INMdok (Leibniz Institute for New Materials)
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Integrating Biophysics in Toxicology
Get PDFIntegration of biophysical stimulation in test systems is established in diverse branches of biomedical sciences including toxicology. This is largely motivated by the need to create novel experimental setups capable of reproducing more closely in vivo physiological conditions. Indeed, we face the need to increase predictive power and experimental output, albeit reducing the use of animals in toxicity testing. In vivo, mechanical stimulation is essential for cellular homeostasis. In vitro, diverse strategies can be used to model this crucial component. The compliance of the extracellular matrix can be tuned by modifying the stiffness or through the deformation of substrates hosting the cells via static or dynamic strain. Moreover, cells can be cultivated under shear stress deriving from the movement of the extracellular fluids. In turn, introduction of physical cues in the cell culture environment modulates differentiation, functional properties, and metabolic competence, thus influencing cellular capability to cope with toxic insults. This review summarizes the state of the art of integration of biophysical stimuli in model systems for toxicity testing, discusses future challenges, and provides perspectives for the further advancement of in vitro cytotoxicity studies
Modulating Myeloid Immune Cell Migration Using Multivalently Presented Monosaccharide Ligands for Advanced Immunotherapy
Get PDFAbstract Due to their importance for the outcome of the inflammatory response, the motile myeloid cells are a focus of novel treatment options. The interplay of selectins and their ligands with leukocytes and endothelial cells, which mediate endothelial attachment and transmigration of immune cells, can be modulated by selectin-binding structures. Here, a library of selectin-targeting ligands coupled to either gold, silver, iron oxide nanospheres, or quantum dots of 5–10 nm in size is used to systematically study their impact on immune cell motility. The multivalent presentation of the carbohydrate mimetics results in very low sub-nanomolar binding to L-selectin. Using human primary monocytes, granulocytes, lymphocytes, and macrophages, it is shown that the ligands exhibit only minor effects on uptake, whereas the motility of leukocytes is critically affected as observed in migration assays evaluated by flow cytometry. The carbohydrate mimetic ring structure, sulfation, in particular, and the degree of ligand presentation, are constituents which cohere in this process. Specific carbohydrate ligands can thus selectively regulate leukocyte subsets. These data form the basis for advanced immunotherapy which inhibits the amplification of inflammation by restricting leukocyte influx to injured tissue sites. Furthermore, the targeting ligands may complement existing treatment options for inflammatory diseases
The synergistic effect of chlorotoxin-mApoE in boosting drug-loaded liposomes across the BBB
Get PDFWe designed liposomes dually functionalized with ApoE-derived peptide (mApoE) and chlorotoxin (ClTx) to improve their blood–brain barrier (BBB) crossing. Our results demonstrated the synergistic activity of ClTx-mApoE in boosting doxorubicin-loaded liposomes across the BBB, keeping the anti-tumour activity of the drug loaded: mApoE acts promoting cellular uptake, while ClTx promotes exocytosis of liposomes
Quantitative analysis of F-actin alterations in adherent human mesenchymal stem cells: influence of slow-freezing and vitirfication-based cryopreservation
Get PDFCryopreservation is an essential tool to meet the increasing demand for stem cells in medical applications. To ensure maintenance of cell function upon thawing, the preservation of the actin cytoskeleton is crucial, but so far there is little quantitative data on the influence of cryopreservation on cytoskeletal structures. For this reason, our study aims to quantitatively describe cryopreservation induced alterations to F-actin in adherent human mesenchymal stem cells, as a basic model for biomedical applications. Here we have characterised the actin cytoskeleton on single-cell level by calculating the circular standard deviation of filament orientation, F-actin content, and average filament length. Cryo-induced alterations of these parameters in identical cells pre and post cryopreservation provide the basis of our investigation. Differences between the impact of slow-freezing and vitrification are qualitatively analyzed and highlighted. Our analysis is supported by live cryo imaging of the actin cytoskeleton via two photon microscopy. We found similar actin alterations in slow-frozen and vitrified cells including buckling of actin filaments, reduction of F-actin content and filament shortening. These alterations indicate limited functionality of the respective cells. However, there are substantial differences in the frequency and time dependence of F-actin disruptions among the applied cryopreservation strategies; immediately after thawing, cytoskeletal structures show least disruption after slow freezing at a rate of 1°C/min. As post-thaw recovery progresses, the ratio of cells with actin disruptions increases, particularly in slow frozen cells. After 120 min of recovery the proportion of cells with an intact actin cytoskeleton is higher in vitrified than in slow frozen cells. Freezing at 10°C/min is associated with a high ratio of impaired cells throughout the post-thawing culture
Distribution of SiO2 nanoparticles in 3D liver microtissues
Get PDFIntroduction: Nanoparticles (NPs) are used in numerous products in technical fields and biomedicine; their potential adverse effects have to be considered in order to achieve safe applications. Besides their distribution in tissues, organs, and cellular localization, their impact and penetration during the process of tissue formation occurring in vivo during liver regeneration are critical steps for establishment of safe nanomaterials. Materials and methods: In this study, 3D cell culture of human hepatocarcinoma cells (HepG2) was used to generate cellular spheroids, serving as in vitro liver microtissues. In order to determine their differential distribution and penetration depth in HepG2 spheroids, SiO2 NPs were applied either during or after spheroid formation. The NP penetration was comprehensively studied using confocal laser scanning microscopy and scanning electron microscopy. Results: Spheroids were exposed to 100 µg mL-1 SiO2 NPs either at the beginning of spheroid formation, or during or after formation of spheroids. Microscopy analyses revealed that NP penetration into the spheroid is limited. During and after spheroid formation, SiO2 NPs penetrated about 20 µm into the spheroids, corresponding to about three cell layers. In contrast, because of the addition of SiO2 NPs simultaneously to cell seeding, NP agglomerates were located also in the spheroid center. Application of SiO2 NPs during the process of spheroid formation had no impact on final spheroid size. Conclusion: Understanding the distribution of NPs in tissues is essential for biomedical applications. The obtained results indicate that NPs show only limited penetration into already formed tissue, which is probably caused by the alteration of the tissue structure and cell packing density during the process of spheroid formation
Scaling of bird wings and feathers for efficient flight
Get PDFAves are an incredibly diverse class of animals, ranging greatly in size and thriving in a wide variety of environments. Here, we explore the scaling trends of bird wings in connection with their flight performance. The tensile strength of avian bone is hypothesized to be a limiting factor in scaling the humerus with mass, which is corroborated by its experimentally determined allometric scaling trend. We provide a mechanics analysis that explains the scaling allometry of the wing humerus length, LH, with body weight W, LH ∝ W0.44. Lastly, wing feathers are demonstrated to generally scale isometrically with bird mass, with the exception of the spacing between barbules, which falls within the same range for birds of all masses. Our findings provide insight into the “design” of birds and may be translatable to more efficient bird-inspired aircraft structures
Thiol-Methylsulfone Based Hydrogels: Enhanced Control on Gelation Kinetics for 3D Cell Encapsulation
Get PDFHydrogels are useful temporal matrices for cell culture technologies. The successful mixing and encapsulation of cells within the gel requires the selection of efficient and cytocompatible gelation reactions occurring in the minute timescale under physiological conditions. The thiol-methylsulfonyl (MS) chemical reaction is introduced here as a novel chemistry to encapsulate cells in polymeric matrices. Thiol-MS crosslinking does not require a light activation step and can occur within the seconds-to-minutes timescale by adjusting the pH in the physiological range 8.0-6.6. This reaction is cytocompatible and the reaction product is hydrolytically stable in cell culture media up to 4 weeks. Cell encapsulation protocols enabling comfortable handling and yielding homogenous distribution of the embedded cells are described. All these features are relevant for the application of this crosslinking reaction to biomedical scenarios. Finally, this manuscript also compares the performance of thiol-MS hydrogels with the established thiol-maleimide and thiol-vinylsulfone hydrogels. The benefit of thiol-MS crosslinking in terms of control over hydrogelation kinetics is demonstrated
Nachhaltige Materialien auf Basis von Cyclodextrinen für Korrosionsschutz und selbstheilende Beschichtungen
Get PDFIn dieser Arbeit wurden nachhaltige Materialien auf Basis von Cyclodextrinen hergestellt. Dafür sollten dünne Schichten auf Kupfer aufgebracht werden, um es vor degradativen Einflüssen wie der Oxidation zu schützen. Zur Herstellung dieser Monoschichten konnte die sogenannte „Self-Assembly“ (Selbstanordnung) Methode angewendet werden. Neben Cyclodextrin-Derivaten konnte ein Disulfid auf Kupfer abgeschieden werden, was bereits bei geringer Abscheidekonzentration Eigenschaften wie Barriereschichten zeigte. Daneben konnte über die Selbstanordnung von Cyclodextrinen auf einem Polymerrückgrat Polyrotaxane mit nachhaltigen Eigenschaften erhalten werden. Zur Herstellung konnte die rotaxa-Polymerisation durchgeführt werden. Diese ist eine freie radikalische Eintopfpolymerisation in Wasser. Es konnte erfolgreich die Anzahl der Ringe auf dem Polymerrückgrat gesteuert und gezielt verringert werden. Zudem konnte durch Wahl eines geeigneten Reglers die Quervernetzung des eingesetzten Monomers 2,3-Dimethyl-1,3-butadien unterdrückt werden. Durch Kupplung der aufgefädelten Ringe konnte ein Netzwerk gebildet werden. Nach Einfluss von Hitze ist dieses Netzwerk in der Lage Kratzer selbst zu heilen. In diese sogenannte Slide-Ring Gele konnten auch modifizierte Nanopartikel eingearbeitet werden, was die Schichthärte erhöht, aber das Nanokompositsystem nicht bei der Selbstheilung gestört hatte.In this work, sustainable cyclodextrins based materials were produced. Self-Assembly is a powerful tool to create ordered systems such as monolayers or polyrotaxanes. Applied as thin (mono)layers on copper, they enabled extended resistance against external influences such as oxidation. For the preparation of these monolayers with high controllability self-assembly was used. In addition to cyclodextrin derivatives, a disulfide was successfully deposited on copper, which showed resistances such as barrier layers even at low concentrations. For the synthesis of the polyrotaxanes the water based free radical one-pot rotaxa-polymerization was used. The number of rings on the polymer backbone was successfully controlled and reduced in order to allow better network formation when applied as a coating. In addition a suitable regulator suppressed the crosslinking of the monomer 2,3-dimethyl-1,3-butadiene. Coatings based on this polyrotaxanes embedded thermal induced healing of scratches. The combination with modified nanoparticles resulted in nanocomposites that combined superior self-healing abilities with extended layer hardness
Lokale und globale Ablösemechanismen in mikrostrukturierten Haftstrukturen
Get PDFIn dieser Arbeit wurden die Hafteigenschaften bio-inspirierter Mikrostrukturen untersucht. Es wurde ein Aufbau entwickelt, der eine Kombination aus Kraftmessungen und optischer in situ Beobachtung der realen Kontaktfläche mit Hilfe der frustrierten Totalreflexion ermöglicht. Die vorliegende Arbeit zeigt, dass Defekte an der Grenzfläche, Systemparameter (z. B. Maschinensteifigkeit, Fehlausrichtung) und äußere Einflüsse (z. B. Luftdruck) die Ablösemechanismen der Haftstrukturen verändern. Durch den maßgeblichen Einfluss von Defekten in der Kontaktfläche ergab sich eine breite Verteilung in der Haftfestigkeit der einzelnen Fibrillen im Array. Es konnte beobachtet werden, dass bereits bis zu 30 % der Fibrillen den Kontakt zum Substrat verloren, bevor die maximale Haftkraft erreicht wurde. Die Ergebnisse dieser Arbeit verdeutlichen, dass zur Optimierung der Adhäsionseigenschaften das Gesamtsystem betrachtet werden muss und nicht von Einzelfibrillen auf ein gesamtes Array geschlossen werden kann. Anhand von Weibullfunktionen lässt sich die Verteilung der Haftfestigkeiten und daraus die Qualität von Arrays beschreiben. Diese Verteilung konnte mit Hilfe des korrelativen Ansatzes zum ersten Mal nachgewiesen und bestimmt werden. Die neu entwickelte Methode liefert somit einen geeigneten Zugang Haftstrukturarrays hinsichtlich ihrer Qualität zu quantifizieren und anwendungsrelevanter Einflussfaktoren zu testen.In this work, synthetic bio-inspired adhesive structures were investigated. For this purpose, a setup was developed that allows a combination of adhesion force measurements and optical in situ investigation of the real contact area with the help of frustrated total internal reflection and thus visualizes the underlying detachment mechanisms. The present work shows that defects at the interface, system parameters (e. g. machine stiffness, misalignment) and external influences (e. g. air pressure) play a decisive role and change the detachment mechanisms. The strong influence of defects resulted in a broad distribution in the adhesive strength of the individual fibrils in the array and thus a loss of approximately 30 % of the fibrils in contact before reaching the maximum adhesive force. This demonstrates that the overall system must be considered in order to optimize the adhesion properties and cannot be extrapolated from individual fibrils to an entire array. It is also known that the distribution of adhesive strength can be described with the help of a Weibull distribution according to the model of fracture mechanics. In this work this distribution could be measured for the first time using the correlative measurement method and is compared to the theoretical models. In general, this work offers a new method to investigate detachment mechanisms and to quantify the influence of external parameters on fibrillar arrays
Selbstheilende Fahrzeuglacke auf Basis von Cyclodextrin-Polyrotaxanen - Polyrotaxan-Lack : Teilvorhaben: Lackierung mit Polyrotaxanen, Untersuchung des Selbstheilungsvermögens und Langzeit-Bewitterungstests : Schlussbericht : Laufzeit des Vorhabens: 01.05.2016-30.04.2019
Get PDFPolyrotaxane bestehen aus linearen Polymeren, auf die zyklische Moleküle aufgefädelt sind. Durch Vernetzung von Polyrotaxanen erhält man elastische Gele, sogenannte Slide-Ring Gels (SRGs), die nach mechanischer Beanspruchung selbst wieder ausheilen können. Polyrotaxane sind zwar seit etwa 25 Jahren bekannt, jedoch war ihre Synthese bislang zu aufwändig für eine industrielle Anwendung. Cyclodextrine eignen sich in besonderer Weise zur Synthese von Polyrotaxanen, da sie in wässriger Lösung auf Polymere wie Polyethylenglykol spontan auffädeln können. Polyrotaxane wurden bislang durch Auffädeln von Cyclodextrinen auf Polymere wie Polyethylenglykol oder Polyimino-undecamethylen erzeugt. Ein besonderes Problem bereitet dabei die Anknüpfung der Stopper-Gruppen, ohne die die Ringe wieder abfädeln würden. Die Synthese von Polyrotaxanen wurde in einer Reihe von Publikationen beschrieben. Bislang gibt es nur ein mehrstufiges Verfahren, das die Synthese im kg-Maßstab erlaubt. Diese Synthese erfordert jedoch den Einsatz des giftigen und reproduktionstoxischen Lösungsmittels Dimethylformamid. Die aufgefädelten Ringe im Polyrotaxan sind zwar an die Polymerkette gebunden, besitzen aber dennoch Translations- und Rotationsfreiheitsgrade. Diese einzigartige Topologie erlaubt die Konstruktion von mobilen, dreidimensionalen Netzwerken, den Slide Ring Gels (SRG)s, durch kovalente Verknüpfung der aufgefädelten Ringe. Bei mechanischer Beanspruchung können sich die Ringe auf der Kette bewegen und so einem Stoß ausweichen. Folglich zeigen SRGs hohe elastische Dehnungen und sehr gute Quellfähigkeiten.[...