Is Engineered Tissue the Future of Bladder Reconstruction: Con

The potential of tissue engineering has been a subject of significant interest since the seminal work by Vacanti and colleagues in the late 1980s [[1]Vacanti J. Morse M. Saltzman M. et al.Selective cell transplantation using bioabsorbable artificial polymers as matrices.J Pediatr Surg. 1988; 23: 3-9Abstract Full Text PDF PubMed Scopus (529) Google Scholar] and the subsequent clinical trial on tissue-engineered bladder reconstruction by Atala et al. in 2006 [[2]Atala A. Bauer S.B. Soker S. Yoo J.J. Retik A.B. Tissue-engineered autologous bladders for patients needing cystoplasty.Lancet. 2006; 367: 1241-1246Abstract Full Text Full Text PDF PubMed Scopus (1588) Google Scholar]. However, despite early encouraging results, implementation of tissue-engineering therapies in clinical practice has faced formidable hurdles. We make the case here that engineered tissue holds promise but does not represent the future of bladder reconstruction owing to significant challenges and limitations. It is crucial to acknowledge the enduring success of current urinary diversion and neobladder reconstruction using ileum and/or colon. These well-established methods have reliably served patients for many years, providing functional and stable outcomes [[3]Mitra A.P. Cai J. Miranda G. et al.Management trends and outcomes of patients undergoing radical cystectomy for urothelial carcinoma of the bladder: evolution of the University of Southern California experience over 3,347 cases.J Urol. 2022; 207: 302-313Crossref PubMed Scopus (30) Google Scholar]. This proven track record presents a significant benchmark against which tissue engineering techniques must be measured. The successful augmentation cystoplasty performed with engineered tissue in seven patients with spina bifida by Atala et al. [[2]Atala A. Bauer S.B. Soker S. Yoo J.J. Retik A.B. Tissue-engineered autologous bladders for patients needing cystoplasty.Lancet. 2006; 367: 1241-1246Abstract Full Text Full Text PDF PubMed Scopus (1588) Google Scholar] in 2006 was a major breakthrough. Bladders augmented with a collagen-polyglycoic acid (C/PGA) composite scaffold seeded with autologous urothelial and bladder muscle cells showed better compliance and an increase in capacity without adverse event. Regrettably, subsequent attempts to replicate these results have failed. Joseph et al. [[4]Joseph D.B. Borer J.G. De Filippo R.E. Hodges S.J. McLorie G.A. Autologous cell seeded biodegradable scaffold for augmentation cystoplasty: phase II study in children and adolescents with spina bifida.J Urol. 2014; 191: 1389-1395Crossref PubMed Scopus (145) Google Scholar] attempted a similar technique using C/PGA in ten patients with spina bifida and observed no significant improvement in bladder capacity. Moreover, serious adverse events, such as bowel obstruction and bladder rupture [[4]Joseph D.B. Borer J.G. De Filippo R.E. Hodges S.J. McLorie G.A. Autologous cell seeded biodegradable scaffold for augmentation cystoplasty: phase II study in children and adolescents with spina bifida.J Urol. 2014; 191: 1389-1395Crossref PubMed Scopus (145) Google Scholar], underscore the complexities involved in achieving consistent success with tissue-engineered bladders. A significant obstacle is identification of the most suitable tissue for bladder reconstruction. Small intestinal submucosa, which initially seemed promising, has proven cytotoxic to urothelial cells and inhibits proper regeneration [[5]Polak J.M. Mantalaris S. Harding S.E. Advances in tissue engineering. Imperial College Press, London, UK2008Crossref Google Scholar]. Mesenchymal stem cells show potential, but the regeneration of smooth muscle cells and the organization of muscle layers, crucial for bladder function, have proven challenging [[6]Adamowicz J. Kowalczyk T. Drewa T. Tissue engineering of urinary bladder – current state of art and future perspectives.Cent Eur J Urol. 2013; 66: 202-206Google Scholar]. In addition, prior attempts to use regenerated smooth-muscle fibers yielded a disorganized arrangement deviating from the ideal multilayer architecture, which resulted in bladder motor hyperactivity [[7]Adamowicz J. Juszczak K. Bajek A. et al.Morphological and urodynamic evaluation of urinary bladder wall regeneration: muscles guarantee contraction but not proper function—a rat model research study.Transplant Proc. 2012; 44: 1429-1434Crossref PubMed Scopus (29) Google Scholar]. For patients with muscle-invasive bladder cancer, which represent the largest population that would benefit from a neobladder reconstruction, the main challenge is the inability to use autologous stem cells from the urinary tract [[8]Bajek A. Drewa T. Joachimiak R. Marszałek A. Gagat M. Grzanka A. Stem cells for urinary tract regeneration.Cent Eur J Urol. 2012; 65: 7-10Crossref Scopus (11) Google Scholar]. This necessitates exploration of alternative stem-cell sources. However, the differentiation process could carry inherent risks, including concerns regarding genomic stability and the potential for neoplastic transformation [[6]Adamowicz J. Kowalczyk T. Drewa T. Tissue engineering of urinary bladder – current state of art and future perspectives.Cent Eur J Urol. 2013; 66: 202-206Google Scholar]. These challenges further complicate the current feasibility of tissue engineering as a definitive solution for bladder reconstruction in oncology. Several challenges must be addressed in order to develop an alternative that surpasses the current standard of care. These include ensuring the mechanical properties of bladder function, obtaining and maintaining an appropriately sized graft, promoting neovascularization, preventing fibrotic reactions, and achieving adequate neoinnervation [[9]Wang X. Zhang F. Liao L. Current applications and future directions of bioengineering approaches for bladder augmentation and reconstruction.Front Surg. 2021; 8664404Google Scholar]. Clinical trials conducted over the past two decades have yielded disappointing results, underscoring the imperative for further investigation [[9]Wang X. Zhang F. Liao L. Current applications and future directions of bioengineering approaches for bladder augmentation and reconstruction.Front Surg. 2021; 8664404Google Scholar]. For instance, a phase 1 open-label exploratory study of an autologous neourinary conduit for incontinent urinary diversion after radical cystectomy (NCT01087697) showed promise initially, but ultimately yielded unsatisfactory outcomes. All patients required explantation of the tissue-engineered conduit because of stomal stenosis in three of the six patients, and neourinary conduit stricture in the remaining three [[10]Bivalacqua T. Steinberg G. Smith N. et al.LBA6 Final results of a phase 1 clinical trial evaluating the use of a tissue engineered neo-urinary conduit using adipose derived smooth muscle cells for urinary reconstruction.J Urol. 2018; 199: e579Google Scholar]. Although immunostaining revealed the presence of urothelium, smooth muscle, and neuronal tissue, the neoconduits were not functional, leading to issues of contracture, dilation of the upper urinary tract, and the ultimate need for explantation. These setbacks underscore the intricacy and uncertainty surrounding tissue engineering in bladder reconstruction and emphasizing the need for a comprehensive examination of alternative approaches. Bladder transplantation represents an intriguing future alternative to tissue-engineered bladders. Nassiri et al. [[11]Nassiri N. Cacciamani G. Gill I.S. Robotic bladder autotransplantation: preclinical studies in preparation for first-in-human bladder transplant.J Urol. 2023; 210: 600-610Crossref Scopus (3) Google Scholar] successfully performed robotic allograft autotransplantation of a vascularized composite bladder in two porcine models, one cadaver, and three brain-dead research donors. However, concerns persist regarding the need of immunosuppression post-transplantation and the impact this could have in patients who would need immunotherapy as part of their bladder cancer treatment. Additionally, challenges related to innervation and contractility of the transplanted bladder remain significant obstacles to overcome. While we acknowledge the potential promise of tissue engineering, it is imperative to recognize the significant challenges and current limitations that have impeded its widespread clinical application and hindered substantial progress over the past two decades. Given the enduring success of current surgical techniques using ileum or colon, it is premature to state that the future of bladder reconstruction resides in tissue engineering. Conflicts of interest: The authors have nothing to disclose. Disclosure: During preparation of this manuscript, the authors used ChatGPT-3.5 to improve the structure, grammar, and language of the text. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.