Biomaterials have immense potential for studying fundamental biological processes and developing therapies to help regenerate or replace the structure and function of injured tissues. In order to accomplish this, they need to be designed to mimic the structure and function of Nature’s most important material, the extracellular matrix (ECM) surrounding the cells of tissues. Using peptide amphiphile (PA) and DNA aptamer nanostructures, this work investigates the use of these hybrid materials containing these two types of nanostructures as advanced artificial extracellular matrices. This platform addresses several challenges associated with controlling interactions between cells and a synthetic matrix environment, including the ability to bind, sequester, and release growth factor proteins, coordinate complex cellular processes, and dynamically control cell signaling. The first part of this work demonstrated the utility of aptamer-PAs to enhance aptamer function. Nanofibers that present an aptamer for platelet-derived growth factor BB (PDGF-BB) promote superior binding to the protein than the aptamer alone or nanofibers without the aptamer. It is suggested that the supramolecular nature of the PA nanofibers enables this increased affinity by presenting multiple copies of the aptamer that can rapidly rebind. Furthermore, the dynamic nature of PAs allows the aptamer-PA monomers to optimally rearrange to bind both domains on the PDGF-BB dimer. The aptamer nanofibers also confer greater nuclease stability to the aptamer by slowing the rate of hydrolysis. Imbued with greater affinity and nuclease stability, the therapeutic potential of the aptamer nanofibers is demonstrated by improved inhibition of PDGF-BB mediated proliferation. A different part of this work made use of the modularity of the aptamer-PA system by developing an aptamer-PA specific for vascular endothelial growth factor (VEGF). Using both VEGF and PDGF-BB aptamer-PAs, the activity of the respective proteins is temporally modulated by initially inhibiting the growth factors and then releasing them on-demand through complementary DNA strand displacement. This was found to have a profound effect on the proliferation of cells in two and three dimensions. Additionally, individually tunable release profiles of both proteins are designed to enhance the sprouting of endothelial cells and pericytes in an in vitro angiogenesis model. These results demonstrate that aptamer-PAs are an effective materials platform that mimics the ability of the ECM to form concentration gradients and guide cellular behavior. The last part of this work transitioned beyond the use of aptamer-PAs to control extraneous bioactive signals and instead employed an aptamer for the Met receptor (Hepatocyte Growth Factor Receptor) to directly signal cells as growth factor mimics. Through careful optimization of aptamer density in the nanofibers, aptamer-PA nanofibers promoted activation of the Met receptor and associated downstream signaling. Furthermore, the utility of this aptamer-PA system was demonstrated by dynamically switching “on” and “off” Met signaling through the addition or removal of a complementary DNA strand. This dynamic activation is something that was previously unachieved in peptide-based growth factor mimetic PAs and is a promising strategy for developing biomaterials that mimic the ECMs ability to regulate growth factor signaling. Taken together, these results demonstrate the utility of aptamer peptide amphiphile nanomaterials to mimic key aspects of the native ECM and provide a basis for developing future therapeutic biomaterials.

Creator

• Serrano, Christopher

DOI

• https://doi.org/10.21985/n2-yqhc-5k47

Subject

• Materials Science

Language

• en

Alternate Identifier

• etdadmin_upload_681720
• http://dissertations.umi.com/northwestern:14779

Keyword

• Peptide Amphiphile
• Growth Factor
• Aptamer
• Biomaterials
• Self-assembly
• Extracellular Matrix

Date created

• 2019-01-01

Resource type

• Dissertation

Rights statement

• In Copyright