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
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.