Hemiaminal hydrogel-manganese nanoparticle hybrids boost healing of penetrating orocutaneous fistulas through microenvironmental regulation.

Abstract

Penetrating orocutaneous and oropharyngeal fistulas (POFs) are difficult to treat due to continuous oral muscle movement and saliva leakage, and persistent bacterial infection and inflammation in the oral environment. However, healing biomaterials that can simultaneously block the penetrating wound, exert antibacterial and anti-inflammatory effects and degrade timely to accommodate fistula closure are rarely reported. Here, we report an organic-inorganic hybrid hydrogel termed MPMQb@gel, which exhibits robust mechanical strength, flexibility, and adhesion ability, enabling effective POF blockage. It consists of hemiaminal structure-containing polymeric hydrogel and Mn-polydopamine nanoparticles cross-linked via aldehyde-amine condensation. Triggered by excessive reactive oxygen species (ROS) in the POF microenvironment, MPMQb@gel gradually degrades and releases Mn²⁺, quercetin (Que), and basic fibroblast growth factor (bFGF) to achieve synergistic antibacterial, anti-inflammatory and pro-healing effects. In a New Zealand rabbit model of severe POF infection, this hybrid hydrogel realized complete POF healing within 12 days with administration every 4 days, markedly faster than commercial iodoform gauze-treated group. RNA sequencing and mechanistic analysis reveal that MPMQb@gel suppresses Th1 and Th17 cell differentiation, inhibit the Th17/IL-17-associated signaling axis and modulate the TLR2/STAT3 pathway to promote a stable immune microenvironment, thereby attenuating the inflammatory response and ultimately promoting POF repair. Collectively, by addressing the critical challenge of reconciling wound contraction with the requirement for durable occlusion through a controllably biodegradable organic-inorganic hybrid hydrogel, this work offers a transformative therapeutic strategy for POFs and penetrating wounds.