Effects of delayed delivery of dexamethasone-21-phosphate via subcutaneous microdialysis implants on macrophage activation in rats

Abstract

Macrophage activation is of interest in the biomaterials field since macrophages with an M(Dex) characteristic phenotype, i.e., CD68+CD163+, are believed to result in improved integration of the biomaterial as well as improved tissue remodeling and increased biomaterial longevity. To facilitate delivery of a macrophage modulator, dexamethasone-21-phosphate (Dex), microdialysis probes were subcutaneously implanted in male Sprague-Dawley rats. Dex localized delivery was delayed to the third day post implantation as means to alter macrophage activation state at an implant site. To better elucidate the molecular mechanisms associated with M(Dex) macrophage activation, CCL2 was quantified in dialysates, gene expression ratios were determined from excised tissue surrounding the implant, histological analyses, and immunohistochemical analyses (CD68, CD163) were performed. Dex delayed infusion resulted in the up-regulation of IL-6 at the transcript level in the tissue in contact with the microdialysis probe and decreased CCL2 concentrations collected in dialysates. Histological analyses showed increased cellular density as compared to controls in response to Dex delayed infusion. Dex delayed infusion resulted in an increased percentage of CD68+CD163+, M(Dex), macrophages in the tissue surrounding the microdialysis probe as compared to probes that served as controls.

Porous, Dexamethasone-loaded polyurethane coatings extend performance window of implantable glucose sensors in vivo

“…Similar results were found in reports by Klueh et al where the inflammation around implanted sensor probes was diminished when Dex was locally delivered [20]. Moreover, several studies have reported on a decrease in macrophage density as a function of Dex release from indwelling microdialysis probes and osmotic pumps [36–38]. …”

In Vivo Chemical Sensors: Role of Biocompatibility on Performance and Utility

“…Keeler and coworkers examined macrophage production of chemokine (C-C motif) ligand 2 (CCL2), a pro-inflammatory chemokine, in the subcutaneous tissue surrounding microdialysis probes that released a water soluble analogue of DX (dexamethasone-21-phosphate; DXP). 9 Levels of CCL2 in the dialysate solutions were decreased for the DXP-releasing probes relative to controls at 4–6 days post-implantation, corresponding to the expected timeframe in which macrophages infiltrate the implant site. The macrophages in the tissue samples were analyzed via fluorescence immunohistochemistry for expression of CD68 and CD163 (general and M2c macrophage markers, respectively) in order to determine if altered macrophage polarization was responsible for the differences in CCL2 concentrations.…”

“…In contrast, M2a and M2c macrophages, stimulated via IL-4/IL-13 or IL-10/glucocorticoids/secosteroids respectively, are pro-angiogenic. 9,110…”

Dexamethasone-Enhanced Microdialysis and Penetration Injury

“…The time course required for altering macrophages was also examined by Stenken et al by delivering DEX through an implanted microdialysis probe in the subcutaneous space of male rats ( Keeler et al, 2015a , b ). They investigated a 3-day post-implantation time period for initiating DEX infusion.…”

“…The resulting foreign body response to the implanted microdialysis probes was examined by immunohistochemical and molecular means at the gene and protein level. The delayed delivery of DEX resulted in an upregulation of IL-6 gene transcripts as well as a moderate decrease in CCL2 concentrations ( Keeler et al, 2015a , b ). The delayed DEX treatment resulted in an increase in cellular density in the tissue surrounding the microdialysis probe.…”