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(2023)ThesisTissue 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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(2024)ThesisDespite their wide application range owing to the high biocompatibility, conventional single network (SN) hydrogels always suffer from brittleness and weakness. To address this issue, double network (DN) gels consisting of two different polymer networks have been developed to achieve high mechanical performance. Stimulus responsiveness is another potential target for hydrogel bioapplications. Accordingly, the main aim of this thesis is to uncover some fundamental principles for tailoring the properties of tough and mechanochemically active hybrid DN hydrogels via structural control that are suitable for biomedical applications. Poly(ethylene glycol) (PEG) linked by different bonds and ionically linked sodium alginate were selected as covalent and physical networks, respectively. To understand the structure-property relationships of DN hydrogels with strong covalent bonds, PEG (meth)acrylate hydrogels with varying monomer molecular weights (MW) and architectures (linear vs. 4-arm) with and without alginate were used. Compression testing results showed that while PEG SN hydrogels behaved similarly with varied MW and stronger using 4-arm monomers, alginate reinforced DN gels were stronger and tougher when the PEG network was looser with larger MW and/or linear monomers. When using weak dynamic disulfide bonds, alginate reinforced disulfide networks using 4-arm PEG thiol (PEG4SH) with varied MW and mass fractions were investigated with the goal of achieving tough and stretchable DN hydrogels with a capacity for mechanochemical reactions. Tensile testing results demonstrated that the fracture strain and stress of DN gels benefited from looser PEG networks with lower mass concentrations and larger MW of PEG4SH monomers, while stiffness increased with a higher density of disulfide bonds. Considering the mechanochemical response, thiols produced by disulfide bond rupture were sensed by reaction with fluorophores. DN gels showed increased integrated fluorescence intensities upon stretching, demonstrating the activated response of disulfide bond rupture despite alginate reinforcement. Higher mechanochemical reaction rates were obtained from the most stretchable DN gels with looser PEG networks and less alginate reinforcement. In summary, this thesis presents a comprehensive study on how to design tough and mechanochemically active hydrogels using alginate reinforced covalent networks. These results are expected to aid the development of mechanoresponsive DN hydrogels with controllable properties for biomedical applications.