A theranostic ultrasound approach to improve chronic wound treatment using phase-change contrast agents

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ABSTRACT Chronic wounds are a growing public health threat, with over 6.5 million people affected in the US alone, costing upwards of $30 billion annually. The single-most-important cause of delayed wound healing is bacterial infection, often in the form of biofilms that impede antibiotic penetration and force the bacteria into a “dormant” state where they are more tolerant to antibiotics. Antibiotics work so poorly against biofilm-infected wounds due to 1) poor drug penetration and 2) the presence of drug-tolerant persister cells within biofilms. These factors contribute to a 70% infection recurrence rate. Failure to completely eradicate biofilms during antibiotic therapy can result in significant quality-of-life reduction, hospitalization, sepsis, amputation and death. Comorbidities such as diabetes and cardiovascular disease further complicate therapeutic strategies. Every day in the US, 230 patients suffer an amputation due to a chronic wound infection, the majority due to diabetic foot infections. There is an urgent need for improved wound care therapies but with the void in the drug- development platform, innovation is mostly centered around wound closure rather than improving antibiotic efficacy. Recently, the technology of acoustically active cavitation agents, microbubbles and phase-change contrast agents (PCCA), for ultrasound-mediated drug delivery has made several substantial advances and is currently in clinical trials for other applications. In this proposal, we will develop a non-invasive theranostic ultrasound platform to improve delivery of anti-persister drugs into biofilm-infected wounds. Our encouraging preliminary data in an in vivo diabetic mouse model observed improved traditional therapeutic clearance of MRSA biofilms by 94% in chronic wounds using a topical-only approach. Importantly, we achieved complete eradication (below limit of detection) in 3 out of 8 animals. In this project, we propose to optimize the efficacy of our acoustically responsive biocompatible particles and therapeutic ultrasound parameters to potentiate various antibiotics against biofilms of the most common pathogens in chronic wound infections (Staphylococcus aureus, Pseudomonas aeruginosa and Enterococcus faecalis) in vitro, in conjunction with investigating mechanisms of action by quantifying therapeutic penetration and cavitation activity in vitro (specific aim 1). We will then evaluate this approach in a polymicrobial diabetic chronic wound infection model (specific aim 2). For this, we will focus on Pseudomonas aeruginosa and Staphylococcus aureus, the two organisms that most commonly co-infect chronic wounds. Measures of wound healing, wound closure and reduction in bacterial burden will be quantified and benchmarked against current standard of care systemic antibiotic administration, where cavitation activity will also be evaluated for its ability to predict early response to therapy. Our proposed approach has the potential to have a substantial impact on the treatment of polymicrobial biofilms in chronic wounds.