Cell-instructive hydrogel gradient arrays

• Applicants: Dr.-Ing. Uwe Freudenberg; Dr.-Ing. Ralf Zimmermann
• Subject Area: Biomaterials
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266473652

Spatio-temporally varying mechanical and biomolecular cues of the extracellular microenvironment determine cell fate decisions in living tissues and thus need to be recapitulated in effectively cell-instructive materials. Towards this aim, we propose an interdisciplinary research program to employ a set of recently introduced in situ forming, growth factor-affine starPEG-GAG hydrogels in combination with advanced microfluidics methodology for (i) producing bioresponsive polymer matrices with orthogonally graded mechanical and biomolecular characteristics, (ii) integrating GAG-hydrogel gradient arrays into a 3D cell culture platform, and (iii) performing parallelized studies of matrix-controlled cellular response patterns. The research to realize these goals will be organized in 3 work packages (WPs). In WP 1 we plan to establish 3D nanoplotting technologies to produce hydrogel materials with spatially controlled stiffness (200 Pa - 6 kPa) and to unravel fundamental principles of the molecular transport within growth factor-affine GAG hydrogels. The obtained results will be used in WP 2 to integrate GAG-hydrogel arrays of orthogonally graded mechanical properties and morphogen distributions in a 3D cell culture platform. In particular we intend to use microfluidic principles to deliver growth factors with spatially and temporally varying concentrations into the hydrogel. To validate the concept and to provide a basis for future applications of the cell culture platform it is planned to perform within WP 3 selected cell culture experiments. Specifically, we intend to explore the impact of mechanical gradients on the polarization of hepatocytes and to systematically investigate the growth factor gradient induced migration of early endothelial progenitor cells in hydrogels of spatially varying network density. The suggested approach is expected to pave the way for a new level of exogenous cell fate control through engineered multi-biofunctional polymer matrices, enabling more faithful tissue models for in vitro studies and more effective cell based regenerative therapies in vivo.

• DFG Programme: Research Grants