Nanoscale Electrostatic Assemblies for Multi-Agent Drug Delivery from

描述（由申请人提供）：对生物医学植入物涂层有强烈的需求，这种涂层可以将适当的治疗药物，包括敏感的生物药物，以精确和控制的水平输送到体内的局部区域。目前药物包被植入物的最新技术基本上局限于那些在给定时间内洗脱单一药物的植入物，通常具有基于药物成分从薄膜涂层扩散的速率或均质体聚合物降解速率的药物释放谱。在任何一种情况下，都不可能引入复杂的释放谱，例如使用标准方法的顺序释放或两种或两种以上药物；然而，在许多情况下，需要一种以上的治疗方法，并且必须在种植体生命周期的不同时间引入。此外，使用传统的可降解聚合物（如PLGA）递送pH或溶剂敏感的重组蛋白药物或植入物应用所需的生长因子要困难得多，这可能会使药物暴露在低pH和恶劣的加工条件下。这项工作的主要目的是利用静电多层组装的纳米制造工具，通过将药物与可降解多离子交替使用，每次创建一个纳米级的涂层，从而使药物以一层接一层的方式从植入物表面进行复杂的、多组分的、顺序的或分级的释放。该方法简单，成本低，并且允许使用替代静电组装过程无限调整膜成分，从而使膜在生物条件下降解，一次释放一系列药物层。具体目标包括控制可降解多离子的组成，多层膜的组装条件，以及操纵薄膜的纳米级结构，以确保与薄膜的构建相反的顺序输送。体外细胞培养研究抗菌药物和生长因子的释放将用于确定这些系统的功效和最佳剂量水平。动物模型，包括小动物大规模兔研究，将用于确定抗菌、生长因子和2或3种药物组合涂层的功效。一个能更好地复制人类骨骼力学的大型动物山羊模型将在最有前途的纳米涂层上进行。保存敏感的生物药物疗效将是这些研究的关键。这种新方法有几个重要的高冲击应用，包括支架，缝合线，骨和其他外科植入物的涂层。这项工作的重点将放在骨科植入物上，在这个领域，多种治疗方法的控制递送可以消除额外的手术，促进快速愈合。我们将研究用治疗量的抗生素、血管生成因子和骨形态发生生长因子来涂覆假体，它们可以依次释放，分别使关节区消毒、骨愈合和生长。植入物上高度可控的被动涂层的概念在商业上是可行的，并且具有破坏性，并且有望在分子水平上控制设备表面的输送，这将导致许多植入设备的更广泛应用。

DESCRIPTION (provided by applicant): There is a strong need for biomedical implant coatings which can act to deliver the appropriate therapeutics, including sensitive biologic drugs, to localized areas in the body with a level of precision and control. The current state-of-art for drug-coated implants is essentially limited to those which elute a single drug over a given time period, usually with a drug release profile based on the rate of diffusion of the drug component from the thin film coating or the rate of degradation of a homogeneous bulk polymer. In either case, it is not possible to introduce complex release profiles such as the sequential release or two or more drugs utilizing standard methods; yet there are many situations in which more than one therapeutic is needed, and must be introduced at different times during the lifetime of the implant. Furthermore, it is considerably more difficult to deliver pH or solvent sensitive recombinant protein drugs or growth factors often needed for implant applications using traditional degradable polymers such as PLGA, which can expose the drug to low pH and harsh processing conditions. The primary aim of this work is to utilize the enabling nanofabrication tool of electrostatic multilayer assembly to create coatings one nanoscale layer at a time by alternating drugs with degradable polyions such that complex, multicomponent, sequential or graduated release of drugs takes place from implant surfaces in a layer-by-layer fashion. This method is simple, low cost, and allows infinite tuning of film composition using an alternate electrostatic assembly process, resulting in films that degrade under biological conditions to release series of drugs layers at a time. Specific Aims include the control of degradable polyion composition, multilayer film assembly conditions, and manipulation of nanometer scale structure of the thin films to ensure delivery in inverse order to construction of the film. In vitro cell culture studies of release of antibacterial agents and growth factors will be used to determine efficacy and optimal dose levels of these systems. Animal models that include a small animal large scale rabbit study will be used to determine efficacy of antibacterial, growth factor, and combination coatings that delivery 2 or 3 agents will be performed. A large animal goat model that better replicates human bone mechanics will be performed on the most promising nanoscale coatings. Preservation of sensitive biologic drug efficacy will be key to these studies. This novel approach has several important high- impact applications, including coatings of stents, sutures, bone and other surgical implants. The focus of this work will be on orthopedic implants, an area where the controlled delivery of multiple therapeutics could eliminate additional surgeries and promote rapid healing. We will investigate the coating of prostheses with therapeutic quantities of antibiotics, angipgenic factors, and bone morphogenetic growth factors that can be released sequentially to enable disinfection of the joint area, bone healing and growth respectively. The concept of highly controlled, passive coatings on implants is both commercially feasible and disruptive, and promises molecular level control of delivery from the device surface, which should lead to broader applications for a number of implant devices.