C. Zgheib1, J. Xu1, M. M. Hodges1, J. Hu1, L. C. Dewberry1, S. A. Hilton1, S. Seal2, K. W. Liechty1 1Laboratory For Fetal And Regenerative Biology, Department Of Surgery, School Of Medicine, University Of Colorado Denver – Anschutz Medical Campus And Colorado Children’s Hospital,Aurora, CO, USA 2Advanced Materials Processing And Analysis Centre, Nanoscience Technology Center (NSTC), Mechanical Materials Aerospace Eng, University Of Central Florida,Orlando, FL, USA
Introduction: Delayed wound healing is one of the most common complications associated with diabetes. These wounds do not heal properly due to chronic inflammation and impaired angiogenesis. We have previously shown that local delivery of the anti-inflammatory miR-146a using cerium oxide nanoparticles carrying miR-146a (CNPs+miR-146a) accelerates diabetic wound healing by promoting an anti-inflammatory M2 macrophage phenotype and reducing the inflammatory response. M2 macrophages have been shown to stimulate angiogenesis through the production of pro-angiogenic growth factors such as VEGF. Thus, we hypothesize that in addition to normalizing the inflammatory response, CNPs+miR-146a enhance diabetic wound healing through the correction of impaired angiogenesis.
Methods: To test this hypothesis, 8 mm full-thickness excisional wounds were created on the dorsal skin of diabetic mice and immediately treated with 10 uM of CNPs+miR-146a or PBS. Digital images of wounds were taken for calculation of wound surface area. Subsets of these wounds were harvested 7 days after wounding and miR-146a, miR-15b, VEGF, and BCL2 gene expression were analyzed.
Results: Our data show that at 7 days post-wounding, CNPs+miR-146a treatment resulted in improvement in wound closure over PBS-treated control wounds in diabetic mice. In addition, CNPs+miR-146a treatment rectified the compromised angiogenesis by increasing the levels of VEGF and BCL2. This is partly due to the downregulation of the levels of miR-15b, an anti-angiogenesis microRNA.
Conclusion: Our findings demonstrate that local delivery of miR-146a via conjugation with CNPs accelerates healing of diabetic wounds by normalizing inflammation and promoting angiogenesis. This CNP-based platform for miR-146a delivery is a promising effective adjunct therapy and warrants further studies prior to future clinical translation.