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. 2011 Mar 15;96(4):621-31.
doi: 10.1002/jbm.a.33015. Epub 2011 Jan 25.

Temporal Progression of the Host Response to Implanted Poly(ethylene Glycol)-Based Hydrogels

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Free PMC article

Temporal Progression of the Host Response to Implanted Poly(ethylene Glycol)-Based Hydrogels

Aaron D Lynn et al. J Biomed Mater Res A. .
Free PMC article

Abstract

Poly(ethylene glycol) (PEG) hydrogels hold great promise as in vivo cell carriers for tissue engineering. To ensure appropriate performance of these materials when implanted, the host response must be well understood. The objectives for this study were to characterize the temporal evolution of the foreign body reaction (FBR) to acellular PEG-based hydrogels prepared from PEG diacrylate precursors when implanted subcutaneously in immunocompentent c57bl/6 mice by (immuno)histochemical analysis and gene expression. Compared with a normal FBR elicited by silicone (SIL), PEG hydrogels without or with a cell adhesion ligand RGD elicited a strong early inflammatory response evidenced by a thick band of macrophages as early as day 2, persisting through two weeks, and by increased interleukin-1β expression. PEG-only hydrogels showed a slower, but more sustained progression of inflammation over PEG-RGD. Temporal changes in gene expression were observed in response to PEG-based materials and in general exhibited, elevated expression of inflammatory and wound healing genes in the tissues surrounding the implants, while the expression patterns were more stable in response to SIL. While a stabilized FBR was achieved with SIL and to a lesser degree with PEG-RGD, the PEG-only hydrogels had not yet stabilized after 4 weeks. In summary, PEG-only hydrogels elicit a strong early inflammatory reaction, which persists throughout the course of the implantation even as a collagenous capsule begins to form. However, the incorporation of RGD tethers partially attenuates this response within 2 weeks leading to an improved FBR to PEG-based hydrogels.

Figures

Figure 1
Figure 1
Host response to subcutaneously implanted PEG-only (a,d,g), PEG-RGD (b,e,h) and SIL (c,f,i) materials in immunocompetent c57bl/6 mice over 28 days. Tissue was stained with Masson's Trichome, which stains connective tissue blue, nuclei dark red/purple and cytoplasm red/pink. The sections were imaged with a 10× objective at day 2 (a,b,c), 14 (d,e,f) or 28 (g,h,i). * denotes location of implant. Scale bar is 500μm.
Figure 2
Figure 2
Ventral side capsule formed in response to subcutaneously implanted PEG-only (a,d,g), PEG-RGD (b,e,h) and SIL (c,f,i) disks in immunocompetent c57bl/6 mice over 28 days. Tissue was stained with Masson's Trichome, which stains connective tissue blue, nuclei dark red/purple and cytoplasm red/pink. The sections were imaged with a 40× objective at day 2 (a,b,c), 14 (d,e,f) or 28 (g,h,i). * denotes location of implant. Scale bar is 100μm.
Figure 3
Figure 3
Ventral side capsule, stained for macrophages, in response to subcutaneously implanted PEG-only (a,d,g), PEG-RGD (b,e,h) and SIL (c,f,i) disks in immunocompetent c57bl/6 mice over a 28 day study. Tissues were stained with an antibody for mac3 (brown), counter stained with methyl green, which stains the cytoplasm of cells green, and imaged with a 40× objective at day 2 (a,b,c), 14 (d,e,f) or 28 (g,h,i). * denotes location of implant. Scale bar is 100μm.
Figure 4
Figure 4
Semi-quantitative analysis of subcutaneously implanted PEG-only, PEG-RGD and SIL. Capsule thickness was measured at day 28 on both the ventral (a) and dorsal (b) side of the implanted material. The frontier layer of inflammatory cells was measured on the ventral (c) and dorsal (d) side of the implant at day 14 and 28. Symbols represent significant difference, p < 0.05, from PEG-only (*) and PEG-RGD (#) implants.
Figure 5
Figure 5
Gene expression, as measured by real-time RT-PCR, in tissues surrounding subcutaneously implanted PEG-only, PEG-RGD and SIL over 28 days. Genes were selected to represent markers of inflammation: a) Interleukin 1β, b) Interleukin 12β and c) inducible nitric oxide synthase), immunoregulation: d) Interleukin 10, and wound healing: e) arginase type I and f) vascular endothelial growth factor A. Bars represent statistical significance between time points within the same material. * - p < 0.05.

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