Abstract
Supporting the wound healing process by sending the appropriate cytokine signals can shorten healing time and overcome chronic inflammation syndromes. Even though adhesion peptides consisting of Arg-Gly-Asp (RGD) are commonly used to enhance cell-surface interactions, peptide-mediated cytokine delivery has not been widely exploited so far. Cytokines interact with high affinity with their cognitive receptors but also with sulfated glycosaminoglycans (GAGs), both of which form a base for incorporation of cytokines into functional biomaterials. Here, we report on a mussel-derived surface coating as a prospective cytokine delivery system using covalently bound heparin mimetics, receptor-derived chemokine-binding peptides, and heparin-binding peptides (HBP). The latter enabled non-covalent immobilization of heparin on the surface followed by chemokine binding and release, whereas the former allowed direct non-covalent chemokine immobilization. The peptide displayed excellent binding to custom-made polystyrene 96-well plates, enabling convenient testing of several compounds. Released chemokine successfully induced migration in Jurkat cells, especially for the non-covalent heparin immobilization approach using HBPs as evaluated in a transwell assay. In comparison, heparin-mimetic coatings, comprised of sulfated peptides and GAG derivatives, proved less efficient with respect to amount of immobilized chemokine and migratory response. Thus, our study provides a roadmap for further rational optimization and translation into clinics.
Highlights
Chemokines are a family of small 8–12 kDa proteins that mediate migration and arrest of their target cells
Our focus was based on the final outcome of CXC chemokine ligand 12 (CXCL12) release and on the feasibility of the production of the release system. This led us to the design, on the one hand, of a peptide carrying covalently attached heparin mimicking moieties and, on the other hand, heparin-binding peptides allowing for non-covalent immobilization of heparin followed by chemokine binding
A two-layer approach, where immobilized heparin-binding peptides (HBP) are subsequently loaded with heparin, was identified to be the best condition for a prospective chemokine delivery system, as the highest amount of CXCL12 was bound and the strongest effects on cell migration were detected
Summary
Chemokines are a family of small 8–12 kDa proteins that mediate migration and arrest of their target cells. They are crucial players in tissue regeneration as they orchestrate the recruitment of various cell types to the wound site, modulating the immune response and directing angiogenesis. Simple adsorption to the material already promotes tissue regeneration (Ji et al, 2013), but stabilization against rapid protein clearance and a controlled release to reduce side effects is desirable. Affinity-based delivery systems are to be exploited, where a binding ligand is immobilized to the material, which reversibly binds the unmodified chemokine
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