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.
