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The importance of Mg in the human body, its key role in bone tissue development, in addition to its application to improve and modify physical, thermal, and mechanical properties of bioactive silicate glasses, make Mg a very interesting element as a component of bioactive glasses for medical applications. Although Mg is a typical element in the composition of numerous developed bioactive glasses, the analysis of the literature reveals that further research is required to gain comprehensive understanding about the effects of MgO on bioactive glass structure and properties. This article presents a comprehensive overview of the field of Mg‐containing bioactive glasses discussing available compositions and summarizing existing knowledge on effects of MgO on glass properties. The biomedical applications of several developed glasses are discussed highlighting the distinct effects of Mg in relevant areas, such as bioactivity and cell response, and focusing on the most common applications for these glasses, such as bone cements, bioactive coatings, and scaffolds for bone tissue engineering. The effect of Mg on bone development is discussed and avenues for future research in the field are proposed, emphasizing the need to investigate unstudied properties of (already developed) Mg‐containing glass compositions, such as angiogenesis‐stimulating action and the effect on osteoclast functions, to develop new Mg‐containing bioactive glasses as well as to make products of different shape designs such as nanoparticles, fibers, and complex porous structures.

With an increasing demand for efficacious, safe, and affordable vaccines for human and animal use, process intensification in cell culture-based viral vaccine production demands advanced process strategies to overcome the limitations of conventional batch cultivations. However, the use of fed-batch, perfusion, or continuous modes to drive processes at high cell density (HCD) and overextended operating times has so far been little explored in large-scale viral vaccine manufacturing. Also, possible reductions in cell-specific virus yields for HCD cultivations have been reported frequently. Taking into account that vaccine production is one of the most heavily regulated industries in the pharmaceutical sector with tough margins to meet, it is understandable that process intensification is being considered by both academia and industry as a next step toward more efficient viral vaccine production processes only recently. Compared to conventional batch processes, fed-batch and perfusion strategies could result in ten to a hundred times higher product yields. Both cultivation strategies can be implemented to achieve cell concentrations exceeding 107 cells/mL or even 108 cells/mL, while keeping low levels of metabolites that potentially inhibit cell growth and virus replication. The trend towards HCD processes is supported by development of GMP-compliant cultivation platforms, i.e., acoustic settlers, hollow fiber bioreactors, and hollow fiber-based perfusion systems including tangential flow filtration (TFF) or alternating tangential flow (ATF) technologies. In this review, these process modes are discussed in detail and compared with conventional batch processes based on productivity indicators such as space-time yield, cell concentration, and product titers. In addition, options for the production of viral vaccines in continuous multi-stage bioreactors such as two- and three-stage systems are addressed. While such systems have shown similar virus titers compared to batch cultivations, keeping high yields for extended production times is still a challenge. Overall, we demonstrate that process intensification of cell culture-based viral vaccine production can be realized by the consequent application of fed-batch, perfusion, and continuous systems with a significant increase in productivity. The potential for even further improvements is high, considering recent developments in establishment of new (designer) cell lines, better characterization of host cell metabolism, advances in media design, and the use of mathematical models as a tool for process optimization and control.

Cardiac fibroblast differentiation to myofibroblast is a crucial process in the development of cardiac fibrosis and is tightly dependent on transforming growth factor beta-1 (TGF-β1). The transcription factor forkhead box O1 (FoxO1) regulates many cell functions, including cell death by apoptosis, proliferation, and differentiation. However, several aspects of this process remain unclear, including the role of FoxO1 in cardiac fibroblast differentiation and the regulation of FoxO1 by TGF-β1. Here, we report that TGF-β1 stimulates FoxO1 expression, promoting its dephosphorylation, nuclear localization and transcriptional activity in cultured cardiac fibroblasts. TGF-β1 also increases differentiation markers such as α-smooth muscle actin, connective tissue growth factor, and pro-collagen I, whereas it decreases cardiac fibroblast proliferation triggered by fetal bovine serum. TGF-β1 also increases levels of p21waf/cip-cycle inhibiting factor protein, a cytostatic factor promoting cell cycle arrest and cardiac fibroblast differentiation. In addition, TGF-β1 increases cardiac fibroblast contractile capacity as assessed by collagen gel contraction assay. The effect of TGF-β1 on cardiac fibroblast differentiation was prevented by FoxO1 down-regulation and enhanced by FoxO1 overexpression. Thus, our findings reveal that FoxO1 is regulated by TGF-β1 and plays a critical role in cardiac fibroblast differentiation. We propose that FoxO1 is an attractive new target for anti-fibrotic therapy.

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