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BIOMED PhD Research Proposal
Design of a Novel Reloadable Controlled Cytokine Release System To Prevent Bioprosthetic Heart Valve Failure
Emily Lurier, PhD Candidate, School of Biomedical Engineering, Science and Health System, Drexel University
Kara Spiller, Assistant Professor, PhD, School of Biomedical Engineering, Science and Health Systems, Drexel University
Heart valve disease affects approximately 5 million people in America each year due to birth defects in pediatric patients or cardiovascular disease in adults. Replacement of the diseased valve tissue is required to maintain healthy heart function. Bioprosthetic heart valves (BHVs), typically derived from bovine or porcine tissues, are used as valve replacements but can fail due to degradation and stiffening in pediatric patients as soon as 3-5 years post-implantation. The mechanism or timing by which this damage occurs is not well understood, however, macrophages, the primary cells of the inflammatory response, are hypothesized to be responsible for causing this damage.
The cascade of macrophage behavior after biomaterial implantation begins within the first day after implantation. Optimal biomaterials would first recruit M1 macrophages to remove damaged tissue, cellular debris and pathogens via phagocytosis. Then, the implant site would recruit M2 macrophages to promote tissue integration into the biomaterial. However, this transition is typically disrupted when the biomaterial elicits a chronic inflammatory response, in which the materials are degraded or encapsulated in a fibrous capsule inhibiting the biomaterial from interacting with the body. In this case, promoting an initial M2a macrophage response to the implanted biomaterial has been shown to have improved biomaterial-tissue integration in vivo.
Therefore, this project proposes to develop a novel reloadable controlled release method using the well- established conjugation system biotin and avidin with the goal of controlling the macrophage response to implanted BHVs to promote the longevity of the implant in vivo. Biotin, a small molecule, has an incredibly high affinity for avidin, a large protein with four binding sites for biotin. However, the affinity between biotin and avidin decreases when biotin is conjugated to a large protein, resulting in release of the biotinylated protein. The BHVs and an anti-inflammatory cytokine will be conjugated to biotin, and then avidin will be used to link the biotinylated molecule to the biotinylated BHV. The advantage of conjugating proteins using biotin- avidin is that there are a wide variety of commercially available biotinylation reagents and biotinylated systems can be reloaded at subsequent time points. This project will be completed by (1) determining the effects of the different macrophage phenotypes on bovine pericardium-derived BHVs, (2) developing a controlled release system using the BHVs to promote the M2a phenotype, and (3) determining the reloadability of the release system in vitro and in vivo.