title: Peptide-functionalized starPEG/heparin hydrogels direct mitogenicity, cell morphology and cartilage matrix distribution in vitro and in vivo.
abstract: Cell-based tissue engineering is a promising approach for treating cartilage lesions, but available strategies still provide a distinct composition of the extracellular matrix and an inferior mechanical property compared to native cartilage. To achieve fully functional tissue replacement more rationally designed biomaterials may be needed, introducing bioactive molecules which modulate cell behavior and guide tissue regeneration. This study aimed at exploring the impact of cell-instructive, adhesion-binding (GCWGGRGDSP called RGD) and collagen-binding (CKLER/CWYRGRL) peptides, incorporated in a tunable, matrixmetalloprotease (MMP)-responsive multi-arm poly(ethylene glycol) (starPEG)/heparin hydrogel on cartilage regeneration parameters in vitro and in vivo. MMP-responsive-starPEG-conjugates with cysteine termini and heparin-maleimide, optionally pre-functionalized with RGD, CKLER, CWYRGRL or control peptides, were cross-linked by Michael type addition to embed and grow mesenchymal stromal cells (MSC) or chondrocytes. While starPEG/heparin-hydrogel strongly supported chondrogenesis of MSC according to COL2A1, BGN and ACAN induction, MMP-degradability enhanced cell viability and proliferation. RGD-modification of the gels promoted cell spreading with intense cell network formation without negative effects on chondrogenesis. However, CKLER and CWYRGRL were unable to enhance the collagen content of constructs. RGD-modification allowed more even collagen type II distribution by chondrocytes throughout the MMP-responsive constructs, especially in vivo. Collectively, peptide-instruction via heparin-enriched MMP-degradable starPEG allowed adjustment of self-renewal, cell morphology and cartilage matrix distribution in order to guide MSC and chondrocyte-based cartilage regeneration towards an improved outcome. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Germany.
authors.forename: Eliane
authors.initials: E
authors.lastname: Hesse
authors.affiliation: Leibniz Institute of Polymer Research Dresden (IPF), Max Bergmann Centre of Biomaterials Dresden (MBC), Dresden University of Technology, Centre for Regenerative Therapies Dresden (CRTD), Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Freudenberg
authors.affiliation: Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Niemietz
authors.affiliation: Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Greth
authors.affiliation: Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Weisser
authors.affiliation: Centre for Orthopaedic and Trauma Surgery, Orthopaedic University Hospital Heidelberg, Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hagmann
authors.affiliation: Leibniz Institute of Polymer Research Dresden (IPF), Max Bergmann Centre of Biomaterials Dresden (MBC), Dresden University of Technology, Centre for Regenerative Therapies Dresden (CRTD), Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Binner
authors.affiliation: Leibniz Institute of Polymer Research Dresden (IPF), Max Bergmann Centre of Biomaterials Dresden (MBC), Dresden University of Technology, Centre for Regenerative Therapies Dresden (CRTD), Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Werner
authors.affiliation: Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Germany.
authors.forename: Wiltrud
authors.identifier: 0000-0003-4694-2768
authors.initials: W
authors.lastname: Richter
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D020100:Hydrogels / Q000494:pharmacology*; D016513:Mice, SCID; D008934:Mitogens / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D012212:Rheology; D013552:Swine
chemical_list: D020100:Hydrogels; D008934:Mitogens; D009842:Oligopeptides; D010455:Peptides; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D006493:Heparin