Adsorbed polymer conjugates to adaptively inhibit blood coagulation activation by medical membranes.

Adaptive drug release can combat coagulation and inflammation activation at the blood-material interface with minimized side effects. For that purpose, poly(styrene-alt-maleic-anhydride) copolymers were conjugated to heparin via coagulation-responsive linker peptides and shown to tightly adsorb onto poly(ethersulfone) (PES)-surfaces from aqueous solutions as monolayers. Coagulation-responsive release of unfractionated as well as low molecular weight heparins from the respective coatings was demonstrated to be functionally beneficial in human plasma and whole blood incubation with faster release kinetics resulting in stronger anticoagulant effects. Coated poly(ethersulfone)/poly(vinylpyrrolidone) (PES/PVP) flat membranes proved the technology to offer an easy, effective and robust anticoagulant interfacial functionalization of hemodialysis membranes. In perspective, the modularity of the adaptive release system will be used for inhibiting multiple activation processes.

Inflammation-Controlled Anti-Inflammatory Hydrogels.

While autoregulative adaptation is a common feature of living tissues, only a few feedback-controlled adaptive biomaterials are available so far. This paper herein reports a new polymer hydrogel platform designed to release anti-inflammatory molecules in response to the inflammatory activation of human blood. In this system, anti-inflammatory peptide drugs, targeting either the complement cascade, a complement receptor, or cyclophilin A, are conjugated to the hydrogel by a peptide sequence that is cleaved by elastase released from activated granulocytes. As a proof of concept, the adaptive drug delivery from the gel triggered by activated granulocytes and the effect of the released drug on the respective inflammatory pathways are demonstrated. Adjusting the gel functionalization degree is shown to allow for tuning the drug release profiles to effective doses within a micromolar range. Feedback-controlled delivery of covalently conjugated drugs from a hydrogel matrix is concluded to provide valuable safety features suitable to equip medical devices with highly active anti-inflammatory agents without suppressing the general immunosurveillance.

Poly(2-alkyl-2-oxazoline)-Heparin Hydrogels-Expanding the Physicochemical Parameter Space of Biohybrid Materials.

Poly(ethylene glycol) (PEG)-glycosaminoglycan (GAG) hydrogel networks are established as very versatile biomaterials. Herein, the synthetic gel component of the biohybrid materials is systematically varied by combining different poly(2-alkyl-2-oxazolines) (POx) with heparin applying a Michael-type addition crosslinking scheme: POx of gradated hydrophilicity and temperature-responsiveness provides polymer networks of distinctly different stiffness and swelling. Adjusting the mechanical properties and the GAG concentration of the gels to similar values allows for modulating the release of GAG-binding growth factors (VEGF165 and PDGF-BB) by the choice of the POx and its temperature-dependent conformation. Adsorption of fibronectin, growth of fibroblasts, and bacterial adhesion scale with the hydrophobicity of the gel-incorporated POx. In vitro hemocompatibility tests with freshly drawn human whole blood show advantages of POx-based gels compared to the PEG-based reference materials. Biohybrid POx hydrogels can therefore enable biomedical technologies requiring GAG-based materials with customized and switchable physicochemical characteristics.

Bioresponsive starPEG-heparin hydrogel coatings on vascular stents for enhanced hemocompatibility.

Hydrogel coatings can improve the biocompatibility of medical devices. However, stable surface bonding and homogeneity of hydrogel coatings are often challenging. This study exploits the benefits of biohybrid hydrogels of crosslinked four-armed poly(ethylene glycol) and heparin to enhance the hemocompatibility of cobalt­chromium (CoCr) vascular stents. A bonding layer of dual silane and poly(ethylene-alt-maleic anhydride) (PEMA) treatment was applied to the stent to provide covalent immobilization and hydrophilicity for the homogeneous spreading of the hydrogel. A spray coating technology was used to distribute the aqueous solution of the reactive hydrogel precursors onto the sub-millimeter struts of the stents, where the solution polymerized to a homogeneous hydrogel film. The coating was mechanically stable on the stent after ethanol dehydration, and the stents could be stored in a dry state. The homogeneity and stability of the coating during stent expansion were verified. Quasistatic and dynamic whole blood incubation experiments showed substantial suppression of the pro-coagulant and inflammatory activity of the bare metal by the coating. Translation of the technology to industrial coating devices and future surface modification of stents with anti-inflammatory hydrogels are discussed.

Structure-Property Functions of Inorganic Chemical Binders for Refractories.

For refractory application, amongst others, inorganic chemical binders are used to shape and process loose, unpacked materials. The binder influences the chemical composition within the ceramic body during setting, aging and firing and thus the finally reached properties of the refractory material. For an effective design of tailored materials with required properties, the mode of action of the binder systems should carefully be investigated. A combination of both structure analysis techniques and macroscopic property investigations proved to be a powerful tool for a detailed description of structure-property correlations. This is shown on the basis of X-ray powder diffraction and nuclear magnetic resonance spectroscopy analyses combined with observation of (thermo)mechanical and chemical investigations.

Amphiphilic Copolymers for Versatile, Facile, and In Situ Tunable Surface Biofunctionalization.

Precision surface engineering is key to advanced biomaterials. A new platform of PEGylated styrene-maleic acid copolymers for adsorptive surface biofunctionalization is reported. Balanced amphiphilicity renders the copolymers water-soluble but strongly affine for surfaces. Fine-tuning of their molecular architecture provides control over adsorptive anchorage onto specific materials-which is why they are referred to as "anchor polymers" (APs)-and over structural characteristics of the adsorbed layers. Conjugatable with an array of bioactives-including cytokine-complexing glycosaminoglycans, cell-adhesion-mediating peptides and antimicrobials-APs can be applied to customize materials for demanding biotechnologies in uniquely versatile, simple, and robust ways. Moreover, homo- and heterodisplacement of adsorbed APs provide unprecedented means of in situ alteration and renewal of the functionalized surfaces. The related options are exemplified with proof-of-concept experiments of controlled bacterial adhesion, human umbilical vein endothelial cell, and induced pluripotent cell growth on AP-functionalized surfaces.

Ergodic and nonergodic many-body dynamics in strongly nonlinear lattices.

The study of nonlinear oscillator chains in classical many-body dynamics has a storied history going back to the seminal work of Fermi et al. [Los Alamos Scientific Laboratory Report No. LA-1940, 1955 (unpublished)]. We introduce a family of such systems which consist of chains of N harmonically coupled particles with the nonlinearity introduced by confining the motion of each individual particle to a box or stadium with hard walls. The stadia are arranged on a one-dimensional lattice but they individually do not have to be one dimensional, thus permitting the introduction of chaos already at the lattice scale. For the most part we study the case where the motion is entirely one dimensional. We find that the system exhibits a mixed phase space for any finite value of N. Computations of Lyapunov spectra at randomly picked phase space locations and a direct comparison between Hamiltonian evolution and phase space averages indicate that the regular regions of phase space are not significant at large system sizes. While the continuum limit of our model is itself a singular limit of the integrable sinh Gordon theory, we do not see any evidence for the kind of nonergodicity famously seen in the work of Fermi et al. Finally, we examine the chain with particles confined to two-dimensional stadia where the individual stadium is already chaotic and find a much more chaotic phase space at small system sizes.

Antioxidative, Antifungal and Additive Activity of the Antimicrobial Peptides Leg1 and Leg2 from Chickpea.

The fight against food waste benefits from novel agents inhibiting spoilage. The present study investigated the preservative potential of the antimicrobial peptides Leg1 (RIKTVTSFDLPALRFLKL) and Leg2 (RIKTVTSFDLPALRWLKL) recently identified in chickpea legumin hydrolysates. Checkerboard assays revealed strong additive antimicrobial effects of Leg1/Leg2 with sodium benzoate against Escherichia coli and Bacillus subtilis with fractional inhibitory concentrations of 0.625 and 0.75. Additionally, Leg1/Leg2 displayed antifungal activity with minimum inhibitory concentrations of 500/250 µM against Saccharomyces cerevisiae and 250/125 µM against Zygosaccharomyces bailii. In contrast, no cytotoxic effects were observed against human Caco-2 cells at concentrations below 2000 µM (Leg1) and 1000 µM (Leg2). Particularly Leg2 showed antioxidative activity by radical scavenging and reducing mechanisms (maximally 91.5/86.3% compared to 91.2/94.7% for the control ascorbic acid). The present results demonstrate that Leg1/Leg2 have the potential to be applied as preservatives protecting food and other products against bacterial, fungal and oxidative spoilage.

DNAzymes as Catalysts for l-Tyrosine and Amyloid ß Oxidation.

Single-stranded deoxyribonucleic acids have an enormous potential for catalysis by applying tailored sequences of nucleotides for individual reaction conditions and substrates. If such a sequence is guanine-rich, it may arrange into a three-dimensional structure called G-quadruplex and give rise to a catalytically active DNA molecule, a DNAzyme, upon addition of hemin. Here, we present a DNAzyme-mediated reaction, which is the oxidation of l-tyrosine toward dityrosine by hydrogen peroxide. With an optimal stoichiometry between DNA and hemin of 1:10, we report an activity of 101.2 ± 3.5 µUnits (µU) of the artificial DNAzyme Dz-00 compared to 33.0 ± 1.8 µU of free hemin. Exemplarily, DNAzymes may take part in neurodegeneration caused by amyloid beta (Aß) aggregation due to l-tyrosine oxidation. We show that the natural, human genome-derived DNAzyme In1-sp is able to oxidize Aß peptides with a 4.6% higher yield and a 33.3% higher velocity of the reaction compared to free hemin. As the artificial DNAzyme Dz-00 is even able to catalyze Aß peptide oxidation with a 64.2% higher yield and 337.1% higher velocity, an in-depth screening of human genome-derived DNAzymes may identify further candidates with similarly high catalytic activity in Aß peptide oxidation.

3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics via p21 and ROCK.

The mechanical properties of cancer cells and their microenvironment contribute to breast cancer progression. While mechanosensing has been extensively studied using 2D substrates, much less is known about it in a physiologically more relevant 3D context. Here it is demonstrated that breast cancer tumor spheroids, growing in 3D polyethylene glycol-heparin hydrogels, are sensitive to their environment stiffness. During tumor spheroid growth, compressive stresses of up to 2 kPa build up, as quantitated using elastic polymer beads as stress sensors. Atomic force microscopy reveals that tumor spheroid stiffness increases with hydrogel stiffness. Also, constituent cell stiffness increases in a Rho associated kinase (ROCK)- and F-actin-dependent manner. Increased hydrogel stiffness correlated with attenuated tumor spheroid growth, a higher proportion of cells in G0/G1 phase, and elevated levels of the cyclin-dependent kinase inhibitor p21. Drug-mediated ROCK inhibition not only reverses cell stiffening upon culture in stiff hydrogels but also increases tumor spheroid growth. Taken together, a mechanism by which the growth of a tumor spheroid can be regulated via cytoskeleton rearrangements in response to its mechanoenvironment is revealed here. Thus, the findings contribute to a better understanding of how cancer cells react to compressive stress when growing under confinement in stiff environments.

Tailored and biodegradable poly(2-oxazoline) microbeads as 3D matrices for stem cell culture in regenerative therapies.

We present the synthesis of hydrogel microbeads based on telechelic poly(2-oxazoline) (POx) crosslinkers and the methacrylate monomers (HEMA, METAC, SPMA) by inverse emulsion polymerization. While in batch experiments only irregular and ill-defined beads were obtained, the preparation in a microfluidic (MF) device resulted in highly defined hydrogel microbeads. Variation of the MF parameters allowed to control the microbead diameter from 50 to 500 µm. Microbead elasticity could be tuned from 2 to 20 kPa by the POx:monomer composition, the POx chain length, net charge of the hydrogel introduced via the monomer as well as by the organic content of the aqueous phase. The proliferations of human mesenchymal stem cells (hMSCs) on the microbeads were studied. While neutral, hydrophilic POx-PHEMA beads were bioinert, excessive colonization of hMSCs on charged POx-PMETAC and POx-PSPMA was observed. The number of proliferated cells scaled roughly linear with the METAC or SPMA comonomer content. Additional collagen I coating further improved the stem cell proliferation. Finally, a first POx-based system for the preparation of biodegradable hydrogel microcarriers is described and evaluated for stem cell culturing.