Urethra Reconstruction with Tissue-Engineering Technology

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Urethral stricture is a disease characterized by a pathological narrowing of the urethra. Treatment for this condition often requires surgery using autologous grafts (urethroplasty). It is common practice to use patient’s own tissue like genital and extragenital skin, tunica vaginalis, buccal mucosa as a source of the graft. Alternative and safer approach is to use tissue-engineered graft created in a laboratory using patient’s autologous cells and biocompatible matrix (scaffold). The article presents the up-to-date achievements in lab-created tissue-engineered graft, describes all components needed to build a tissue-engineered structure of the graft for urethroplasty, and summarizes authors’ thoughts on advantages and disadvantages of various approaches to choose both cellular component and the matrix of future construction. The article reviews clinical studies conducted in the field of tissue engineering of the graft material for urethraplasty.

About the authors

I. A. Vasyutin

Sechenov First Moscow State Medical University

Author for correspondence.
Email: ivasyutin@yahoo.com
ORCID iD: 0000-0003-0594-7423

Аспирант кафедры гистологии, цитологии и эмбриологии лечебного факультета, младший научный сотрудник Института регенеративной медицины.

Адрес: 119991, Москва, ул. Трубецкая, д. 8, стр. 2.

SPIN-код: 1872-8347

Russian Federation

A. V. Lyundup

Sechenov First Moscow State Medical University

Email: lyundup@gmail.com
ORCID iD: 0000-0002-0102-5491

Кандидат медицинских наук, заведующий отделом передовых клеточных технологий Института регенеративной медицины.

Адрес: 119991, Москва, ул. Трубецкая, д. 8, стр. 2

SPIN-код: 4954-3004

A. Z. Vinarov

Sechenov First Moscow State Medical University

Email: avinarov@mail.ru
ORCID iD: 0000-0001-9510-9487

Доктор медицинских наук, профессор, главный научный сотрудник НИИ уронефрологии и репродуктивного здоровья человека. 

Адрес: 119435, Москва, ул. Большая Пироговская, д. 2, стр. 1.

SPIN-код: 5174-2233

D. V. Butnaru

Sechenov First Moscow State Medical University

Email: butnaru_dv@mail.ru
ORCID iD: 0000-0003-2173-0566

Кандидат медицинских наук, директор Института регенеративной медицины.

Адрес: 119991, Москва, ул. Трубецкая, д. 8, стр. 2.

SPIN-код: 2408-5133

S. L. Kuznetsov

Sechenov First Moscow State Medical University

Email: vakmedbiol@rambler.ru
ORCID iD: 0000-0002-0704-1660

Доктор медицинских наук, профессор, член-корр. РАН, заведующий кафедрой гистологии, цитологии и эмбриологии лечебного факультета.

Адрес: 125009, Москва, ул. Моховая, д. 11, стр. 3.

SPIN-код: 3824-2646


  1. Latini JM, McAninch JW, Brandes SB, et al. SIU/ICUD Consultation On Urethral Strictures: Epidemiology, etiology, anatomy, and nomenclature of urethral stenoses, strictures, and pelvic fracture urethral disruption injuries. Urology. 2014;83(3 Suppl):S1–7. doi: 10.1016/j.urology.2013.09.009.
  2. Santucci RA, Joyce GF, Wise M. Male urethral stricture disease. J Urol. 2007;177(5):1667–1674. doi: 10.1016/j.juro.2007.01.041.
  3. Lee YJ, Kim SW. Current management of urethral stricture. Korean J Urol. 2013;54(9):561–569. doi: 10.4111/kju.2013.54.9.561.
  4. Atala A, Kasper FK, Mikos AG. Engineering complex tissues. Sci Transl Med. 2012;4(160):160rv12. doi: 10.1126/scitranslmed.3004890.
  5. Atala A, Danilevskiy M, Lyundup A, et al. The potential role of tissue-engineered urethral substitution: clinical and preclinical studies. J Tissue Eng Regen Med. 2017;11(1):3–19. doi: 10.1002/term.2112.
  6. Young B, Lowe JS, Steven A, Heath JW. Wheater’s functional histology: a text and colour atlas. 5th ed. Elsevier, Churchill Livingstone; 2006. 448 p.
  7. Кузнецов С.Л., Мушкамбаров Н.Н. Гистология, цитология и эмбриология. Учебник для студентов медицинских ВУЗов. — М.: МИА; 2007. — 600 с. [Kuznetsov SL, Mushkambarov NN. Gistologiya, tsitologiya i embriologiya. Uchebnik dlya studentov meditsinskikh VUZov. Moscow: MIA; 2007. 600 p. (In Russ).]
  8. Orabi H, AbouShwareb T, Zhang Y, et al. Cell-seeded tubularized scaffolds for reconstruction of long urethral defects: a preclinical study. Eur Urol. 2013;63(3):531–538. doi: 10.1016/j.eururo.2012.07.041.
  9. Fossum M, Skikuniene J, Orrego A, Nordenskjold A. Prepubertal follow-up after hypospadias repair with autologous in vitro cultured urothelial cells. Acta Paediatr. 2012;101(7):755–760. doi: 10.1111/j.1651-2227.2012.02659.x.
  10. Raya-Rivera A, Esquiliano DR, Yoo JJ, et al. Tissue-engineered autologous urethras for patients who need reconstruction: an observational study. Lancet. 2011;377(9772):1175–1182. doi: 10.1016/s0140-6736(10)62354-9.
  11. De Filippo RE, Kornitzer BS, Yoo JJ, Atala A. Penile urethra replacement with autologous cell-seeded tubularized collagen matrices. J Tissue Eng Regen Med. 2015;9(3):257–264. doi: 10.1002/term.1647.
  12. Bhargava S, Patterson JM, Inman RD, et al. Tissue-engineered buccal mucosa urethroplasty-clinical outcomes. Eur Urol. 2008;53(6):1263–1271. doi: 10.1016/j.eururo.2008.01.061.
  13. Li C, Xu YM, Song LJ, et al. Urethral reconstruction using oral keratinocyte seeded bladder acellular matrix grafts. J Urol. 2008;180(4):1538−1542. doi: 10.1016/j.juro.2008.06.013.
  14. Mikami H, Kuwahara G, Nakamura N, et al. Two-layer tissue engineered urethra using oral epithelial and muscle derived cells. J Urol. 2012;187(5):1882−1889. doi: 10.1016/j.juro.2011.12.059.
  15. Xie M, Xu Y, Song L, et al. Tissue-engineered buccal mucosa using silk fibroin matrices for urethral reconstruction in a canine model. Surg Res. 2014;188(1):1−7. doi: 10.1016/j.jss.2013.11.1102.
  16. Li H, Xu Y, Xie H, et al. Epithelial-differentiated adipose-derived stem cells seeded bladder acellular matrix grafts for urethral reconstruction: an animal model. Tissue Eng Part A. 2014;20(3–4):774–784. doi: 10.1089/ten.tea.2013.0122.
  17. Wu S, Liu Y, Bharadwaj S, et al. Human urine-derived stem cells seeded in a modified 3D porous small intestinal submucosa scaffold for urethral tissue engineering. Biomaterials. 2011;32(5):1317–1326. doi: 10.1016/j.biomaterials.2010.10.006.
  18. Bodin A, Bharadwaj S, Wu S, et al. Tissue-engineered conduit using urine-derived stem cells seeded bacterial cellulose polymer in urinary reconstruction and diversion. Biomaterials. 2010;31(34):8889−8901. doi: 10.1016/j.biomaterials.2010.07.108.
  19. Beaghler M, Grasso M 3rd. Flexible cystoscopic bladder biopsies: a technique for outpatient evaluation of the lower urinary tract urothelium. Urology. 1994;44(5):756–759. doi: 10.1016/s0090-4295(94)80223-8.
  20. Lamb CR, Trower ND, Gregory SP. Ultrasound-guided catheter biopsy of the lower urinary tract: technique and results in 12 dogs. J Small Anim Pract. 1996;37(9):413–416. doi: 10.1111/j.1748-5827.1996.tb02438.x.
  21. Cilento BG, Freeman MR, Schneck FX, et al. Phenotypic and cytogenetic characterization of human bladder urothelia expanded in vitro. J Urol. 1994;152(2 Pt 2):665–670. doi: 10.1016/s0090-4295(98)00161-7.
  22. Duffey B, Monga M. Principles of endoscopy. In: Wein AJ, Kavoussi LR, Campbell MF, editors. Campbell-Walsh urology. 10th ed. Philadelphia, PA: Elsevier Saunders; 2012. p. 192–203. doi: 10.1016/b978-1-4160-6911-9.00008-6.
  23. Zhang YY, Ludwikowski B, Hurst R, Frey P. Expansion and long-term culture of differentiated normal rat urothelial cells in vitro. In Vitro Cell Dev Biol Anim. 2001;37(7):419–429. doi: 10.1290/1071-2690(2001)037<0419:ealtco>2.0.co;2.
  24. Bhargava S, Chapple CR. Buccal mucosal urethroplasty: is it the new gold standard? BJU Int. 2004;93(9):1191–1193. doi: 10.1111/j.1464-410x.2003.04860.x.
  25. Peterson AC, Webster GD. Management of urethral stricture disease: developing options for surgical intervention. BJU Int. 2004;94(7):971–976. doi: 10.1111/j.1464-410x.2004.05088.x
  26. Filipas D, Fisch M, Fichtner J, et al. The histology and immunohistochemistry of free buccal mucosa and full-skin grafts after exposure to urine. BJU Int. 1999;84(1):108–111. doi: 10.1046/j.1464-410x.1999.00079.x.
  27. Souza GF, Calado AA, Delcelo R, et al. Histopathological evaluation of urethroplasty with dorsal buccal mucosa: an experimental study in rabbits. Int Braz J Urol. 2008;34(3):345–354. doi: 10.1590/s1677-55382008000300012.
  28. Osman NI, Hillary C, Bullock AJ, et al. Tissue engineered buccal mucosa for urethroplasty: progress and future directions. Adv Drug Deliv Rev. 2015;82–83:69–76. doi: 10.1016/j.addr.2014.10.006.
  29. Bhargava S, Chapple CR, Bullock AJ, et al. Tissue-engineered buccal mucosa for substitution urethroplasty. BJU Int. 2004;93(6):807–811. doi: 10.1111/j.1464-410x.2003.04723.x.
  30. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–228. doi: 10.1089/107632701300062859.
  31. van Dijk A, Niessen HW, Zandieh Doulabi B, et al. Differentiation of human adipose-derived stem cells towards cardiomyocytes is facilitated by laminin. Cell Tissue Res. 2008;334(3):457–467. doi: 10.1007/s00441-008-0713-6.
  32. Brzoska M, Geiger H, Gauer S, Baer P. Epithelial differentiation of human adipose tissue-derived adult stem cells. Biochem Biophys Res Commun. 2005;330(1):142–150. doi: 10.1016/j.bbrc.2005.02.141.
  33. Shi JG, Fu WJ, Wang XX, et al. Transdifferentiation of human adipose-derived stem cells into urothelial cells: potential for urinary tract tissue engineering. Cell Tissue Res. 2012;347(3):737–746. doi: 10.1007/s00441-011-1317-0.
  34. Yang B, Zheng JH, Zhang YY. Myogenic differentiation of mesenchymal stem cells for muscle regeneration in urinary tract. Chin Med J (Engl). 2013;126(15):2952–2959.
  35. Kanematsu A, Yamamoto S, Iwai-Kanai E, et al. Induction of smooth muscle cell-like phenotype in marrow-derived cells among regenerating urinary bladder smooth muscle cells. Am J Pathol. 2005;166(2):565–573. doi: 10.1016/s0002-9440(10)62278-x.
  36. Jack GS, Zhang R, Lee M, et al. Urinary bladder smooth muscle engineered from adipose stem cells and a three dimensional synthetic composite. Biomaterials. 2009;30(19):3259–3270. doi: 10.1016/j.biomaterials.2009.02.035.
  37. Васютин И.А., Люндуп А.В., Кузнецов С.Л. Моча как источник стволовых клеток для регенеративной медицины мочевыводящих путей. / II Национальный конгресс по регенеративной медицине; Декабрь 3−5, 2015; Москва. — С. 41. [Vasyutin IA, Lyundup AV, Kuznetsov SL. Mocha, kak istochnik stvolovykh kletok dlya regenerativnoi meditsiny mochevyvodyashchikh putei. (Conference proceedigs) II Natsional’nyi kongress po regenerativnoi meditsine; 2015 dec 3−5; Moscow. p. 41. (In Russ).] Доступно по: http://www.mediexpo.ru/fileadmin/user_upload/content/pdf/thesis/thesis_nkrm2015.pdf. Ссылка активна на 21.01.2017.
  38. Zhang Y, McNeill E, Tian H, et al. Urine derived cells are a potential source for urological tissue reconstruction. J Urol. 2008;180(5):2226–2233. doi: 10.1016/j.juro.2008.07.023.
  39. Bharadwaj S, Liu G, Shi Y, et al. Multipotential differentiation of human urine-derived stem cells: potential for therapeutic applications in urology. Stem Cells. 2013;31(9):1840–1856. doi: 10.1002/stem.1424.
  40. Bharadwaj S, Liu G, Shi Y, et al. Characterization of urine-derived stem cells obtained from upper urinary tract for use in cell-based urological tissue engineering. Tissue Eng Part A. 2011;17(15–16):2123–2132. doi: 10.1089/ten.tea.2010.0637.
  41. Osborn SL, Thangappan R, Luria A, et al. Induction of human embryonic and induced pluripotent stem cells into urothelium. Stem Cells Transl Med. 2014;3(5):610–619. doi: 10.5966/sctm.2013-0131.
  42. Yang L, Geng Z, Nickel T, et al. Differentiation of human induced-pluripotent stem cells into smooth-muscle cells: two novel protocols. PLoS One. 2016;11(1):e0147155. doi: 10.1371/journal.pone.0147155.
  43. De Filippo RE, Yoo JJ, Atala A. Urethral replacement using cell seeded tubularized collagen matrices. Urology. 2002;168(4 Pt 2):1789–1793. doi: 10.1016/s0022-5347(05)64414-x.
  44. Feng C, Xu YM, Fu Q, et al. Reconstruction of three-dimensional neourethra using lingual keratinocytes and corporal smooth muscle cells seeded acellular corporal spongiosum. Tissue Eng Part A. 2011;17(23–24):3011–3019. doi: 10.1089/ten.tea.2011.0061.
  45. Wu S, Liu Y, Bharadwaj S, et al. Human urine-derived stem cells seeded in a modified 3D porous small intestinal submucosa scaffold for urethral tissue engineering. Biomaterials. 2011;32(5):1317–1326. doi: 10.1016/j.biomaterials.2010.10.006.
  46. Davis NF, Mooney R, Piterina AV, et al. Construction and evaluation of urinary bladder bioreactor for urologic tissue-engineering purposes. Urology. 2011;78(4):954–960. doi: 10.1016/j.urology.2011.06.036.
  47. Keane T, Saldin L, Badylak S. Decellularization of mammalian tissues: preparing extracellular matrix bioscaffolds. In: Tomlins P, editor. Characterisation and design of tissue scaffolds. Woodhead Publishing; 2015. р. 75–103. doi: 10.1016/B978-1-78242-087-3.00004-3.
  48. Feng C, Xu YM, Fu Q, et al. Evaluation of the biocompatibility and mechanical properties of naturally derived and synthetic scaffolds for urethral reconstruction. J Biomed Mater Res A. 2010;94(1):317–325. doi: 10.1002/jbm.a.32729.
  49. Ralston DR, Layton C, Dalley AJ, et al. The requirement for basement membrane antigens in the production of human epidermal/dermal composites in vitro. Br J Dermatol. 1999;140(4):605–615. doi: 10.1046/j.1365-2133.1999.02758.x.
  50. Martino MM, Briquez PS, Ranga A, et al. Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix. Proc Natl Acad Sci U S A. 2013;110(12):4563–4568. doi: 10.1073/pnas.1221602110.
  51. Catelas I, Dwyer JF, Helgerson S. Controlled release of bioactive transforming growth factor beta-1 from fibrin gels in vitro. Tissue Eng Part C Methods. 2008;14(2):119–128. doi: 10.1089/ten.tec.2007.0262.
  52. de Kemp V, de Graaf P, Fledderus JO, et al. Tissue engineering for human urethral reconstruction: systematic review of recent literature. PLoS One. 2015;10(2):e0118653. doi: 10.1371/journal.pone.0118653.
  53. Kundu AK, Gelman J, Tyson DR. Composite thin film and electrospun biomaterials for urologic tissue reconstruction. Biotechnol Bioeng. 2011;108(1):207–215. doi: 10.1002/bit.22912.
  54. Tomlins P, editor. Characterisation and design of tissue scaffolds. Woodhead Publishing; 2015. 294 р. doi: 10.1016/c2013-0-16452-5.
  55. Chen G, Kawazoe N. Preparation of polymer-based porous scaffolds for tissue engineering. In: Tomlins P, editor. Characterisation and design of tissue scaffolds. Woodhead Publishing; 2015. р. 105–125. doi: 10.1016/B978-1-78242-087-3.00005-5.
  56. Nakanishi Y, Chen G, Komuro H, et al. Tissue-engineered urinary bladder wall using PLGA mesh-collagen hybrid scaffolds: a comparison study of collagen sponge and gel as a scaffold. J Pediatr Surg. 2003;38(12):1781–1784. doi: 10.1016/j.jpedsurg.2003.08.034.
  57. Salem SA, Hwei NM, Bin Saim A, et al. Polylactic-co-glycolic acid mesh coated with fibrin or collagen and biological adhesive substance as a prefabricated, degradable, biocompatible, and functional scaffold for regeneration of the urinary bladder wall. J Biomed Mater Res A. 2013;101(8):2237–2247. doi: 10.1002/jbm.a.34518.
  58. Auger FA, Remy-Zolghadri M, Grenier G, Germain L. A truly new approach for tissue engineering: the LOEX self-assembly technique. Ernst Schering Res Found Workshop. 2002;(35):73–88. doi: 10.1007/978-3-662-04816-0_6.
  59. Magnan M, Levesque P, Gauvin R, et al. Tissue engineering of a genitourinary tubular tissue graft resistant to suturing and high internal pressures. Tissue Eng Part A. 2009;15(1):197–202. doi: 10.1089/ten.tea.2007.0303.
  60. Глыбочко П.В., Аляев Ю.Г., Николенко В.Н., и др. Заместительная уретропластика с использованием тканеинженерной конструкции на основе децеллюляризированной сосудистой матрицы и аутологичных клеток слизистой оболочки щеки: первый опыт // Урология. — 2015. — №3 — С. 4–10. [Glybochko PV, Aljaev JuG, Nikolenko VN, et al. Tissue-engineered substitution urethroplasty based on decellularized vascular matrix and autologous cells of the buccal mucosa: the first experience. Urologiia. 2015;(3):4–10. (In Russ).]

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