Evaluation of toxicity and biocompatibility of a novel Mg-Nd-Gd-Sr alloy in the osteoblastic cell.

BACKGROUND: We investigated the toxicity and biocompatibility of a novel Mg-3Nd-1Gd-0.3Sr-0.2Zn-0.4Zr (abbreviated to Mg-Nd-Gd-Sr) alloy in the osteoblastic cell line MC3T3-E1 as osteoblasts play an important role in bone repair and remodeling. METHODS: We used cytotoxicity tests and apoptosis to investigate the effects of the Mg-Nd-Gd-Sr alloy on osteoblastic cells. Cell bioactivity, cell adhesion, cell proliferation, mineralization, ALP activity, and expression of BMP-2 and OPG by osteoblastic cells were also used to investigate the biocompatibility of Mg-Nd-Gd-Sr alloy. RESULTS: The results showed that the Mg-Nd-Gd-Sr alloy had no obvious cytotoxicity, and did not induce apoptosis to MC3T3-E1 cells. Compared with the control group, the number of adherent cells within 12 h was increased significantly in each experimental group (P < 0.05); the OD value of MC3T3-E1 cells was increased significantly in each experimental group on days 1 and 3 of culture (P < 0.05); the number of mineralized nodules formed in each experimental group was significantly increased (P < 0.05), and ALP activity was significantly increased in each experimental group (P < 0.05). RT-PCR results showed that the mRNA expression of BMP-2 and OPG was significantly higher in each experimental group compared with the control group (P < 0.05). Western blotting showed that the Mg-Nd-Gd-Sr alloy extract significantly increased the protein expression of BMP-2 and OPG compared with the control group (P < 0.05). CONCLUSIONS: Our data indicated that the novel Mg-Nd-Gd-Sr-Zn-Zr alloy had no obvious cytotoxic effects, and did not cause apoptosis to MC3T3-E1 cells; meanwhile it promoted cell adhesion, cell proliferation, mineralization, and ALP activity of osteoblasts. During this process, there was an increase in the expressions of BMP-2 and OPG mRNAs and proteins.

NiTi Alloys Exposure Alters miR-124 Expression in Physiological and Osteoarthritic Osteoblasts.

PURPOSE OF THE STUDY Nitinol (NiTi) is a biomaterial widely used in medicine based on super-elastic and shape memory properties. miR-124 has a key role in inflammatory process, osteoblasts differentiation, and mineralization. The aim of study was evaluating the differences in gene expression of miR-124 of human physiological osteoblasts (HOB) and human osteoarthritic osteoblasts (OSBA) as a response to NiTi alloy in different heat treatments. MATERIAL AND METHODS The cells were cultivated with NiTi discs with/without addition of bacterial lipopolysaccharide (LPS) for 72 hours. MicroRNAs were isolated, underwent reverse transcription and were analyzed by RT-PCR. RESULTS As a response to LPS, HOB overexpressed miR-124, while in OSBA expression change did not occur. Overexpression was also observed in both cell lines as a response to hydrogen and helium treated NiTi discs. HOB expressed significantly higher amount of miR-124 than OSBA as a response to hydrogen treatment of NiTi discs. In addition, hydrogen treatment caused significantly higher expression in HOB than LPS. The combination of NiTi disc and LPS treatment in HOB didn't cause any expression changes. Comparing to LPS-only treatment, the expression in HOB with combination of LPS and alloy was significantly lower. In OSBA, the expression was increased by the combination of LPS and hydrogen disc, in case of helium disc, the expression was decreased. CONCLUSIONS In conclusion, human physiological and osteoarthritic osteoblasts respond to NiTi alloy with both surface (hydrogen and helium atmosphere) treatment by overexpression of miR-124. The effect of LPS as inflammatory modulator suggests the presence of an "anti-inflammatory preconditioning" in osteoarthritic osteoblasts, as physiological osteoblasts overexpression was significantly higher. Key words: nitinol, osteoblast, miR-124, lipopolysaccharide.

In Situ Upregulating Heat Shock Protein 70 via Gastric Nano-Heaters for the Interference of Helicobacter pylori Infection.

Taking inspiration from the mechanism of Helicobacter pylori infection can lead to innovative antibacterial ways to fight antibiotics resistance. Herein, a gastric nano-heater iron-cobalt alloy shielded with graphitic shells (FeCo@G) is developed to interfere with H. pylori infection under an alternating magnetic field. FeCo@G shows a high and stable specific loss power (SLP = 534.1 W g-1) in the acidic environment and provides efficient magnetothermal stimulation in the stomach. Such stimulation upregulates the cytoprotective heat shock protein 70 (HSP70) in gastric epithelial cells, which antagonizes the infection of H. pylori. This finding is further supported by the transcriptomic analysis verifying the upregulation of HSP70 in the stomach. Moreover, the nano-heater shows a high inhibition rate of H. pylori in vivo with good biocompatibility; 95% of FeCo@G is excreted from the mouse's gastrointestinal tract within 12 h. In summary, FeCo@G allows magnetothermal therapy to be used in harsh gastric environments, providing an approach for the therapy against H. pylori.

Effect and mechanism of a novel Mg-Nd-Gd-Sr alloy on osteogenic differentiation of bone marrow mesenchymal stem cells.

We investigated the effect and mechanism of a novel Mg-3Nd-1Gd-0.3Sr-0.2Zn-0.4Zr (abbreviated to Mg-Nd-Gd-Sr) alloy on the osteogenic differentiation of bone marrow mesenchymal stem cells extracted from Sprague-Dawley rats. Cultured cells were divided into five groups: a control group cultured in osteogenic induction medium alone without Mg-Nd-Gd-Sr alloy extract, and four experimental groups cultured in the same medium with 25%, 50%, 75%, and 100% Mg-Nd-Gd-Sr alloy extracts, respectively. After 14 days of culture, ALP activity was determined and expressions of osteogenesis-related factors Runx2, OCN, and OPN at the mRNA level and Runx2, OCN, and OPN at the protein level were detected by RT-PCR and western blot, respectively. After 21 days of culture, mineralized nodules were detected by alizarin red staining. The results showed that bone marrow mesenchymal stem cells from Sprague-Dawley rats were successfully isolated in vitro using the whole bone marrow adherence method. Flow cytometry revealed that the cells expressed high levels of CD44 and CD90, but low levels of CD31 and CD45. Alizarin red staining indicated the formation of mineralized nodules in all five groups. Compared with the control group, the number of mineralized nodules was increased significantly in the four experimental groups (p < 0.05). The ALP activity in each group was significantly higher on day 14 than on day 7, and was significantly higher in the four experimental groups compared with the control group (p < 0.05). Moreover, the ALP activity was highest when the concentration of Mg-Nd-Gd-Sr alloy extract was 75% (p < 0.05). RT-PCR results showed that, compared with the control group, the mRNA expression of Runx2, OPN, and OCN was significantly higher in the four experimental groups (p < 0.05), and the highest mRNA expression of Runx2, OPN, and OCN was observed in the 75% experimental group (p < 0.05). Western blotting showed that Mg-Nd-Gd-Sr alloy extract significantly increased the protein expression of Runx2, OCN, and OPN compared with the control group (p < 0.05). Our data indicate that the novel Mg-Nd-Gd-Sr alloy can promotes the osteogenic differentiation of bone marrow mesenchymal stem cells isolated from Sprague-Dawley rats. During this process, there is an increase in the expressions of Runx2, OPN, and OCN mRNAs and Runx2, OCN, and OPN proteins.

Copper fabric improves the metabolic profile of obese mice: Potential role of the gut microbiota.

Copper and copper alloys have antimicrobial activity through the rapid contact killing of viruses, bacteria and yeasts on their surface. Dysregulation of host microbiota can contribute to the pathogenesis of inflammatory diseases such as obesity, diabetes and cardiovascular disease. Anecdotal evidence noted improved overall well-being in individuals sleeping on copper-containing fabric bedding. We hypothesized that the beneficial effect of copper-infused fabric bedding on cardiometabolic health is linked to changes in gut microbiota composition. This study utilized a mouse model of diet-induced obesity to assess the beneficial effects of copper-infused fabric bedding on metabolic health. Body composition, inflammatory markers, metabolic and cardiovascular status and changes in the faecal microbiota composition were evaluated for up to 2 months in mice fed with a normal chow diet or high fat high cholesterol diet in the presence of bedding made with and without copper-infused fabric. Results showed that mice subjected to diet-induced obesity and housed in cages with copper-infused fabric liner displayed less body weight gain than mice in cages with control fabric. Mice housed with copper-infused fabric also displayed improved glucose tolerance and reduced inflammation biomarker lipocalin-2. We also observed a beneficial shift in gut bacterial composition of obese mice housed with copper fabric bedding. Taken in conjunction, our study provides direct animal-based evidence supporting the beneficial effects of copper fabric on metabolic health.

In vitro and in vivo assessment of the effect of biodegradable magnesium alloys on osteogenesis.

Magnesium (Mg) and some of its alloys are considered promising biodegradable metallic biomaterials for bone implant applications. The osteogenesis effect of Mg alloys is widely reported; however, the underlying mechanisms are still not clear. In this study, pure Mg, Mg-3Zn, and Mg-2Zn-1Mn were prepared, and their degradation behavior, biocompatibility, and osteogenesis effect were systematically assessed both in vitro and in vivo. Primary rat bone marrow-derived mesenchymal stem cells (BMSCs) were used to evaluate the biocompatibility of the prepared Mg alloys, and a rat femur fracture model was used to assess the stimulating effect of these alloys on bone-tissue formation. Mg-2Zn-1Mn showed higher corrosion resistance and more stable degradation behavior than pure Mg and Mg-3Zn. Extracts of the three materials showed significant stimulating effects on osteogenic differentiation of BMSCs along with non-cytotoxicity. Implantation of Mg-2Zn-1Mn wires into the femur of rats demonstrated superior histocompatibility, stable degradation, and notable promotion of osteogenesis without systemic toxicity. Moreover, the results of both in vitro and in vivo assessments demonstrated that bone morphogenetic proteins and fibroblast growth factor receptors are involved in the stimulating effect of Mg alloys. STATEMENT OF SIGNIFICANCE: This work reports the degradation behavior, biocompatibility, and osteogenic effect of pure Mg and Mg-3Zn and Mg-2Zn-1Mn alloys in both in vitro and in vivo conditions. Mg-2Zn-1Mn showed higher corrosion resistance and more stable degradation behavior than pure Mg and Mg-3Zn. The extracts of the three materials showed a significant stimulating effect on osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) along with non-cytotoxicity. Mg-2Zn-1Mn wires implanted into the femur of rats showed good histocompatibility, stable degradation, and notable promotion of osteogenesis without systemic toxicity. The results of the present study suggest that bone morphogenetic proteins (BMPs) and fibroblast growth factor receptors (FGFRs) are involved in the stimulating effect of Mg alloys on osteogenesis.

In vitro and in vivo degradation assessment and preventive measures of biodegradable Mg alloys for biomedical applications.

Magnesium (Mg) and its alloys have been widely explored as a potential biodegradable implant material. However, the fast degradation of Mg-based alloys under physiological environment has hindered their widespread use for implant applications till date. The present review focuses on in vitro and in vivo degradation of biodegradable Mg alloys, and preventive measures for biomedical applications. Initially, the corrosion assessment approaches to predict the degradation behavior of Mg alloys are discussed along with the measures to control rapid corrosion. Furthermore, this review attempts to explore the correlation between in vitro and in vivo corrosion behavior of different Mg alloys. It was found that the corrosion depends on experimental conditions, materials and the results of different assessment procedures hardly matches with each other. It has been demonstrated the corrosion rate of magnesium can be tailored by alloying elements, surface treatments and heat treatments. Various researches also studied different biocompatible coatings such as dicalcium phosphate dihydrate (DCPD), ß-tricalcium phosphate (ß-TCP), hydroxyapatite (HA), polycaprolactone (PCL), polylactic acid (PLA), and so on, on Mg alloys to suppress rapid degradation and examine their influence on new bone regeneration as well. This review shows the need for a standard method of corrosion assessment to predict the in vivo corrosion rate based on in vitro data, and thus reducing the in vivo experimentation.

Nutrient alloying elements in biodegradable metals: a review.

As a new generation of biomedical metallic materials, biodegradable metals have become a hot research topic in recent years because they can completely degrade in the human body, thus preventing secondary surgery, and reducing the pain and economic burden for patients. Clinical applications require biodegradable metals with adequate mechanical properties, corrosion resistance, and biocompatibility. Alloying is an important method to create biodegradable metals with required and comprehensive performances. Since nutrient elements already have important effects on various physiological functions of the human body, the alloying of nutrient elements with biodegradable metals has attracted much attention. The present review summarizes and discusses the effects of nutrient alloying elements on the mechanical properties, biodegradation behavior, and biocompatibility of biodegradable metals. Moreover, future research directions of biodegradable metals with nutrient alloying elements are suggested.

Surface Roughness of Titanium Orthopedic Implants Alters the Biological Phenotype of Human Mesenchymal Stromal Cells.

Metal orthopedic implants are largely biocompatible and generally achieve long-term structural fixation. However, some orthopedic implants may loosen over time even in the absence of infection. In vivo fixation failure is multifactorial, but the fundamental biological defect is cellular dysfunction at the host-implant interface. Strategies to reduce the risk of short- and long-term loosening include surface modifications, implant metal alloy type, and adjuvant substances such as polymethylmethacrylate cement. Surface modifications (e.g., increased surface rugosity) can increase osseointegration and biological ingrowth of orthopedic implants. However, the localized responses of cells to implant surface modifications need to be better characterized. As an in vitro model for investigating cellular responses to metallic orthopedic implants, we cultured mesenchymal stromal/stem cells on clinical-grade titanium disks (Ti6Al4V) that differed in surface roughness as high (porous structured), medium (grit blasted), and low (bead blasted). Topological characterization of clinically relevant titanium (Ti) materials combined with differential mRNA expression analyses (RNA-seq and real-time quantitative polymerase chain reaction) revealed alterations to the biological phenotype of cells cultured on titanium structures that favor early extracellular matrix production and observable responses to oxidative stress and heavy metal stress. These results provide a descriptive model for the interpretation of cellular responses at the interface between native host tissues and three-dimensionally printed modular orthopedic implants, and will guide future studies aimed at increasing the long-term retention of such materials after total joint arthroplasty. Impact statement Using an in vitro model of implant-to-cell interactions by culturing mesenchymal stromal cells (MSCs) on clinically relevant titanium materials of varying topological roughness, we identified mRNA expression patterns consistent with early extracellular matrix (ECM) production and responses to oxidative/heavy metal stress. Implants with high surface roughness may delay the differentiation and ECM formation of MSCs and alter the expression of genes sensitive to reactive oxygen species and protein kinases. In combination with ongoing animal studies, these results will guide future studies aimed at increasing the long-term retention of widely used titanium materials after total joint arthroplasty.

Biosensitive and antibacterial coatings on metallic material for medical applications.

Metallic materials are commonly used for load-bearing implants and as internal fixation devices. It is customary to use austenitic stainless steel, especially surgical grade type 316L SS as temporary and Ti alloys as permanent implants. However, long-term, poor bonding with bone, corrosion, and release of metal ions, such as chromium and nickel occur. These ions are powerful allergens and carcinogens and their uncontrolled leaching may be avoided by surface coatings. Therefore, bioactive glasses (BGs) became a vital biomedical material, which can form a biologically active phase of hydroxycarbonate apatite on their surface when in contact with physiological fluids. To reduce the high coefficient of friction and the brittle nature of BGs, polymers are normally incorporated to avoid the high-temperature sintering/densification of ceramic-only coatings. For medical application, electrophoretic deposition (EPD) is now used for polymer (organic) and ceramic (inorganic) components at room temperature due to its simplicity, control of coating thickness and uniformity, low cost of equipment, ability to coat substrates of intricate shape and to supply thick films in composite form, high purity of deposits as well as no phase transformation during coating. Although extensive research has been conducted on polymer/inorganic composite coatings, only some studies have reported multifunctional properties, such as biological antibacterial activity, enhanced cell adhesion, controlled drug release ability, and mechanical properties. This review will focus on biodegradable coatings, including zien, chitosan, gelatin, cellulose loaded with antibacterial drugs/metallic ions/natural herbs on biostable substrates (PEEK/PMMA/PCL/PLLA layers), which have the potential of multifunctional coating for metallic implants.

Tissue responses after implantation of biodegradable Mg alloys evaluated by multimodality 3D micro-bioimaging in vivo.

The local response of tissue triggered by implantation of degradable magnesium-based implant materials was investigated in vivo in a murine model. Pins (5.0 mm length by 0.5 mm diameter) made of Mg, Mg-10Gd, and Ti were implanted in the leg muscle tissue of C57Bl/6N mice (n = 6). Implantation was generally well tolerated as documented by only a mild short term increase in a multidimensional scoring index. Lack of difference between the groups indicated that the response was systemic and surgery related rather than material dependent. Longitudinal in vivo monitoring utilizing micro-computed tomography over 42 days demonstrated the highest and most heterogeneous degradation for Mg-10Gd. Elemental imaging of the explants by micro X-ray fluorescence spectrometry showed a dense calcium-phosphate-containing degradation layer. In order to monitor resulting surgery induced and/or implant material associated local cell stress, sphingomyelin based liposomes containing indocyanine green were administered. An initial increase in fluorescent signals (3-7 days after implantation) indicating cell stress at the site of the implantation was measured by in vivo fluorescent molecular tomography. The signal decreased until the 42nd day for all materials. These findings demonstrate that Mg based implants are well tolerated causing only mild and short term adverse reactions.

Short-Term In Vivo Response to Anodized Magnesium Alloy as a Biodegradable Material for Bone Fracture Fixation Devices.

Biodegradable materials based on magnesium alloys have a huge potential for bone fracture fixation devices due to their adequate mechanical properties and biocompatibility. However, their fast degradation and the consequent liberation of hydrogen gas at the initial stages of implantation is the major limitation for their use. In this study, the AZ91D magnesium alloy was surface treated by an environment-friendly, nontoxic, and low-cost anodizing process and the early in vivo response was studied in a rat transcortical model. Adequate maturation of woven bone around implants-detected at day 7 post implantation-to lamellar bone was observed from day 15. Lamellar bone after 15 and 30 days of implantation presented similar volume, mineralization pattern, mineral to protein content, and estimated bone maturity between anodized AZ91D and polylactic acid (control) implants. Histology observation showed neither release of hydrogen bubbles in the region closed to the anodized AZ91D implant nor systemic effects on liver, kidney, and spleen. Thus, anodizing of AZ91D in the conditions stated here induced an adequate short-term in vivo response, which postulates their use as potential biodegradable fracture fixation devices for bone healing.

Is there a future for additive manufactured titanium bioglass composites in biomedical application? A perspective.

Additive manufacturing (AM) of orthopedic implants is growing in popularity as it offers almost complete design flexibility and freedom, meaning complex geometries mimicking specific body parts can be easily produced. Novel composite materials with optimized functionalities present opportunities for 3D printing osteoconductive implants with desirable mechanical properties. Standard metals for bone implants, such as titanium and its alloys, are durable and nontoxic but lack bioactivity. Bioactive glasses promote strong bone formation but are susceptible to brittle failure. Metal-bioactive glass composites, however, may combine the mechanical reliability of metals with the bone-bonding ability of bioactive glasses, potentially reducing the incidence of implant failure. Processing such composites by AM paves the way for producing unprecedented bespoke parts with highly porous lattices, whose stiffness can be tailored to meet the mechanical properties of natural bone tissue. This Perspective focuses on titanium-bioactive glass composites, critically discussing their processability by AM and highlighting their potential as a next-generation implantable biomaterial.

In vivo evaluation of bending strengths and degradation rates of different magnesium pin designs for oral stapler.

Magnesium alloys have been potential biodegradable implants in the areas of bone, cardiovascular system, gastrointestinal tract, and so on. The purpose of this study is to evaluate Mg-2Zn alloy degradation as a potential suture material. The study included Sprague-Dawley (SD) rats in vivo. In 24 male SD rats, tests in the leg muscle were conducted using traditional surgical incision and insertion of magnesium alloys of different designs into the tissue. The material degradation topography, elemental composition, and strength of the pins were analyzed. This paper explores magnesium pins with different cross-sectional shapes and diameters to establish a suitable pin diameter and shape for use as an oral stapler, which must have a good balance of degradation rate and strength. The results showed there were good bending strengths over different degradation periods in groups with diameters of 0.8 mm and 0.5 mm, and no significantly different bending strength between the groups of triangle and round cross-section shapes with same diameter of 0.3 mm, although the degradation rate still needs to be improved.

Copper alloys' metal migration and bioaccessibility in saliva and gastric fluid.

The oral bioaccessibility of copper alloys and pure metals was assessed using in vitro methods with synthetic saliva and gastric fluid. The metal-specific migration rates from polished alloy surfaces are higher in gastric (pH 1.5) than in saliva fluid (pH 7.2). In both media, migrations are higher for lead than for other metals. The bioaccessible metal concentrations in massive copper alloys, after 2 h in gastric fluid, was only <0.01%-0.18%, consistent with the low surface reactivity of copper alloys (defined as 1 mm spheres). The average metal-specific migrations of cobalt, copper, nickel and lead from most of the tested copper alloys in gastric media are comparable to the ones from their pure metals. The data further show that the bioaccessibility of metals in massive copper alloys primarily depends on the bioelution medium, the exposed surface area and the composition of the alloy. The tested copper alloys show only limited evidence for influence of alloy surface microstructure. This is contrary to findings for other alloys such as stainless steel. Additional investigations on other copper alloys could allow to further refine these conclusions. These findings are useful for establishing the hazard and risk profile of copper alloys following oral exposure.

Investigation of mechanical properties and biocorrosion behavior of in situ and ex situ Mg composite for orthopedic implants.

In the present study, the biocorrosion and mechanical properties of in situ and ex situ ZK60 matrix composites were investigated. For this purpose, ex situ composite samples containing 10 and 20 vol% SiC particles were prepared by stir casting method, while the in situ composite samples were produced by precipitation hardening at 175 °C and 225 °C. Microstructural examinations confirmed the homogeneous distribution of reinforcements and precipitations for ex situ and in situ composites, respectively. Moreover, the ex situ composites had higher hardness than the in situ composites due to the presence of ceramic particles. The samples were subjected to potentiodynamic polarization and electrochemical impedance spectroscopy in the SBF solution. The results showed that ex situ composites had a higher corrosion rate than in situ composites. The results of the MTT assay displayed that all samples had acceptable biocompatibility. Additionally, SEM micrographs obtained after immersion of both composites in the SBF solution for 7 and 28 days showed the formation of the hydroxyapatite layer on the surface of the samples. Both composites showed almost excellent wear resistance, and SEM micrographs approved that abrasive wear and adhesive wear were the dominant mechanisms for ex situ and in situ composites, respectively.

Microstructural examination and corrosion behavior of selective laser melted and conventionally manufactured Ti6Al4V for dental applications.

The selective laser melting of Ti6Al4V would induce definite changes in the microstructure that may affect its corrosion properties. Microstructural examination showed the formation of relatively thin beta (ß) lamella in selective laser melted (SLM) Ti6Al4V compared to wrought Ti6Al4V. X-ray diffraction analysis (XRD) analysis confirmed the presence of alpha and beta phases in both SLM and wrought Ti6Al4V. However, the higher concentration of the ß phase in SLM Ti6Al4V compared to wrought Ti6Al4V was evident in the microstructure. As candidate dental implant materials, the corrosion behavior of both SLM and wrought Ti6Al4V was assessed in artificial saliva (AS) and deionized water (DI) containing various species i.e. fluoride (F), calcium chloride (CaCl2) and lactic acid (LA). Electrochemical impedance spectroscopy and potentiodynamic polarization analysis was carried out to estimate the corrosion behavior of SLM and wrought Ti6Al4V at room temperature. SLM Ti6Al4V offered better corrosion resistance than wrought Ti6Al4V in all solutions at pH > 6. However, wrought Ti6Al4V comparatively presented high corrosion resistance in AS + LA, DI + CaCl2 and DI + LA solutions (pH < 6). The lower dissolution rate of SLM Ti6Al4V (at pH > 6) was attributed to larger ß content in the microstructure compared to wrought Ti6Al4V.

Metabolic Fingerprinting on Synthetic Alloys for Medulloblastoma Diagnosis and Radiotherapy Evaluation.

Diagnostics is the key in screening and treatment of cancer. As an emerging tool in precision medicine, metabolic analysis detects end products of pathways, and thus is more distal than proteomic/genetic analysis. However, metabolic analysis is far from ideal in clinical diagnosis due to the sample complexity and metabolite abundance in patient specimens. A further challenge is real-time and accurate tracking of treatment effect, e.g., radiotherapy. Here, Pd-Au synthetic alloys are reported for mass-spectrometry-based metabolic fingerprinting and analysis, toward medulloblastoma diagnosis and radiotherapy evaluation. A core-shell structure is designed using magnetic core particles to support Pd-Au alloys on the surface. Optimized synthetic alloys enhance the laser desorption/ionization efficacy and achieve direct detection of 100 nL of biofluids in seconds. Medulloblastoma patients are differentiated from healthy controls with average diagnostic sensitivity of 94.0%, specificity of 85.7%, and accuracy of 89.9%, by machine learning of metabolic fingerprinting. Furthermore, the radiotherapy process of patients is monitored and a preliminary panel of serum metabolite biomarkers is identified with gradual changes. This work will lead to the application-driven development of novel materials with tailored structural design and establishment of new protocols for precision medicine in near future.

The bioeffects of degradable products derived from a biodegradable Mg-based alloy in macrophages via heterophagy.

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.