Adventitial Injection of Hyaluronic Acid/Sodium Alginate Hydrogel Loaded With IL-33 Antibody Decreases Neointimal Hyperplasia.

Abstract

Introduction: Neointimal hyperplasia is one of the persistent complications after vascular interventions, and is the major cause of treatment failure. Interleukin-33 (IL-33) emerges as a crucial factor in many biological processes and plays an important role in vascular diseases. Adventitial injection is catching attention for its effectiveness and fewer side effects. We hypothesize that targeting IL-33 by adventitial injection can be a therapeutic method to inhibit neointimal hyperplasia.

Method: IL-33 expression was examined in human vein graft. The hydrogel was fabricated by the interaction of hyaluronic acid, sodium alginate, and CaCO₃; and phosphate buffered saline (PBS) or IL-33 antibody or recombinant IL-33 was mixed within the hydrogel uniformly. A rat aortic wire injury-induced neointimal hyperplasia model was developed; rats were divided into three groups and received an adventitial injection of a hydrogel loaded with PBS or IL-33 antibody or recombinant IL-33 after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with PBS, IL-33 antibody, or IL-33 was also used in a mouse carotid artery ligation neointimal hyperplasia model.

Result: There was a high expression of IL-33 in human vein graft neointima. Hydrogel can be successfully injected into the aortic wall and is encapsulated by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection and was partly degraded at day 21. There was a significantly thinner neointimal thickness and less proliferation and inflammation in the IL-33 antibody group compared to the control group. On the contrary, the IL-33 group has a thicker neointima, increased proliferation, and inflammation. The mouse carotid artery ligation model showed similar results.

Conclusions: IL-33 plays a role in arterial neointimal hyperplasia in both human and rodent models; adventitial injection of hydrogel loaded with IL-33 antibody can effectively decrease neointimal thickness. Neutralizing IL-33 by IL-33 antibody may be a potential therapeutic method to inhibit intimal hyperplasia after vascular interventions.