Versatile Platform for Sustained Gene Silencing Improves Excisional Wound Healing in Diabetic Rats

Christopher E. Nelson, John R. Martin, Mukesh K. Gupta, Elizabeth J. Adolph, Fang Yu, Jeffrey M. Davidson, Scott A. Guelcher, Craig L. Duvall*

Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212, USA

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Summary
We recently developed a platform for sustained, local gene silencing based on pH-responsive, micellar, small interfering RNA (siRNA)-loaded nanoparticles (si-NPs) loaded into biodegradable, tissue inductive scaffolds. Using this platform, we demonstrated that sustained, local silencing of prolyl hydroxylase domain protein 2 (PHD2) activated hypoxia induced factor 1α (HIF1α) controlled genes and increased angiogenesis in mouse subcutaneous poly(ester urethane) (PEUR) implants. Herein, we extend this technology to a new class of biodegradable scaffolds, poly(thioketal urethanes) (PTK-URs), which are specifically degraded by cell-generated reactive oxygen species (ROS). In a diabetic rat excisional wound model, PTK-URs improved wound stenting and tissue infiltration relative to PEURs. In this same pathological wound model, PHD2 si-NP delivery from PEURs and PTK-URs improved wound site angiogenesis. These combined data demonstrate that PTK-UR scaffolds are an effective material for healing of diabetic excisional wounds by both serving as a regenerative tissue template and by providing efficient, local delivery of PHD2 si-NPs.

 

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