Delivery Of mIR Through Biodegradable Scaffolds
Mohamed M. Ibrahim, MD1, Michael Ogilvie, MD1, Junquan Lin, BS2, Huajia Diao, PhD2, Ulla Milbreta, PhD2, Hongyan Long, B.Eng2, Sing Yian Chew, PhD2, Howard Levinson, MD1.
1Duke University Medical Center, Durham, NC, USA, 2School of Chemical & Biomedical Engineering, Nanyang Technological University, Singapore, Singapore.
In severe burns, around 40% patients develop hypertrophic scar contractures (HSc). HSc develop over 6-months and costs millions of dollars-annually. HSc are caused by myofibroblasts. MicroRNAs have emerged as key regulators in skin fibrosis and several candidate miRs (let7c and miR124) have been found to regulate myofibroblast differentiation.
We created biodegradable miR delivery scaffolds from poly(CL-co-ethyl ethylene phosphate)(PCLEEP). PCLEEP scaffolds were imaged by scanning electron microscopy. Release kinetics of siRNA were studied. Four groups of scaffolds were implanted in rodents: 1)Scaffolds without miR, 2)Negative scrambled miRs, 3)Scaffolds with 5µg miR-124, and 4)Scaffolds with 5µg let-7c. Explants from rodents were stained with Masson’s trichrome. Fibrous capsules around scaffolds were quantified and graphed
SEM analysis demonstrated a fiber diameter ranging from.3-2 µm. Drug release kinetic studies demonstrated the scaffolds elute miR up to 30 days. Rodent experiments demonstrated that scaffolds incorporate without evidence of extrusion or toxicity. In mice, scaffolds loaded with let7c showed the least capsular-formation, followed by miR124 and anti-let7c. In rats, scaffolds loaded with miR124 demonstrated the smallest capsular thickness followed by let7c and anti-let7c.(*P<0.05)
PCLEEP scaffolds are bioincorporated and useful for drug delivery. Animal experiments with miR loaded PCLEEP scaffolds showed reduction in fibrosis. Ongoing investigations will include analysis of myofibroblast formation, as well as temporal analysis of the inflammatory response.
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