes with appropriate integration of mechanical, biodegradable, and biofunctional properties, which promote bone formation while simultaneously preventing implant-associated infections, remains a great challenge. Herein we designed and synthesized a brushite/Ag3PO4-coated Mg-Nd-Zn-Zr scaffolds through chemical solution deposition of a composite coating onto the fluorinated Mg-based scaffolds generated with template replication method. The coated Mg-based open-porous scaffolds exhibit hierarchically-structured surface with cube-shaped Ag3PO4 nanoparticles uniformly distributed on top of microsized brushite grains. Immersion test reveals that the initial degradation rate of the coated scaffolds could be reduced by ~81% compared to the original scaffolds. The mean corrosion rate in 4 weeks falls into 0.10–0.15 mm/year to meet clinical requirements. The compatibility and ALP activity of cells grown in the extracts from the coated Mg-based scaffolds were increased compared with Ti control and original scaffolds, mainly due to the favorable microenvironment generated by Mg biodegradation. Besides, the coated Mg-based scaffold demonstrated potent antimicrobial activity via the synergistic actions of alkaline degradation products of Mg and the Ag species in the coating, achieving >99.5% antibacterial rate against both gram-positive and gram-negative bacteria with relatively low silver content. Taken together, this study presents a new candidate of brushite/Ag3PO4-coated Mg-based scaffold with appropriate degradation characteristics, cytocompatibility, and antimicrobial activities for bone tissue engineering applications.

Zn-based alloys as biodegradable materials for cardiovascular stents have drawn more and more attention in recent years. However, the hot plastic deformation of Zn-based alloys does not get enough attention. In this study, Zn-3Cu-0.5Fe alloy was prepared and then hot extruded at 140, 180, 220 and 260 °C. Effects of extrusion temperature on the microstructure, mechanical properties and degradation behavior were investigated. Nano-scaled particles precipitated during extrusion and the quantity decreased with the increasing of extrusion temperature. As the extrusion temperature increased from 140 to 260 °C, the grain size increased from 1.15 to 4.38 μm, the yield strength and ultimate tensile strength increased from 203 ± 3.23 and 221 ± 1.56 MPa to 269 ± 2.65 and 302 ± 8.01 MPa, increased by 32.5% and 45%, while the degradation rate was decreased gradually from 62.8 ± 0.72 μm/year to 49.9 ± 3.35 μm/year, decreased by 20.5%. In addition, the degradation behavior changes from a relatively uniform degradation mode to a localized degradation mode with the increase of the grain size. Dislocation gliding is replaced by grain-boundary movement and dynamic recrystallization (DRX) in the room temperature tensile deformation process. Lower extrusion temperature is beneficial for higher elongation and degradation rate as well as relatively uniform degradation mode, which is better suitable for the clinical application of cardiovascular stents.

Mg–1.50Zn–0.25Gd (at.%) alloy reinforced by icosahedral quasicrystalline phase (I-phase) was fabricated and then subjected to cyclic extrusion and compression (CEC) at 250, 300, 350 and 400 °C, respectively. The effects of CEC parameters including passes and temperatures on microstructure evolution and room temperature tensile mechanical properties were characterized and discussed. The results show that more passes are beneficial for secondary phase precipitation, grain refinement and basal texture weakening; while moderate temperature is beneficial for secondary phase precipitation and basal texture weakening by particle stimulated recrystallization nucleation (PSN), and lower temperature is beneficial for grain refinement. The alloy has the highest yield strength after CEC at 250 °C because of grain refinement and basal texture strengthening, while it has the highest elongation after being processed with 8 passes of CEC due to grain refinement and basal texture weakening. The processing passes have more important effects on microstructure evolution and mechanical properties than that of temperature during CEC. Keywords: Magnesium alloys, Cyclic extrusion and compression (CEC), Microstructure, Texture weakening, Mechanical properties

The influence of cells on the corrosion behavior of biomedical magnesium alloy is an important but less studied topic, which is helpful for understanding the inconsistent corrosion rates between in vitro and in vivo experiments. In this work, macrophages were directly cultured on Mg-2.1Nd-0.2Zn-0.5Zr (wt %, abbreviated as JDBM) alloy surface for 72 or 168 hours. Macrophages retained good viability and the generation of reactive oxygen species (ROS) was greatly promoted on the alloy. Weight loss, Mg(2+) concentration, and cross-section observation results demonstrated that macrophages accelerated the in vitro corrosion of JDBM. The coverage of cell body did not affect the local thickness of corrosion product layer. The corrosion product layer had a porous inner Mg(OH)2 layer and a dense outer layer mainly composed of O, P, Mg, and Ca. The uniform acceleration of JDBM corrosion was attributed to the omnidirection diffusion of ROS from macrophages. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2476-2487, 2016.