Tailored Release of Bioactive Factors from Composite Multidomain Peptide Hydrogels
Wickremasinghe, Navindee Charya
Hartgerink, Jeffrey D; Marti, Angel A; Mikos, Antonios G
Doctor of Philosophy
Multidomain peptides (MDP) self-assemble to form nanofibrous scaffolds well suited to tissue engineering and regeneration strategies. MDPs can present bioactive cues that promote vital biological responses. Orthogonal self-assembly of MDP and growth factor-loaded liposomes generate supramolecular composite hydrogels. This thesis demonstrates the ability to create a unique hydrogel, developed by stepwise self-assembly of multidomain peptide fibers and liposomes, and presents its potential for in vivo applications. Chapter One of the thesis presents an introduction to the above work with background spanning from the role of self-assembling peptides and hydrogels in tissue engineering, to current strategies for therapeutic angiogenesis and wound healing. Chapter Two addresses the design and characterization of a composite hydrogel containing MDP and liposomes. Results showed that structural and mechanical integrity of the peptide nanofibers, lipid vesicles and the composite gel are retained. The two-component gel allows for controlled release of bioactive factors at multiple time points and indicates bimodal release of two growth factors from the same system. These MDP-Liposome Composites (MLCs) were injected in vivo for targeted, localized delivery of growth factors, and Chapter Three details how they functioned in vivo. Placental growth factor-1 (PlGF-1) was shown to temporally stimulate VEGF-receptor activation in vitro in endothelial cells, and robust vessel formation in vivo. MLCs provide a novel method for the time controlled delivery of growth factors from within highly biocompatible and injectable hydrogels. Time controlled release guided by MLCs induces an unprecedented level of growth factor-mediated neovascular maturity. Use of cytokine-loaded MDP hydrogels to accelerate diabetic wound healing is another in vivo application explored in Chapter Four of this thesis. Delivery of a pro-healing cytokine IL-4 via MDP hydrogels have resulted in enhanced healing of full-thickness dermal wounds on the backs of genetically diabetic mice. Compared to controls, wounds treated with IL-4-MDP composite gels showed higher wound closure, M2 macrophage polarization, re-epithelialization, granulation tissue formation and angiogenesis. The conclusion chapter, Chapter Five, discusses how the above in vivo success of composite MDP hydrogels speaks to their potential to function as a unique protein delivery platform for tissue regeneration.