Wound Healing Society

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An Effective “Anti-Inflammatory/Anti-ROS” Combination Therapy That Accelerates Diabetic Wound Healing
Carlos Zgheib1, Junyi Hu1, Junwang Xu1, Maggie M. Hodges1, Sarah A. Hilton1, Lindel C. Dewberry1, Sudipta Seal2, Kenneth W. Liechty, MD, FACS1.
1Laboratory for Fetal and Regenerative Biology, University Of Colorado Denver and Colorado Children's Hospital, Aurora, CO, USA, 2Advanced Materials Processing and Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL, USA.

Background: Diabetic wounds have become one of the most challenging public health issues of the 21st century with an annual cost of $1.5 billion in the US alone and yet no effective treatment is available. Diabetic wounds don't heal properly due to many deficiencies including elevated inflammation and oxidative stress. We have previously shown that this abnormal inflammatory response is due to decreased levels of a key regulator of the NFkB pro-inflammatory signaling, miR-146a. We have also shown that cerium oxide nanoparticles (CNP) act as antioxidants and scavenge reactive oxygen species (ROS) in wounds. Thus, we propose the hypothesis that combined targeting of inflammation and oxidative stress via local delivery of CNP carrying miR-146a (CNP+miR-146a) will effectively improve diabetic wound healing. Methods: 8 mm full-thickness wounds were created on the dorsal skin of diabetic and non-diabetic mice and treated with 108pfu Lenti-miR-GFP, 108pfu Lenti-miR-146a, or 10uM of CNP+miR-146a. Rate of wound closure was measured until the wounds were fully healed. Subsets of these wounds were harvested 7 days post-wounding and miR-146a, NFkB, IRAK1, TRAF6, IL-6, IL-8, and NOX2 gene expression was analyzed. Inflammatory cell infiltration was analyzed by CD45 immunostaining. Results: CNP+miR-146a effectively decreased the: activation of NFkB pro-inflammatory signaling, upregulation of IL-6 and IL-8 levels, recruitment of pro-inflammatory CD45+ cells, and NOX2 (ROS producer) expression. These corrections lead to a dramatic improvement in the rate of diabetic wounds closure. Conversely, although it was successful in decreasing inflammation, Lenti-miR-146a did not accelerate diabetic wound closure. Conclusions: Our findings demonstrate that "CNP+miR-146a Combination Therapy" significantly accelerated diabetic wound healing by modulating inflammation and oxidative stress. This novel therapy has the potential for future clinical application and could bring new hope to patients suffering from diabetic wounds.


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