Publikationen am Institut für Chemie und Biotechnik

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Cao-Riehmer, Jialan; Chande, Charmi; Köhler, Michael;
Microtoxicology by microfluidic instrumentation: a review. - In: Lab on a chip, ISSN 1473-0189, (2022), insges. 24 S.

Microtoxicology is concerned with the toxic effects of small amounts of substances. This review paper discusses the application of small amounts of noxious substances for toxicological investigation in small volumes. The vigorous development of miniaturized methods in microfluidics over the last two decades involves chip-based devices, micro droplet-based procedures, and the use of micro-segmented flow for microtoxicological studies. The studies have shown that the microfluidic approach is particularly valuable for highly parallelized and combinatorial dose-response screenings. Accurate dosing and mixing of effector substances in large numbers of microcompartments supplies detailed data of dose-response functions by highly concentration-resolved assays and allows evaluation of stochastic responses in case of small separated cell ensembles and single cell experiments. The investigations demonstrate that very different biological targets can be studied using miniaturized approaches, among them bacteria, eukaryotic microorganisms, cell cultures from tissues of multicellular organisms, stem cells, and early embryonic states. Cultivation and effector exposure tests can be performed in small volumes over weeks and months, confirming that the microfluicial strategy is also applicable for slow-growing organisms. Here, the state of the art of miniaturized toxicology, particularly for studying antibiotic susceptibility, drug toxicity testing in the miniaturized system like organ-on-chip, environmental toxicology, and the characterization of combinatorial effects by two and multi-dimensional screenings, is discussed. Additionally, this review points out the practical limitations of the microtoxicology platform and discusses perspectives on future opportunities and challenges.
Nolte, Oliver; Geitner, Robert; Volodin, Ivan A.; Rohland, Philip; Hager, Martin; Schubert, Ulrich Sigmar;
State of charge and state of health assessment of viologens in aqueous-organic redox-flow electrolytes using in situ IR spectroscopy and multivariate curve resolution. - In: Advanced science, ISSN 2198-3844, Bd. 9 (2022), 17, 2200535, S. 1-10

Aqueous-organic redox flow batteries (RFBs) have gained considerable interest in recent years, given their potential for an economically viable energy storage at large scale. This, however, strongly depends on both the robustness of the underlying electrolyte chemistry against molecular decomposition reactions as well as the device's operation. With regard to this, the presented study focuses on the use of in situ IR spectroscopy in combination with a multivariate curve resolution approach to gain insight into both the molecular structures of the active materials present within the electrolyte as well as crucial electrolyte state parameters, represented by the electrolyte's state of charge (SOC) and state of health (SOH). To demonstrate the general applicability of the approach, methyl viologen (MV) and bis(3-trimethylammonium)propyl viologen (BTMAPV) are chosen, as viologens are frequently used as negolytes in aqueous-organic RFBs. The study's findings highlight the impact of in situ spectroscopy and spectral deconvolution tools on the precision of the obtainable SOC and SOH values. Furthermore, the study indicates the occurrence of multiple viologen dimers, which possibly influence the electrolyte lifetime and charging characteristics.
Strutynska, Nataliia Yu.; Grynyuk, Iryna I.; Vasyliuk, Olga M.; Prylutska, Svitlana V.; Vovchenko, Ludmila L.; Kraievska, I. A.; Slobodyanik, Nikolai S.; Ritter, Uwe; Prylutskyy, Yury I.;
Novel whitlockite/alginate/C60 fullerene composites: synthesis, characterization and properties for medical application. - In: The Arabian journal for science and engineering, ISSN 2191-4281, Bd. 47 (2022), 6, S. 7093-7104

The hybrid composite materials in form of spheres based on whitlockite-related calcium phosphate, Alginate (20, 30 or 50 wt.%) and C60 Fullerene (C60; 2 or 5 wt.%) were fabricated. According to XRD, elemental analysis and SEM data, the whitlockite-related (hexagonal system, space group R3c) calcium phosphate containing 0.42 wt.% of sodium was obtained in the form of particles with size 50-80 nm. It has been found that the addition of Alginate (20 wt.%) to prepared calcium phosphate leads to an increase in the compressive strength of composite by two times (from 137 to 358 MPa), and value of Young's modulus on 20% (from 460 to 558 MPa), while the presence of C60 in composition did not significant influence on this characteristic. The antibacterial activity of prepared composites with different composition and amounts (2.5, 5 or 10 mM) against Lactobacillus rhamnosus, Lactobacillus salivarius, Staphylococcus aureus and Pseudomonas aeruginosa was studied. All prepared samples did not effect on Lactobacillus. The addition of 5 wt.% C60 to phosphate-Alginate (30 wt.%) composite resulted in a tenfold decrease in the survival rate of the S. aureus strain at 5 and 10 mM of samples while P. aeruginosa was less sensitive to action of this sample and inhibition of bacteria growth was occurred only at its amount 10 mM. Thus, the results of mechanical properties and impact of created nanostructured hybrid composites on normal human microbiota (Lactobacillus) as well as pathogenic strain (S. aureus and P. aeruginosa) indicate the suitability of these promising materials for further biological test for bone therapy.
Nozdrenko, Dmytro; Prylutska, Svitlana; Bogutska, Kateryna; Cherepanov, Vsevolod; Senenko, Anton; Vygovska, Oksana; Khrapatyi, Sergii; Ritter, Uwe; Prylutskyy, Yuriy; Piosik, Jacek;
Analysis of biomechanical and biochemical markers of rat muscle soleus fatigue processes development during long-term use of C60 fullerene and N-acetylcysteine. - In: Nanomaterials, ISSN 2079-4991, Bd. 12 (2022), 9, 1552, S. 1-15

The development of an effective therapy aimed at restoring muscle dysfunctions in clinical and sports medicine, as well as optimizing working activity in general remains an urgent task today. Modern nanobiotechnologies are able to solve many clinical and social health problems, in particular, they offer new therapeutic approaches using biocompatible and bioavailable nanostructures with specific bioactivity. Therefore, the nanosized carbon molecule, C60 fullerene, as a powerful antioxidant, is very attractive. In this study, a comparative analysis of the dynamic of muscle soleus fatigue processes in rats was conducted using 50 Hz stimulation for 5 s with three consistent pools after intraperitoneal administration of the following antioxidants: C60 fullerene (a daily dose of 1 mg/kg one hour prior to the start of the experiment) and N-acetylcysteine (NAC; a daily dose of 150 mg/kg one hour prior to the start of the experiment) during five days. Changes in the integrated power of muscle contraction, levels of the maximum and minimum contraction force generation, time of reduction of the contraction force by 50% of its maximum value, achievement of the maximum force response, and delay of the beginning of a single contraction force response were analyzed as biomechanical markers of fatigue processes. Levels of creatinine, creatine phosphokinase, lactate, and lactate dehydrogenase, as well as pro- and antioxidant balance (thiobarbituric acid reactive substances, hydrogen peroxide, reduced glutathione, and catalase activity) in the blood of rats were analyzed as biochemical markers of fatigue processes. The obtained data indicate that applied therapeutic drugs have the most significant effects on the 2nd and especially the 3rd stimulation pools. Thus, the application of C60 fullerene has a (50-80)% stronger effect on the resumption of muscle biomechanics after the beginning of fatigue than NAC on the first day of the experiment. There is a clear trend toward a positive change in all studied biochemical parameters by about (12-15)% after therapeutic administration of NAC and by (20-25)% after using C60 fullerene throughout the experiment. These findings demonstrate the promise of using C60 fullerenes as potential therapeutic nanoagents that can reduce or adjust the pathological conditions of the muscular system that occur during fatigue processes in skeletal muscles.
Dorner-Reisel, Annett; Ritter, Uwe; Moje, Jens; Freiberger, Emma; Scharff, Peter;
Effect of fullerene C60 thermal and tribomechanical loading on Raman signals. - In: Diamond and related materials, ISSN 0925-9635, Bd. 126 (2022), 109036, S. 1-14

Fullerene C60 powder was loaded by 1 N normal force and exposed to sliding under different frequencies for 15 min. It is shown that the velocity of the sliding movement determines the stability of the fullerene C60 powder. At slow velocity of movement with a frequency of 1 Hz under 1 N normal force, the fullerene C60 structure remains undamaged after 15 min sliding. On the contrary, high sliding velocities of 10 Hz and 50 Hz affected fragmentation of the fullerene C60, which resulted in a reduction of the coefficient of friction (COF). During sliding with 1 Hz, the friction reached the highest level with an average COF of 0.59 ± 0.03. The faster relative motion under 1 N normal force gave a lower average COF with 0.39 ± 0.03. The initial fullerene C60 powder formed a thick compressed layer in the tribomechanical loaded zone. As proven by Raman spectroscopy, operating the tribomechanical sliding test at 50 Hz stimulated the re-attraction of fresh C60 fullerene island onto the fragmented layer from outside of the loaded powder regions. The COF was increasing again up to 0.44 ± 0.04 for 1 N normal force and 50 Hz frequency. The fragmentation and decomposition of fullerene C60 with increasing sliding velocity is attributed to thermal heating up during fast relative movement. Raman spectra of the tribomechanical loaded fullerene C60 are compared with Raman spectra from slowly heated up C60 in air and with Raman spectra of laser irradiated fullerene C60.
Mai, Patrick; Hampl, Jörg; Baca, Martin; Brauer, Dana; Singh, Sukhdeep; Weise, Frank; Borowiec, Justyna; Schmidt, André; Küstner, Johanna Merle; Klett, Maren; Gebinoga, Michael; Schroeder, Insa S.; Markert, Udo R.; Glahn, Felix; Schumann, Berit; Eckstein, Diana; Schober, Andreas;
MatriGrid® based biological morphologies: tools for 3D cell culturing. - In: Bioengineering, ISSN 2306-5354, Bd. 9 (2022), 5, 220P1-41

Recent trends in 3D cell culturing has placed organotypic tissue models at another level. Now, not only is the microenvironment at the cynosure of this research, but rather, microscopic geometrical parameters are also decisive for mimicking a tissue model. Over the years, technologies such as micromachining, 3D printing, and hydrogels are making the foundation of this field. However, mimicking the topography of a particular tissue-relevant substrate can be achieved relatively simply with so-called template or morphology transfer techniques. Over the last 15 years, in one such research venture, we have been investigating a micro thermoforming technique as a facile tool for generating bioinspired topographies. We call them MatriGrid®s. In this research account, we summarize our learning outcome from this technique in terms of the influence of 3D micro morphologies on different cell cultures that we have tested in our laboratory. An integral part of this research is the evolution of unavoidable aspects such as possible label-free sensing and fluidic automatization. The development in the research field is also documented in this account.
Baca, Martin; Brauer, Dana; Klett, Maren; Fernekorn, Uta; Singh, Sukhdeep; Hampl, Jörg; Groß, Gregor Alexander; Mai, Patrick; Friedel, Karin; Schober, Andreas;
Automated analysis of acetaminophen toxicity on 3D HepaRG cell culture in microbioreactor. - In: Bioengineering, ISSN 2306-5354, Bd. 9 (2022), 5, 196, S. 1-16

Real-time monitoring of bioanalytes in organotypic cell cultivation devices is a major research challenge in establishing stand-alone diagnostic systems. Presently, no general technical facility is available that offers a plug-in system for bioanalytics in diversely available organotypic culture models. Therefore, each analytical device has to be tuned according to the microfluidic and interface environment of the 3D in vitro system. Herein, we report the design and function of a 3D automated culture and analysis device (3D-ACAD) which actively perfuses a custom-made 3D microbioreactor, samples the culture medium and simultaneously performs capillary-based flow ELISA. A microstructured MatriGrid® has been explored as a 3D scaffold for culturing HepaRG cells, with albumin investigated as a bioanalytical marker using flow ELISA. We investigated the effect of acetaminophen (APAP) on the albumin secretion of HepaRG cells over 96 h and compared this with the albumin secretion of 2D monolayer HepaRG cultures. Automated on-line monitoring of albumin secretion in the 3D in vitro mode revealed that the application of hepatotoxic drug-like APAP results in decreased albumin secretion. Furthermore, a higher sensitivity of the HepaRG cell culture in the automated 3D-ACAD system to APAP was observed compared to HepaRG cells cultivated as a monolayer. The results support the use of the 3D-ACAD model as a stand-alone device, working in real time and capable of analyzing the condition of the cell culture by measuring a functional analyte. Information obtained from our system is compared with conventional cell culture and plate ELISA, the results of which are presented herein.
Tong, Ciqing; Wondergem, Joeri A. J.; van den Brink, Marijn; Kwakernaak, Markus C.; Chen, Ying; Hendrix, Marco M. R. M.; Voets, Ilja K.; Danen, Erik Hendrik Julius; Le Dévédec, Sylvia; Heinrich, Doris; Kieltyka, Roxanne E.;
Spatial and temporal modulation of cell instructive cues in a filamentous supramolecular biomaterial. - In: ACS applied materials & interfaces, ISSN 1944-8252, Bd. 14 (2022), 15, S. 17042-17054

Supramolecular materials provide unique opportunities to mimic both the structure and mechanics of the biopolymer networks that compose the extracellular matrix. However, strategies to modify their filamentous structures in space and time in 3D cell culture to study cell behavior as encountered in development and disease are lacking. We herein disclose a multicomponent squaramide-based supramolecular material whose mechanics and bioactivity can be controlled by light through co-assembly of a 1,2-dithiolane (DT) monomer that forms disulfide cross-links. Remarkably, increases in storage modulus from ∼200 Pa to >10 kPa after stepwise photo-cross-linking can be realized without an initiator while retaining colorlessness and clarity. Moreover, viscoelasticity and plasticity of the supramolecular networks decrease upon photo-irradiation, reducing cellular protrusion formation and motility when performed at the onset of cell culture. When applied during 3D cell culture, force-mediated manipulation is impeded and cells move primarily along earlier formed channels in the materials. Additionally, we show photopatterning of peptide cues in 3D using either a photomask or direct laser writing. We demonstrate that these squaramide-based filamentous materials can be applied to the development of synthetic and biomimetic 3D in vitro cell and disease models, where their secondary cross-linking enables mechanical heterogeneity and shaping at multiple length scales.
Visaveliya, Nikunjkumar R.; Mazétyté-Stasinskiené, Raminta; Köhler, Michael;
Stationary, continuous, and sequential surface-enhanced raman scattering sensing based on the nanoscale and microscale polymer-metal composite sensor particles through microfluidics: a review. - In: Advanced optical materials, ISSN 2195-1071, Bd. 10 (2022), 7, 2102757, S. 1-25

Surface-enhanced Raman scattering (SERS) is a label-free and accurate analytical technique for the detection of a broad range of various analytes such as, biomolecules, pesticides, petrochemicals, as well as, cellular and other biological systems. A key component for the SERS analysis is the substrate which is required to be equipped with plasmonic features of metal nanostructures that directly interact with light and targeted analytes. Either metal nanoparticles can be deposited on the solid support (glass or silicon) which is suitable for stationary SERS analysis or dispersed in the solution (freely moving nanoparticles). Besides these routinely utilizing SERS substrates, polymer-metal composite particles are promising for sustained SERS analysis where metal nanoparticles act as plasmon-active (hence SERS-active) components and polymer particles act as support to the metal nanoparticles. Composite sensor particles provide 3D interaction possibilities for analytes, suitable for stationary, continuous, and sequential analysis, and they are reusable/regenerated. Therefore, this review is focused on the experimental procedures for the development of multiscale, uniform, and reproducible composite sensor particles together with their application for SERS analysis. The microfluidic reaction technique is highly versatile in the production of uniform and size-tunable composite particles, as well as, for conducting SERS analysis.
Nozdrenko, Dmytro; Matvienko, Tatiana; Vygovska, Oksana; Soroca, Vasil; Bogutska, Kateryna; Zholos, Alexander; Scharff, Peter; Ritter, Uwe; Prylutskyy, Yuriy;
Post-traumatic recovery of muscle soleus in rats is improved via synergistic effect of C60 fullerene and TRPM8 agonist menthol. - In: Applied nanoscience, ISSN 2190-5517, Bd. 12 (2022), 3, S. 467-478

Functional biomechanical parameters of muscle soleus contraction in rats as well as selected blood biochemical parameters were studied during the first 3 days of post-traumatic syndrome progression caused by the destruction of muscle cells by compression. Single administration of the antioxidant C60 fullerene and the selective agonist of TRPM8 channels menthol were used as therapeutic agents. Injection of C60 fullerene at a concentration of 1 mg/kg into the damaged muscle improved its contractile function by 25-28%. The use of combined injections of C60 fullerene and menthol (at the concentration 1 mg/kg) improved this index by additional 27-39% and simultaneously stabilized the decrease in muscle strength observed throughout the experiment. A tendency towards a decrease in the indexes of the above described biochemical parameters by 10-15% were found with the therapeutic administration of C60 fullerene. With combined injections of C60 fullerene and menthol, the above described biochemical parameters decreased by an additional 17-24%. The synergism between the action of menthol and C60 fullerene on the post-traumatic recovery of skeletal muscle function opens up new perspectives for the clinical application of this combination therapy.