Kinetic and Mechanistic Release Studies on Hyaluronan Hydrogels for Their Potential Use as a pH-Responsive Drug Delivery Device.

Hyaluronic acid, a biocompatible polymer, holds significant potential for drug delivery applications. Its variable degree of protonation, which entails tunable physical properties, makes it an ideal candidate for developing pH-sensitive hydrogels. Like other smart drug delivery systems, pH-responsive hydrogels can enhance medical treatment and expedite the healing process.

Natural Presentation of Glycosaminoglycans in Synthetic Matrices for 3D Angiogenesis Models.

Glycosaminoglycans (GAGs) are long, linear polysaccharides that occur in the extracellular matrix of higher organisms and are either covalently attached to protein cores, as proteoglycans or in free form. Dependent on their chemical composition and structure, GAGs orchestrate a wide range of essential functions in tissue homeostasis. Accordingly, GAG-based biomaterials play a major role in tissue engineering.

Glycan-Lectin Interactions in Cancer and Viral Infections and How to Disrupt Them.

Glycan-lectin interactions play an essential role in different cellular processes. One of their main functions is involvement in the immune response to pathogens or inflammation. However, cancer cells and viruses have adapted to avail themselves of these interactions.

Bottom-up assembly of biomedical relevant fully synthetic extracellular vesicles.

Extracellular vesicles (EVs) are fundamental for intercellular communication and influence nearly every process in cell physiology. However, because of their intricate molecular complexity, quantitative knowledge on their signaling mechanisms is missing, particularly impeding their therapeutic application. We used a complementary and quantitative engineering approach based on sequential synthetic bottom-up assembly of fully functional EVs with precisely controlled lipid, protein, and RNA composition.

Small Physical Cross-Linker Facilitates Hyaluronan Hydrogels.

In this study, we demonstrate that small charged molecules (NH, GluA, dHA) can form physical cross-links between hyaluronan chains, facilitating polymerization reactions between synthetically introduced thiol groups (HA-DTPH). These hybrid hydrogels can be obtained under physiological conditions ideally suited for 3D cell culture systems. The type and concentration of a physical crosslinker can be adjusted to precisely tune mechanical properties as well as degradability of the desired hydrogel system.

Tuning RGD Motif and Hyaluronan Density to Study Integrin Binding.

Well-controlled surfaces with immobilized substrates enable novel approaches to investigate specific aspects of biological processes related to cell adhesion or motility. A subset of integrins, cellular transmembrane glycoproteins, recognize the evolutionarily conserved tripeptide sequence RGD, and anchor cells to their surrounding proteins as well as mediate bidirectional signaling. In this study, the main question was how co-presentation of hyaluronan (HA), an essential component of the extracellular matrix (ECM), and the RGD motif affect integrin binding.

Effect of Co-presentation of Adhesive Ligands and Short Hyaluronan on Lymphendothelial Cells.

Controlled activation of lymphangiogenesis through functional biomaterials represents a promising approach to support wound healing after surgical procedures, yet remains a challenge. In a synthetic biological approach, we therefore set out to mimic the basal microenvironment of human primary dermal lymphatic endothelial cells (LECs) during lymphangiogenesis. As the extracellular matrix component hyaluronan (HA) regulates lymphangiogenesis, we designed a bifunctional surface in which adhesive peptide ligands and short HA oligosaccharides (sHA) tethered to nanoparticles are copresented to the basal side of LECs in a controlled, concentration-dependent manner.

Charge-Controlled Synthetic Hyaluronan-Based Cell Matrices.

The extracellular matrix (ECM) represents a highly charged and hydrated network in which different cells in vertebrate tissues are embedded. Hydrogels as minimal ECM mimetics with a controlled chemistry offer the opportunity to vary material properties by varying the negative network charge. In this paper, a synthetic biology model of the ECM based on natural and highly negatively charged polyelectrolyte hyaluronic acid (HA) is characterized with specific emphasis on its charge-related bioactivity.

A Trickster in Disguise: Hyaluronan's Ambivalent Roles in the Matrix.

Hyaluronan (HA) is a simple but diverse glycosaminoglycan. It plays a major role in aging, cellular senescence, cancer, and tissue homeostasis. In which way HA affects the surrounding tissues greatly depends on the molecular weight of HA.

Charged Triazole Cross-Linkers for Hyaluronan-Based Hybrid Hydrogels.

Polyelectrolyte hydrogels play an important role in tissue engineering and can be produced from natural polymers, such as the glycosaminoglycan hyaluronan. In order to control charge density and mechanical properties of hyaluronan-based hydrogels, we developed cross-linkers with a neutral or positively charged triazole core with different lengths of spacer arms and two terminal maleimide groups. These cross-linkers react with thiolated hyaluronan in a fast, stoichiometric thio-Michael addition.

Template-assisted extrusion of biopolymer nanofibers under physiological conditions.

Biomedical applications ranging from tissue engineering to drug delivery systems require versatile biomaterials based on the scalable and tunable production of biopolymer nanofibers under physiological conditions. These requirements can be successfully met by a novel extrusion process through nanoporous aluminum oxide templates, which is presented in this study. With this simple method we are able to control the nanofiber diameter by chosing the size of the nanopores and the concentration of the biopolymer feed solution.

Controlled Immobilization Strategies to Probe Short Hyaluronan-Protein Interactions.

Well-controlled grafting of small hyaluronan oligosaccharides (sHA) enables novel approaches to investigate biological processes such as angiogenesis, immune reactions and cancer metastasis. We develop two strategies for covalent attachment of sHA, a fast high-density adsorption and a two-layer system that allows tuning the density and mode of immobilization. We monitored the sHA adlayer formation and subsequent macromolecular interactions by label-free quartz crystal microbalance with dissipation (QCM-D).

Minimal synthetic cells to study integrin-mediated adhesion.

To shed light on cell-adhesion-related molecular pathways, synthetic cells offer the unique advantage of a well-controlled model system with reduced molecular complexity. Herein, we show that liposomes with the reconstituted platelet integrin αIIb β3 as the adhesion-mediating transmembrane protein are a functional minimal cell model for studying cellular adhesion mechanisms in a defined environment. The interaction of these synthetic cells with various extracellular matrix proteins was analyzed using a quartz crystal microbalance with dissipation monitoring.

Interface Immobilization Chemistry of RGD-based Peptides Regulates Integrin Mediated Cell Adhesion.

The interaction of specific surface receptors of the integrin family with different extracellular matrix-based ligands is of utmost importance for the cellular adhesion process. A ligand consists of an integrin-binding group, here cyclic RGDfX, a spacer molecule that lifts the integrin-binding group from the surface and a surface anchoring group. (-RGDfX-) peptides are bound to gold nanoparticle structured surfaces via polyproline, polyethylene glycol or aminohexanoic acid containing spacers of different lengths.

A molecular mechanotransduction pathway regulates collective migration of epithelial cells.

Collective movement of epithelial cells drives essential multicellular organization during various fundamental physiological processes encompassing embryonic morphogenesis, cancer and wound healing. Yet the molecular mechanism that ensures the coordinated movement of many cells remains elusive. Here we show that a tumour suppressor protein, merlin, coordinates collective migration of tens of cells, by acting as a mechanochemical transducer.

Dual-functionalized nanostructured biointerfaces by click chemistry.

The presentation of biologically active molecules at interfaces has made it possible to investigate the responses of cells to individual molecules in their matrix at a given density and spacing. However, more sophisticated methods are needed to create model surfaces that present more than one molecule in a controlled manner in order to mimic at least partially the complexity given in natural environments. Herein, we present dual-functionalized surfaces combining quasi-hexagonally arranged gold nanoparticles with defined spacings and a newly developed PEG-alkyne coating to functionalize the glass in the intermediate space.

Polarizing cytoskeletal tension to induce leader cell formation during collective cell migration.

The collective migration of cells is fundamental to epithelial biology. One of the hallmarks of collective behavior in migrating cohesive epithelial cell sheets is the emergence of so called leader cells. These cells exhibit a distinct morphology with a large and highly active lamellipodium.

Diffusion and interaction in PEG-DA hydrogels.

Polyethylenglycol (PEG) hydrogels are widely used as tuneable substrates for biological and technical applications due to their good biocompatibility and their high hydrophilicity. Here we compare the mesh size and diffusion characteristics of PEG hydrogels by analyzing the diffusion of solutes with different, well-defined sizes over long and short time scales. Interestingly, one can tune the mesh size and the density of the gel simply by changing the inital concentrations of the PEG-diacrylate (PEG-DA) polymer, which also enhances the solute uptake in equilibrium through the interaction with the PEG chains.

A photoactivatable nanopatterned substrate for analyzing collective cell migration with precisely tuned cell-extracellular matrix ligand interactions.

Collective cell migration is involved in many biological and pathological processes. Various factors have been shown to regulate the decision to migrate collectively or individually, but the impact of cell-extracellular matrix (ECM) interactions is still debated. Here, we developed a method for analyzing collective cell migration by precisely tuning the interactions between cells and ECM ligands.

Adhesion maturation of neutrophils on nanoscopically presented platelet glycoprotein Ibα.

Neutrophilic granulocytes play a fundamental role in cardiovascular disease. They interact with platelet aggregates via the integrin Mac-1 and the platelet receptor glycoprotein Ibα (GPIbα). In vivo, GPIbα presentation is highly variable under different physiological and pathophysiological conditions.

Desmosine-inspired cross-linkers for hyaluronan hydrogels.

We designed bioinspired cross-linkers based on desmosine, the cross-linker in natural elastin, to prepare hydrogels with thiolated hyaluronic acid. These short, rigid cross-linkers are based on pyridinium salts (as in desmosine) and can connect two polymer backbones. Generally, the obtained semi-synthetic hydrogels are form-stable, can withstand repeated stress, have a large linear-elastic range, and show strain stiffening behavior typical for biopolymer networks.

Spatial organization and mechanical properties of the pericellular matrix on chondrocytes.

A voluminous polymer coat adorns the surface of many eukaryotic cells. Although the pericellular matrix (PCM) often extends several microns from the cell surface, its macromolecular structure remains elusive. This massive cellular organelle negotiates the cell's interaction with surrounding tissue, influencing important processes such as cell adhesion, mitosis, locomotion, molecular sequestration, and mechanotransduction.

Biselectivity of isoDGR peptides for fibronectin binding integrin subtypes α5β1 and αvβ6: conformational control through flanking amino acids.

Integrins are the major class of cell adhesion proteins. Their interaction with different ligands of the extracellular matrix is diverse. To get more insight into these interactions, artificial ligands endowed with a well-defined activity/selectivity profile are necessary.

Investigating cell-ECM contact changes in response to hypoosmotic stimulation of hepatocytes in vivo with DW-RICM.

Hepatocyte volume regulation has been shown to play an important role in cellular metabolism, proliferation, viability and especially in hepatic functions such as bile formation and proteolysis. Recent studies on liver explants led to the assumption that cell volume changes present a trigger for outside-in signaling via integrins, a protein family involved in mediating cellular response to binding to the extracellular matrix (ECM). However, it remains elusive how these volume change related signaling events are transducted on a single cell level and how these events are influenced and controlled by ECM interactions.

Splinelike interpolation in particle tracking microrheology.

Converting time dependent creep compliance to frequency dependent complex shear modulus is an important step in analyzing the results of particle tracking microrheology. Fitting a function to the whole time range and transforming it to calculate the shear modulus is one way of solving this problem. However, the creep compliance of many samples, such as gels of biopolymers, shows different trends under different time regimes.