Electronic Theses and Dissertations Archive

Date

2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biomedical Engineering

Committee Chair

Gary Bowlin

Committee Member

Isaac Rodriguez

Committee Member

Marie van der Merwe

Committee Member

Marko Radic

Abstract

Neutrophils, key mediators of the acute host response to implanted biomaterials, engage in inflammatory signaling, form neutrophil extracellular traps (NETs), and generate reactive oxygen species (ROS). Upon contact with foreign materials, neutrophils release pro-inflammatory cytokines and chemokines that recruit additional immune cells and promote pro-inflammatory phenotypes in neutrophils and macrophages. Neutrophils may also undergo NETosis, a process involving the release of chromatin-based NETs to sequester and degrade foreign material. In excess, NET formation can impede tissue integration by physically isolating biomaterial surfaces while amplifying inflammation through the release of degradative enzymes and inflammatory mediators. Neutrophil-derived ROS contribute to oxidative stress at the biomaterial interface. Although essential for antimicrobial defense, dysregulation following biomaterial implantation can lead to sustained acute inflammation and impaired implant performance. The overall goal of this dissertation was to build upon prior observations that whole Manuka honey modulates neutrophil inflammatory behavior and to identify specific honey-derived compounds responsible for these effects. We hypothesized that pinobanksin, pinocembrin, chrysin, and methyl syringate would attenuate neutrophil inflammatory signaling, NET formation, and ROS production in response to pro-inflammatory stimuli. Additionally, we investigated whether these compounds act synergistically within whole Manuka honey or exhibit enhanced activity when administered individually at optimized concentrations. To address these aims, high-throughput in vitro assays were developed using HL60 cell models to screen candidate compounds and establish proof of concept. These studies identified methyl syringate as a consistent modulator of NETosis. Subsequent experiments using isolated primary human neutrophils validated the HL60 model and demonstrated that methyl syringate reduced NET formation and intracellular ROS activity. Multiplex ELISA analysis of neutrophil supernatants revealed that both whole Manuka honey and methyl syringate reduced the release of pro-inflammatory cytokines, while methyl syringate preserved the secretion of pro-angiogenic growth factors and enzymes associated with tissue remodeling. Finally, these findings were translated to a biomaterial context by incorporating Manuka honey into small-diameter polymeric vascular grafts using a novel touch-spinning fabrication technique. The resulting grafts retained mechanical properties comparable to native vasculature and preserved Manuka honey’s ability to reduce neutrophil NETosis, supporting their use in mitigating acute inflammation at the biomaterial–tissue interface.

Comments

Data is provided by the student.

Library Comment

Dissertation or thesis originally submitted to ProQuest/Clarivate.

Notes

Open Access

Download

Share

COinS