Nanoscale Electrostatic Assemblies for Multi-Agent Drug Delivery from

描述（由申请人提供）：迫切需要生物医学植入物涂层，其可以用于以一定的精度和控制水平将适当的治疗剂（包括敏感的生物药物）递送到体内的局部区域。药物涂层植入物的当前技术水平基本上限于在给定时间段内包埋单一药物的植入物，通常具有基于药物组分从薄膜涂层的扩散速率或均匀本体聚合物的降解速率的药物释放曲线。在任一种情况下，都不可能引入复杂的释放曲线，例如使用标准方法的顺序释放或两种或更多种药物;然而，在许多情况下，需要一种以上的治疗剂，并且必须在植入物的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递送植入物应用经常需要的pH或溶剂敏感性重组蛋白药物或生长因子要困难得多，这会使药物暴露于低pH和苛刻的加工条件。这项工作的主要目的是利用静电多层组装的纳米纤维工具，通过交替药物与可降解的聚离子，使复杂的，多组分的，顺序的或渐进的药物释放发生在植入物表面的一层一层的方式来创建涂层一个纳米级层。该方法简单、成本低，并且允许使用交替的静电组装过程无限调节膜组成，从而产生在生物条件下降解以一次释放一系列药物层的膜。具体目标包括控制可降解聚离子组合物、多层膜组装条件和操纵薄膜的纳米级结构以确保以与膜的构造相反的顺序递送。将使用体外细胞培养研究释放抗菌剂和生长因子，以确定这些系统的有效性和最佳剂量水平。将使用包括小动物大规模家兔研究的动物模型来确定抗菌剂、生长因子和组合涂层的功效，其中将进行2种或3种药剂的递送。一个更好地复制人类骨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。保持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影响力的应用，包括涂层的支架，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，多种治疗剂的控制输送可以消除额外的手术并促进快速愈合。我们将研究使用治疗量的抗生素、血管生成因子和骨形态发生生长因子的假体涂层，这些因子可以依次释放，以分别实现关节区域的消毒、骨愈合和生长。植入物上高度受控的被动涂层的概念在商业上是可行的，并且具有破坏性，并且承诺从装置表面递送的分子水平控制，这将导致许多植入装置的更广泛应用。

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.