Description
- Abstract:
- Antibiotic resistance and the emergence of multidrug resistant bacteria poses a great public health threat and complicates treatment of infections. One of the most impactful mechanisms of bacterial resistance is the production of β-lactamase enzymes; these enzymes are produced by a broad range of bacteria and hydrolyze the β-lactam ring in commonly prescribed antibiotics, thus thwarting their efficacy. In this work, we developed hydrogels that macroscopically degrade in the presence of β-lactamases and β-lactamase-producing bacteria to serve as a platform for bacteria-triggered drug delivery. Within the hydrogel backbone is a β-lactamase-cleavable crosslinker which was functionalized on both ends with maleimides that undergo Michael-type addition with thiol-terminated, multiarm poly(ethylene glycol) macromers. The responsive behavior of these hydrogels was demonstrated in vitro in solutions of β-lactamases and β-lactamase-producing bacteria and in an ex vivo infected porcine skin model. To model controlled release of encapsulated cargo, fluorescent polystyrene nanoparticles were incorporated into the hydrogel. We observed highly linearly correlated degradation and nanoparticle release kinetics, thus demonstrating a bacteria-responsive, controlled release mechanism of our hydrogel platform technology. Non-responsive hydrogels lacking the β-lactam crosslinker remained stable in β-lactamases and β-lactamase-producing bacteria and exhibited no nanoparticle release. Altogether, these bacteria-responsive hydrogels have the potential to be used for site-specific, on-demand delivery of encapsulated antibacterial therapeutics to provide effective treatment, reduce harmful off-site toxicity, and potentially mitigate further antibiotic resistance development.
- Notes:
- Thesis (Sc. M.)--Brown University, 2023
Citation
LaRose, Cassi,
"β-Lactamase-Degradable Biomaterials for the Controlled Release of Therapeutics"
(2023).
Engineering Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:m8b5xxmb/
