Advancements in Bladder Substitution Techniques and Tissue Engineering for Improved Patient Outcomes

Artificial Bladder: Filling the Void Alexander Kutikov, MD (talk prepared in 2002, reviewed in 2011)

Bladder Regeneration: Overview • Introduction • Use of GI Segments • Approaches to Bladder Replacement • Alloplastic Bladders • Tissue Engineered Bladders • In-Situ Regenerated • In-Vitro Regenerated • Summary

Introduction: Bladder Disease • 400 Million Suffer from Bladder Dz • Cancer • Trauma • Infection • Inflammation • Iatrogenic Injuries • Congenital Anomalies • Many Require Bladder Replacement

Current Treatment • Bladder replacement w/ GI segments • > 100 year-old method • Remains the standard of care

Problems w/ Using Bowel = GI Tissue - Designed to Absorb Solutes GU Tissue - Designed to Excrete Solutes

Compliations of GI Neo-Bladders • Altered Electrolyte Metabolism • Altered Hepatic Metabolism • Abnormal Drug Metabolism • Infection • Calculus Formation • Nutritional Disturbances • Growth Retardation • Osteomalacia • Cancer

Ideal Bladder Substitute • Adequate Urine Storage • Complete Evacuation of Urine (volitional) • Preserve Renal Function • Biocompatible • Resistant to Urinary Encrustation • Resistant to Bacterial Infection Must be superior to GI segments

Approaches to Bladder Substitution • Alloplastic Bladders • Tissue Engineered Bladders • In-Situ Regenerated • In-Vitro Generated

Alloplastic Organs

Alloplastic Bladder • First prosthetic bladder reported in 1960 • Box-shaped silicone reservoir attached to • anterior abdominal wall • Silicone tube brought out onto the skin served as outlet • Hydronephrosis due to ureteral prosthetic • anastomosis main reason for failure • No dog survived more than 1 month

Alloplastic Bladder:Mayo Clinic Model Rigid polysulfone shell Distensible silicone shell Fluid 8 Fr silicone tubes in ureters • Implanted intraperitoneally • No dog survived > 10 wks

Alloplastic Bladder: Reasons for Failure • Infections w/ abscess formation * • Urinary leaks at anastomoses * • Mechanical failure of device* • Urinary encrustation • Formation of constrictive capsule • RF 2o to Hydronephrosis * - Applies to Mayo Clinic Model

Dacron-covered silicone tubes through renal parenchyma Subcutaneous compressible reservoirs Y-shaped Dacron-reinforced silicone reservoir drains into urethra Alloplastic Bladder: Aachen Model 7 years to develop

Alloplastic Bladder: Aachen Model • Implanted into 5 sheep • Functioned effectively in 2 sheep for 18 mo • Urinary leakage in 3 animals due to anastamotic or material failure • Kidney structure and function preserved in all cases • No further publications on use of Aachen Model since 1996

Alloplastic Bladder: Lessons Learned • Minimize anastomoses btwn living tissue and alloplasts • Transrenal-parenchymal insertion of urteral prosthesis offers hope • Infection is a major hurdle to overcome • Antibiotic-coated solid materials under investigation TISSUE ENGINEERING: potential solution to both problems

Tissue Engineering: Definition Use of living cells to restore, maintain, or enhance tissues or organs

Tissue Engineering: Principles Strategies for Treatment of Diseased/Injured Tissue: • Implantation of freshly isolated or cultured cells • In Situ tissue regeneration • Implantation of tissues assembled in vitro from cells and scaffolds

Tissue Engineering: In Situ Regeneration

Tissue Engineering: In Situ Regeneration • Numerous Materials Have been Tried as Matrices • Most Successful: • Small bowel submucosa • Acellular submucola of porcine small bowel • Bladder Acellular Matrix Grafts (BAMG) • Acellular collagen and elastin producedby stripping stromal and epithelial cellsfrom bladder wall

Distended Normal Bladder S/p hemicystectomy of dome BAMG grafted bladder 7 mo post Tissue Engineering: In Situ Regeneration

B/f Surgery S/p Surgery 7 mo s/p Surgery Tissue Engineering: In Situ Regeneration

Tissue Engineering: In Situ Regeneration Histology a/f 4 months

Tissue Engineering: In Situ Regeneration • Bladder wall structurally and functionallynearly identical to native bladder • No significant rejection of graft seen • Similar results obtained with SIS and BAMG grafts • Human trials with BAMG and SIS being attempted

Tissue Engineering: Principles Strategies for Treatment of Diseased/Injured Tissue: • Implantation of freshly isolated or cultured cells • In Situ tissue regeneration • Implantation of tissues assembled in vitro

Tissue Engineering: In Vitro Assembly

SMOOTH MUSCLE UROTHELIUM Tissue Engineering: In Vitro Assembly

Tissue Engineering: In Vitro Assembly • Potential for genetic/phenotypic screeing of harvested cells • allows selection against transformed phenotypes

Tissue Engineering: In Vitro Assembly • Potential for genetic/phenotypic screening of harvested cells • allows selection against transformed phenotypes • Cells could also be genetically modified to acquire desired properties (e.g. antimicrobial, growth factors, etc.)

Tissue Engineering: In Vitro Assembly Bx to implant of graft = 5 weeks

Tissue Engineering: In Vitro Assembly

Tissue Engineering: In Vitro Assembly Native bladder wall Tissue-engineered Neo-bladder

Tissue Engineering: In Vitro Assembly • Function of Tissue Engineered Neo-Bladder: • Mean bladder capacity was 95% of precystecomy volume • Mean compliance was no different than preoperative values

Summary • GI Segments: employed as neobladders >100 years; it’s time for change. • Alloplastic Neobladders: little hope w/ current materials. • Tissue Engineering: hold much hope, • but remains experimental. Human studies humbling to date.

Advancements in Bladder Substitution Techniques and Tissue Engineering for Improved Patient Outcomes