Thursday, May 16, 2024
5/16/2024
Project Summary Biofilm, a protective extracellular-polymeric substance that surrounds bacterial colonies, is associated with more than 80% of microbial infections. In the United States, the management cost for biofilm- associated infections reaches 94 billion US dollars and is responsible for 0.5 million deaths annually. In particular, millions of wound patients suffer from biofilm-associated infections that lead to persistent inflammation and edema, and ultimately hinder wound healing. Biofilm bacteria are 1,000 times more resistant to antibiotics than free-floating bacteria. In a clinical setting, it is common to remove biofilm from the wound with debridement or enzymes. However, these methods do not remove biofilm in space deep in the wounded tissue, thus allowing biofilm recurrence. To this end, we recently invented a self-locomotive, antimicrobial micro-robot (SLAM) that can invade and remove biofilm. The SLAM is prepared by activating diatom biosilica doped with MnO2 nanocatalysts (MnO2-diatom) to generate oxygen microbubbles using a 3 % hydrogen peroxide solution. The activated MnO2-diatoms propel themselves to enter the biofilm. Within the biofilm, the activated MnO2-diatoms continue to generate microbubbles that fuse and produce mechanical energy high enough to fracture biofilm. It takes 10 minutes for the activated MnO2-diatoms to remove more than 99.9 % of 0.8 mm-thick P. aeruginosa biofilm with similar depth to full-thickness skin. No adverse toxic effects are observed after cleaning. With this success, our overall goals are to improve biofilm removal from the infected wound using SLAM and, in turn, to promote skin regeneration in the wound. We hypothesize that the activated MnO2-diatoms would detach biofilm from wounds and, in turn, increase access of antibiotics to residual biofilm bacteria. The subsequently enhanced wound disinfection would serve to improve the efficacy of regenerative medicine to skin regeneration in wounds. We will examine this hypothesis by using the vancomycin and a pair of keratinocyte growth factor (KGF)-2 and fibroblast growth factor (FGF)-2 as a model antibiotic and regenerative medicine, respectively. Our specific aims are to: (1) evaluate the efficacy of activated MnO2-diatoms to remove biofilm in wounds, (2) examine if activated MnO2- diatoms improve the efficacy of vancomycin to prevent biofilm re-growth, and (3) investigate the extent that activated MnO2-diatoms increase the KGF2/FGF2 efficacy in stimulating skin regeneration. We will conduct each aim study using the P. aeruginosa or methicillin-resistant S. aureus biofilm-infected excisional wound of male and female CD1 mice. We will assess the biofilm removal and skin regeneration in wounds using a multimodal optical imaging system through collaboration with the Boppart group with expertise in bioimaging. We will also determine the matrix metalloproteinase-9 and tissue inhibitor to metalloproteinase levels in the wound fluid, CD34+/CD45- stem cell mobilization, pro-inflammation and edema, and minimal toxicity of SLAM under guidance by Dr. Neitzel, a dermatologist. Overall, this proposed study will significantly impact efforts to treat non-healing, biofilm-infected wounds using innovative SLAMs. In the end, this study will save wound patients from disability and death.
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