Mucoadhesive drug delivery system for oral submucous fibrosis in three-dimensional multicellular and in vivo models: novel approach towards translational therapeutics

Abstract

Objective

This study aimed to develop and evaluate protease enzyme-based mucoadhesive buccal patches—Patch B (bromelain alone) and Patch C (bromelain with collagenase)—for the non-invasive management of Oral Submucous Fibrosis (OSMF).

Study design

The physicochemical properties, enzymatic activity, and therapeutic efficacy of the patches were analyzed. Arecoline was used to induce fibrosis and inflammation in a 3D co-culture model of KB-3–1 oral cancer cells and McCoy fibroblasts, mimicking the OSMF microenvironment. An OSMF-induced rabbit model was used to assess clinical outcomes.

Results

Patch B (pH 6.8–7.03) and Patch C (pH 5.92–6.98) exhibited rapid hydration and equilibrium swelling. Patch C showed enhanced collagen degradation due to synergistic enzymatic activity, while Patch B had superior biocompatibility (0.57 % haemolysis) and retained bromelain activity after six months. In the 3D co-culture model, arecoline-induced upregulation of MMP-2, MMP-9, IL-6, and collagen type IV was significantly downregulated by both patches, demonstrating their anti-inflammatory and anti-fibrotic potential. In vivo, the patches improved mouth opening and reduced the severity of fibrosis, as confirmed by histopathological analysis, which showed significant reductions in collagen deposition. Patch B demonstrated selective cytotoxicity toward cancer cells, with minimal impact on normal fibroblasts.

Conclusion

Bromelain-based buccal patches provide a targeted, non-invasive therapeutic approach for OSMF by reducing fibrosis and inflammation while minimizing systemic effects. Due to their effectiveness and safety profile in preclinical animals, these patches provide significant translational potential for future human clinical trials and non-surgical therapy of OSMF.