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The chemical synthesis of polysiloxanes from monomeric starting materials involves a series of hydrolysis, condensation and modification reactions with complex monomeric and oligomeric reaction mixtures. Real-time monitoring and precise process control of the synthesis process is of great importance to ensure reproducible intermediates and products and can readily be performed by optical spectroscopy. In chemical reactions involving rapid and simultaneous functional group transformations and complex reaction mixtures, however, the spectroscopic signals are often ambiguous due to overlapping bands, shifting peaks and changing baselines. The univariate analysis of individual absorbance signals is hence often only of limited use. In contrast, batch modelling based on the multivariate analysis of the time course of principal components (PCs) derived from the reaction spectra provides a more efficient tool for real time monitoring. In batch modelling, not only single absorbance bands are used but information over a broad range of wavelengths is extracted from the evolving spectral fingerprints and used for analysis. Thereby, process control can be based on numerous chemical and morphological changes taking place during synthesis. “Bad” (or abnormal) batches can quickly be distinguished from “normal” ones by comparing the respective reaction trajectories in real time. In this work, FTIR spectroscopy was combined with multivariate data analysis for the in-line process characterization and batch modelling of polysiloxane formation. The synthesis was conducted under different starting conditions using various reactant concentrations. The complex spectral information was evaluated using chemometrics (principal component analysis, PCA). Specific spectral features at different stages of the reaction were assigned to the corresponding reaction steps. Reaction trajectories were derived based on batch modelling using a wide range of wavelengths. Subsequently, complexity was reduced again to the most relevant absorbance signals in order to derive a concept for a low-cost process spectroscopic set-up which could be used for real-time process monitoring and reaction control.
It is known that the costs related with drug research and development (R&D) and the timelines to develop a new drug increased over the past years. In parallel, the success rates of drug projects along the pharmaceutical R&D phases are still very low, and the outcome of all R&D efforts is stagnating. In consequence, the R&D efficiency defined as the financial investment per drug has been steadily decreasing. As innovation is the major growth driver of the pharmaceutical industry, reliable data on R&D efficiency and new concepts to overcome these challenges are of great interest for R&D managers and the sustainability of the pharmaceutical industry as a whole. This book chapter reviews publications on R&D performance indicators of the past years, such as the success rates and timelines per phase. Additionally, it illustrates the factors influencing the success rates, timelines, and costs of pharmaceutical R&D most and, thus, the denominators of the R&D efficiency.
Glioblastoma WHO IV belongs to a group of brain tumors that are still incurable. A promising treatment approach applies photodynamic therapy (PDT) with hypericin as a photosensitizer. To generate a comprehensive understanding of the photosensitizer-tumor interactions, the first part of our study is focused on investigating the distribution and penetration behavior of hypericin in glioma cell spheroids by fluorescence microscopy. In the second part, fluorescence lifetime imaging microscopy (FLIM) was used to correlate fluorescence lifetime (FLT) changes of hypericin to environmental effects inside the spheroids. In this context, 3D tumor spheroids are an excellent model system since they consider 3D cell–cell interactions and the extracellular matrix is similar to tumors in vivo. Our analytical approach considers hypericin as probe molecule for FLIM and as photosensitizer for PDT at the same time, making it possible to directly draw conclusions of the state and location of the drug in a biological system. The knowledge of both state and location of hypericin makes a fundamental understanding of the impact of hypericin PDT in brain tumors possible. Following different incubation conditions, the hypericin distribution in peripheral and central cryosections of the spheroids were analyzed. Both fluorescence microscopy and FLIM revealed a hypericin gradient towards the spheroid core for short incubation periods or small concentrations. On the other hand, a homogeneous hypericin distribution is observed for long incubation times and high concentrations. Especially, the observed FLT change is crucial for the PDT efficiency, since the triplet yield, and hence the O2 activation, is directly proportional to the FLT. Based on the FLT increase inside spheroids, an incubation time 30 min is required to achieve most suitable conditions for an effective PDT.
We investigated the excitation modes of the light-harvesting protein phycocyanin (PC) from Thermosynechococcus vulcanus in the crystalline state using UV and near-infrared Raman spectroscopy. The spectra revealed the absence of a hydrogen out-of-plane wagging (HOOP) mode in the PC trimer, which suggests that the HOOP mode is activated in the intact PC rod, while it is not active in the PC trimer. Furthermore, in the PC trimer an intense mode at 984 cm−1 is assigned to the C–C stretching vibration while the mode at 454 cm−1 is likely due to ethyl group torsion. In contrast, in the similar chromophore phytochromobilin the C5,10,15-D wag mode at 622 cm−1 does not come from a downshift of the HOOP. Additionally, the absence of modes between 1200 and 1300 cm−1 rules out functional monomerization. A correlation between phycocyanobilin (PCB) and phycoerythrobilin (PEB) suggests that the PCB cofactors of the PC trimer appear in a conformation similar to that of PEB. The conformation of the PC rod is consistent with that of the allophycocyanin (APC) trimer, and thus excitonic flow is facilitated between these two independent light harvesting compounds. This excitonic flow from the PC rod to APC appears to be modulated by the vibration channels during HOOP wagging, C = C stretching, and the N–H rocking in-plan vibration.
A full understanding of the relationship between surface properties, protein adsorption, and immune responses is lacking but is of great interest for the design of biomaterials with desired biological profiles. In this study, polyelectrolyte multilayer (PEM) coatings with gradient changes in surface wettability were developed to shed light on how this impacts protein adsorption and immune response in the context of material biocompatibility. The analysis of immune responses by peripheral blood mononuclear cells to PEM coatings revealed an increased expression of proinflammatory cytokines tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1β, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 and the surface marker CD86 in response to the most hydrophobic coating, whereas the most hydrophilic coating resulted in a comparatively mild immune response. These findings were subsequently confirmed in a cohort of 24 donors. Cytokines were produced predominantly by monocytes with a peak after 24 h. Experiments conducted in the absence of serum indicated a contributing role of the adsorbed protein layer in the observed immune response. Mass spectrometry analysis revealed distinct protein adsorption patterns, with more inflammation-related proteins (e.g., apolipoprotein A-II) present on the most hydrophobic PEM surface, while the most abundant protein on the hydrophilic PEM (apolipoprotein A-I) was related to anti-inflammatory roles. The pathway analysis revealed alterations in the mitogen-activated protein kinase (MAPK)-signaling pathway between the most hydrophilic and the most hydrophobic coating. The results show that the acute proinflammatory response to the more hydrophobic PEM surface is associated with the adsorption of inflammation-related proteins. Thus, this study provides insights into the interplay between material wettability, protein adsorption, and inflammatory response and may act as a basis for the rational design of biomaterials.
An advanced ‘clickECM’ that can be modified by the inverse-electron demand Diels-Alder reaction
(2021)
The extracellular matrix (ECM) represents the natural environment of cells in tissue and therefore is a promising biomaterial in a variety of applications. Depending on the purpose, it is necessary to equip the ECM with specific addressable functional groups for further modification with bioactive molecules, for controllable cross-linking and/or covalent binding to surfaces. Metabolic glycoengineering (MGE) enables the specific modification of the ECM with such functional groups without affecting the native structure of the ECM. In a previous approach (S. M. Ruff, S. Keller, D. E. Wieland, V. Wittmann, G. E. M. Tovar, M. Bach, P. J. Kluger, Acta Biomater. 2017, 52, 159–170), we demonstrated the modification of an ECM with azido groups, which can be addressed by bioorthogonal copper-catalyzed azide-alkyne cycloaddition (CuAAC). Here, we demonstrate the modification of an ECM with dienophiles (terminal alkenes, cyclopropene), which can be addressed by an inverse-electron-demand Diels-Alder (IEDDA) reaction. This reaction is cell friendly as there are no cytotoxic catalysts needed. We show the equipment of the ECM with a bioactive molecule (enzyme) and prove that the functional groups do not influence cellular behavior. Thus, this new material has great potential for use as a biomaterial, which can be individually modified in a wide range of applications.
Porous silica materials are often used for drug delivery. However, systems for simultaneous delivery of multiple drugs are scarce. Here we show that anisotropic and amphiphilic dumbbell core–shell silica microparticles with chemically selective environments can entrap and release two drugs simultaneously. The dumbbells consist of a large dense lobe and a smaller hollow hemisphere. Electron microscopy images show that the shells of both parts have mesoporous channels. In a simple etching process, the properly adjusted stirring speed and the application of ammonium fluoride as etching agent determine the shape and the surface anisotropy of the particles. The surface of the dense lobe and the small hemisphere differ in their zeta potentials consistent with differences in dye and drug entrapment. Confocal Raman microscopy and spectroscopy show that the two polyphenols curcumin (Cur) and quercetin (QT) accumulate in different compartments of the particles. The overall drug entrapment efficiency of Cur plus QT is high for the amphiphilic particles but differs widely between Cur and QT compared to controls of core–shell silica microspheres and uniformly charged dumbbell microparticles. Furthermore, Cur and QT loaded microparticles show different cancer cell inhibitory activities. The highest activity is detected for the dual drug loaded amphiphilic microparticles in comparison to the controls. In the long term, amphiphilic particles may open up new strategies for drug delivery.
In recent years, the development and application of decellularized extracellular matrices (ECMs) for use as biomaterials have grown rapidly. These cell-derived matrices (CDMs) represent highly bioactive and biocompatible materials consisting of a complex assembly of biomolecules. Even though CDMs mimic the natural microenvironment of cells in vivo very closely, they still lack specifically addressable functional groups, which are often required to tailor a biomaterial functionality by bioconjugation. To overcome this limitation, metabolic glycoengineering has emerged as a powerful tool to equip CDMs with chemical groups such as azides. These small chemical handles are known for their ability to undergo bioorthogonal click reactions, which represent a desirable reaction type for bioconjugation. However, ECM insolubility makes its processing very challenging. In this contribution, we isolated both the unmodified ECM and azide-modified clickECM by osmotic lysis. In a first step, these matrices were concentrated to remove excessive water from the decellularization step. Next, the hydrogel-like ECM and clickECM films were mechanically fragmentized, resulting in easy to pipette suspensions with fragment sizes ranging from 7.62 to 31.29 μm (as indicated by the mean d90 and d10 values). The biomolecular composition was not impaired as proven by immunohistochemistry. The suspensions were used for the reproducible generation of surface coatings, which proved to be homogeneous in terms of ECM fragment sizes and coating thicknesses (the mean coating thickness was found to be 33.2 ± 7.3 μm). Furthermore, they were stable against fluid-mechanical abrasion in a laminar flow cell. When primary human fibroblasts were cultured on the coated substrates, an increased bioactivity was observed. By conjugating the azides within the clickECM coatings with alkyne-coupled biotin molecules, a bioconjugation platform was obtained, where the biotin–streptavidin interaction could be used. Its applicability was demonstrated by equipping the bioactive clickECM coatings with horseradish peroxidase as a model enzyme.
Der ultraschnelle Mechanismus der Alken-Hydrosylilierung lässt sich von den Flüssigsiliconen (LSRs) auf VNB-EPDM-Mischungen übertragen. In der Verarbeitung würde diese für VNB-EPDM die Wettbewerbsfähigkeit hinsichtlich realisierbarer kürzester Zykluszeiten und neue Marktsegmente alternativ zu den LSR-Materialien eröffnen, u.a. in speziellen Dichtungsanwendungen. Peroxidisch vernetzte EPDM-Mischungen können in wässrig-sauren und wässrig-alkalischen Medien eine bessere chemische Beständigkeit als LSR-Materialien bieten. Sie sind duch die radikalische Vernetzung in der Kinetik aber im Vergleich zu additionsvernetzbaren Elastomeren als deutlich träger einzustufen. Ein weiterer Aspekt ist die Permeationsbeständigkeit gegenüber Gasen und Lösemitteldämpfen, die in dieser Arbeit näher untersucht worden ist. In dieser Eigenschaft unterscheiden sich VNB-EPDM und LSR deutlich voneinander. Mit der Bestimmung von zeit- und temperaturabhängigen Permeationsraten von n-Hexan-Lösemitteldämpfen erfolgt ein Vergleich beider Elastomerklassen. Auf die Theorie der Gaspermeation und der sogenannten Pervaporation wird grundlegend eingegangen und zusätzlich der weitere Einfluss von Rezepturbestandteilen beleuchtet. Des Weiteren werden stationäre Permeationskoeffizienten für die Lösemittel-Dampf-Evaporation berechnet, indem die Ausprägung des Quelldrucks im Inneren der Elastomerwerkstoffe durch signifikante Volumenquellungen als eigentliche Triebkraft herangeszogen wird.
Cancer cells invade confined microchannels via a self-directed mesenchymal-to-amoeboid transition
(2019)
Cancer cell invasion through physical barriers in the extracellular matrix (ECM) requires a complex synergy of traction force against the ECM, mechanosensitive feedback, and subsequent cytoskeletal rearrangement. PDMS microchannels were used to investigate the transition from mesenchymal to amoeboid invasion in cancer cells. Migration was faster in narrow 3 μm-wide channels than in wider 10 μm channels, even in the absence of cell-binding ECM proteins. Cells permeating narrow channels exhibited blebbing and had smooth leading edge profiles, suggesting an ECM-induced transition from mesenchymal invasion to amoeboid invasion. Live cell labeling revealed a mechanosensing period in which the cell attempts mesenchymal-based migration, reorganizes its cytoskeleton, and proceeds using an amoeboid phenotype. Rho/ROCK (amoeboid) and Rac (mesenchymal) pathway inhibition revealed that amoeboid invasion through confined environments relies on both pathways in a time- and ECM dependent manner. This demonstrates that cancer cells can dynamically modify their invasion programming to navigate physically confining matrix conditions.
Despite its success against cancer, photothermal therapy (PTT) (>50 °C) suffers from several limitations such as triggering inflammation and facilitating immune escape and metastasis and also damage to the surrounding normal cells. Mild-temperature PTT has been proposed to override these shortcomings. We developed a nanosystem using HepG2 cancer cell membrane-cloaked zinc glutamate-modified Prussian blue nanoparticles with triphenylphosphine-conjugated lonidamine (HmPGTL NPs). This innovative approach achieved an efficient mild-temperature PTT effect by downregulating the production of intracellular ATP. This disrupts a section of heat shock proteins that cushion cancer cells against heat. The physicochemical properties, anti-tumor efficacy, and mechanisms of HmPGTL NPs both in vitro and in vivo were investigated. Moreover, the nanoparticles cloaked with the HepG2 cell membrane substantially prolonged the circulation time in vivo. Overall, the designed nanocomposites enhance the efficacy of mild-temperature PTT by disrupting the production of ATP in cancer cells. Thus, we anticipate that the mild-temperature PTT nanosystem will certainly present its enormous potential in various biomedical applications.
Although integrins are responsible for the interaction of cells with their environment, e.g., the extracellular matrix or artificial substrates, there is still a lack of knowledge about their role in cell adhesion and migration on protein-coated substrates with microtopography. Understanding such interactions could lead to new applications in e.g., medical implants as well as shed light on processes such as embryonic development, angiogenesis, wound healing, and tumor progression. In this work, the influence of surface topography and chemistry on αvβ3 and α5β1 integrin-mediated cell adhesion and migration of healthy and malignant human cell types (human coronary artery endothelial cells, human osteosarcoma cells, and human skin fibroblasts cells) was studied, using microgrooved and flat substrates covered by two different extracellular proteins, fibronectin and vitronectin. Although some general behaviors can be observed, cell migration (speed, directionality, and persistence time) and morphological adaptation (cell area, aspect ratio, and circularity) of cells on protein coated microgrooved substrates are mainly dependent on the cell type and its specific integrin expression.
Energy consumption by air-conditioning is expansive and leads to the emission of millions of tons of CO2 every year. A promising approach to circumvent this problem is the reflection of solar radiation: Rooms that would not heat up by irradiation will not need to be cooled down. Especially, transparent conductive metal oxides exhibit high infrared (IR) reflectivity and are commonly applied as low-emissivity coatings (low-e coatings). Indium tin oxide (ITO) coatings are the state-of-the-art application, though indium is a rare and expensive resource. This work demonstrates that aluminum-doped zinc oxide (AZO) can be a suitable alternative to ITO for IR-reflection applications. AZO synthesized here exhibits better emissivity to be used as roofing membrane coatings for buildings in comparison to commercially available ITO coatings. AZO particles forming the reflective coating are generated via solvothermal synthesis routes and obtain high conductivity and IR reflectivity without the need of any further post-thermal treatment. Different synthesis parameters were studied, and their effects on both conductive and optical properties of the AZO nanoparticles were evaluated. To this end, a series of characterization methods, especially 27Al-nuclear magnetic resonance spectroscopy (27Al-NMR) analysis, have been conducted for a deeper insight into the particles’ structure to understand the differences in conductivity and optical properties. The optimized AZO nanoparticles were coated on flexible transparent textile-based roofing membranes and tested as low-e coatings. The membranes demonstrated higher thermal reflectance compared with commercial ITO materials with an emissivity value lowered by 16%.
An ultraviolet visible (UV–Vis) spectroscopy method was developed that can quantitatively characterize a technical copper surface to determine oxide layers and organic impurities. The oxide layers were produced by a heating step at 175 ℃ for four different times (range = 1–10 min). Partial least squares (PLS) regression was used to establish a relation between the UV–Vis spectra and film thickness measurements using Auger electron spectroscopy depth profiles. The validation accuracy of the regression is in the range of approximately 2.3 nm. The prediction model allowed obtaining an estimation of the oxide layer thickness with an absolute error of 2.9 nm. Alternatively, already known methods cannot be used because of the high roughness of the technical copper surfaces. An integrating sphere is used to measure the diffuse reflectance of these surfaces, providing an average over all angles of illumination and observation.
Polyurethane thermosets have a wide range of applications. In this study, alternative raw materials were used to enhance sustainability. In two newly developed biobased polyurethanes (PUs), the cross-linker content was varied, which caused phase separation and therefore affected the turbidity. To investigate this phenomenon, UV–Vis–NIR spectroscopy was utilized. Spectra were recorded from 200 to 2500 nm in transmittance mode, and multivariate data analysis was applied to the three UV, Vis, and NIR sections separately. For the two different PU classes, each with five different cross-linker contents, classification by principal component analysis combined with linear or quadratic discriminant analysis was possible with an accuracy between 93% and nearly 100%. The best separation was achieved in the NIR range. Partial least-squares regression models were determined to predict the cross-linker content. As mentioned, the model for the NIR range is the most suitable, with the highest R2 (validation) of 0.99 for PU1 and 0.98 for PU2. The corresponding root-mean-square error of prediction values of the external validation was the lowest, with 0.82% (PU1) and 1.25% (PU2). Therefore, UV–Vis–NIR absorbance spectroscopy, especially NIR, is a suitable tool for monitoring the appropriate material composition of turbid PU thermosets in line.
Monodisperse polystyrene spheres are functional materials with interesting properties, such as high cohesion strength, strong adsorptivity, and surface reactivity. They have shown a high application value in biomedicine, information engineering, chromatographic fillers, supercapacitor electrode materials, and other fields. To fully understand and tailor particle synthesis, the methods for characterization of their complex 3D morphological features need to be further explored. Here we present a chemical imaging study based on three-dimensional confocal Raman microscopy (3D-CRM), scanning electron microscopy (SEM), focused ion beam (FIB), diffuse reflectance infrared Fourier transform (DRIFT), and nuclear magnetic resonance (NMR) spectroscopy for individual porous swollen polystyrene/poly (glycidyl methacrylate-co-ethylene di-methacrylate) particles. Polystyrene particles were synthesized with different co-existing chemical entities, which could be identified and assigned to distinct regions of the same particle. The porosity was studied by a combination of SEM and FIB. Images of milled particles indicated a comparable porosity on the surface and in the bulk. The combination of standard analytical techniques such as DRIFT and NMR spectroscopies yielded new insights into the inner structure and chemical composition of these particles. This knowledge supports the further development of particle synthesis and the design of new strategies to prepare particles with complex hierarchical architectures.
Human retinal pigment epithelial (RPE) cells express the transmembrane Ca2+-dependent Cl− channel bestrophin-1 (hBest1) of the plasma membrane. Mutations in the hBest1 protein are associated with the development of distinct pathological conditions known as bestrophinopathies. The interactions between hBest1 and plasma membrane lipids (cholesterol (Chol), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and sphingomyelin (SM)) determine its lateral organization and surface dynamics, i.e., their miscibility or phase separation. Using the surface pressure/mean molecular area (π/A) isotherms, hysteresis and compressibility moduli (Cs−1) of hBest1/POPC/Chol and hBest1/SM/Chol composite Langmuir monolayers, we established that the films are in an LE (liquid-expanded) or LE-LC (liquid-condensed) state, the components are well-mixed and the Ca2+ ions have a condensing effect on the surface molecular organization. Cholesterol causes a decrease in the elasticity of both films and a decrease in the ΔGmixπ values (reduction of phase separation) of hBest1/POPC/Chol films. For the hBest1/SM/Chol monolayers, the negative values of ΔGmixπ are retained and equalized with the values of ΔGmixπ in the hBest1/POPC/Chol films. Shifts in phase separation/miscibility by cholesterol can lead to changes in the structure and localization of hBest1 in the lipid rafts and its channel functions.
In vitro cultured cells produce a complex extracellular matrix (ECM) that remains intact after decellularization. The biological complexity derived from the variety of distinct ECM molecules makes these matrices ideal candidates for biomaterials. Biomaterials with the ability to guide cell function are a topic of high interest in biomaterial development. However, these matrices lack specific addressable functional groups, which are often required for their use as a biomaterial. Due to the biological complexity of the cell-derived ECM, it is a challenge to incorporate such functional groups without affecting the integrity of the biomolecules within the ECM. The azide-alkyne cycloaddition (click reaction, Huisgen-reaction) is an efficient and specific ligation reaction that is known to be biocompatible when strained alkynes are used to avoid the use of copper (I) as a catalyst. In our work, the ubiquitous modification of a fibroblast cell-derived ECM with azides was achieved through metabolic oligosaccharide engineering by adding the azide-modified monosaccharide Ac4GalNAz (1,3,4,6 tetra-O-acetyl-N-azidoacetylgalactosamine) to the cell culture medium. The resulting azide-modified network remained intact after removing the cells by lysis and the molecular structure of the ECM proteins was unimpaired after a gentle homogenization process. The biological composition was characterized in order to show that the functionalization does not impair the complexity and integrity of the ECM. The azides within this ‘‘clickECM” could be accessed by small molecules (such as an alkyne modified fluorophore) or by surface-bound cyclooctynes to achieve a covalent coating with clickECM.
Controlled adhesion of HUVEC on polyelectrolyte multilayers by regulation of coating conditions
(2021)
Adhesion of host cells on the surface of implants is necessary for a healthy ingrowth of the implanted material. One possibility of surface modification is the coating of the implant with a second material with advantageous physical–chemical surface properties for the biological system. The coverage with blood proteins takes place immediately after implantation. It is followed by host–cell interaction on the surface. In this work, the effect of polyelectrolyte multilayer coatings (PEMs) on adhesion and activity of human umbilical vein endothelial cells (HUVECs) was studied. The PEMs were formed from poly(styrenesulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) from solutions with different concentrations of NaCl varying between 0 and 1.0 M. The adhesion of HUVEC and their viability on the PEM is related to the amount of adsorbed proteins from the applied cell growth medium. The amount of adsorbed proteins is controlled not only by the surface charge but also by the internal excess charge of the PEM. The internal excess charge of the PEM was controlled by changing the electrolyte concentration in the deposition solutions.