Modeling the human bladder tissue using three dimensional in vitro approaches as a tool for drug screening platforms

The main function of bladder tissue is urine accumulation and excretion, and it is composed of five layers (mucus layer, epithelial layer, lamina propria, muscular layer, and perivesical tissue). Distinct conditions can compromise morphology and function of the bladder tissue, including congenital disorders, trauma, inflammation and/or cancer. Bladder cancer (BC) is one of the most common genitourinary tract complications, being classified as non-muscle invasive BC (NMIBC) or muscle-invasive BC (MIBC). NMIBC usually affects the mucosa and submucosa of the bladder tissue, requiring tumor resection, followed by intravesical administration of mitomycin-C. MIBC commonly affects the deeper layers of bladder, being associated with the origin of metastases, and it is recommended to perform a radical cystectomy followed by cisplatin-based neoadjuvant chemotherapy. In vitro techniques have been explored as drug screening platforms to test new therapeutic regimens, specifically 3D models that are gaining more attention with a wide range of applications. These 3D structures suitably recreate morphology, complexity and function of bladder tissue or tumor microenvironment (cell-cell and cell-extracellular matrix interactions). Additionally, 3D models represent a useful tool prior to in vivo assays. Different platforms can be developed for closer resembling in vivo urothelial epithelium and bladder tumor, and therefore, for studying tissue and/or tumor morphology, drugs permeability, among others. Following these purposes, 3D bladder models are already being designed, namely spheroids, multilayer models, organ-on-chip, bioprinting, and organoids. Hence, this review aims to highlight and summarize the current advances in the development of 3D in vitro bladder models. STATEMENT OF SIGNIFICANCE: Bladder cancer is classified as NMIBC or MIBC by tissue layer involvement. NMIBC and MIBC are treated with surgery and chemotherapy accordingly. 3D in vitro models accurately mimic bladder tissue and tumor environment. Organoids, spheroids, and hydrogels are established drug screening tools. 3D models show strong potential for translation into clinical applications.