Date of Graduation

8-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Cell & Molecular Biology

Advisor/Mentor

Stenken, Julie A.

Committee Member

Paul, David W.

Second Committee Member

Durdik, Jeannine M.

Third Committee Member

Muldoon, Timothy J.

Fourth Committee Member

Du, Yuchun

Keywords

Biomaterials; Cytokines; Dexamethasone; Iloprost; Macrophage activation; Sponges

Abstract

Altering the foreign body reaction by targeting macrophages has been of interest in the biomaterials field to improve the integration of longevity of implanted biomedical devices. The objective of this dissertation was to study the effect of locally delivered bioactive modulators on macrophage activation at the implantation site of different biomaterials in rats. Iloprost, a prostacyclin analog, was tested for its ability to direct macrophages to their pro-wound healing phenotype after the implantation of microdialysis probe in the subcutaneous space of male Sprague Dawley rats. This study showed that iloprost can shift macrophage activation states in vivo to the pro-wound healing phenotype and decrease the levels of the pro-inflammatory chemokine (CCL2) at two days post implantation. It also demonstrated the need of more experiments to confirm iloprost effect in shifting macrophage activation to their CD163+CD68+ pro-wound healing phenotype at a longer time point than two days post implantation.

To achieve this goal, iloprost was studied for its ability to modulate macrophages to their pro-wound healing, pro-tissue remodeling phenotype at 7 days post implantation time point, after the implantation of the PVA sponges and compared to dexamethasone effect on macrophage activation. This project focused on assessing macrophage activation caused by implanted polyvinyl alcohol non-biodegradable vs. collagen biodegradable sponges in the subcutaneous space of male Sprague Dawley rats. Like dexamethasone, iloprost was able to shift the macrophage to their CD163+CD68+ pro-wound healing phenotype and decreased the levels of CCL2 found in the collected wound fluid from the explanted sponges. Additionally, iloprost administration significantly decreased the number of infiltrating cells around PVA sponge.

Once the ability of iloprost to modulate the macrophages phenotype was confirmed, a material-based study was designed to compare macrophage activation caused by implanted polyvinyl alcohol non-biodegradable vs. collagen biodegradable sponges in the subcutaneous space of male Sprague Dawley rats. Collagen scaffolds, isolated from the same rat strain, were synthesized and implanted subcutaneously to perform this study. The administration of iloprost and dexamethasone lead to a decrease in the levels of pro-inflammatory CCL2, and an increase in the population of CD163+CD68+ in both sponge models compared to their correspondent control sponges. Although, the levels of CCL2 in the wound fluid collected from the collagen control sponges were significantly less those collected from the PVA sponges, both materials initiated an inflammatory response cascade that was similar in terms of collagen distribution, and CD163+CD68+ macrophages around the implant.

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