Hydrogels, composed of water-swollen polymer networks, can form stable 3D scaffolds, and have been integral in numerous applications in tissue engineering. They can be used to mimic the native extracellular matrix (ECM) to provide the necessary chemical and physical stimuli for cells cultured therein to dictate cellular functions such as growth, adhesion, differentiation and invasion. Culturing cells in 3D hydrogels in vitro better recapitulates their natural behaviour in vivo compared to traditional cell culture methods using 2D tissue culture polystyrene. The development of better cell culture systems has important implications towards accurately studying biochemical mechanisms and discovering more efficacious drug therapies. Our lab has developed biomimetic hydrogel scaffolds comprising hyaluronic acid (HA), a bioactive polysaccharide that is naturally found in the ECM of many tissues and the tumor microenvironment. Chemically modifying HA with furan groups, and reacting them with maleimide-based crosslinkers and pendant bioactive molecules allows for the defined control of hydrogel physical and chemical properties. Herein, we report our recent progress in improving the biomimetic properties of these hydrogels. First, we have developed enzyme-degradable hydrogels that are remodelled by cancer cell-secreted matrix metalloproteinases, resulting in cancer cell invasion, and better recapitulating their genotypes and phenotypes naturally found in vivo. Drug screening using this biomimetic 3D platform shows cellular bioactivities that are not observed with conventional 2D cell culture. Second, we altered HA hydrogel porosity, an important parameter to ensure adequate gas and nutrient diffusion, by using a modified cryogelation technique. While previous cryogelation techniques have been applied to polysaccharide-based hydrogels, they resulted in opaque hydrogels, thus limiting their widespread use in cell culture due to the difficulty in visualizing live cells using conventional microscopy. By incorporating soluble mono- and disaccharide additives during cryogelation, we synthesized macroporous, photosensitive HA scaffolds that remain transparent following removal of these additives. This enables live cell visualization using confocal microscopy, as well as the 3D spatial control of immobilized bioactive growth factors using multiphoton patterning.

Stimuli-responsive hyaluronan-based hydrogels provide biochemically-defined, biomimetic scaffolds for 3D cell culture

253rd National Meeting (2017)

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