Growth factors are signalling molecules that orchestrate cell proliferation, survival and migration. As such, they have been identified as promising therapeutics to promote tissue repair. However, there is currently a lack of approaches that enable their effective delivery.
A promising strategy to make growth factor-based therapies more potent is to mimic the way the extracellular matrix (ECM) coordinates the presentation of growth factors in time and space. For example, the ECM contains domains that bind growth factors with high affinity and contains enzymatically cleavable domains whose cleavage leads to a transient increase of the available growth factor. One mechanism that evolved to achieve a delayed, on-demand activation of growth factors is the traction force mediated release of the transforming growth factor-beta β (TGF-β) from the lasso-resembling Large Latent Complex (LLC). While the use of bioactive ECM-derived motifs has already extended the capabilities of growth factor delivery scaffolds, traction forces have not yet been explored as a general stimulus to trigger an on-demand release of growth factors.
This thesis presents the design of synthetic, functional mimics of the LLC, termed the Traction Activated Payloads (TrAPs). TrAPs consist of an aptamer and a cell adhesive peptide. The single-stranded oligonucleotide aptamer binds a growth factor via affinity interactions, which are disrupted when the cell pulls on the complex via integrins.
This thesis demonstrates the versatility of the platform by showing: (i) that TrAPs can be designed to deliver multiple different growth factors and (ii) that TrAPs retain their functionality when conjugated to both a variety of surfaces and therapeutically relevant collagen scaffolds. This thesis further demonstrates that TrAPs can be combined with various cell adhesive peptides, making this platform the first step towards the design of cell type-specific, sequential growth factor activation.