RESUMO
Chronic bladder dysfunction due to bladder disease or trauma is detrimental to affected patients as it can lead to increased risk of upper urinary tract dysfunction. Current treatment options include surgical intervention that enlarge the bladder with autologous bowel tissue to alleviate pressure on the upper urinary tract. This highly invasive procedure, termed bladder augmentation enterocystoplasty (BAE), significantly increases risk of patient morbidity and mortality due to the incompatibility between the bowel and bladder tissue. Therefore, patients would significantly benefit from an alternative treatment strategy that can regenerate healthy tissue and restore overall bladder function. Previous research has demonstrated the potential of citrate-based scaffolds co-seeded with bone marrow-derived stem/progenitor cells as an alternative graft for bladder augmentation. Recognizing that contact guidance is known to influence tissue regeneration, we hypothesized that patterned scaffolds would modulate cell responses and improve overall quality of the regenerated bladder tissue. We fabricated microgrooved (MG) scaffolds using citrate-based biomaterial poly(1,8-octamethylene-citrate-co-octanol) (POCO) and co-seeded them with human bone marrow derived mesenchymal stem cells (MSCs) and CD34+ hematopoietic stem/progenitor cells (HSPCs). Microgrooved POCO scaffolds supported MSC and HSPC attachment, and MSC alignment within the microgrooves. All scaffolds were characterized and assessed for bladder tissue regeneration in an established nude rat bladder augmentation model. In all cases, normal physiological function was maintained post-augmentation, even without the presence of stem/progenitor cells. Urodynamic testing at 4-weeks post-augmentation for all experimental groups demonstrated that capacity increased and compliance was normal. Histological evaluation of the regenerated tissue revealed that cell-seeded scaffolds restored normal bladder smooth muscle content and resulted in increased revascularization and peripheral nerve regeneration. The presence of microgrooves on the cell-seeded scaffolds increased microvasculature formation by 20% and urothelium layer thickness by 25% in the regenerating tissue. Thus, this work demonstrates that micropatterning affects bladder regeneration to improve overall anatomical structure and re-establish bladder physiology.
RESUMO
Urinary bladder insult can be caused by environmental, genetic, and developmental factors. Depending upon insult severity, the bladder may lose its ability to maintain capacity and intravesical pressures resulting in renal deterioration. Bladder augmentation enterocystoplasty (BAE) is employed to increase bladder capacity to preserve renal function using autologous bowel tissue as a "patch." To avoid the clinical complications associated with this procedure, we have engineered composite grafts comprised of autologous bone marrow mesenchymal stem cells (MSCs) with CD34+ hematopoietic stem/progenitor cells (HSPCs) co-seeded onto a pliable synthetic scaffold [POCO; poly(1,8-octamethylene-citrate-co-octanol)] or a biological scaffold (SIS; small intestinal submucosa) to regenerate bladder tissue in a baboon bladder augmentation model. We set out to determine the protein expression profile of bladder tissue that has undergone regeneration with the aforementioned stem cell seeded scaffolds along with baboons that underwent BAE. Data demonstrate that POCO and SIS grafted animals share high protein homogeneity between native and regenerated tissues while BAE animals displayed heterogenous protein expression between the tissues following long-term engraftment. We posit that stem cell seeded scaffolds can recapitulate tissue that is almost indistinguishable from native tissue at the protein level and may be used in lieu of procedures such as BAE.
