Wade, Ryan Joseph

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  • Publication
    Engineering Extracellular Matrix Signals into Fibrous Hyaluronic Acid Hydrogels
    (2015-01-01) Wade, Ryan Joseph
    Hydrogels have gained widespread use in biomedical applications for their ability to mimic certain features of the natural extracellular matrix (ECM) including tissue-like mechanics, water-swollen environments, and biodegradability. Despite these advantages, hydrogels typically do not present the fibrous architecture of natural ECM, even though this structure can guide cell behavior and tissue function. With this in mind, the overall goal of this dissertation is the translation of hydrogels from hyaluronic acid (HA) macromers into more complex, fibrous networks with spatiotemporal control. First, HA macromers that contain protease-cleavable and fluorescent peptides were synthesized and shown to form both isotropic hydrogels and electrospun fibrous hydrogels through a photoinitiated polymerization. These scaffolds were susceptible to protease-mediated cleavage in vitro in a protease dose dependent manner and in vivo in a subcutaneous mouse model using transdermal fluorescent imaging to monitor degradation. Importantly, materials containing an alternate and non-protease-cleavable peptide sequence were stable in both in vitro and in vivo settings. Next, the ability to spatially pattern fibrous hydrogels with biomolecules was investigated using thiol-ene reactions of thiolated molecules to electrospun norbornene modified HA (NorHA). This approach permitted pattern features as small as 50 μm and patterning of multiple molecules. Spatial control over cell adhesion and morphology was also demonstrated as cells responded to fiber organization and patterns of cell adhesive peptides. Finally, protease-degradable and non-degradable fluorophores were developed to visually detect protease-activity on NorHA scaffolds from both exogenously added and cell-secreted (HT-1080 cells) proteases. Overall, this work represents unique approaches to generate fibrous hydrogels with previously unrealized biocomplexity for the fields of tissue engineering and regenerative medicine.