2018, Zimmermann, Ralf, Werner, Carsten, Sterling, James

Glycosaminoglycans (GAGs) are a class of linear polysaccharides that are ubiquitous in the extracellular matrix (ECM) and on cell surfaces. Due to their key role in development, homeostasis, pathogenesis, and regeneration, GAGs are increasingly used in the design of ECM-mimicking hydrogels to stimulate tissue formation and regenerative processes via specifically orchestrated cell-instructive signals. These applications first and foremost build on the ability of GAGs to effectively bind, protect, and release morphogens. The specificity and strength of morphogen-GAG interactions are largely governed by the number and spatial distribution of negatively charged sulfate groups carried by GAGs. Herein, we summarize a mean-field approach to quantify the density of ionizable groups, GAG concentration, and cross-linking degree of GAG-containing hydrogels on the basis of microslit electrokinetic experiments. We further present and discuss a continuum model of mucosa that accounts for charge regulation by glycan-ion pairing in biological contexts and under conditions of macromolecular crowding. Finally, we discuss the modulation of the morphogen binding and transport in GAG hydrogels by selective desulfation of the GAG component.

2018, Bray, Laura J., Secker, Constanze, Murekatete, Berline, Sievers, Jana, Binner, Marcus, Welzel, Petra B., Werner, Carsten

Bone is the most common site for breast-cancer invasion and metastasis, and it causes severe morbidity and mortality. A greater understanding of the mechanisms leading to bone-specific metastasis could improve therapeutic strategies and thus improve patient survival. While three-dimensional in vitro culture models provide valuable tools to investigate distinct heterocellular and environmental interactions, sophisticated organ-specific metastasis models are lacking. Previous models used to investigate breast-to-bone metastasis have relied on 2.5D or singular-scaffold methods, constraining the in situ mimicry of in vitro models. Glycosaminoglycan-based gels have demonstrated outstanding potential for tumor-engineering applications. Here, we developed advanced biphasic in vitro microenvironments that mimic breast-tumor tissue (MCF-7 and MDA-MB-231 in a hydrogel) spatially separated with a mineralized bone construct (human primary osteoblasts in a cryogel). These models allow distinct advantages over former models due to the ability to observe and manipulate cellular migration towards a bone construct. The gels allow for the binding of adhesion-mediating peptides and controlled release of signaling molecules. Moreover, mechanical and architectural properties can be tuned to manipulate cell function. These results demonstrate the utility of these biomimetic microenvironment models to investigate heterotypic cell–cell and cell–matrix communications in cancer migration to bone.