MMP-2 Responsive Functional Bladder Acellular Matrix Scaffold Combined With Urine Derived Stem Cells for Bladder Nerve Regeneration.

The inadequate nerve networks in regenerated bladders remain a significant challenge in bladder tissue engineering. Our previous studies have demonstrated that incorporating basic fibroblast growth factor (bFGF) and urine-derived stem cells (USCs) into bladder acellular matrix (BAM) enhances bladder repair. While these approaches have shown promising results in regenerating bladder epithelium and smooth muscle, the outcomes of neural regeneration are still not satisfactory. Therefore, this study introduces the 1-14aa sequence from the NGF polypeptide (NMP), a small molecule NGF peptidomimetic, which could improve neural regeneration in the body. Utilizing the tissue inhibitors of metalloproteinases (TIMP) that is cleaved by MMP-2 to design an MMP-2 responsive NMP delivery system, which could control the release of NMP according to the amount of MMP-2 in the local microenvironment. By chemical cross-linking, NMP-TIMP and bFGF were conjugated with BAM seeded with USCs to compose BAM/USCs/bFGF/NMP-TIMP functional biomaterial. Using a rat bladder reconstruction model, the functional biomaterial significantly enhanced the regeneration of endothelial cells, capillaries, smooth muscle cells, nerve fibers, and the bladder functions. In summary, the BAM/USCs/bFGF/NMP-TIMP functional biomaterial may offer a promising strategy for tissue-engineered bladder by promoting bladder regeneration, especially the regeneration of bladder nerves.