DataSheet1_Drug-loaded mucoadhesive microneedle patch for the treatment of oral submucous fibrosis.docx

Oral submucous fibrosis is a chronic, inflammatory and potentially malignant oral disease. Local delivery of triamcinolone to lesion site is a commonly used therapy. The existing methods for local drug delivery include topical administration and submucosal injection. However, in the wet and dynamic oral microenvironment, these methods have drawbacks such as limited drug delivery efficiency and injection pain. Therefore, it is urgently needed to develop an alternative local drug delivery system with high efficiency and painlessness. Inspired by the structure of band-aid, this study proposed a novel double-layered mucoadhesive microneedle patch for transmucosal drug delivery. The patch consisted of a mucoadhesive silk fibroin/tannic acid top-layer and a silk fibroin microneedle under-layer. When applying the annealing condition for the medium content of β-sheets of silk fibroin, the microneedles in under-layer displayed both superior morphology and mechanical property. The mechanical strength of per needle (0.071N) was sufficient to penetrate the oral mucosa. Sequentially, the gelation efficiency of silk fibroin and tannic acid in top-layer was maximized as the weight ratio of tannic acid to silk fibroin reached 5:1. Moreover, in vitro results demonstrated the double-layered patch possessed undetectable cytotoxicity. The sustained release of triamcinolone was observed from the double-layered patch for at least 7 days. Furthermore, compared with other commercial buccal patches, the double-layered patch exhibited an enhanced wet adhesion strength of 37.74 kPa. In addition, ex vivo mucosal tissue penetration experiment confirmed that the double-layered patch could reach the lamina propria, ensuring effective drug delivery to the lesion site of oral submucous fibrosis. These results illustrate the promising potential of the drug-loaded mucoadhesive microneedle patch for the treatment of oral submucous fibrosis.

口腔黏膜下纤维化（Oral submucous fibrosis）是一种慢性、炎症性且具有潜在恶性的口腔疾病。将曲安奈德（triamcinolone）局部递送至病灶部位是该疾病的常用治疗手段。当前主流的局部给药方式包括表面给药（topical administration）与黏膜下注射（submucosal injection）。然而在湿润且动态变化的口腔微环境中，此类给药方式存在给药效率低下、注射伴随疼痛等缺陷。因此，亟需开发一种兼具高效性与无痛性的新型局部给药系统。受创可贴结构的启发，本研究提出了一种用于跨黏膜给药（transmucosal drug delivery）的新型双层黏膜粘附微针贴片（mucoadhesive microneedle patch）。该贴片由黏膜粘附性丝素蛋白（silk fibroin）/单宁酸（tannic acid）顶层与丝素蛋白微针底层构成。当针对丝素蛋白β-折叠（β-sheets）的中等含量优化退火工艺条件时，底层微针展现出优异的形貌与力学性能。单根微针的力学强度可达0.071N，足以穿透口腔黏膜。后续实验发现，当单宁酸与丝素蛋白的质量比达到5:1时，顶层的丝素蛋白与单宁酸的凝胶化效率达到峰值。此外，体外实验结果证实该双层贴片未检出细胞毒性。该双层贴片可持续释放曲安奈德至少7天。与多款商用口腔贴片相比，该双层贴片的湿粘强度提升至37.74 kPa。另外，离体黏膜组织穿透实验证实，该双层贴片可抵达固有层（lamina propria），确保药物能够有效递送至口腔黏膜下纤维化的病灶部位。上述研究结果表明，载药黏膜粘附微针贴片在口腔黏膜下纤维化的治疗中具备良好的应用潜力。