In situ inflammatory-regulated drug-loaded hydrogels for promoting pelvic floor repair

Abstract

Biomedical hydrogel has been widely used as regenerative biomaterials, however, an immune inflammatory response of hydrogel constantly crops up in body due to crosslinking agent, external stimulus or small molecule residues. Here we present a strategy to treat pelvic organ prolapse (POP) by combining both anti-inflammatory and promote tissue regeneration, using drug-loaded hydrogel to reconstruct the pelvic floor and minimize multiple inflammations. Photo-crosslinked gelatin hydrogel (GelMA) loaded with Puerarin (Pue) regulate inflammation by inhibiting the aggregation of neutrophils and eosinophils, simultaneously intervene the matrix regenerating/remodeling via TGF-β/MMPs pathway to repair the fascia of pelvic floor in rabbit models (POP model). The assessment of inflammatory cytokines expression (IL-3, IL-6, TNF-α, TGF-β1) in human uterus fibroblasts (HUVs), and extracellular matrix (ECM) related factors (COL-1, COL-3, MMP2, MMP9) was performed in rabbit. Immune microenvironment was analyzed by immunohistochemistry in rabbit samples. Pue-loaded GelMA (Pue@GelMA) down regulate inflammatory cytokines (IL-3 and IL-6) and matrix metalloproteinase 2/9 (MMP 2/9), and up regulate 1/3 type collagen (COL-1/3) in vitro. In this study, Pue@GelMA was able to regulate immune microenvironment through restricting the aggregation of neutrophils and eosinophils and remodel the distribution of ECM collagen in vivo. In the POP model, Pue@GelMA can effectively inhibits the inflammatory response caused by material implanted and promote fascia regenerate. This Hydrogel drug loading system was considered as an safe and effective method to treat POP without persistent complications, and it can also be applied to other prolapse diseases (e.g., intestinal hernia) or complex diseases treatment.

Keywords: Drug delivery; Hydrogel; Inflammation; Pelvic organ prolapse; Puerarin.