Modification of Biocorrosion and Cellular Response of Magnesium Alloy WE43 by Multiaxial Deformation

The study shows that multiaxial deformation (MAD) treatment leads to grain refinement in magnesium alloy WE43. Compared to the initial state, the MAD-processed alloy exhibited smoother biocorrosion dynamics in a fetal bovine serum and in a complete cell growth medium. Examination by microCT demonstrated retardation of the decline in the alloy volume and the Hounsfield unit values. An attendant reduction in the rate of accumulation of the biodegradation products in the immersion medium, a less pronounced alkalization, and inhibited sedimentation of biodegradation products on the surface of the alloy were observed after MAD. These effects were accompanied with an increase in the osteogenic mesenchymal stromal cell viability on the alloy surface and in a medium containing their extracts. It is expected that the more orderly dynamics of biodegradation of the WE43 alloy after MAD and the stimulation of cell colonization will effectively promote stable osteosynthesis, making repeat implant extraction surgeries unnecessary.

Cross Talk Between Macrophages and Cancer Cells in the Bone Metastatic Environment

The skeleton is a common site for cancer metastases with the bone microenvironment providing the appropriate conditions for cancer cell colonization. Once in bone, cancer cells effectively manipulate their microenvironment to support their growth and survival. Despite previous efforts to improve treatment modalities, skeletal metastases remain with poor prognoses. This warrants an improved understanding of the mechanisms leading to bone metastasis that will aid development of effective treatments. Macrophages in the tumor microenvironment are termed tumor associated macrophages (TAMs) and their crosstalk with cancer cells is critical in regulating tumorigenicity in multiple cancers. In bone metastases, this crosstalk is also being increasingly implicated but the specific signaling pathways remain incompletely understood. Here, we summarize the reported functions, interactions, and signaling of macrophages with cancer cells during the metastatic cascade to bone. Specifically, we review and discuss how these specific interactions impact macrophages and their profiles to promote tumor development. We also discuss the potential of targeting this crosstalk to inhibit disease progression. Finally, we identify the remaining knowledge gaps that will need to be addressed in order to fully consider therapeutic targeting to improve clinical outcomes in cancer patients.

[18F](2S,4R)-4-Fluoroglutamine as a New Positron Emission Tomography Tracer in Myeloma

The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both bone marrow (BM) and extramedullary disease. However, new tracers are actively searched because [18F]FDG-PET has some limitations and there is a portion of MM patients who are negative. Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed so far and is investigated in this study in preclinical models. Firstly, we have synthesized enantiopure (2S,4R)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of 3H-labelled Gln. We then radiosynthesized [18F]4-FGln, tested its uptake in two different in vivo murine MM models, and checked the effect of Bortezomib, a proteasome inhibitor currently used in the treatment of MM. Both [18F]4-FGln and [18F]FDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice, challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice, subcutaneously injected with human MM JJN3 cells, showed high values of both [18F]4-FGln and [18F]FDG uptake. Bortezomib significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicle at post treatment PET. However, a reduction of glutaminolytic, but not of glycolytic, tumor volume was evident in mice showing the highest response to Bortezomib. Our data indicate that [18F](2S,4R)-4-FGln is a new PET tracer in preclinical MM models, yielding a rationale to design studies in MM patients.

Cell colonization potential of thermoplastic silicone-based polyurethane nonwovens for novel heart valve prosthesis

Heart valve tissue engineering aims at creating living valves through colonization of scaffolds with patient’s own cells. Various cell sources have been explored focusing mainly on endothelialization of the scaffold surface. Endothelial like cells, such as endothelial progenitor cells (EPCs), which can be isolated from peripheral blood or bone marrow could be a suitable option. In this study we investigated cell colonization potential of ovine EPCs (OEPCs) on thermoplastic silicone-based polyurethane (TSPU) polymer scaffolds. TSPU nonwovens with and without vascular endothelial growth factor (VEGF) functionalization were used. SEM images showed that by day 3 the cells were growing as patches on the surface of both polymer groups. The cell patches continued growing and started covering more of the nonwoven surface. On day 7 the cells had almost covered the scaffold surface. The cells were more uniformly distributed as monolayer on the functionalized TSPU compared to the non-functionalized nonwovens. Live/Dead staining provided bright green fluorescence on the samples, indicating metabolically active alive cells. These static cell seeding experiments demonstrated that functionalized TPSU nonwovens support endothelialization. The feasibility of TPSU nonwovens as heart valve prosthesis scaffold could be further explored with animal studies in an ovine model.

The Key Role of Exosomes on the Pre-metastatic Niche Formation in Tumors

Exosomes or other extracellular vesicles released from cells play an important role in cell-to-cell communication by transferring bio-information (DNA, coding/non-coding RNA, and proteins), which indicates parental cell status to recipient cells in the extracellular environment. Increasingly, evidence shows that tumor-derived exosomes mediate tumor pre-metastatic niche (PMN) remodeling to establish a supportive and receptive niche to promote tumor cell colonization and metastasis. Uptake of genetic information by target cells in the extracellular environment triggers epigenetic changes that contribute to PMN formation. Here, we provide a comprehensive overview of the current understanding of exosomes-mediated reprogramming of cells in PMN formation.

THE EFFECT OF MULTIAXIAL DEFORMATION ON THE DYNAMICS OF BIODEGRADATION AND CELL COLONIZATION OF ALLOY WE43

Introduction. The development of materials for bioresorbable implants is an urgent issue in medicine and materials science. Magnesium alloys are promising materials for this purpose. In particular, alloy WE43 (Mg-Y-Nd-Zr) has proven itself well in this field. However, the use of magnesium alloys is limited by a high degradation rate, which is often accompanied with nonuniform corrosion, which negatively affects the load bearing capacity of the product. In addition, the increased degradation rate usually seriously worsens the biocompatibility of magnesium alloys. Therefore, the study of the corrosion resistance of magnesium alloys, as well astheir biocompatibility, is an urgent task.Purpose of the study was to investigate the effect of multiaxial deformation (MAD), aimed at increasing the mechanical characteristics of the alloy WE43, on its biodegradation kinetics, as well as on cell colonization.Materials and methods. The alloy WE43 in two states – homogenized (WE43 hom) and strengthened by MAD (WE43 MAD) was investigated in this work. The kinetics of biodegradation was investigated on an xCELLigence RTCA Systems analyzer. A method for estimating the volume of hydrogen was used to study the process of gas formation, which was recorded using an automated digital microscope LionheartTM FX. The corrosive medium was a solution based on Dulbecco’s Modified Eagle’s Medium. A culture of mesenchymal multipotent stromal cells was used to study the colonization of the alloy surface by cells.Results. MAD of the alloy WE43 leads to a decrease in the biodegradation rate and the intensity of gas formation. The period of stabilization of biodegradation for the alloy after the MAD is 16 hours versus 3 hours for the alloy after homogenization. In this case, the volume of released hydrogen was 65.0 ± 4.4 mm3H2/mm3 alloy and 211.0 ± ± 21.1 mm3H2/mm3 alloy for the alloy after MAD and homogenization, respectively. MAD improves the biocompatibility of the alloy WE43, stimulating the colonization of mesenchymal multipotent stromal cells.Conclusion. MAD reduces biodegradation and improves the biocompatibility of the alloy WE43, which makes it a promising medical material, including for the purposes of oncoorthopedics

Magnetic Superporous Poly(2-hydroxyethyl methacrylate) Hydrogel Scaffolds for Bone Tissue Engineering

Magnetic maghemite (γ-Fe2O3) nanoparticles obtained by a coprecipitation of iron chlorides were dispersed in superporous poly(2-hydroxyethyl methacrylate) scaffolds containing continuous pores prepared by the polymerization of 2-hydroxyethyl methacrylate (HEMA) and ethylene dimethacrylate (EDMA) in the presence of ammonium oxalate porogen. The scaffolds were thoroughly characterized by scanning electron microscopy (SEM), vibrating sample magnetometry, FTIR spectroscopy, and mechanical testing in terms of chemical composition, magnetization, and mechanical properties. While the SEM microscopy confirmed that the hydrogels contained communicating pores with a length of ≤2 mm and thickness of ≤400 μm, the SEM/EDX microanalysis documented the presence of γ-Fe2O3 nanoparticles in the polymer matrix. The saturation magnetization of the magnetic hydrogel reached 2.04 Am2/kg, which corresponded to 3.7 wt.% of maghemite in the scaffold; the shape of the hysteresis loop and coercivity parameters suggested the superparamagnetic nature of the hydrogel. The highest toughness and compressive modulus were observed with γ-Fe2O3-loaded PHEMA hydrogels. Finally, the cell seeding experiments with the human SAOS-2 cell line showed a rather mediocre cell colonization on the PHEMA-based hydrogel scaffolds; however, the incorporation of γ-Fe2O3 nanoparticles into the hydrogel improved the cell adhesion significantly. This could make this composite a promising material for bone tissue engineering.