Date of Graduation

5-2015

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

Durdik, Jeannine M.

Second Committee Member

Du, Yuchun

Third Committee Member

Thallapuranam, Suresh

Fourth Committee Member

Zaharoff, David A.

Keywords

Pure sciences; Biological sciences; Health and environmental sciences; Dexamethasone; Foreign body response; Implants; Macrophage activation; Microdialysis

Abstract

The implantation of biomaterials in the body leads to a reaction known as the foreign body response (FBR) which leads to the eventual encapsulation of the biomaterial. This encapsulation proves to be detrimental to certain biomaterials, such as implanted glucose sensors, which rely on interacting with the extracellular space for proper function. Altering the FBR has become of interest in an effort to increase the longevity and integration of biomaterials. One strategy for altering the FBR is by targeting the macrophage, shown to play an important role in the FBR. In this work, the microdialysis sampling technique was used to deliver modulators to an implant site in an effort to alter the predominant macrophage activation state present. Simultaneously, analytes were collected from the same implant site to further characterize the biochemical signals present during the FBR as well as in a predominantly M2c environment. With the use of 100kDa molecular weight cut-off microdialysis membranes, it was first necessary to find a suitable perfusion fluid to use for this work which did not cause additional inflammation. An acceptable perfusion fluid was found to consist of Ringer's + 4% w/v Dextran-500 + 0.1% w/v BSA. Further, it was found that Dexamethasone-21-phosphate (Dex), when delivered immediately through the microdialysis probe, resulted in a significant increase in M2c macrophages found in the tissue surrounding the treatment. Immediate Dex administration also resulted in the significant down-regulation of CCL2 and IL-6 transcripts as well as significantly decreased CCL2 concentrations found in treatment dialysates. The delayed infusion of Dex was also investigated to determine if a different/more optimal effect was seen as compared to an immediate administration. The delayed administration of Dex resulted in a significant increase in the number of M2c macrophages in the tissue surrounding the treatment probe. Interestingly, at the transcription level, delayed Dex resulted in a significant up-regulation of IL-6. Further, CCL2 concentrations were reduced in treatment dialysates but in a pattern different from what was seen in response to immediate Dex administration. This work shows that modulators can be used to alter the macrophage activation state at a non-degradable implant site.

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