Multifunctional poly(2-oxazoline)-based macromonomers for the preparation of ECM-analogous multi-compartment cell support structures and biogels for tumor tissue engineering (TTE)

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Despite immense progress in tumor medicine, there is still a significant need for research in order to elucidate the underlying complex molecular and cellular processes and to convert them into efficient therapeutic approaches. Optimized cell culture models can make a decisive contribution to this. In addition to the classic somatic mutation theory, the tumor microenvironment (TME), or in other words, the tumor-related deregulated extracellular matrix (ECM) is increasingly becoming the focus of current research. With the help of tissue engineering (TE), ECM-like models of the tumor matrix can be established that can map the various stages of tumorigenesis and tumor progression in vitro.In the present project, the approach is to be pursued with the help of nano-3D-lithography (two-photon polymerization / 2PP) and a suitable class of functional polymers, the multifunctional poly (oxazolines) (POx), ECM-analogous models of the tumor matrix are built up. These will be available for research in the application area of diagnostic TE (disease modeling) but also in the area of therapeutic TE (regeneration) and will be subjected to initial tests. In the long term, such structures can also be adapted for microfluidic organ models (organ-on-a-chip).In the project, two different types of POx will be synthesized: i) POx with polymerizable end groups for the production of mechanically stable (Schwarz P-) scaffold structures using 2PP and ii) POx with cross-linkable chemical functionalities to generate "biogels" with defined viscosity for the ECM-like embedding of cells within the scaffold structures. Both elements, the scaffolds and biogels, will be equipped with biofunctional molecules analogous to a natural ECM. It is therefore intended to covalently immobilize peptide sequences with a cell adhesive effect (e.g. RGD peptides) on both scaffolds and biogels, as well as peptides with a proteolytic effect (e.g. MMP-sensitive peptides) in the POx biogels. A drug delivery function can optionally be implemented using a copolymer approach with POx and heparin, in which the entire bulk phase functions as a drug reservoir. Alternatively, the POx-based cell carrier structures can also be functionalized in a layer-by-layer process using polyelectrolytes (e.g. poly-L-lysine / heparin) in such a way that an additional drug delivery function is available. The desired combination of a nanoscale structuring process (2PP) and the multifunctional polymer platform results in a qualitatively new design, which avoids significant disadvantages of previous approaches to the generation of artificial ECMs.