Abstract

Healthcare-associated infections are a major global concern. Increased infections among vulnerable populations lead to millions of deaths, annually, complicated by the emergence of multi-drug resistant pathogens. These infections are often facilitated by medical devices serving as abiotic surfaces that facilitate the formation of biofilms. Notably, colonization of prostheses and other bone-associated medical devices can lead to corrective procedures, revisions and death. To address these issues, inspiration can be drawn from natural sources of bone health and defenses against infection. Cathelicidins are endogenous peptides involved in both bone maintenance and infection control. Ceragenins are small molecule mimics of cathelicidins with broad activity against critical pathogens; treatment with ceragenins has been associated with increased bone growth in limited clinical settings. We investigate the potential mechanisms by which such bone growth is induced and explore application of ceragenins to control pathogen growth around medical devices. This work examines applications of ceragenins to peripherally inserted central catheters and medical adhesives to control growth of pathogens and establishment of biofilms. Biofilm-related infections are particularly dangerous. Suspensions of ceragenin and urethane pre-polymer produced a coating on central lines capable of preventing biofilm and planktonic growth of drug-resistant pathogens for multiple weeks with protection against methicillin-resistant Staphylococcus aureus lasting over a month. Multiple adhesives were developed to protect compromised skin, including where central catheters are inserted, and lead candidates achieved forty-five days of reduction for all selected pathogens. This work also explores the development of a protective coating for titanium devices to prevent infection and increase compatibility with surrounding bone. Plasma-electrolytic oxidation generated a porous calcium phosphate layer, into which ceragenins were loaded. A poly(lactic-co-glycolic acid) suspension with additional ceragenin was added over the top to protect the underlying layers and produce more controlled ceragenin release. The resulting composite coating was protected from infection for multiple days, was protected from wear in tribological studies, and exhibited compatibility for bone integration in rats. Finally, we investigate osteogenic activation of mesenchymal stem cells by ceragenins and LL-37. Migration and proliferation were induced by both, but osteogenesis was only induced by LL-37 while ceragenins induced approximately triple the migration of LL-37. Proteomic analysis of cells undergoing treatment showed stronger activation of CAMKII, LATS1 and subsequent cytoskeletal rearranging by ceragenin CSA-131, while LL-37 activated a broader p38 and CamKII signalling. Previously observed accelerated bone growth is reconciled by ceragrenin-induced migration and compatibility with osteogenic protein BMP2.

Degree

PhD

College and Department

Computational, Mathematical, and Physical Sciences; Chemistry and Biochemistry

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2025-06-20

Document Type

Dissertation

Keywords

Ceragenin, LL-37, osteogenesis, mesenchymal stem cells, healthcare-associated infections, multi-drug resistance, phosphoproteomics, titanium, PICC lines, catheters

Language

english

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