BIOMED PhD Research Proposal

Title:
Modulating Macrophage Response to Biomaterials by Leveraging Biotin-Avidin Interactions

Speaker:
Victoria Nash, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Advisor:
Kara Spiller, PhD
Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Details:
Tissue regeneration is a complex series of events, driven by highly plastic immune cells: macrophages. Typically, “pro-inflammatory” macrophages act early to support angiogenesis, while later acting “pro-reparative” macrophages support newly sprouted vasculature, assisting in tissue repair. This temporal switch is crucial to prevent either chronic inflammation or fibrosis. Approaches used in biomaterials engineering to temporally influence macrophage phenotype are surface coating or encapsulation of cytokines, however these are not amenable to a variety of biomaterials. Affinity interactions, such as heparin or albumin have been leveraged for drug delivery. They rely on weak interactions, like hydrogen bonding, to retain and deliver the drug. However, these systems require specific biomaterial formulations to 1) incorporate heparin or albumin into the material and 2) provide a favorable environment for weak interactions to occur between the drug and biomaterial for drug delivery. While these systems work for small molecules and some amino acids, they are limited for cytokine delivery because weak interactions are not stable enough for effective delivery.

Biotin-avidin affinity becomes a favorable option because biotin, avidin (or its variants), can be directly conjugated to proteins, biomaterials, and even cells, without altering its bioactivity. Historically, avidin was first used as a model adjuvant, then explored as a protein carrier for adjuvants in vaccines, but modern uses of the affinity pair, biotin-avidin, range from analytical assays to targeted radioimmunotherapy. Biotin-avidin interactions are rarely used for drug release, due to biotin’s low dissociation rate from avidin (Kd = 10-15 M). However, release can be triggered by introducing free biotin to the system, promoting the release of biotinylated molecules from avidin. Yet it is not known how bioconjugation parameters can affect biotin-avidin interactions, potentially leading to controlled release profiles. Or even how biotin or avidin influence macrophage phenotype in the absence of additional cytokines. Therefore, the goal of this study is to determine how bioconjugation parameters can control biotin-avidin interactions to release a biotinylated cytokine to modulate macrophage phenotype in response to biomaterials.