Multipotent bone marrow cell-seeded polymeric composites drive long-term, definitive urinary bladder tissue regeneration

Abstract

Abstract To date, there are no efficacious translational solutions for end-stage urinary bladder dysfunction. Current surgical strategies including urinary diversion and bladder augmentation enterocystoplasty (BAE) utilize autologous intestinal segments (e.g. ileum) to increase bladder capacity to protect renal function. Considered the standard of care, BAE is fraught with numerous short- and long-term clinical complications. Previous clinical trials employing tissue engineering approaches for bladder tissue regeneration have also been unable to translate bench-top findings into clinical practice. Major obstacles still persist which need to be overcome in order to advance tissue engineered products into the clinical arena. These include scaffold/bladder incongruencies, the acquisition and utlity of appropriate cells for anatomic and physiologic tissue recapitulation, and the choice of appropriate animal model for testing. Here we demonstrate that the elastomeric, bladder biomechanocompatible poly(1,8-octamethylene-citrate-co-octanol) (PRS; synthetic) scaffold co-seeded with autologous bone marrow-derived mesenchymal stem cells (MSCs) and CD34+ hematopoietic stem/progenitor cells (HSPCs) supports robust long-term, functional bladder tissue regeneration within the context of a clinically relevant baboon bladder augmentation model simulating bladder trauma. Partially cystectomized baboons were independently augmented with either autologous ileum or stem cell-seeded small intestinal submucosa (SIS; a commercially available biological scaffold) or PRS grafts. Stem cell synergism promoted functional tri-layer bladder tissue regeneration including whole graft neurovascularization in both cell-seeded grafts. However, PRS-augmented animals demonstrated fewer clinical complications and more advantageous tissue characterization metrics compared to ileum and SIS-augmented animals. Two-year study data demonstrate that PRS/stem cell-seeded grafts drive bladder tissue regeneration and are a suitable alternative to BAE.