|Transmission electron microscopic images show the structure of BioNanomatrix, a stent-coating material developed by Endomimetics to inhibit the proliferation of smooth muscle cells and prevent platelets from clotting.|
Cardiovascular disease is the leading cause of death in the United States today, resulting in the implantation of more than two million stents each year. However, 15 to 45% of all bare-metal stents result in restenosis, requiring follow-up procedures, while 2% of drug-eluting stents clot off over four years. As a result, approximately 45% of stent thrombosis patients die each year. Seeking to improve stent technologies, Endomimetics LLC (Birmingham, AL) has developed a stent coating material that inhibits blood-clot formation, prevents blood vessels from renarrowing, and encourages the normal arterial lining to heal.
"Stents save lives, but they carry their own risks," remarks Brigitta C. Brott, Endomimetics's chief medical officer and a practicing interventional cardiologist at the University of Alabama at Birmingham. "And although bare-metal stents have been approved by the FDA since the early 1990s, they involve the significant risk of arterial renarrowing over the six to nine months after implant." In response, drug-eluting stents were introduced in 2003. But while these devices inhibit renarrowing, they also inhibit the normal healing process and are associated with an increased risk of clotting, according to Brott. To avoid clotting, patients must take anticlotting medications--sometimes for years.
Renarrowing occurs when smooth muscle cells grow excessively and scar tissue forms over a stent, whereas clotting develops when there is inadequate healing over the stent, exposing stent struts to the blood flow. To reduce the proliferation of smooth muscle cells, Endomimetics's BioNanomatrix material releases nitric oxide over a two-month period, preventing renarrowing and clotting. A completely natural, peptide-based nanofiber, this material also encompasses cell-adhesive amino acid sequences known as YIGSR, which attract the normal endothelial cells that line the arteries, further reducing the risk of blood-clot formation by covering over the surface of the stents. Thus, the components of the nanomatrix work together to inhibit clotting, enhance healing by endothelial cells, and inhibit excessive proliferation of smooth muscle cells. "Our approach is to develop a stent material that enables the artery to heal over in an all-natural way, enabling it to create its own lining again," Brott says.
Using a water-evaporation self-assembly process, BioNanomatrix is fabricated from two separate segments that combine to form into hollow nanofibers containing a hydrophobic tail on their inner surface. The fibers' more-hydrophilic surface areas feature either YIGSR--part of the normal basement membrane of a blood vessel--or a polylysine tail, which is used to deliver nitric oxide. Through water evaporation, the material dries progressively onto the surface of the stent. During this process, the hydrophobic portions of the fibers form hollow tubes, creating many fibers several hundreds of layers thick that form a loose coating mesh on the stent surface.
Incorporated into the polylysine tail, nitric oxide enhances endothelial cell growth while significantly inhibiting the proliferation of smooth muscle cells and clotting, Brott explains. However, one of the problems with drug-eluting stents is that they incorporate a polymer for releasing nitric oxide. This polymer contains a solvent that can cause an inflammatory response. "The ability to provide sustained nitric oxide release over a two-month period without the use of solvents is really the core of BioNanomatrix technology," she adds.
To test BioNanomatrix's ability to release nitric oxide over a two- and four-week period, Endomimetics performed a pilot study in order to compare bare-metal with coated stents in rabbit iliac arteries. While the bare-metal stent induced the proliferation of smooth muscle cells, causing stent renarrowing, the BioNanomatrix-coated stent resulted in reduced narrowing with no hint of platelets or inflammatory cells, Brott notes.
"Some of the most significant findings from our in vitro testing resulted from comparing our coating with collagen--a normal component of arteries--and stainless steel--a common stent material," Brott explains. "Compared with collagen, the nitric oxide-releasing nanomatrix led to a 150-fold decrease in platelet adhesion, while compared with stainless steel, it resulted in a 47-fold reduction in platelet adhesion."
Endomimetics's objective is to make its nanofiber stent-coating material available for both drug-eluting and bare-metal coronary stents, peripheral stents, and other applications, including vascular bypass grafts, heart valves, and in-dwelling catheters. Looking ahead, Brott comments that the coating material could also benefit future biodegradable stents. "If you have a stent that degrades over time but the artery is not completely healed over, there is a risk that little pieces of the stent can float downstream. Thus, because our coating may ensure that the artery over the stent is completely healed, it is attracting the attention of stent manufacturers interested in developing biodegradable technologies."