Self-Assembly and\nWound Healing Activity of Biomimetic\nCycloalkane-Based Lipopeptides

The self-assembly of lipopeptide (peptide amphiphile)\nmolecules\nbearing single linear lipid chains has been widely studied, as has\ntheir diverse range of bioactivities. Here, we introduce lipopeptides\nbearing one or two cycloalkane chains (cycloheptadecyl or cyclododecyl)\nconjugated to the collagen-stimulating pentapeptide KTTKS used in\nMatrixyl formulations. The self-assembly of all four molecules is\nprobed using fluorescence probe measurements to detect the critical\naggregation concentration (CAC), and cryogenic-TEM and small-angle\nX-ray scattering (SAXS) to image the nanostructure. The peptide conformation\nis studied using circular dichroism (CD) and FTIR spectroscopies.\nAll the cycloalkane lipopeptides show excellent compatibility with\ndermal fibroblasts. The compounds bearing one or two cyclododecyl\nchains (denoted as DKT and DDKT, respectively) show wound healing\nin diabetic rats, the improvement being markedly enhanced for DDKT.\nInterestingly, the revival of hair follicles and blood vessels in\nthe dermis were observed, which are the critical markers of effective\nwound repair. Analysis of H&E-stained tissue images (from a rat\nmodel) shows that the rat groups treated with DDKT and DKT displayed\na significantly increased amount of regenerated hair follicles, indicating\na faster healing process for DDKT compared to the control group. Collagen\ndeposition was also enhanced, especially for DDKT, and by day 20,\nthe DDKT-treated groups had developed a dense collagen network accompanied\nby a regenerated epidermis. At the same time, the number of blood\nvessels in DDKT-treated diabetic wounds was significantly higher than\nin control groups and neovascularization was substantially enhanced,\nas assayed using α-SMA (a marker for vascular smooth muscle\ncells) and CD31 (a marker specific to vascular endothelial cells).\nThese results suggest that the lead lipopeptide DDKT exhibits a remarkable\npro-vascularization capability and shows great promise for future\napplication as a wound-healing biomaterial.