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INSTITUTE FOR BIOFUNCTIONAL POLYMER MATERIALS

MATRIX ENGINEERING

Core Research

Uwe Freudenberg
Andrea Meinhardt

Decellularized or reconstituted biopolymer matrices and modular, multi-biofunctional hydrogels are designed as cell-instructive and morphogenetic matrices to enable regenerative therapies as well as advanced tissue and disease models.

Cell-instructive biofunctional hydrogels

Glycosaminoglycan-based hydrogels are developed for the sustained administration of soluble signaling molecules (cytokines, chemokines, growth factors, drugs) utilizing extracellular matrix-derived binding principles. The polymer networks are prepared by a theory-driven design concept using variable building blocks and crosslinking strategies to afford independently tunable elasticity, degradability, signal molecule affinity, cell adhesiveness in ways to respond to cell-based or external triggers (enzyme activity, temperature, light or pH). Being used to embed cells, applied via injection to form in situ, and micro-processed by microfluidics, micromolding, cryogelation and printing techniques, customized hydrogel variants enable a broad range of new therapeutic concepts.

SELECTED REFERENCES

Freudenberg U., Liang Y., Kiick K.L., Werner C. Glycosaminoglycan-Based Biohybrid Hydrogels: A Sweet and Smart Choice for Multifunctional Biomaterials. Advanced Materials Oct;28(40):8861- 8891 (2016).

Lohmann N., Schirmer L., Atallah P., Wandel E., Ferrer R.A., Werner C., Simon J.C., Franz S., Freudenberg U. Glycosaminoglycan-based hydrogels capture inflammatory chemokines and rescue defective wound healing in mice. Science Translational Medicine 9 (2017).

Freudenberg U., Sommer J.-U., Levental K.R., Welzel P.B., Zieris A., Chwalek K., Schneider K., Prokoph S., Prewitz M., Dockhorn R., Werner C. Using Mean Field Theory to Guide Biofunctional Materials Design. Advanced Functional Materials 22 (7), 1391–1398 (2012).



Key functional characteristics of extracellular matrices (ECM) (modified from Freudenberg et al., Advanced Materials 2016; Copyright Advanced Materials 2016)
SEM image of a µ-cryogel synthesized via photo-crosslinking of a poly(ethylen glycol) diacrylate (PEGDA) precursor droplet with Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) as photoinitiator at -10°C.

DECELLULARIZED MATRICES

Decellularized extracellular matrices (ECM) derived from tissue, organs or cell cultures are prepared to faithfully reproduce specific cellular microenvironments in vitro. Macromolecular crowding conditions as well as customized decellularization and processing/re-assembly protocols are developed and applied to tune structural and compositional features of fibrillar biopolymer matrix types.

SELECTED REFERENCES

Prewitz M.C., Seib F.P., von Bonin M., Friedrichs J., Stißel A., Niehage C., Müller K., Anastassiadis K., Waskow C., Hoflack B., Bornhäuser M., Werner C. Tightly anchored tissue-mimetic matrices as instructive stem cell microenvironments. Nature Methods 10(8):788-94 (2013).

Magno V., Friedrichs J., Weber H.M., Prewitz M.C., Tsurkan M.V., Werner C. Macromolecular crowding for tailoring tissue-derived fibrillated matrices. Acta Biomaterialia 55:109-119 (2017).

Scanning electron micrograph of a decellularized matrix of mesenchymal stromal cells grown on a poly(octadecene-alt-maleic anhydride – Fibronectin (POMA-FN) coated surface. White structures within the matrix network represent tethered glycosaminoglycan (GAG) aggregates. Scale 2µm
(Prewitz MC et al., Nat Meth 2013, 10 (8), 788–794)

Developing tissue-, organ- and disease in vitro models

Cell-instructive polymer matrices offer unprecedented options to reproduce tissue development, homeostasis and regeneration as well as pathologic scenarios based on 3D co- or organoid cultures in vitro. By adjusting the hydrogel’s degradability and stiffness, and decorating it with selected adhesive peptides to mimic the native ECM environment the polymer matrices can be adapted towards each cellular need. Sulfated glycosaminoglycans (GAGs) possess the unique ability to modulate morphogen gradients in vitro, thereby directing cell morphogenesis and growth leading to the formation of 3D vascular and renal tubular networks as well as the reconstruction of tissue-specific (bone marrow) stem cell niches. Multiphasic and graded materials made out of the GAG-containing hydrogels are being applied in combinatorial approaches aiming at guiding 3D organoid growth, such as kidney or cancer organoids.

SELECTED REFERENCES

Chwalek K., Tsurkan M.V., Freudenberg U., Werner C. Glycosaminoglycan-based hydrogels to modulate heterocellular communication in in vitro angiogenesis models. Scientific Reports 4, 8 (2014).

Prewitz M.C., Seib F.P., von Bonin M., Friedrichs J., Stissel A., Niehage C., Muller K., Anastassiadis, K., Waskow, C., Hoflack, B., Bornhäuser, M., Werner, C.. Tightly anchored tissue-mimetic matrices as instructive stem cell microenvironments. Nature Methods 10, 788-794 (2013).

Sebinger D.D.R., Ofenbauer A., Gruber P., Malik S., Werner C. ECM modulated early kidney development in embryonic organ culture. Biomaterials 34, 6670-6682 (2013).

Weber H.M., Tsurkan M.V., Magno V., Freudenberg U., Werner C. Heparin-based hydrogels induce human renal tubulogenesis in vitro. Acta Biomaterialia 57, 59-69 (2017).

MCF-7 breast cancer spheroids in triple-cultures with HUVECs and mesenchymal stromal cells to mimic the vascular bone marrow niche (CD31 – green; Phalloidin – red); scale: 150µm
(Bray LJ, et al., Biomaterials 53 (2015) 609e620)