Translational Research and Early Favorable Clinical Results of a Novel Polyphosphazene (Polyzene-F) Nanocoating
Translational Research and Early Favorable Clinical Results of a Novel Polyphosphazene (Polyzene-F) Nanocoating
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DOI：
10.1007/s40883-019-00097-3
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发表时间：
2019-12-01
影响因子：
2.6
通讯作者：
Kueller, Alexander
中科院分区：
文献类型：
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作者：
Bates, Mark C.;Yousaf, Ahmed;Kueller, Alexander
这份手稿是一个独特的氟化聚磷腈纳米层装置表面改性相关的临床前和早期临床研究结果的审查。Polyzene-F（PzF）是一种新型、高分子量、高纯度的聚磷腈，旨在增强医疗器械表面与人体组织或血液之间的生物界面。该聚合物还具有独特的机械性能，首次允许植入物铺设纳米级厚度< 50 nm的涂层。该涂层具有固有的抗血栓特性，并且由于有利的蛋白质粘附，在植入后不久呈现仿生特性。在过去的1.5年里，PzF经历了广泛的临床前测试，包括实验室内皮细胞迁移和血小板粘附研究，随后在16种不同的动物模型中进行了越来越复杂的评估。与不同表面以及未涂层对照相比，涂层始终显示出血小板粘附减少、凝血减少、炎症减少和愈合加速。这些临床前研究结果已转化为早期令人信服的临床证据，表明PzF涂层植入物可以实现增强愈合和减少血栓形成。现在有两种PzF纳米涂层产品获得美国食品和药物协会（FDA）批准，栓塞球体和冠状动脉支架。这是对PzF涂层的历史、临床前发现和当前临床结果的首次详细概述，重点是冠状动脉支架Cobra-PzF。在过去的几十年里，我们看到了医疗技术的显著进步，包括开发用于治疗心脏和血管疾病的微创手术替代方案。治疗或预防心脏病发作、中风和肢体丧失的关键进展之一是支架的发展。支架是一种小型的金属网状装置，可以通过腹股沟或手腕放置的小导管在阻塞的血管内扩张。这些支架在血管愈合时提供结构支撑。支架和其他永久性装置植入物的挑战之一与我们的身体如何对异物作出反应有关。支架最可怕的并发症之一是凝血，这可能导致治疗动脉的突然闭合。就心脏支架而言，突然关闭可能会导致心脏病发作甚至猝死，而颈部动脉（颈动脉）支架内的凝血可能会导致中风。其他正常的身体防御机制包括复杂的免疫反应，触发炎症，并可能导致疤痕，导致早期复发的堵塞或所谓的“再狭窄”。“为了消除再狭窄，许多支架现在都涂有减缓或阻止愈合的药物。这种方法的缺点是需要长期的血液稀释药物，如血小板和阿司匹林。在这篇文章中，我们回顾了一种新方法的历史和目前的临床发现，这种新方法可能使医疗植入物对导致后续并发症的正常异物防御反应不可见。这项创新涉及开发一种名为Polyzene-F的新化合物（CeloNova BioSciences，圣安东尼奥，TX），该化合物可以以极薄的层放置在设备表面。这种新的涂层非常薄，即使用最强的显微镜也看不见，福尔斯属于一种新的材料科学类别，称为纳米技术。纳米技术涉及在分子水平上测量的材料，而不是在医疗器械领域使用的传统测量方法。我们描述了在实验台上进行的许多实验，以及动物研究和早期临床结果，这些结果支持以下假设：使用Polyzene-F涂层的植入物预期会产生增强的生物学反应。使用这种新型涂层支架（Cobra-PzF）研究的最初类型的心脏病患者是那些出血风险高的患者，因为我们知道这些患者对血液稀释药物的耐受性较低。这个最初的狭窄焦点是根据我们团队和其他人的经验选择的，这表明动物研究并不总是预测人类对新治疗的反应，再加上药物洗脱支架每天都在变得更好。我们在已完成的Cobra-PzF临床试验中确实看到了凝血和复发（再狭窄）较低的信号，但这些研究并未在我们称之为“随机试验”的研究中直接比较该器械与替代支架。“有一项正在进行的大型随机试验，比较了Polyzene-F纳米涂层支架（Cobra PzF）与当代药物洗脱支架在高出血风险患者中的应用，该试验应在2019年完成招募。与此同时，美国FDA批准的Polyzene-F涂层微珠（Embozene，Boston Scientific，马尔伯勒，MA）正在研究用于治疗肿瘤和癌症。如果在目前批准的Polyzene-F涂层器械上进行的正在进行的随机试验中证明了增强的生物反应，则这种新的表面增强可能会更广泛地应用于各种医疗器械植入物。
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 Summary Over 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.