A team of researchers led by an NIBIB grantee at Vanderbilt University has created a biodegradable scaffold that enables sustained, local delivery of gene-silencing factors called siRNA to promote tissue regeneration. The team recently used the scaffold to successfully deliver siRNA to mice in order to locally silence a gene normally responsible for inhibiting blood vessel formation.
The technology could provide a new approach for the treatment of chronic wounds, which afflict over six million patients in the U.S. and cost an estimated $25 billion dollars per year to treat. Because diabetic patients are at increased risk for developing chronic wounds, these numbers are expected to rise as diabetes rates climb.
Using gene silencing to heal wounds
Blood vessels deliver important factors to wounds, such as oxygen, micronutrients, and growth factors. Studies suggest that increasing angiogenesis -the formation of new blood vessels— may help to heal wounds.
One way to enhance the development of blood vessels is through the delivery of growth factors directly to wounds; yet multiple growth factors are needed to produce mature blood vessels, and their concentration as well as the timing of their application must be carefully orchestrated to facilitate proper growth.
An alternative approach involves delivering siRNA—short, double-stranded RNA molecules designed to silence a gene of interest—to cells in order to influence genes that induce the formation of new blood vessels. While this method also ultimately results in an increase in pro-angiogenic growth factors, this approach leverages natural mechanisms in the cell that produce a symphony of related factors, initiating a robust "growth program" that induces formation of mature, stable vasculature.
Yet, delivering a sufficient amount of siRNA to cells is a notoriously difficult task, one that has prevented this therapy from being adopted clinically for wound healing.
"Many biologic drugs such as siRNA exhibit transient activity," said Craig Duvall, Ph.D., Assistant Professor of Biomedical Engineering at Vanderbilt University, who led the study. "This is especially true in sites where cells are rapidly dividing, as is the case in wounds. Every time those cells divide, the siRNA effectively gets diluted out. So, with a single dose of siRNA, you may achieve activity for only a few days."
A new technology for siRNA delivery
In a manuscript published online in December 2013 in Advanced Materials, Duvall and colleagues reported the use of a novel tissue scaffold that can deliver siRNA to nearby cells over a period of several weeks. Using an siRNA dose 10-100-fold lower than previous studies, the research team efficiently silenced the expression of PHD2—a protein that normally inhibits blood vessel formation— locally within a biodegradable tissue scaffold. At 33 days post-implant, the scaffolds that delivered PHD2 siRNA had a three-fold increase in the volume of local blood vessels.