Controlled release films and functional surfaces targeting infection, inflammation, and bleeding

Abstract

Uncontrolled bleeding and infection are leading causes of patient morbidity and mortality following traumatic injury. Traditional pressure based methods of hemorrhage management are not suitable for incompressible or complex wounds. There is increasing interest in non-pressure based hemostatic dressings; however, many of these existing dressings are not amenable for use in complex sites and are often accompanied by adverse side effects. Additionally, patients are typically administered broad-spectrum antibiotics to prevent and eliminate existing infection. The systemic overuse of antibiotics has led to a worldwide increase in drug-resistant bacteria. As an alternative to these conventional treatments, local therapeutic delivery has the potential to effectively treat cellular dysfunction while avoiding drug toxicity. This thesis focuses on developing degradable layer-by-layer (LbL) assembled multilayer films as local delivery coatings to address infection, inflammation, and bleeding. These films were engineered to deliver potent antibiotics such as vancomycin and exploratory drugs such as antimicrobial peptides, which prevent the development of drug resistant bacteria. Active films with large drug loadings and a range of drug release profiles were developed by taking advantage of film architectures, assembly techniques (spray versus dip LbL), and film component interactions. Due to the prevalence of infection and inflammation, degradable coatings for the concurrent release of antibiotics and anti-inflammatory therapeutics were also designed. These films have the potential to address a wide range of infection and inflammation requirements, from short term infection and inflammation eradication for trauma relief to infection prevention and long term inflammation mitigation from biomedical implants. All films were successfully applied to medically relevant substrates, including bandages and sutures, and were shown to be active in vitro against Staphylococcus aureus and cyclooxygenase. To address current complications with bleeding control, multilayer films were developed based on hydrogen bonding interactions found to occur between a polyphenol, tannic acid, and an essential clotting factor, thrombin. These thin films were used to coat a common clinically applied absorbent and porous gelatin sponge without reducing its liquid absorption capabilities. Coated sponges were shown to be highly effective in promoting hemostasis in a porcine spleen injury model. The therapeutic films developed in this thesis have the potential to be applied to any clinical substrate. Additionally, drug loading and release can be tuned based on the desired application.