title: Enzyme responsive GAG-based natural-synthetic hybrid hydrogel for tunable growth factor delivery and stem cell differentiation.
abstract: We describe an enzymatically formed chondroitin sulfate (CS) and poly(ethylene glycol) (PEG) based hybrid hydrogel system, which by tuning the architecture and composition of modular building blocks, allows the application-specific tailoring of growth factor delivery and cellular responses. CS, a negatively charged sulfate-rich glycosaminoglycan of the extracellular matrix (ECM), known for its growth factor binding and stem cell regulatory functions, is used as a starting material for the engineering of this biomimetic materials platform. The functionalization of CS with transglutaminase factor XIII specific substrate sequences is utilized to allow cross-linking of CS with previously described fibrin-mimetic TG-PEG hydrogel precursors. We show that the hydrogel network properties can be tuned by varying the degree of functionalization of CS as well as the ratio and concentrations of PEG and CS precursors. Taking advantage of TG-PEG hydrogel, compatible tagged bio-functional building blocks, including RGD peptides or matrix metalloproteinase sensitive domains, can be incorporated on demand allowing the three-dimensional culture and expansion of human bone marrow mesenchymal stem cells (BM-MSCs). The binding of bone morphogenetic protein-2 (BMP-2) in a CS concentration dependent manner and the BMP-2 release mediated osteogenic differentiation of BM-MSCs indicate the potential of CS-PEG hybrid hydrogels to promote regeneration of bone tissue. Their modular design allows facile incorporation of additional signaling elements, rendering CS-PEG hydrogels a highly flexible platform with potential for multiple biomedical applications.
authors.affiliation: Pharmaceutical Production Research Facility, University of Calgary, 2500 University Dr., Calgary, AB, T2N 1N4, Canada; Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW., Calgary, AB, T2N 1N4, Canada. Electronic address: fanjum@ucalgary.ca.
authors.forename: Fraz
authors.initials: F
authors.lastname: Anjum
authors.affiliation: Department of Obstetrics, University Hospital Zurich, University of Zurich, Schmelzbergstr. 12, 8091, Zurich, Switzerland.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Lienemann
authors.affiliation: Department of Obstetrics, University Hospital Zurich, University of Zurich, Schmelzbergstr. 12, 8091, Zurich, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Metzger
authors.affiliation: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, 3330 Hospital Dr., Calgary, AB, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Dr., Calgary, AB, T2N 4N1, Canada; Department of Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr., Calgary, AB, T2N 4N1, Canada.
authors.forename: Jeff
authors.initials: J
authors.lastname: Biernaskie
authors.affiliation: Pharmaceutical Production Research Facility, University of Calgary, 2500 University Dr., Calgary, AB, T2N 1N4, Canada; Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW., Calgary, AB, T2N 1N4, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kallos
authors.affiliation: Department of Obstetrics, University Hospital Zurich, University of Zurich, Schmelzbergstr. 12, 8091, Zurich, Switzerland. Electronic address: martin.ehrbar@usz.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Ehrbar
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D003692:Delayed-Action Preparations; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D002809:Chondroitin Sulfates
keywords: Chondroitin sulphate; Factor XIII; Hydrogels; Matrix metalloproteinase (MMP); Polyethylene glycol