Engineering new self-assembling biomaterials based on beta-sheet-forming peptides.

摘要

This thesis deals with the development of novel strategies for self-assembling biomaterials based on short β-sheet fibril-forming peptides. These materials are potentially useful for a variety of biomedical applications, including tissue engineering and controlled drug release, and several aspects of these materials have been explored in this thesis in an effort to improve their clinical utility. First, a strategy for rapidly and uniformly triggering peptide self-assembly was developed. Stimulus-sensitive liposomes were utilized to sequester salts and release them in response to stimuli such as warming to body temperature or exposure to near infra-red light. Triggered salt release in turn initiated rapid self-assembly of extravesicular peptide and the transformation of the peptide/liposome suspension from a solution to a hydrogel. We show that peptide self-assembly can be rapidly, uniformly, and specifically triggered, with the storage modulus increasing three orders of magnitude upon triggering. This rapid triggering strategy is potentially useful for injectable biomaterial applications. In the second research thrust, a self-assembling peptide was developed that also possessed enzymatic activity for the cross-linking enzyme tissue transglutaminase. We then utilized tissue transglutaminase to conjugate cell-interactive peptides to the self-assembled structure and investigated cell attachment to these functionalized scaffolds. Such a strategy is potentially useful for designing biospecific self-assembling scaffolds for tissue engineering or wound healing. In the final research focus, to modulate the nanostructure of the self-assembled fibrillar structures, we developed a series of self-assembling polyethylene glycol-conjugated peptides. We found that polyethylene glycol conjugation significantly altered fibril morphology, including width, length, and degree of lateral aggregation. As previous β-sheet fibrillar self-assembled materials have shown particular intransigence to such modification of the fibrillar structure, this strategy may be a useful route for tailoring the physical properties of these materials. As a whole, the strategies developed in this thesis address previous shortcomings of β-sheet peptide-based self-assembling materials in an effort to bring them closer to clinical application.