Translational Research and Early Favorable Clinical Results of a Novel Polyphosphazene (Polyzene-F) Nanocoating

Abstract

This manuscript is a review of the preclinical and early clinical findings related to a unique fluorinated polyphosphazene nanolayer device surface modification. Polyzene-F (PzF) is a novel, high-molecular weight, highly pure polyphosphazene that was designed to enhance the biologic interface between a medical device surface and human tissue or blood. The polymer also has unique mechanical properties that for the first time allow implants to be paved with a coating that has a nanoscale thickness of < 50 nm. The coating has inherent thrombus resistant properties and takes on biomimetic properties soon after implant due to favorable protein adhesion. Over the last 1.5 decades, PzF has undergone extensive preclinical testing including benchtop endothelial cell migration and platelet adhesion studies followed by increasingly sophisticated evaluation in 16 different animal models. The coating consistently has shown reduced platelet adhesion, decreased clotting, reduced inflammation, and accelerated healing compared with different surfaces as well as uncoated controls. These preclinical findings have translated into early compelling clinical evidence that suggest enhanced healing and reduced thrombosis can be achieved with a PzF-coated implant. There are now two PzF nanocoated products approved by the US Food and Drug Association (FDA), embolic spheres, and a coronary stent. This is the first detailed overview of the history, preclinical findings, and current clinical results attributed to the PzF coating with emphasis on the coronary stent Cobra-PzF.Lay SummaryOver the last few decades, we have seen remarkable advances in medical technology including the development of less invasive surgical alternatives for the treatment of heart and vascular disease. One of the key advances in treating or preventing heart attack, stroke, and limb loss has been the development of stents. Stents are small, metallic, mesh-like devices that can be expanded within blocked vessels via small catheters placed through the groin or wrist. These stents provide structural support while the vessel heals. One of the challenges with stents and other permanent device implants is related to how our bodies react to foreign materials. One of the most feared complications of stents is clotting, which can result in abrupt closure of the treated artery. In the case of heart stents, abrupt closure can cause a heart attack or even sudden death whereas clotting within stents in the neck arteries (carotids) can cause stroke. Additional normal body defense mechanisms include complicated immune responses that trigger inflammation and can cause scarring resulting in early recurrence of the blockage or so-called “restenosis.” In an effort to eliminate restenosis, many stents are now coated with drugs that slow or prevent healing. The downside of this approach has been the need for long-term blood-thinning medications like Plavix and aspirin. In this article, we review the history and current clinical findings of a new way to potentially make medical implants invisible to the normal foreign body defense responses that cause subsequent complications. The innovation involves the development of a new compound called Polyzene-F (CeloNova BioSciences, San Antonio, TX) that can be placed on the surface of a device in a layer that is extremely thin. This new coating is so thin it cannot be seen with even the strongest available microscopes and falls into a new category of material science called nanotechnology. Nanotechnology involves materials that are measured on a molecular level rather than the traditional measurements used in the field of medical devices. We describe many experiments done on the benchtop alongside animal studies and early clinical results that support the hypothesis that an enhanced biologic response can be expected for implants coated with Polyzene-F. The initial types of heart disease patients being studied with this new coated stent (Cobra-PzF) are those at high risk for bleeding since we know these patients are less tolerant of blood-thinning medicine. This initial narrow focus was selected based on the experience from our team and others suggesting animal studies do not always predict how humans respond to new treatments coupled with the knowledge that drug-eluting stents are getting better each day. We do see signals in the completed Cobra-PzF clinical trials that clotting and recurrence (restenosis) are low, but these studies do not directly compare this device to alternative stents in a type of study we call a “randomized trial.” There is an ongoing large randomized trial comparing the Polyzene-F nanocoated stent (Cobra PzF) with contemporary drug-eluting stents in patients at high risk for bleeding, which should complete enrollment in 2019. At the same time, the US FDA-approved Polyzene-F-coated microbeads (Embozene, Boston Scientific, Marlborough, MA) are being studied for the treatment of tumors and cancer. If an enhanced biologic response is proven in the ongoing randomized trials being conducted on the currently approved Polyzene-F-coated devices, then this new surface enhancement may have broader application for a variety of medical device implants.