Nanostructured Fibrin Hydrogels

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Abstract

In the present thesis we propose the development of artificial (hybrid) fibrin hydrogels with a well-defined nanostructure for their future use in biomedical applications. Fibrin hydrogels are currently commercially available as a haemostat, sealant and adhesive in surgical procedures. These biomaterials have also been widely investigated in fields such as tissue engineering and drug delivery. However, despite their high resemblance to natural fibrin networks, artificial fibrin hydrogels often present important limitations, including poor mechanical properties, high susceptibility to enzymatic degradation, and rapid cell-mediated matrix contraction when in contact with cells; during in vivo remodelling processes these phenomena often lead to non-functional artificial fibrin constructs. It is often postulated that these phenomena can be controlled via the modulation of the mechanical properties and nanostructure of the biomaterial. In this thesis we demonstrate, through a number of rheological and turbidity studies, the ability to modulate fibrin’s mechanical and nanostructural properties by acting on the concentration of a number of gel components, as well as on fibrin’s native knob:hole affinity interactions using poly(ethylene glycol)-peptide derivatives. We also evaluate the Michael-type addition chemistry as a conjugation tool for the preparation of multifunctional polymer-peptide derivatives, with the perspective of developing hybrid fibrin-polymer hydrogels with improved physico-chemical and biological properties. With this aim, we first report on a comprehensive kinetic and stability study for the selection of an appropriate Michael-type acceptor with fast conjugation and slow hydrolysis and thiol-exchange kinetics that can be used as a heterobifunctional cross-linker for the preparation of peptide-based bioconjugates. Secondly, we report on the synthesis of different hyaluronic acid (HA)-peptide conjugates, where HA is initially functionalised with a suitable Michael-type acceptor and subsequently conjugated with cysteine-containing fibrin-interacting peptides. We propose that the resultant fibrin-binding HA-peptide conjugates prepared in this thesis can be used for the future preparation of in situ gelling, injectable formulations to provide hybrid HA/fibrin hydrogels with a homogeneous and controllable nanostructure. These new materials are postulated to have the potential to counteract the matrix contraction phenomena often seen with fibrin gels by simultaneously acting on the networks’ mechanical and structural properties, their osmotic action and their anti-inflammatory behaviour.

Keyword(s)

Fibrin Hyaluronic acid PEGylated peptides Knob:hole interactions Nanostructured hydrogels

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