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- ItemGlycerylphytate as an ionic crosslinker for 3D printing of multi-layered scaffolds with improved shape fidelity and biological features(London : Royal Society of Chemistry, 2020) Mora-Boza, A.; Włodarczyk-Biegun, M.K.; Del Campo, A.; Vázquez-Lasa, B.; Román, J.S.The fabrication of intricate and long-term stable 3D polymeric scaffolds by a 3D printing technique is still a challenge. In the biomedical field, hydrogel materials are very frequently used because of their excellent biocompatibility and biodegradability, however the improvement of their processability and mechanical properties is still required. This paper reports the fabrication of dual crosslinked 3D scaffolds using a low concentrated (<10 wt%) ink of gelatin methacryloyl (GelMA)/chitosan and a novel crosslinking agent, glycerylphytate (G1Phy) to overcome the current limitations in the 3D printing field using hydrogels. The applied methodology consisted of a first ultraviolet light (UV) photopolymerization followed by a post-printing ionic crosslinking treatment with G1Phy. This crosslinker provides a robust framework and avoids the necessity of neutralization with strong bases. The blend ink showed shear-thinning behavior and excellent printability in the form of a straight and homogeneous filament. UV curing was undertaken simultaneously to 3D deposition, which enhanced precision and shape fidelity (resolution ≈150 μm), and prevented the collapse of the subsequent printed layers (up to 28 layers). In the second step, the novel G1Phy ionic crosslinker agent provided swelling and long term stability properties to the 3D scaffolds. The multi-layered printed scaffolds were mechanically stable under physiological conditions for at least one month. Preliminary in vitro assays using L929 fibroblasts showed very promising results in terms of adhesion, spreading, and proliferation in comparison to other phosphate-based traditional crosslinkers (i.e. TPP). We envision that the proposed combination of the blend ink and 3D printing approach can have widespread applications in the regeneration of soft tissues.
- ItemToxicological Responses of α-Pinene-Derived Secondary Organic Aerosol and Its Molecular Tracers in Human Lung Cell Lines(New York, NY : ACS Publ., 2021) Khan, Faria; Kwapiszewska, Karina; Zhang, Yue; Chen, Yuzhi; Lambe, Andrew T.; Kołodziejczyk, Agata; Jalal, Nasir; Rudzinski, Krzysztof; Martínez-Romero, Alicia; Fry, Rebecca C.; Surratt, Jason D.; Szmigielski, RafalSecondary organic aerosol (SOA) is a major component of airborne fine particulate matter (PM2.5) that contributes to adverse human health effects upon inhalation. Atmospheric ozonolysis of α-pinene, an abundantly emitted monoterpene from terrestrial vegetation, leads to significant global SOA formation; however, its impact on pulmonary pathophysiology remains uncertain. In this study, we quantified an increasing concentration response of three well-established α-pinene SOA tracers (pinic, pinonic, and 3-methyl-1,2,3-butanetricarboxylic acids) and a full mixture of α-pinene SOA in A549 (alveolar epithelial carcinoma) and BEAS-2B (bronchial epithelial normal) lung cell lines. The three aforementioned tracers contributed ∼57% of the α-pinene SOA mass under our experimental conditions. Cellular proliferation, cell viability, and oxidative stress were assessed as toxicological end points. The three α-pinene SOA molecular tracers had insignificant responses in both cell types when compared with the α-pinene SOA (up to 200 μg mL-1). BEAS-2B cells exposed to 200 μg mL-1 of α-pinene SOA decreased cellular proliferation to ∼70% and 44% at 24- and 48-h post exposure, respectively; no changes in A549 cells were observed. The inhibitory concentration-50 (IC50) in BEAS-2B cells was found to be 912 and 230 μg mL-1 at 24 and 48 h, respectively. An approximate 4-fold increase in cellular oxidative stress was observed in BEAS-2B cells when compared with untreated cells, suggesting that reactive oxygen species (ROS) buildup resulted in the downstream cytotoxicity following 24 h of exposure to α-pinene SOA. Organic hydroperoxides that were identified in the α-pinene SOA samples likely contributed to the ROS and cytotoxicity. This study identifies the potential components of α-pinene SOA that likely modulate the oxidative stress response within lung cells and highlights the need to carry out chronic exposure studies on α-pinene SOA to elucidate its long-term inhalation exposure effects. © 2021 American Chemical Society.
- ItemMultifunctional coatings combining bioactive peptides and affinity-based cytokine delivery for enhanced integration of degradable vascular grafts(Cambridge : Royal Soc. of Chemistry, 2020) Clauder, Franziska; Zitzmann, Franziska D.; Friebe, Sabrina; Mayr, Stefan G.; Robitzki, Andrea A.; Beck-Sickinger, Annette G.Insufficient endothelialization of cardiovascular devices is a high-risk factor for implant failure. Presentation of extracellular matrix (ECM)-derived coatings is a well-known strategy to improve implant integration. However, the complexity of the system is challenging and strategies for applying multifunctionality are required. Here, we engineered mussel-derived surface-binding peptides equipped with integrin (c[RGDfK]) and proteoglycan binding sites (FHRRIKA) for enhanced endothelialization. Surface-binding properties of the platform containing l-3,4-dihydroxyphenylalanine (DOPA) residues were confirmed for hydrophilized polycaprolactone-co-lactide scaffolds as well as for glass and polystyrene. Further, heparin and the heparin-binding angiogenic factors VEGF, FGF-2 and CXCL12 were immobilized onto the peptide in a modular assembly. Presentation of bioactive peptides greatly enhanced human umbilical vein endothelial cell (HUVEC) adhesion and survival under static and fluidic conditions. In subsequent investigations, peptide-heparin-complexes loaded with CXCL12 or VEGF had an additional increasing effect on cell viability, differentiation and migration. Finally, hemocompatibility of the coatings was ensured. This study demonstrates that coatings combining adhesion peptides, glycosaminoglycans and modulators are a versatile tool to convey ECM-inspired multifunctionality to biomaterials and efficiently promote their integration. © 2020 The Royal Society of Chemistry.
- ItemA New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma([Cairo] : Hindawi, 2021) Diesinger, Torsten; Lautwein, Alfred; Bergler, Sebastian; Buckert, Dominik; Renz, Christian; Dvorsky, Radovan; Buko, Vyacheslav; Kirko, Siarhei; Schneider, Edith; Kuchenbauer, Florian; Kumar, Mukesh; Günes, Cagatay; Genze, Felicitas; Büchele, Berthold; Simmet, Thomas; Haslbeck, Martin; Masur, Kai; Barth, Thomas; Müller-Enoch, Dieter; Wirth, Thomas; Haehner, Thomas; Granito, AlessandroCytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD. © 2021 Torsten Diesinger et al.
- ItemTargeted delivery of functionalized PLGA nanoparticles to macrophages by complexation with the yeast Saccharomyces cerevisiae(Chichester : John Wiley and Sons Ltd, 2020) Kiefer, R.; Jurisic, M.; Dahlem, C.; Koch, M.; Schmitt, M.J.; Kiemer, A.K.; Schneider, M.; Breinig, F.Nanoparticles (NPs) are able to deliver a variety of substances into eukaryotic cells. However, their usage is often hampered by a lack of specificity, leading to the undesired uptake of NPs by virtually all cell types. In contrast to this, yeast is known to be specifically taken up into immune cells after entering the body. Therefore, we investigated the interaction of biodegradable surface-modified poly(lactic-co-glycolic acid) (PLGA) particles with yeast cells to overcome the unspecificity of the particulate carriers. Cells of different Saccharomyces cerevisiae strains were characterized regarding their interaction with PLGA-NPs under isotonic and hypotonic conditions. The particles were shown to efficiently interact with yeast cells leading to stable NP/yeast-complexes allowing to associate or even internalize compounds. Notably, applying those complexes to a coculture model of HeLa cells and macrophages, the macrophages were specifically targeted. This novel nano-in-micro carrier system suggests itself as a promising tool for the delivery of biologically active agents into phagocytic cells combining specificity and efficiency.
- ItemPhysics inspired compact modelling of BiFeO3 based memristors([London] : Macmillan Publishers Limited, part of Springer Nature, 2022) Yarragolla, Sahitya; Du, Nan; Hemke, Torben; Zhao, Xianyue; Chen, Ziang; Polian, Ilia; Mussenbrock, ThomasWith the advent of the Internet of Things, nanoelectronic devices or memristors have been the subject of significant interest for use as new hardware security primitives. Among the several available memristors, BiFeO3 (BFO)-based electroforming-free memristors have attracted considerable attention due to their excellent properties, such as long retention time, self-rectification, intrinsic stochasticity, and fast switching. They have been actively investigated for use in physical unclonable function (PUF) key storage modules, artificial synapses in neural networks, nonvolatile resistive switches, and reconfigurable logic applications. In this work, we present a physics-inspired 1D compact model of a BFO memristor to understand its implementation for such applications (mainly PUFs) and perform circuit simulations. The resistive switching based on electric field-driven vacancy migration and intrinsic stochastic behaviour of the BFO memristor are modelled using the cloud-in-a-cell scheme. The experimental current–voltage characteristics of the BFO memristor are successfully reproduced. The response of the BFO memristor to changes in electrical properties, environmental properties (such as temperature) and stress are analyzed and consistant with experimental results.