Cyclodextrin-based Microparticle Polymer Formulations for the Slow and Sustained

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 deliverymicroparticles 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 fieldof 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 andthen 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.