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Nanofibrous matrices have been successfully implemented as scaffolds in a novel in vitro biofilm model that enables the combination of bacterial biofilms with human tissue models for chronic infection research.

The widespread resistance of clinically relevant bacteria against established antibiotics emphasizes the urgent need for novel therapeutics. In this context, wound infections constitute a specific challenge, as most systemically applied antibiotics are insufficiently available at the site of infection. Therefore, the local treatment of infected wounds poses a particular challenge regarding the appropriate release kinetics of actives and their residence time in the wound bed. Consequently, design and development of novel, drug-loaded wound dressings constitute a major research focus for the effective treatment of wound infections. In this study, we employed electrospinning to design drug-loaded wound dressings, incorporating the therapeutically promising antimicrobial peptide tyrothricin. By parallel electrospinning, we combined different ratios of water-soluble polyvinylpyrrolidone and water-insoluble methacrylate copolymer (EudragitE), in order to take advantage of their specific mechanical stability and dissolution properties. We fabricated fiber mats constituting mechanically stable wound dressings with a controlled drug release profile, combining an initial burst release above the minimal inhibitory concentration of known wound pathogens and a subsequent prolonged antimicrobial effect of the active ingredient. Antimicrobial activity against Staphylococcusaureus and Staphylococcusepidermidis was successfully proven, thereby introducing our tyrothricin-loaded fiber mats as a promising prospective therapy against typical wound-associated pathogens.

Estuarine dams are dams constructed within the salt or tidal intrusion limits of estuaries for securing freshwater resources or flood control. In this work, we deal with the global distribution of estuarine dams and their sedimentological impact on estuaries. Approximately 10 percent of all estuaries we analyzed (about 2400 estuaries for which river mouth width is greater than 90 m) were affected by estuarine dams and direct human modifications are responsible for more than 1,000 km2 of the observed estuarine surface area loss worldwide. Our field and numerical studies revealed that regardless of estuarine type, estuarine dams amplified the tidal range and reduced the tidal currents. The estuarine turbidity maximum moved seaward, and the suspended sediment concentration tended to decrease. While the morphologic changes depended on the estuarine type, the surficial sediment texture shifted to being muddier for all types. This work is one of the first to show the global extent of estuaries of an estuarine dam and their systematic effects on estuarine sedimentary processes.

The use of polymeric nanocapsules as a binder system to produce fluidized bed granules with improved in vivo bioavailability has recently been reported. This study evaluated how the nanocapsules influence the growth behavior of the fluidized bed granules. Phenytoin-loaded nanocapsules were sprayed top-down sprayed onto a substrate. A linear correlation (r = 0.9863) between the volume of the sprayed suspension and the mean particle size was found. Well-defined solid bridges were observed in the granule structure by Scanning Electron Microscopy. The surface area coverage of the granules was 0.145%, suggesting arrangement of the nanocapsules on the surface and in the solid bridges, corroborating the Raman images. The granules had a cohesive nature without powder segregation. The use of nanocapsules promotes the controlled release of phenytoin, and these data contribute to the understanding of the role of polymeric nanocapsules as a binder in fluid bed granulation to produce granules for posterior tableting or capsule filling processes.

Selective manipulation of the epitranscriptome could be beneficial for the treatment of cancer and also broaden the understanding of epigenetic inheritance. Inhibitors of the tRNA methyltransferase DNMT2, the enzyme catalyzing the

The cultivation of cells forming three-dimensional structures like organoids holds great potential in different fields of life sciences and is gaining increasing interest with regards to clinical applications and personalised medicine. However, conventional hydrogels used as cell cultivation matrices (e.g. Matrigel®) contain animal-derived components in varying quantities, implicating low reproducibility of experiments and limited applicability for clinical use. Based on the strong need for developing novel, well defined, and animal-free hydrogels for 3D cell cultures, this study presents a comprehensive analysis of pancreas organoid cultivation in two synthetic hydrogels. Besides established visualisation techniques to monitor organoid formation and growth, confocal Raman microscopy was used for the first time to evaluate the gel matrices and organoid formation within the gels. The approach revealed so far not accessible information about material-cell interactions and the composition of the organoid lumen in a non-invasive and label-free manner. Confocal Raman microscopy thereby enabled a systematic characterisation of different hydrogels with respect to cell culture compatibility and allowed for the rational selection of a hydrogel formulation to serve as a synthetic and fully defined alternative to animal-derived cultivation matrices.

Purpose The quality testing and approval procedure for most pharmaceutical products is a streamlined process with standardized procedures for the determination of critical quality attributes. However, the evaluation of semisolid dosage forms for topical drug delivery remains a challenging task. The work presented here highlights confocal Raman microscopy (CRM) as a valuable tool for the characterization of such products. Methods CRM, a laser-based method, combining chemically-selective analysis and high resolution imaging, is used for the evaluation of different commercially available topical acyclovir creams. Results We show that CRM enables the spatially resolved analysis of microstructural features of semisolid products and provides insights into drug distribution and polymorphic state as well as the composition and arrangement of excipients. Further, we explore how CRM can be used to monitor phase separation and to study skin penetration and the interaction with fresh and cryopreserved excised human skin tissue. Conclusion This study presents a comprehensive overview and illustration of how CRM can facilitate several types of key analyses of semisolid topical formulations and of their interaction with their biological target site, illustrating that CRM is a useful tool for research, development as well as for quality testing in the pharmaceutical industry. Graphical abstract

The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modification of the obtained cysteine mutants with maleimides, followed by computational elucidation of the possible binding modes. In infected cells, antiviral activity against Dengue virus serotype 2 using prodrugs of the inhibitors was observed. In summary, a novel inhibitor scaffold targeting an allosteric site shared between flaviviral NS2B/NS3 proteases is presented whose efficacy is demonstrated in vitro and in cellulo.

Medicated chewing gums represent an orally administered dosage form with promising potential for local and systemic drug delivery. However, compared to other solid oral dosage forms, formulation development and release mechanism of medicated chewing gums are extremely complex, and thus only few products reached the approval for the market so far. Therefore, Quality by Design (QbD) approaches for rational formulation development of medicated chewing gums are needed to utilize their full potential. For chewing gum tablets, which are manufactured by direct compression, QbD approaches derived from tableting processes might be exerted. In this context, the SeDeM-Diagram-Expert-System implements the QbD approach while indicating whether a blend is suitable for direct compression and comprises powder properties, which need to be improved to facilitate the formulation development. Here, we present the successful application of the SeDeM-Diagram-Expert-System to the formulation development of medicated chewing gum tablets manufactured by direct compression. Furthermore, limitations of the SeDeM-System for medicated chewing gum tablets are evaluated and potential modifications of the system are suggested and discussed for future use.

Controlling physicochemical properties of light-unresponsive drugs, by light, prima facie, a paradox approach. We expanded light control by ion pairing light-unresponsive salicylate or ibuprofen to photoswitchable azobenzene counterions, thereby reversibly controlling supramolecular structures, hence the drugs' physicochemical and kinetic properties. The resulting ion pairs photoliquefied into room-temperature ionic liquids under ultraviolet light. Aqueous solutions showed trans-cis-dependent supramolecular structures under a light with wormlike aggregates decomposing into small micelles and vice versa. Light control allowed for permeation through membranes of cis-ibuprofen ion pairs within 12 h in contrast to the trans ion pairs requiring 72 h. In conclusion, azobenzene ion-pairing expands light control of physicochemical and kinetic properties to otherwise light-unresponsive drugs.

In the fast-developing fields of pharmaceutical research and industry, the implementation of Raman spectroscopy and related technologies has been very well received due to the combination of chemical selectivity and the option for non-invasive analysis of samples. This chapter explores established and potential applications of Raman spectroscopy, confocal Raman microscopy and related techniques from the early stages of drug development research up to the implementation of these techniques in process analytical technology (PAT) concepts for large-scale production in the pharmaceutical industry. Within this chapter, the implementation of Raman spectroscopy in the process of selection and optimisation of active pharmaceutical ingredients (APIs) and investigation of the interaction with excipients is described. Going beyond the scope of early drug development, the reader is introduced to the use of Raman techniques for the characterization of complex drug delivery systems, highlighting the technical requirements and describing the analysis of qualitative and quantitative composition as well as spatial component distribution within these pharmaceutical systems. Further, the reader is introduced to the application of Raman techniques for performance testing of drug delivery systems addressing drug release kinetics and interactions with biological systems ranging from single cells up to complex tissues. In the last part of this chapter, the advantages and recent developments of integrating Raman technologies into PAT processes for solid drug delivery systems and biologically derived pharmaceutics are discussed, demonstrating the impact of the technique on current quality control standards in industrial production and providing good prospects for future developments in the field of quality control at the terminal part of the supply chain and various other fields like individualized medicine. On the way from the active drug molecule (API) in the research laboratory to the marketed medicine in the pharmacy, therapeutic efficacy of the active molecule and safety of the final medicine for the patient are of utmost importance. For each step, strict regulatory requirements apply which demand for suitable analytical techniques to acquire robust data to understand and control design, manufacturing and industrial large-scale production of medicines. In this context, Raman spectroscopy has come to the fore due to the combination of chemical selectivity and the option for non-invasive analysis of samples. Following the technical advancements in Raman equipment and analysis software, Raman spectroscopy and microscopy proofed to be valuable methods with versatile applications in pharmaceutical research and industry, starting from the analysis of single drug molecules as well as complex multi-component formulations up to automatized quality control during industrial production.

Raman spectroscopy represents an upcoming analytical technique in the field of skin research and dermal drug delivery. In the last few decades, significant progress in optical equipment like lasers and detectors as well as in microscopy and software development paved the way for chemically selective three-dimensional Raman imaging with high spatial resolution. Potential applications range from analysis of physiological and pathophysiological skin conditions (e.g. non-destructive cancer detection in clinics) up to surgery guidance. In the field of drug delivery and cosmetics , Raman microscopy is successfully applied for investigating interactions with skin as well as for elucidation of drug penetration kinetics within the different skin tissue layers, thus strongly supporting rational development and improving product safety of novel skin therapeutics. This chapter provides a brief introduction about skin anatomy and dermal drug delivery systems, as well as state-of-the-art analytics in skin research. Furthermore, the potential of Raman spectroscopy for application in skin research, particularly its advantages and limitations in the field, is comprehensively elaborated. Subsequently, an overview about skin research studies applying Raman spectroscopy is given comprising various in vitro as well as in vivo implementations. Finally, employment of Raman spectroscopy for advanced diagnosis and surgery guidance are discussed and a future perspective in the field of skin research is given.