Tissue engineering is an exciting and rapidly evolving technology. In this review, we discuss the recent progress made in the field of urethral reconstruction and consider the clinical implications and further advancement of these endeavours

Chapple, Christopher R

Mangera, Altaf

English

PubMed

Mangera, A.

Chapple, C.R.

White Rose Research Online

Tissue engineering in urethral reconstructionAltaf Mangera1* and Christopher R Chapple1,2Addresses: 1Department of Urology Research, Sheffield Teaching Hospitals NHS Trust, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK;2Sheffield Hallam University, 38-40 Howard Street, Sheffield, S1 1WB, UK*Corresponding author: Atlaf Mangera (mangeraaltaf@hotmail.com)F1000 Medicine Reports 2010, 2:65 (doi:10.3410/M2-65)The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/medicine/content/2/65AbstractTissue engineering is an exciting and rapidly evolving technology. In this review, we discuss the recentprogress made in the field of urethral reconstruction and consider the clinical implications andfurther advancement of these endeavours.Introduction and contextThe urethra serves as a conduit that allows urine to flowout of the bladder. In this review, we will discussthe development of tissue engineering to replace excisedmale anterior urethra. The anterior urethra represents theportion of the urethra extending from the external urethralmeatus back to the distal end of the distal sphinctermechanism. The anterior urethra has a segmental bloodsupply with both a proximal and retrograde supply bywayof the dorsal arteries, an important consideration whenapplying a living graft in need of sufficient vascular supplyin order to survive. The anterior urethra is lined by astratified columnar epithelium.Tissue-engineered grafts have been used experimentallyto treat disorders ranging from stricture disease tohypospadias deformity. The term ‘urethral stricture’generally refers to anterior urethral disease or a scarringprocess involving the spongy erectile tissue of the corpusspongiosum. Urethral stricturing is a consequence ofischemic spongiofibrosis occurring within the urethra.Occasionally, a specific cause may be identified,although the majority of strictures are idiopathic.Anterior urethral strictures are managed according totheir size and position, commencing with the lessinvasive urethral dilatation, urethral stenting, or ure-throtomy and progressing to anastomotic or substitutionurethroplasty (or both). Tissue-engineered grafts arerequired for substitution urethroplasty. The substitutiongraft of choice is a full-thickness buccal mucosal graftbecause it is easy to harvest, tough, resilient, easy tohandle, and picks up a blood supply very effectively [1].It has a privileged immunology and fibroblast behaviourunlike that of skin and has less associated fibrosis.In patients in whom a greater amount of mucosa needsto be harvested, labial (lip) and lingual (tongue) mucosamay also be harvested. The initial results using these areseen to be transposable to those seen with buccal mucosa[2-5]. The use of oral grafts is associated with numerouspotential complications. Intraoperative haemorrhage,postoperative infection, pain and swelling, damage tosalivary ducts, initial limited oral opening, alteredsensation or numbness, scarring, and even deformityhave been reported. However, in a survey of 295 patients,Barbagli et al. [6] found that 98.4% would undergo thesurgery again despite the risk of complications.Recent advancesGiven the success of oral grafts, tissue-engineered graftsof the urethra are required only in cases of extensivestricture disease or in recurrent cases in which a previousoral graft was used. Therefore, a lot of this work remainswithin the realms of preclinical research. Clinicians haveused unseeded and seeded (with cells) matrices inpatients to fashion a new urethra.el-Kassaby et al. [7] used acellular bladder matrix in ninepatients with a healthy wound bed, with good resultsPage 1 of 4(page number not for citation purposes)Published: 08 September 2010© 2010 Medicine Reports Ltdfor non-commercial purposes provided the original work is properly cited. You may not use this work for commercial purposes.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial License(http://creativecommons.org/licenses/by-nc/3.0/legalcode), which permits unrestricted use, distribution, and reproduction in any medium,seen in eight of these patients, whereas in the six patientsdeemed to have a poor wound bed, only two had a goodresult, suggesting the importance of a healthy wound bedfor use of the acellular bladder matrix graft. Palminteriet al. [8] used porcine small intestinal submucosa (SIS) asan acellular urethroplasty matrix, with 94% success inthe short term, and Fiala et al. [9] reported 80% successrates at medium-term follow-up, whereas Hauser et al.[10] reported poorer results with acellular SIS grafts.Acellular grafts do not show promise in patients whohave had failed urethroplasty or have a poor bloodsupply.Given the varying success rates with acellular grafts,researchers have begun looking at the use of cell-seededgrafts. Cells obtained from the patient are multiplied inthe laboratory and attached to a suitable matrix to be re-implanted in the patient. Results from cell-seeded graftsare awaited with much anticipation. The drawbacks of acell-seeded graft are that it requires a period of cellculture in a cleanroom laboratory and that at present it isnot suitable as an ‘off the shelf’ product. There are alsocost and time implications. However, the cellularcomposition and mechanical properties of cell-seededgrafts can be approximated better to match urethraltissue.Research in our own laboratory first reported on the useof tissue-engineered buccal mucosa implanted intohumans [11]. We obtained fibroblasts and keratinocytesfrom oral mucosal biopsies and cultured these in thelaboratory. The multiplied cells were then attached to adonor de-epidermised dermis and cultured at an air-fluidinterface to produce a graft for implantation. Cellculturing techniques allow a virtually infinite amountof tissue to be produced with just one biopsy and thistissue may be used at many time points (for instance, if arepeat procedure was required). This is an importantconsideration in the cohort of patients in whom thistechnology may be used.Our pilot clinical study [12] reported on five patients, allwith extensive stricture disease secondary to lichensclerosis. From the five patients, three have a patenturethra (at the time of writing), although all threerequired some form of instrumentation. The patientsselected for our study were all complex and the outcomesmust be placed in that context [13]. Moreover, it wouldnot be ethical to extend this experimental application topatients with low-burden stricture disease.Our tissue-engineered grafts were modelled upon buccalmucosa. The histological similarities may be seen inFigures 1a and b. We noted that graft contraction andfibrosis occurred post-implantation and we are currentlylooking at techniques to overcome this. Whether thehyperinflammatory response was due to the lichensclerosis or a reaction to the graft matrix is difficult toascertain in this group of patients.Recently, Fossum and Nordenskjold [14] described theuse of autologous urothelial cells obtained from bladderwashings to repair hypospadias deformity in a paediatricpopulation. The cells were obtained from saline irriga-tion of the bladder and subsequently were expanded inthe laboratory and finally returned to patients. Resultswere encouraging but the authors acknowledge thatmore work needs to be carried out to improve the tissue-engineering techniques. Similarly, Nagele et al. [15]described a tissue-engineered multilayered urotheliumexpanded from bladder washings.Currently, our work in the laboratory is concentrated ondeveloping a scaffold that may be used to deliver thetissue-engineered graft and to reduce contraction andfibrosis occurring post-implantation. We are also lookingat ways to manufacture sterile scaffold for clinical use[16]. Feng et al. [17], in a recent study of four differentscaffold materials, assessed mechanical properties andcell attachment to the various seeded grafts.Li et al. [18] described cellularisation of acellular bladdermatrix grafts using autologous oral cells. This work hasreached only the in vitro stage using rabbit oral mucosacells, but the important finding is the biocompatibility ofbladder acellular matrix with oral mucosa cells. Fu et al.[19] successfully attached foreskin epidermal cells on anacellular rabbit bladder matrix and proved this to besuperior in terms of tissue organisation and re-stricturingcompared with an unseeded acellular bladder matrix in arabbit model. The same efforts to seed SIS with urothelialcells and subsequent culture, as attempted by Feil et al.[20], have been unsuccessful.Figure 1. Hematoxylin and eosin histological sections of (a) buccalmucosa and (b) tissue-engineered buccal mucosaMagnifications, ×40.Page 2 of 4(page number not for citation purposes)F1000 Medicine Reports 2010, 2:65 http://f1000.com/reports/medicine/content/2/65In another avenue of research, Aboushwareb and Atala[21] described the promising approach of using adultprogenitor stem cells or amniotic/placental stem cells tocreate new urethral tissue. However, this approach stillrequires much laboratory work. Given the ethicalproblems of using embryonic stem cells, much workhas concentrated on obtaining stem cells from manydifferent tissues, including bone marrow, striatedmuscle, fat, skin, and recently testicles.Implications for clinical practiceThe use of acellular bladder mucosa and SIS grafts hasbeen trialled and has shown results comparable to theexisting use of buccal mucosa in cases with a goodwound bed. In these patients, an oral mucosal graftis most often sufficient. The necessity for a tissue-engineered graft depends on whether a reduction indonor site morbidity is required and on the need forsufficient donor tissue.The more pressing need for tissue-engineered grafts is inthe treatment of long complex strictures, where therequirement for sufficient tissue imposes greater risk ofcomplication from oral mucosal procedures. Thesepatients tend to have a poor wound bed and make thedesign of the replacement graftmore challenging.With thisin mind, we are still searching for the ideal replacementgraft. To this end, researchers are still in search of theoptimum scaffold, seeded by the correct cells, whichdifferentiate and repair without fibrosis. Scaffolds providestructural support and act as an extracellular matrix inwhich cell behaviourmay be regulated. Therefore, the idealscaffold should promote cell adhesion, proliferation,migration, and differentiation and have the appropriatebiomechanical properties [22]. The appropriate cell mustsurvive, proliferate, and differentiate into a cell capable ofallowing the passage of urine without stimulating theinflammatory pathways to cause stricturing.In conclusion, the reconstructive strategy used by theurologist for the treatment of the anterior urethra willdepend on the extent of the disease, underlyingpathology, availability of autologous grafts, and theunderlying wound bed. With further improvements inseeding acellular matrices, the clinical use of tissue-engineered materials is set to increase, especially in thosemost in need of it.AbbreviationSIS, small intestinal submucosa.Competing interestsCRC has served as a consultant, participated in trials for,and has received speaker honoraria and research grantsfrom Pfizer Inc. (New York, NY, USA) and Astellas(Tokyo, Japan), has served as a consultant for Novartis(Basel, Switzerland) and Ono Pharmaceutical Co., Ltd.(Osaka, Japan), has served as a consultant and partici-pated in trials for Mitsubishi Tanabe Pharma Corpora-tion (Osaka, Japan) and Recordati (Milan, Italy), and hasreceived a speaker honorarium from Ranbaxy Labora-tories Ltd. (Gurgaon, India). AM declares that he has nocompeting interests.AcknowledgmentsAM has received a fellowship from the Urology Founda-tion and the Robert Luff Foundation.References1. Fransis K, Vander Eeckt K, Van Poppel H, Joniau S: Results of buccalmucosa grafts for repairing long bulbar urethral strictures.BJU Int 2009, [Epub ahead of print].2. Castagnetti M, Rigamonti W: Aptness and complications of labialmucosa grafts for the repair of anterior urethral defects inchildren and adults: single centre experience with 115 cases.World J Urol 2009, [Epub ahead of print].3. Das SK, Kumar A, Sharma GK, Pandey AK, Bansal H, Trivedi S,Dwivedi US, Bhattacharya V, Singh PB: Lingual mucosal grafturethroplasty for anterior urethral strictures. Urology 2009,73:105-8.4. Barbagli G, De Angelis M, Romano G, Ciabatti PG, Lazzeri M: Theuse of lingual mucosal graft in adult anterior urethroplasty:surgical steps and short-term outcome. Eur Urol 2008, 54:671-6.5. Simonato A, Gregori A, Ambruosi C, Venzano F, Varca V,Romagnoli A, Carmignani G: Lingual mucosal graft urethroplastyfor anterior urethral reconstruction. Eur Urol 2008, 54:79-85.F1000 Factor 3.3 RecommendedEvaluated by Kenneth Angermeier 11 Aug 2008, Guido Barbagli 03Sep 2008, Carlos Giudice 04 Jan 20106. Barbagli G, Fabbri F, Romano G, De Angelis M, Lazzeri M: Evaluationof early, late complications and patient satisfaction in 300patients who underwent oral graft harvesting from a singlecheek using a standardised technique in a referral centerexperience. J Urol 2009, 181(Suppl 4):14.7. el-Kassaby A, Aboushwareb T, Atala A: Randomized comparativestudy between buccal mucosal and acellular bladder matrixgrafts in complex anterior urethral strictures. J Urol 2008,179:1432-6.8. Palminteri E, Berdondini E, Colombo F, Austoni E: Small intestinalsubmucosa (SIS) graft urethroplasty: short-term results. EurUrol 2007, 51:1695-701.F1000 Factor 3.0 RecommendedEvaluated by Hunter Wessells 07 Jan 20089. Fiala R, Vidlar A, Vrtal R, Belej K, Student V: Porcine smallintestinal submucosa graft for repair of anterior urethralstrictures. Eur Urol 2007, 51:1702-8.10. Hauser S, Bastian PJ, Fechner G, Muller SC: Small intestinesubmucosa in urethral stricture repair in a consecutiveseries. Urology 2006, 68:263-6.11. Bhargava S, Chapple CR, Bullock AJ, Layton C, MacNeil S: Tissue-engineered buccal mucosa for substitution urethroplasty. BJUInt 2004, 93:807-11.12. Bhargava S, Patterson JM, Inman RD, MacNeil S, Chapple CR: Tissue-engineered buccal mucosa urethroplasty-clinical outcomes.Eur Urol 2008, 53:1263-9.Page 3 of 4(page number not for citation purposes)F1000 Medicine Reports 2010, 2:65 http://f1000.com/reports/medicine/content/2/6513. Watkin N: Editorial comment on: tissue-engineered buccalmucosa urethroplasty-clinical outcomes. Eur Urol 2008,53:1270-1.14. Fossum M, Nordenskjold A: Tissue-engineered transplants forthe treatment of severe hypospadias. Horm Res Paediatr 2010,73:148-52.15. Nagele U, Maurer S, Feil G: A new option for urethralreconstruction with multilayered urothelium establishedfrom bladder washings. Eur Urol Suppl 2006, 5:47.16. Selim M, Bullock AJ, MacNeil S, Chapple CR: Evaluation ofsterilisation methods on biological and mechanical proper-ties of a synthetic biodegradable electrospun scaffold for thecreation of tissue engineered buccal mucos for clinical use.Eur Urol Suppl 2009, 8:185.17. Feng C, Xu YM, Fu Q, Zhu WD, Cui L, Chen J: Evaluation of thebiocompatibility and mechanical properties of naturallyderived and synthetic scaffolds for urethral reconstruction.J Biomed Mater Res A 2010, 94:317-25.18. Li C, Xu Y, Song L, Cui L, Yin S: [A preliminary experimentalstudy on urethral reconstruction using tissue engineeredoral mucosa]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2008,22:1242-5.19. Fu Q, Deng CL, Liu W, Cao YL: Urethral replacement usingepidermal cell-seeded tubular acellular bladder collagenmatrix. BJU Int 2007, 99:1162-5.20. Feil G, Christ-Adler M, Maurer S, Corvin S, Rennekampff HO, Krug J,Hennenlotter J, Kuehs U, Stenzl A, Sievert KD: Investigations ofurothelial cells seeded on commercially available smallintestine submucosa. Eur Urol 2006, 50:1330-7.21. Aboushwareb T, Atala A: Stem cells in urology. Nat Clin Pract Urol2008, 5:621-31.22. Aboushwareb T, Atala A: Regenerative medicine for theurethra. In Biomaterials and Tissue Engineering in Urology. 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Tissue engineering in urethral reconstruction.

A new option for urethral reconstruction with multilayered urothelium established from bladder washings. Eur Urol Suppl

A: Randomized comparative study between buccal mucosal and acellular bladder matrix grafts in complex anterior urethral strictures.

Aptness and complications of labial mucosa grafts for the repair of anterior urethral defects in children and adults: single centre experience with 115 cases. World J Urol 2009, [Epub ahead of print].

Atala A: Stem cells in urology. Nat Clin Pract Urol

Austoni E: Small intestinal submucosa (SIS) graft urethroplasty: short-term results. Eur Urol

Cao YL: Urethral replacement using epidermal cell-seeded tubular acellular bladder collagen matrix.

Chapple CR: Evaluation of sterilisation methods on biological and mechanical properties of a synthetic biodegradable electrospun scaffold for the creation of tissue engineered buccal mucos for clinical use. Eur Urol Suppl

Chapple CR: Tissueengineered buccal mucosa urethroplasty-clinical outcomes. Eur Urol

Evaluation of early, late complications and patient satisfaction in 300 patients who underwent oral graft harvesting from a single cheek using a standardised technique in a referral center experience.

Evaluation of the biocompatibility and mechanical properties of naturally derived and synthetic scaffolds for urethral reconstruction.

Nordenskjold A: Tissue-engineered transplants for the treatment of severe hypospadias. Horm Res Paediatr

PB: Lingual mucosal graft urethroplasty for anterior urethral strictures. Urology

Regenerative medicine for the urethra. In Biomaterials and Tissue Engineering in Urology. Edited by Atala A.

Results of buccal mucosa grafts for repairing long bulbar urethral strictures.

S: [A preliminary experimental study on urethral reconstruction using tissue engineered oral mucosa]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi

SC: Small intestine submucosa in urethral stricture repair in a consecutive series. Urology

Sievert KD: Investigations of urothelial cells seeded on commercially available small intestine submucosa. Eur Urol

Student V: Porcine small intestinal submucosa graft for repair of anterior urethral strictures. Eur Urol

Tissueengineered buccal mucosa for substitution urethroplasty.

https://eprints.whiterose.ac.uk/115354/1/Tissue%20engineering%20in%20urethral%20reconstruction.pdf

Tissue engineering in urethral reconstruction

Tissue engineering in urethral reconstruction

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