Cyclodextrin-based Microparticle Polymer Formulations for the Slow and Sustained

描述（由申请人提供）：医疗器械失效的主要原因之一是感染。特别是腹壁疝修补术后的合成补片感染是一种常见的手术问题，没有理想的解决方案，通常需要通过昂贵的病态干预切除植入物。预防短期和长期补片感染的选择是次优的。这种情况需要一个紧急的解决方案，因为假肢普遍用于疝手术。我们的长期目标是提供一种基于亲和性的微粒制剂，能够通过局部递送治疗水平的抗生素来预防或治疗疝补片感染。本提案的目的是开发一种基于亲和性的微粒制剂，并证明其在效果上与凯斯西储大学开发的先前研究的疝补片涂层相当，后者能够预防补片感染，但作为器械涂层面临复杂的转化途径。将在感染的慢性疝修补模型中评价本研究中生成的基于亲和力的微粒制剂在长期预防和治疗补片败血症中的作用。中心假设是，与涂层补片相比，微粒制剂中抗生素的持续、长期局部递送可有效治疗和根除疝补片部位感染中涉及的常见细菌病原体。本研究的主要目的是：1）制备基于亲和性的抗生素缓释微粒，并对其进行物理和化学表征; 2）通过处理菌苔和评价疗效，验证缓释平台的体外杀菌效果;和3）通过检查聚合物涂层假体对疝修补术耐久性的影响，和评价治疗水平的抗生素从微粒的长期（30天）释放。我们提出的工作是创新的;它使用一种局部的、持续的方法来实现无感染的假体。预期结果包括一种比器械涂层具有更现实平移可能性的产品，即作为独立平台。这些结果将通过为自近50年前引入补片以来使外科护理复杂化的棘手问题提供解决方案，对普通外科领域产生积极影响。第二阶段的未来工作将把这些概念转化为其他手术放置的器械、手术部位感染和一般伤口敷料。 公共卫生相关性：该提案与公共卫生问题密切相关，因为其长期目标是提供能够通过局部递送治疗水平的抗生素来预防或治疗疝补片感染的基于亲和性的微粒制剂。短期目标是生成一种独立的微粒制剂，在植入时与疝修补补片同时使用，然后加载治疗性抗生素以治疗最常见的感染性微生物，而不影响该补片作为耐用疝修补假体充分发挥作用的能力。我们将使用凯斯西储大学开发的慢性感染小鼠模型评估递送的功效。

DESCRIPTION (provided by applicant): One of the leading causes of failure for medical devices is infection. In particular synthetic mesh infections after ventral hernia repair are a common surgical problem with no ideal solution often requiring implant excision through costly morbid interventions. Options to prevent short and long term mesh infections are suboptimal. This situation calls for an urgent solution as prosthetics are universally used in hernia surgery. Our long-term goal is to provide an affinity-based microparticle formulation capable of preventing or treating hernia mesh infections by locally delivering therapeutic levels of antibiotics. The objective of this proposal is to develop an affinity-based microparticle formulation and demonstrate that it is comparable in effect to previously investigated hernia mesh coatings developed at Case Western Reserve University, which were able to prevent mesh infections but faced a complicated translation pathway as a device coating. The affinity-based microparticle formulations generated in this study will be evaluated in the long- term prevention and treatment of mesh sepsis in an infected chronic hernia repair model. The central hypothesis is that sustained, long-term local; delivery of antibiotics from a microparticle formulation can effectively treat and eradicate common bacterial pathogens involved in hernia mesh site infections comparable to that of a coated mesh. This work will be accomplished in three aims:1) Produce affinity- based antibiotic delivery microparticles and characterize them both physically and chemically; 2) Validate the microbicidal effect of delivery platform in vitro by treating bacterial lawns and evaluating therapeutic efficacy; and 3) Demonstrate that treatment and prevention of device infection in vivo by examining effects of polymer coated prosthetics on durability of hernia repair, and evaluating long-term (30-day) release of therapeutic levels of antibiotics from the microparticles. Our proposed work is innovative; it uses a local, sustained approach to achieve an infection-free prosthetic. The expected outcomes include a product which has a more realistic translation likelihood than device coatings, namely as a stand-alone platform. These results will positively impact the field of general surgery by providing a solution to a vexing problem that has complicated surgical care since meshes were introduced nearly 50 years ago. Future work in Phase II will translate these concepts into other surgically placed devices, surgical site infections, and wound dressings in general. PUBLIC HEALTH RELEVANCE: This proposal is critically concerned with the issue of public health in that its long term goal is to provide an affinity-based microparticle formulation capable of preventing or treating hernia mesh infections by locally delivering therapeutic levels of antibiotics. The short-term goals are to generate a stand-alone microparticle formulation that will be used to concurrently with hernia repair meshes at the time of implantation and then load them with therapeutic antibiotics to treat the most prevalent infectious organisms, without impacting the capacity of that mesh to adequately perform as a durable hernia repair prosthetic. We will assess the efficacy of delivery using a chronic infection mouse model developed at Case Western Reserve University.