Enhancing buccal mucosa graft healing in urethroplasty: unraveling the molecular effects of two distinct therapies: low-dose radiation and low-intensity shockwave therapy

Buccal mucosa graft (BMG) urethroplasty is the gold standard for urethral stricture repair; nevertheless, graft failure remains challenging because of inadequate vascularization, excessive fibrosis and a dysregulated immune response. Low-dose ionizing radiation (LDIR) and low-intensity shockwave therapy (LiSWT) modulate angiogenesis, inflammation and tissue remodeling. However, their impact on BMG healing remains unexplored. This study aimed to assess the effects of LDIR and LiSWT applied separately on BMG integration, with a focus on vascularization, fibrosis, immune modulation and epithelial remodeling. Wistar Han IGS rats underwent urethral stricture induction followed by BMG urethroplasty. Animals were assigned to separate treatment groups receiving either LDIR (0.3 Gy) administered on postoperative days 2–5 or LiSWT (500 impulses, EFD: 0.160 mJ/mm²) applied on days 0, 7 and 14. Graft area perfusion was measured via laser Doppler imaging over time. Histology and spatial transcriptomics were performed on day 21 to assess vascularization, fibrosis, epithelial remodeling, inflammation and molecular signatures. LDIR significantly increased graft perfusion (mean + 68% and + 73% on postoperative days 7 and 14) and vessel density (mean + 81% at day 21), while both therapies markedly reduced fibrosis (mean − 68% with LDIR and − 64% with LiSWT). This study provides the first spatial transcriptomic analysis of BMG healing under LDIR or LiSWT, revealing distinct therapy-specific regenerative signatures at day 21: LDIR upregulated angiogenic pathways, whereas LiSWT primarily promoted epithelial remodeling and differentiation. Insights remain limited to the selected time point (day 21), which may not reflect the entire healing trajectory. When applied independently, LDIR and LiSWT improve BMG integration by improving vascularization and immune modulation while reducing fibrosis, addressing major causes of urethroplasty failure. Their potential as perioperative adjuncts to enhance graft survival and functional recovery, including erectile outcomes, warrants further clinical investigation.