Nanoscale Electrostatic Assemblies for Multi-Agent Drug Delivery from

描述(申请人提供)：生物医学植入涂层有强烈的需求，可以提供适当的治疗方法，包括敏感的生物药物，在一定程度上精确和可控的身体局部区域。目前药物包衣植入物的技术水平基本上限于在给定时间段内洗脱单一药物的植入物，通常具有基于药物成分从薄膜包衣的扩散速率或均质本体聚合物的降解速率的药物释放曲线。在任何一种情况下，都不可能引入复杂的释放曲线，如顺序释放或使用标准方法的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，并且必须在植入物寿命期间的不同时间引入。此外，使用传统的可降解聚合物(如PLGA)提供植入应用通常需要的对pH或溶剂敏感的重组蛋白药物或生长因子的难度要大得多，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的聚离子交替使用，一次一层地创建涂层，以便以逐层方式从植入物表面进行复杂的、多组分的、顺序的或分级的药物释放。这种方法简单、成本低，并允许使用交替的静电组装过程对薄膜成分进行无限调整，从而导致在生物条件下降解的薄膜一次释放一系列药物层。具体目标包括控制可降解的聚离子组成、多层膜的组装条件，以及操纵薄膜的纳米级结构，以确保以与薄膜构造相反的顺序输送。在体外细胞培养研究中，抗菌剂和生长因子的释放将被用于确定这些系统的有效性和最佳剂量水平。动物模型，包括小动物大规模的兔子研究，将被用来确定抗菌、生长因子和复合涂层的有效性，这些涂层将提供2到3种制剂。一个更好地复制人类骨骼力学的大型动物山羊模型将在最有希望的纳米级涂层上进行。保存敏感的生物药物疗效将是这些研究的关键。这种新的方法有几个重要的高影响应用，包括涂层支架，缝合线，骨和其他外科植入物。这项工作的重点将是骨科植入物，在这个领域，多种疗法的受控交付可以消除额外的手术并促进快速愈合。我们将研究在假体表面涂覆治疗量的抗生素、血管生成因子和骨形态生长因子，这些因子可以按顺序释放，分别用于关节区域的消毒、骨的愈合和生长。在植入物上进行高度受控的被动涂层的概念在商业上是可行的，也是具有颠覆性的，并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.