Products Cited in Publications Worldwide Chemical Modification of Human Decellularized Extracellular Matrix for Incorporation into Phototunable Hybrid-Hydrogel Models of Tissue Fibrosis

Chemical Modification of Human Decellularized Extracellular Matrix for Incorporation into Phototunable Hybrid-Hydrogel Models of Tissue Fibrosis

Hewawasam, Rukshika S.; Blomberg, Rachel; Serbedzija, Predrag; Magin, Chelsea M.

DOI: PMID:

Abstract

Tissue fibrosis remains a serious health condition with high morbidity and mortality rates. There is a critical need to engineer model systems that better recapitulate the spatial and temporal changes in the fibrotic extracellular microenvironment and enable study of the cellular and mol. alterations that occur during pathogenesis. Here, we present a process for chem. modifying human decellularized extracellular matrix (dECM) and incorporating it into a dynamically tunable hybrid-hydrogel system containing a poly(ethylene glycol)-α methacrylate (PEGαMA) backbone. Following modification and characterization, an off-stoichiometry thiol-ene Michael addition reaction resulted in hybrid-hydrogels with mech. properties that could be tuned to recapitulate many healthy tissue types. Next, photoinitiated, free-radical homopolymerization of excess α-methacrylates increased crosslinking d. and hybrid-hydrogel elastic modulus to mimic a fibrotic microenvironment. The incorporation of dECM into the PEGαMA hydrogel decreased the elastic modulus and, relative to fully synthetic hydrogels, increased the swelling ratio, the average mol. weight between crosslinks, and the mesh size of hybrid-hydrogel networks. These changes were proportional to the amount of dECM incorporated into the network. Dynamic stiffening increased the elastic modulus and decreased the swelling ratio, average mol. weight between crosslinks, and the mesh size of hybrid-hydrogels, as expected. Stiffening also activated human fibroblasts, as measured by increases in average cellular aspect ratio (1.59 ± 0.02 to 2.98 ± 0.20) and expression of α-smooth muscle actin (αSMA). Fibroblasts expressing αSMA increased from 25.8 to 49.1% upon dynamic stiffening, demonstrating that hybrid-hydrogels containing human dECM support investigation of dynamic mechanosensing. These results improve our understanding of the biomol. networks formed within hybrid-hydrogels: this fully human phototunable hybrid-hydrogel system will enable researchers to control and decouple the biochem. changes that occur during fibrotic pathogenesis from the resulting increases in stiffness to study the dynamic cell-matrix interactions that perpetuate fibrotic diseases.

Keywords

biomaterial ; hybrid-hydrogel ; fibrosis ; decellularized extracellular matrix ; fibroblast activation

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