Biomaterials from a modular peptide scaffold

Abstract

Modular polymer scaffolds are an attractive solution to address the needs of biomaterial design and engineering. Simple modification of the scaffold enables both screening an array of materials as well as optimization of a single material. This thesis describes the development and applications of two different polypeptide scaffolds that may be functionalized with click chemistry on both the side chain and end group. We demonstrate the utility of these scaffolds with the synthesis of biomaterials and biopolymers for drug delivery and tissue engineering applications. One area of focus is the synthesis of a bioinspired polypeptide-hyaluronic acid conjugate. Proteoglycans are an interesting class of biomacromolecules whose applications have been limited by reproducible isolation from natural sources. Synthetic proteoglycans provide an alternative as a reproducible and scalable solution, though many synthetic systems lack biological activity. We have developed a method to synthesize polypeptide-hyaluronic acid conjugates of various architectures that more closely mimic the composition of proteoglycans found in nature. These conjugates exhibit biological activity distinct from native hyaluronic acid of various sizes. The conjugates were also successfully employed in a three dimensional vasculogenesis application. The synthesis of bulk hydrogels based off end to end linking of a polypeptide scaffold was also investigated. This endeavor required optimization of the polymerization conditions to achieve the desired end functionality. Ultimately, these polymers may be end-linked to form a soft hydrogel. Finally, the effects of secondary structure on polymer-drug conjugate efficacy are interrogated by grafting the anticancer drug doxorubicin and poly(ethylene glycol) to polypeptide scaffolds that exhibit different degrees of a-helicity. The drug release, toxicity, and conjugate association with cells was evaluated by in vitro assays.