Magnetic Responsive Hydrogels for Modulating Cell Behaviour

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Copyright: Islam, Md Shariful
Tissue engineering aims to create functional tissues by cultivating cells in a laboratory setting. A primary area of focus to achieve that objective is the development of scaffolds capable of providing a suitable environment for cellular adhesion, growth, and the execution of fundamental cellular functions to establish tissue-scale properties. However, scaffold systems in the laboratory do not benefit from the dynamic forces that are exerted on tissues in an organism. In pursuit of this aim, the overall objective of this thesis was to develop a tissue engineering scaffold system mimicking the natural tissue-like environment, with in-built capabilities for external control of dynamic mechanical properties to modulate cell differentiation. We first developed a magnetic nanoparticle-loaded hydrogel system, where the modulus of the hydrogels can be reversibly altered by applying a magnetic field. To demonstrate versatility, we have used two popular hydrogel systems broadly used in tissue engineering: poly (ethylene glycol dimethacrylate) and gelatine methacryloyl. We analysed the effects of the field-induced change in stiffness on cell behaviour upon the attenuation of a magnetic field. Our studies demonstrate that adipose-derived stem cells (ADSC) and embryonic muscle cells (C2C12 cell line) can perceive these stiffness changes and differentiate towards myofibroblast and myoblast, respectively. We then developed a composite hydrogel system to segregate the magnetic particles within gelatin fibres, which simultaneously provides nanotopography to the adherent cells. We used electrospinning to synthesize magnetic gelatin nanofibers containing 5 wt/v% iron oxide nanoparticles. This concentration was selected to ensure maintenance of fiber morphology while simultaneously ensuring magnetic response. To stabilize the nanofiber structure, we used a crosslinking method involving citric acid and high temperature to stabilize the gelatin via amide bonds between strands. Introducing a magnetic nanofiber mat at the interface of the hydrogel system provides remote actuation of the nanotopography through an external magnetic field. We found that the nanotopography alone directed adipogenesis, while mechanical actuation of the interface drove osteogenesis in adherent ADSCs. The adhesion characteristics suggest that the field influences the nanofiber structure, greatly enhancing focal adhesion. The field induced actuation was also found to stimulate the formation of aligned multinucleated myotubes and markers associated with maturation in adherent C2C12. Finally, we integrated the magnetic nanofiber into hydrogels as a modular system that closely resembles the fibrous network in the natural extracellular matrix. These hydrogels can be reversibly stiffened in response to external magnetic fields within cell-laden 3D constructs. Including a small fraction of short nanofibers (<3%) can significantly influence ADSC and C2C12 differentiation. As before, nanotopography was beneficial to adipogenesis while stiffening promoted enhanced osteogenesis and myogenesis. Together, this body of work provides a modular platform with broad versatility in format to study the effects of nano-topography and dynamic mechanics in cell systems. Moreover, these hydrogels and the magnetic components are cytocompatible with scope for inclusion in tissue bioreactors as a means for dynamic stimulation of cell differentiation for tissue engineering.
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PhD Doctorate
UNSW Faculty