Investigating the Anticancer Potential of Zinc and Magnesium Alloys: From Base Materials to Nanocoated Titanium Implants.

In this work, we show the in vitro anticancer potential of surgical wires, obtained from zinc (ZnMg0.004) or magnesium (MgCa0.7) alloys by spatial technology comprising casting, extrusion, and final drawing processes. We also present the selective anticancer effects of applied soluble multilayer nanocoatings of zinc and magnesium onto titanium surfaces using the pulse laser deposition method. In the latter, the titanium samples were produced via 3D printing using the selective laser melting method and coated with various combinations of zinc and magnesium layers. For cytotoxicity studies, human dental pulp-derived stem cells (hDPSCs) and human osteosarcoma SaOS-2 cell line were used as representatives of healthy and cancer cells. Cells were examined against the 0.3-3.0 cm2/mL material extract ratios obtained from experimental and steel surgical wires, the latter being the current clinical industry standard. The MgCa0.7 alloy wires were approx. 1.5 times more toxic to cancer cells at all examined extract ratios vs. the extracts from steel surgical wires that exhibited comparable toxicity towards healthy and cancer cells. The ZnMg0.004 alloy wires displayed increased toxicity towards cancer cells with decreasing extract ratios. This was also reflected in the increased anticancer effectiveness, calculated based on the viability ratio of healthy cells to cancer cells, from 1.1 to 4.0 times. Healthy cell viability remained at 80-100%, whereas cancer cell survival fluctuated at 20-75%, depending on the extract ratio. Furthermore, the culture of normal or cancer cells on the surface of Zn/Mg-coated titanium allowed us to select combinations of specific coating layers that yielded a comparable anticancer effectiveness to that observed with the experimental wires that ranged between 2 and 3. Overall, this work not only demonstrates the substantial anticancer properties of the studied wires but also indicates that similar anticancer effects can be replicated with appropriate nanocoatings on titanium samples. We believe that this work lays the groundwork for the future potential development of the category of new implants endowed with anticancer properties.

Noggin promotes osteogenesis in human adipose-derived mesenchymal stem cells via FGFR2/Src/Akt and ERK signaling pathway.

The balance between Noggin and bone morphogenetic proteins (BMPs) is important during early development and skeletal regenerative therapies. Noggin binds BMPs in the extracellular space, thereby preventing BMP signaling. However, Noggin may affect cell response not necessarily through the modulation of BMP signaling, raising the possibility of direct Noggin signaling through yet unspecified receptors. Here we show that in osteogenic cultures of adipose-derived stem cells (ASCs), Noggin activates fibroblast growth factor receptors (FGFRs), Src/Akt and ERK kinases, and it stabilizes TAZ proteins in the presence of dexamethasone. Overall, this leads ASCs to increased expression of osteogenic markers and robust mineral deposition. Our results also indicate that Noggin can induce osteogenic genes expression in normal human bone marrow stem cells and alkaline phosphatase activity in normal human dental pulp stem cells. Besides, Noggin can specifically activate FGFR2 in osteosarcoma cells. We believe our findings open new research avenues to further explore the involvement of Noggin in cell fate modulation by FGFR2/Src/Akt/ERK signaling and potential applications of Noggin in bone regenerative therapies.

Chemical Compounds Released from Specific Osteoinductive Bioactive Materials Stimulate Human Bone Marrow Mesenchymal Stem Cell Migration.

In this work, a poly(L-lactide-co-glycolide) (PLGA)-based composite was enriched with one of the following sol-gel bioactive glasses (SBG) at 50 wt.%: A1-40 mol% SiO2, 60 mol% CaO, CaO/SiO2 ratio of 1.50; S1-80 mol% SiO2, 20 mol% CaO, CaO/SiO2 ratio of 0.25; A2-40 mol% SiO2, 54 mol% CaO, 6 mol% P2O5, CaO/SiO2 ratio of 1.35; S2-80 mol% SiO2,16 mol% CaO, 4 mol% P2O5, CaO/SiO2 ratio of 0.20. The composites and PLGA control sheets were then soaked for 24 h in culture media, and the obtained condition media (CM) were used to treat human bone marrow stromal cells (hBMSCs) for 72 h. All CMs from the composites increased ERK 1/2 activity vs. the control PLGA CM. However, expressions of cell migration-related c-Fos, osteopontin, matrix metalloproteinase-2, C-X-C chemokine receptor type 4, vascular endothelial growth factor, and bone morphogenetic protein 2 were significantly increased only in cells treated with the CM from the A1/PLGA composite. This CM also significantly increased the rate of human BMSC migration but did not affect cell metabolic activity. These results indicate important biological markers that are upregulated by products released from the bioactive composites of a specific chemical composition, which may eventually prompt osteoprogenitor cells to colonize the bioactive material and accelerate the process of tissue regeneration.

Microstructure and In Vitro Evaluation of Extruded and Hot Drawn Alloy MgCa0.7 for Biodegradable Surgical Wires.

The MgCa0.7 alloy may be a promising material for biodegradable surgical wires. In this paper, the technology for producing surgical wires from this alloy has been developed, based both on finite element modelling and experimental study. In particular, the extrusion and hot-drawing effects on the mechanical properties, microstructures, in-vitro rates of biocorrosion, and cytotoxicity to human cancer cells (SaOS-2) and healthy (hPDL) ones, have been determined. An approximately 30-40% increase in corrosion rate due to increasing hot-drawing temperature was observed. An effect of hot-drawing temperature on cytotoxicity was also found. Notably, at various stages of the final wires' production, the MgCa0.7 alloy became toxic to cancer cells. This cytotoxicity depended on the alloys' processing parameters and was maximal for the as-extruded rod and for the wires immediately after hot drawing at 440 °C. Thus, the careful selection of processing parameters makes it possible to obtain a product that is not only a promising candidate for biodegradable surgical wires, but one which also has intrinsic bioactive properties that produce antitumor activity.

In vitro cytotoxicity of biodegradable Zn-Mg surgical wires in tumor and healthy cells.

In this work, we examined the in vitro cytotoxicity of new biodegradable surgical wires. The wires made of zinc with the addition of a small amount of magnesium (pure zinc, ZnMg 0.0026, ZnMg 0.0068, and ZnMg 0.08) have been investigated. The wires were produced using a technology based on extrusion and subsequent drawing. The resulting wires with a diameter of 0.8-1.0 mm are designed to be used in surgical operations related to bone joints. For cytotoxicity studies, we have selected human dental pulp stem cells (hDPSC) as the cell population representing normal osteoprogenitor cells. Considering that, after bone surgeries, the chance of osteosarcoma increases, we have compared the results obtained in hDPSC to those obtained with Saos-2 human osteosarcoma cell line. Cultured cells were exposed to the extracts obtained from the materials incubated in culture medium for 24 h with and without preincubation. Extracts of different ratios were examined. The results showed that the extracts obtained from wires made of ZnMg 0.0026 alloy exhibit high toxicity to Saos-2 osteosarcoma cells and low toxicity to hDPSC cells. This was in contrast to all reference materials, i.e., commercial surgical sutures made of steel and polymers, that did not display cytotoxicity toward osteosarcoma cells. Thus, the detected phenomenon for the ZnMg 0.0026 alloy can become the basis for creating biodegradable Zn-Mg surgical wires with antitumor activity.