SELECTIVE TUNING OF BIOGELS AND ANTIBODIES TO ENHANCE TRAPPING OF PATHOGENS
Public Deposited- Creator
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Schiller, Jennifer Lee
- Affiliation: Eshelman School of Pharmacy, Pharmaceutical Sciences Program
- Abstract
- Biological hydrogels (biogels) are ubiquitous in living systems and can function as lubricant, structural support, and barrier. When creating biogels in vitro, their barrier properties can be tuned in a number of ways to exclude unwanted pathogens or particulates based on size and/or electrostatic properties. However, this form of tuning is relatively nonspecific, changes important chemical and functional properties of the biogel, is labor-intensive, and cannot be performed on a preexisting biogel in vivo. This dissertation explored an alternative to extant tuning techniques. Initially, a tunable in vitro model was developed in which third-party crosslinkers in the form of IgG and IgM antibodies were added to basement membrane, a representative biogel, specifically trapping pathogens of interest in a concentration-dependent manner. This model biogel was next used to probe the optimal kinetics of this interaction in combination with mathematical modeling techniques. The ability of freely diffusing antibodies compared to that of antibodies directly conjugated to biogel matrix to trap nanoparticles within biogel mesh were compared to scrutinize the traditional paradigm of strong matrix-antibody bonds. Antibodies participating in weak, transient interactions with the matrix promoted potent trapping of nanoparticles, while immobilized antibodies failed to trap nanoparticles at all, suggesting that the intuitively reasonable assumption that strong, long-lived Fc-matrix bonds promote more potent trapping is incorrect. Finally, the molecular mechanism of antibody-mediated was determined by probing a number of polysaccharide-based biogels with different chemical moieties. IgG and IgM antibodies, both native and glycoengineered, were used to trap nanoparticles in agarose, chitosan, and alginate biogels. These interactions revealed that hydrogen bonds between crosslinkers and biogel constituents, especially those involving a carboxyl group from either matrix constituent or antibody glycan, are essential for trapping interactions. This dissertation provides a blueprint for the design and optimization of de novo antibodies and biogels for pathogen trapping, with applications in fields such as prevention of sexually transmitted infections and wound healing.
- Date of publication
- 2019
- Keyword
- DOI
- Resource type
- Advisor
- Lai, Samuel K
- Huang, Leaf
- Anselmo, Aaron C
- Forest, Gregory
- Kuhlman, Brian A
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill Graduate School
- Graduation year
- 2020
- Language
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This work has no parents.
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