ABSTRACT
The problematic combination of a rising prevalence of skin and soft tissue infections and the growing rate of life-threatening antibiotic resistant infections presents an urgent, unmet need for the healthcare industry. These evolutionary resistances originate from mutations in the bacterial cell walls which prevent effective diffusion of antibiotics. Gram-negative bacteria are of special consideration due to the natural resistance to many common antibiotics due to the unique bilayer structure of the cell wall. The system developed here provides one solution to this problem through a wearable therapy that delivers and utilizes gaseous ozone as an adjunct therapy with topical antibiotics through a novel dressing with drug-eluting nanofibers (NFs). This technology drastically increases the sensitivity of Gram-negative bacteria to common antibiotics by using oxidative ozone to bypass resistances created by the bacterial cell wall. To enable simple and effective application of adjunct therapy, ozone delivery and topical antibiotics have been integrated into a single application patch. The drug delivery NFs are generated via electrospinning in a fast-dissolve PVA mat without inducing decreasing gas permeability of the dressing. A systematic study found ozone generation at 4 mg/h provided optimal ozone levels for high antimicrobial performance with minimal cytotoxicity. This ozone treatment was used with adjunct therapy delivered by the system in vitro. Results showed complete eradication of Gram-negative bacteria with ozone and antibiotics typically used only for Gram-positive bacteria, which showed the strength of ozone as an enabling adjunct treatment option to sensitize bacteria strains to otherwise ineffective antibiotics. Furthermore, the treatment is shown through biocompatibility testing to exhibit no cytotoxic effect on human fibroblast cells.
Subject(s)
Gram-Negative Bacterial Infections , Ozone , Wearable Electronic Devices , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Gram-Negative Bacteria , Gram-Negative Bacterial Infections/microbiology , Humans , Microbial Sensitivity Tests , Ozone/pharmacology , Ozone/therapeutic useABSTRACT
Although serum and fecal biomarkers (e.g., lactoferrin, and calprotectin) have been used in management and distinction between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), none are proven to be a differential diagnostic tool between Crohn's disease (CD) and ulcerative colitis (UC). The main challenge with laboratory-based biomarkers in the stool test is the inability to indicate the location of the disease/inflammation in the gastrointestinal (GI) tract due to the homogenous nature of the collected fecal sample. For the first time, we have designed and developed a battery-free smart capsule that will allow targeted sampling of inflammatory biomarkers inside the gut lumen of the small intestine. The capsule is designed to provide a simple and non-invasive complementary tool to fecal biomarker analysis to differentiate the type of IBD by pinpointing the site of inflammatory biomarkers secretion (e.g., small or large bowel) throughout the GI tract. The capsule takes advantage of the rapid change from an acidic environment in the stomach to higher pH levels in the small intestine to dissolve a pH-sensitive polymeric coating as a means to activate the sampling process of the capsule within the small intestine. A swelling polyacrylamide hydrogel is placed inside the capsule as a milieu to collect the sampled GI fluid while also providing the required mechanical actuation to close the capsule once the sampling is completed. The hydrogel component along with the collected GI fluid can be easily obtained from the capsule through the screw-cap design for further extraction and analysis. As a proof of concept, the capsule's performance in sampling and extraction of bovine serum albumin (BSA) and calprotectin - a key biomarker of inflammation - was assessed within the physiologically relevant ranges. The ratio of extracted biomarkers relative to that in the initial sampling environment remained constant (â¼3%) and independent of the sampling matrix in both in vitro and ex vivo studies. It is believed that the demonstrated technology will provide immediate impact in more effective IBD type differential diagnostic and treatment strategies by providing a non-invasive assessment of inflammation biomarkers profile throughout the digestive tract.