Thermo-sensitive hydrogel with mussel-inspired adhesion enhanced the non-fibrotic repair effect of EGF on colonic mucosa barrier of TNBS-induced ulcerative colitis rats through macrophage polarizing

Abstract

Thermo-sensitive hydrogel is preferable to liquid enema for topical treatments of ulcerative colitis (UC). Poly (ethylene oxide)-poly (propylene oxide)-poly-(ethylene oxide) copolymer branded as Poloxamer was commonly used as thermo-sensitive hydrogel material. However, the rapid erosion and poor mucosal adhesion compromised its practical application after rectal infusion. Herein, inspiring the mussel adhesion, dihydrocaffeic acid-modified poloxamer (P-DA) was designed to overcome these drawbacks. Series of P-DA polymers were synthesized by adjusting the feeding amounts of dihydrocaffeic acid (DA). P-DA polymers with suitable DA graft degree still showed the good thermo-sensitive properties. Moreover, P-DA hydrogels displayed the tougher mechanical strength than Poloxamer 407 hydrogel at the equivalent polymer concentration. Accordingly, in vitro erosion of P-DA hydrogel was significantly delayed in pH7.4 PBS (10 mM). Moreover, the stronger tissue adhesion for P-DA hydrogels was also reached. Epidermal growth factor (EGF) as model protein was delivered by P-DA hydrogels (P-DA-EGF). The stability of EGF was obviously improved by P-DA hydrogels. Moreover, the colonic retention of P-DA hydrogels was significantly prolonged in comparison with Poloxamer 407 hydrogel, leading to a higher mucosal absorption of EGF after their rectal infusion. In vivo animal studies showed that P-DA hydrogels also significantly improved the therapeutic effect of EGF on TNBS-induced ulcerative colitis rats. The colonic morphology and function of goblet cells were obviously restored by P-DA-EGF hydrogels. Moreover, the colonic mucosal healing was not orchestrated with the colonic fibrosis. The mechanism of the colonic mucosal barrier repairing for P-DA-EGF hydrogels was highly associated with polarizing macrophages from an inflammatory (M1) to anti-inflammatory (M2) phenotype. Collectively, the designed mussel-inspired P-DA hydrogel may be a promising system for the rectal delivery of therapeutic proteins.