About 12 million people in the U.S., particularly those with diabetes, experience obstructed arteries in their limbs, known as critical limb ischemia, which leads to reduced blood flow to muscles and blood vessels and the potential for amputation or death. A collaborative team of researchers in the McKelvey School of Engineering at Washington University in St. Louis has proposed a novel treatment using undercover nanoparticles carrying therapeutic proteins to promote regeneration of blood vessels and muscle specifically at injured limbs.
Jianjun Guan, professor of mechanical engineering & materials science, and Fuzhong Zhang, professor of energy, environmental & chemical engineering, will develop and study this new approach in diabetic critical limb ischemia with a four-year, $2.3 million grant from the National Institutes of Health’s National Heart, Lung, and Blood Institute.
Guan, whose lab develops materials to regenerate tissues, and Zhang, whose lab develops therapeutic materials using synthetic biology, plan to combine their expertise to engineer a multifunctional protein, TRIM72, then encapsulate it into nanoparticles to regenerate the damaged tissues. It has shown for the first time that an engineered TRIM72 protein can stimulate vascularization and muscle growth in high blood sugar and ischemic conditions has been reported, said the researchers, who have been collaborating on this and other projects for several years.
“This project is trying to provide a treatment for a common but highly complicated disease,” Zhang said. “It requires integration of expertise and collaboration from multiple fields, including material design, chemistry, biology, synthetic biology and protein engineering to create and tailor the final treatment or therapeutics in a highly sophisticated way,” Zhang said.
In preliminary experiments in an animal model, they disguised the nanoparticles with platelet membrane to keep the body from clearing the nanoparticles. They targeted the affected limbs with an engineered version of TRIM72 created in Zhang’s lab. The nanoparticles, created in Guan’s lab, were given intravenously and slowly released the protein over four weeks, promoting regeneration of the blood vessels and the cells that build muscle tissue in conditions that mimicked diabetic ischemic limbs. Over time, the nanoparticles degrade and disappear, Guan said.
In the continued work, the team will continue engineering the therapeutic system and analyzing its effect on blood vessels and skeletal muscle regeneration in the animal model as well as the restored function of the affected limb.
Collaborating with Guan and Zhang on this project are Gretchen Meyer, assistant professor of physical therapy, of neurology and of orthopaedic surgery, and Mohammed Zayed, MD, PhD, associate professor of surgery and of radiology, both at Washington University School of Medicine.