Artificial Bladder Filling the Void Alexander Kutikov MD

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 à Cancer à Trauma à Infection à Inflammation à Iatrogenic Injuries à 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 • Implanted intraperitoneally • No dog survived > 10 wks 8 Fr silicone tubes in ureters

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

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

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 à Transrenal-parenchymal insertion of urteral prosthesis offers hope • Infection is a major hurdle to overcome à 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: 1. Implantation of freshly isolated or cultured cells 2. In Situ tissue regeneration 3. 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 produced by stripping stromal and epithelial cells from bladder wall

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

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

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

Tissue Engineering: In Situ Regeneration • Bladder wall structurally and functionally nearly 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: 1. Implantation of freshly isolated or cultured cells 2. In Situ tissue regeneration 3. Implantation of tissues assembled in vitro

Tissue Engineering: In Vitro Assembly

Tissue Engineering: In Vitro Assembly SMOOTH MUSCLE UROTHELIUM

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.