Customizable Electrospun Scaffolds For Sustained And Local Delivery Of Sirna In Diabetic Foot Ulcers
Amy C. Kauffman1, Alexandra S. Piotrowski-Daspit1, Themis Kyriakides2, W. Mark Saltzman1.
1Yale University, New Haven, CT, USA, 2Yale School of Medicine, New Haven, CT, USA.
BACKGROUND - Foot ulceration is the leading cause of diabetic related amputations and up to 25% of diabetic patients will develop a foot ulcer during their treatment course. Many of these ulcers fail to heal due to molecular imbalances that can be traced back to inappropriate gene expression promoted by a hyperglycemic state. Thus, treatment should be targeted to correct these local genetic imbalances at the source. Overexpression of thrombospondin-2 (THBS-2) is commonly associated with Type II diabetes. Previous studies have demonstrated accelerated wound healing in THBS-2 total knockout mice compared to control. Our aim is to deliver siRNA targeted for THBS-2 silencing via a bioresorbable scaffold at to the wound site and observe the downstream effects and accelerate healing.
METHODS - Scaffolds were fabricated via electrospinning and composed of polycaprolactone (PCL) blended with highly customizable mildly cationic terpolymers known as poly(amine-co-esters) (PACEs). Physiochemical properties (mechanical, thermal, morphological) were assessed as well as biocompatibility, siRNA loading and efficacy, and degradation.
RESULTS - Three PCL/PACE electrospun scaffold designs demonstrated appropriate tensile strength (Young modulus range 0.7-1.0 MPa), surface hydrophilicity (contact angle <30°), and thermal stability to function as a synthetic skin. All three scaffold designs supported viability of primary human dermal fibroblasts greater than 85%, loading of ~2.5 pmol of siRNA per scaffold (ø6mm, 50 μm thick) and sustained release of siRNA over more than 3 days.
CONCLUSIONS - This work demonstrated the feasibility of use of novel PCL/PACE electrospun scaffolds for sustain local delivery of siRNA in diabetic foot ulcers. Future studies will investigate in-vivo performance in both wild-type and diabetic mouse wound model.
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