ABSTRACT
Objective To observe the host response and the expression of interleukin-4 (IL-4) in different cross-linked hyaluronic acid composite gels at different time points after the implantation in vivo, and to explore the significance of biocompatibility and macrophage polarization in post-implantation inflammatory response and tissue remodeling. Methods New Zealand white rabbits were respectively injected with crosslinked hyaluronic acid-crosslinked hydroxypropyl methylcellulose gel (sample 1), crosslinked hyaluronic acid-hydroxypropyl methylcellulose gel (sample 2) and commercially available modified sodium hyaluronate gel (control) in subcutaneous tissue at both sides of the spine. Then the rabbits were dissected at 1, 4 and 12 weeks after the implantation. The tissues were fixed with 10％formaldehyde solution, embedded in paraffin and sliced. Hematoxylin-eosin (HE) staining was performed to observe the degree of inflammation and fibrosis. Masson staining was performed to observe the formation of collagen fibers. Immunohistochemical staining was performed to observe the expression of IL-4. Results The results of HE staining showed that the inflammatory reaction in the sample 1 and sample 2 groups was significantly higher than that in the control group 1 and 4 weeks after the implantation. The inflammatory cells aggregated, and the wall of capsule and microcapsule was thick. The sample 1 group was more obvious, and the result was mild stimulation. For all the groups, the results were all non-irritating at 12 weeks after the implantation. The results of Masson staining showed that the collagen fibers in the sample 1 and sample 2 groups were increased compared with the control group, mainly distributed around the implantation site, and a small amount among the gels after 1 and 4 weeks. After 12 weeks, the collagen fibers were further increased, especially among the gels, which were consistent with the control group. The results of immunohistochemical staining showed that, at the same time point, the expression of IL-4 in sample 1 and sample 2 groups was higher than that in the control group, and the expression of IL-4 increased gradually with time. The expression of IL-4 in the control and sample 1 group at 12 weeks after the implantation was higher than that at 1 and 4 weeks respectively, and the differences were statistically significant (all P<0.05). In the sample 1 group, the expression of IL-4 at 12 weeks after the implantation was higher than that at 1 week, and the difference was statistically significant (P<0.05). The expression of IL-4 in the sample 1 group was significantly higher than that in the control group at 4 weeks after the implantation, and the difference was statistically significant (P<0.05). Conclusions The two different cross-linked sodium hyaluronate composite gels have good biocompatibility. The formation of collagen fiber and the expression of IL-4 can gradually increased within 12 weeks after the subcutaneous implantation, which is beneficial to the tissue remodeling.