Tissue Engineered Bulking Agent With Adipose-derived Stem Cells And Silk Fibroin Microspheres For The Treatment Of Intrinsic Urethral Sphincter Deficiency

Stress urinary incontinence (SUI) is defined as the involuntary leakage of urine on effort, exertion, sneezing or coughing by the International Continence Society. Intrinsic sphincter deficiency (ISD) is one of the two subtypes of SUI that due to the weakness of the urethral sphincter and exibited obvious atrophic urethral intrinsic sphincter, which is usually related to vaginal delivery injury, especially pudendal nerve damage. It brings severe symptoms of urinary incontinence and results in psychological distress, social isolation and medical care burden.Current treatment for ISD is periurethral or transurethral injection of bulking agents which usually exhibit poor long-term efficacy and are associated with complications such as haematuria, grafts migrate and implant leakage. The ideal bulking agent for ISD treatment should be durable, non-migratory, and hypoallergenic. Furthermore, it can initiate tissue regeneration, renervation and restore natural continence. Tissue engineering is a newly emerging strategy to develop a durable bulking agent for the treatment of ISD. The seeding cells and biocompatible scaffolds are two important factors for the tissue engineering strategy. Adipose-derived stem cells (ADSCs) possess great advantages for tissue regeneration due to they are abundant, could be easily isolated and cultured, and possess multi-potentials to differentiate into mesenchymal lineages. While silk fibroin microspheres is a kind of natural biomaterials that owns superior characteristics such as mechanical properties, biodegradability, biocompatibility, low inflammatory and immunogenic response comparing with other biomaterials.In our study, we combined ADSCs with silk fibroin microspheres as a novel sustainable tissue engineered bulking agent for the treatment of stress urinary incontinence caused by severe intrinsic sphincter deficiency (ISD). Silk fibroin microspheres not only play the role as an ideal carrier, they also function as artificial cushions that can improve urethral coaptation and support the bladder neck immediately after injection. Meanwhile, ADSCs possess a great potential for tissue regeneration. ISD models were established by completely transection of the bilateral pudendal nerve (PNT) and confirmed by the decreased leak-point pressure (LPP) and increased lumen area of urethra. Injection of silk fibroin microspheres could recover LPP and lumen area at4weeks but its efficacy disappears at8,12weeks. Moreover, it was exciting to find that tissue engineered bulking agent brought long-term efficacy (at4,8,12weeks post injection) on the recovery of LPP and lumen area. Concomitantly with the function, tissue engineered bulking agent treated group also improved the urethral sphincter structure as exhibited by better tissue regeneration. Taken together, the findings showed that silk fibroin microspheres alone could work.effectively in short-term, while tissue engineered bulking agent that combined silk fibroin microspheres with ADSCs exhibited promising long-term efficacy. This study developed a new strategy of tissue engineered bulking agent for future ISD therapy.