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Liquid / Minced Buccal Mucosal Graft

Liquid buccal mucosal graft (LBMG) and minced buccal mucosal graft are minimally invasive approaches to urethral reconstruction that combine the biological advantages of buccal mucosa with endoscopic delivery. They remain investigational and have not established a replacement for standard urethroplasty. They sit alongside related emerging strategies — tissue-engineered oral mucosal grafts (TEOMG), extracellular vesicles, and organoid systems — that aim to overcome the limitations of conventional BMG harvest.[1][2][7]

For graft material details, see Buccal Mucosa Graft. For the open-surgical onlay alternatives, see Dorsal Onlay OMG Urethroplasty and Ventral Onlay OMG Urethroplasty. For the standard endoscopic incision, see DVIU.

Liquid Buccal Mucosal Graft (LBMG)​

Concept and rationale​

The LBMG technique, pioneered by Nikolavsky et al. at SUNY Upstate Medical University (2016), is based on the concept that buccal mucosa can be mechanically minced into micrografts, suspended in fibrin glue, and injected endoscopically into a urethrotomy site to promote mucosal engraftment, with the aim of reducing stricture recurrence after DVIU.[1] The rationale addresses the fundamental limitation of DVIU — its high recurrence rate (up to 70–80% for strictures >2 cm) — by providing a biological substrate that promotes re-epithelialization with healthy mucosa rather than fibrotic scar tissue.[1][2]

Preparation of liquid BMG​

  1. Buccal mucosa harvest — a small piece of buccal mucosa is harvested from the inner cheek (autologous oral mucosa from the rabbit in the original animal studies).
  2. Mechanical mincing — the harvested tissue is mechanically minced into micrografts containing epithelial cells, basement membrane, and lamina propria.
  3. Suspension in fibrin glue — the minced micrografts are suspended in fibrin glue (fibrinogen + thrombin), creating a semi-liquid, injectable preparation.
  4. The resulting "liquid BMG" — a viscous suspension that can be delivered through an endoscopic injection needle or catheter.[1][2]

Experimental technique​

LBMG is delivered endoscopically in conjunction with DVIU:[1][2]

  1. Standard direct vision internal urethrotomy (DVIU) is performed to incise the stricture.
  2. Immediately after urethrotomy, the LBMG–fibrin glue mixture is injected into the urethrotomy bed (the raw surface created by the incision).
  3. The fibrin glue serves as a scaffold that holds the micrografts in place against the urethrotomy surface.
  4. A urethral catheter is placed to maintain luminal patency during healing.
  5. The micrografts are expected to engraft, proliferate, and re-epithelialize the urethrotomy site with buccal mucosa; prevention of recurrence is an investigational objective, not an established result.

Preclinical evidence​

The foundational LBMG studies used rabbit stricture models. Subsequent early human work is discussed below.

StudyPhasenDesignKey Results
Nikolavsky 2016 (proof of concept)[1]Phase 1 feasibility; Phase 2 efficacyPhase 1: 3 rabbits; Phase 2: 9 rabbits (6 treated, 3 controls)DVIU + LBMG vs DVIU + fibrin glue onlyPhase 1: 2/3 (67%) showed engraftment at 2–3 wk. Phase 2: 6/6 (100%) treated showed engraftment with stricture resolution / improvement on RUG and urethroscopy at 8–24 wk; 0/3 controls showed engraftment (controls showed fibrosis and chronic inflammation)
Scott 2020 (validation)[2]Single-phase validation26 rabbits (12 treated, 13 controls)Randomized DVIU + LBMG vs DVIU + fibrin glue only; blinded radiographic + histologic assessment8/12 (67%) treated showed engraftment vs 0/13 controls (p = 0.0005); 7/12 (58%) treated showed radiographic improvement vs 5/13 (38%) controls (p = 0.145, NS); median percent change 59% vs 41.6% (p = 0.29, NS)

Key findings from preclinical studies​

  • Engraftment is reproducible — both studies confirmed mechanically minced buccal mucosa micrografts can engraft in the urethra when delivered endoscopically in fibrin glue.[1][2]
  • Histological confirmation — engrafted tissue showed stratified squamous epithelium lining the urethral lumen at the urethrotomy site, in contrast to controls which showed fibrosis and chronic inflammation.[1]
  • Durability — engraftment was maintained at 24 weeks (longest time point assessed), suggesting stable tissue integration.[1][2]
  • Radiographic improvement was not statistically significant in the validation study (p = 0.145), though the trend favored LBMG. The authors attributed this to small sample size and the inherent variability of the rabbit stricture model.[2]
  • No adverse effects — no local or systemic adverse reactions in either study.[1][2]

Current status​

The field has progressed to early human feasibility studies, while remaining investigational. A 2025 uncontrolled pilot enrolled 30 men with primary short bulbar strictures and reported 76.6% success at 30 months. Only 16 completed that follow-up interval. This small study does not demonstrate superiority to DVIU or equivalence to urethroplasty; its role here is to correct the outdated claim that no human studies exist.[3]

The Nikolavsky group has since developed adjacent endoscopic / minimally invasive BMG techniques that have advanced to clinical use:

  • Transurethral ventral inlay BMG urethroplasty (Sterling 2023) — a whole (non-minced) buccal mucosal graft delivered through a minimally invasive transurethral approach, achieving 95% success at 36 months in 44 patients with fossa navicularis / distal urethral strictures.[5]
  • Endoscopic BMG with suturing device (Ungerer 2023) — a single case report of fully endoscopic BMG urethroplasty for membranous stricture, patent at 6 months.[6]

Tissue-Engineered Oral Mucosal Grafts (TEOMG / MukoCell®)​

While not identical to "minced" BMG, tissue-engineered oral mucosal grafts are the most clinically advanced form of expanded / amplified buccal mucosa — a small biopsy is used to generate a full-sized graft. A studied product is MukoCell®, which has national authorization in Germany as a tissue-engineered medicinal product; this is not EU-wide CE marking. The German regulator lists MukoCell under tissue-engineered products. Separately, the EAU strongly recommends restricting autologous tissue-engineered oral mucosa grafts to clinical trials.[4][25]

Concept​

A 0.5 cm buccal mucosa biopsy is taken from the patient's cheek and sent to a laboratory. Over 3 weeks, the buccal mucosal cells are expanded on a collagen matrix scaffold to produce a full-sized graft (up to 7 × 3 cm) implanted using standard urethroplasty techniques.[8][9][11]

Key advantages over native BMG​

  • Minimal oral morbidity — only a 0.5 cm biopsy is needed vs a 5–7 cm graft harvest; oral morbidity is significantly less at 3 weeks and completely absent at 6 and 12 months vs native BMG harvest.[11]
  • Shorter operative time — no intraoperative graft harvest; median 104 min (TEOMG) vs 182 min (native BMG), p < 0.05.[11]
  • Applicable to patients with limited oral mucosa — useful when prior BMG harvest has depleted donor sites.

Clinical outcomes​

StudynDesignSuccessFollow-upKey Findings
Ram-Liebig 2017 (multicenter prospective)[8]99Prospective observational; 8 centers67.3% at 12 mo; 58.2% at 24 mo (Kaplan-Meier)24 moSuccess ranged 85.7% (high experience) to 0% (low experience); 77% had ≥2 prior surgeries; Qmax improved from 8.3 to 25.4 mL/s
Barbagli 2018 (multicenter retrospective)[9]384 techniques (ventral onlay, dorsal onlay, dorsal inlay, combined)84.2%median 55 moNo adverse reactions to engineered material; success comparable across techniques
Karapanos 2021 (single center)[10]77Retrospective68.8%median 38 moAll recurrences in patients with prior surgery / dilations; no oral-urethral adverse events
Karapanos 2023 (comparative)[11]77 (TEOMG) vs 76 (native BMG)Observational comparative68.8% vs 78.9% (p = 0.155, NS)52 mo (TEOMG); 53.5 mo (native BMG)No statistically significant overall difference; this does not establish equivalence. Tables 1/3 and the Discussion show lower observed success after >10 dilations: 5/16 (31.3%) vs 10/12 (83.3%), p = 0.006; shorter OR time and less oral morbidity with TEOMG

Critical observations​

  • Success rates with MukoCell® are highly dependent on surgical experience — 85.7% in experienced centers to near 0% in low-volume centers.[8]
  • The nonrandomized comparison does not establish equivalence to native BMG. In the subgroup with >10 dilations, Tables 1/3 and the Discussion give success of 5/16 (31.3%) versus 10/12 (83.3%), p = 0.006. These counts differ from the paper's abstract; selection and small subgroup sizes limit causal interpretation.[11]
  • Real-world overall success of 58–69% is lower than the 80–90% typically reported for native BMG, likely reflecting inclusion of complex multiply-operated patients and centers with varying experience.[8][10]

Biological Rationale — Oral Mucosal Wound Healing​

Oral mucosa generally heals with less scarring than skin. Mechanistic studies provide hypotheses for regenerative approaches but do not prove that minced or expanded grafts prevent urethral recurrence.[7][12][13][14][15][16]

Fetal-like wound-healing phenotype​

Buccal mucosa heals with minimal scarring — a property shared with fetal skin but lost in adult cutaneous tissue. Key mechanisms:

  • Distinct fibroblast subpopulations — oral mucosal fibroblasts (OMFs) exhibit pro-regenerative, anti-fibrotic gene expression profiles compared with skin fibroblasts.[12][13][14]
  • GAS6 – AXL signaling pathway — a landmark 2025 Science Translational Medicine study identified that OMFs use Growth Arrest Specific-6 (GAS6) – AXL receptor signaling to suppress fibrosis-related mechanosignaling through focal adhesion kinase (FAK). Inhibition of AXL in oral mucosa resulted in fibrotic wounds, while stimulation of AXL by exogenous GAS6 in facial skin yielded regenerative, scarless healing.[13]
  • Rapid re-epithelialization — oral keratinocytes exhibit signatures associated with proliferation and metabolic activity, enabling faster wound closure.[14]
  • Favorable inflammatory profile — oral wounds contain fewer immune mediators, blood vessels, and profibrotic mediators compared with skin wounds, with a more rapid transition from inflammatory to regenerative phases.[15][16]
  • Controlled fibroblast action — tightly regulated collagen deposition and organization prevent excessive fibrosis.[7][16]

These mechanisms support further research. Native oral wound healing, animal engraftment and durable human urethral patency are distinct outcomes and should not be treated as interchangeable evidence.

Future Directions​

Tissue-engineered oral mucosal substitutes​

Beyond MukoCell®, multiple approaches are under investigation:[17][18][19][20]

  • Buccal mucosa cells on acellular human dermis — good acute-stage tissue integration in clinical studies.[17]
  • Buccal mucosa cells on collagen matrix — similar early results.[17]
  • Urothelial cells on synthetic substrates — perform well in early studies.[18]
  • Acellular biomaterials alone — suitable only for onlay grafts; tubularized substitution commonly leads to fibrosis. Cell-seeded constructs are required for tubularized repairs.[18]
  • Buccal epithelial progenitor cells — recent porcine studies show progenitor buccal epithelial cells have higher potential to differentiate toward urothelial-like cells than adipose-derived mesenchymal stem cells, supporting their use as a cell source for urethral tissue engineering.[20]

Extracellular vesicles (EVs)​

Stem-cell-derived EVs (including exosomes) represent a cell-free therapeutic approach:[7][21][22]

  • Adipose-derived stem cell exosomes (ADSC-exos) on nanoyarn scaffolds promoted epithelialization, vascularization, and anti-fibrotic healing in animal urethral defect models without stricture or scar formation.[22]
  • EVs may prevent fibrosis and promote regeneration of urethral tissues without live cell transplantation.[21]
  • Clinical translation requires manufacturing standardization and cost reduction.[7]

Organoid systems​

Organoid technology offers the potential to generate three-dimensional, self-organizing mucosal tissue from small biopsies, potentially providing unlimited graft material. Remains in early preclinical stages.[7]

Comparison of Approaches​

ApproachGraft SourceDeliveryClinical StageSuccessKey AdvantageKey Limitation
Native BMG (standard)[23][24]5–7 cm buccal harvestOpen surgical placementGold standard80–90%Proven long-term outcomesDonor-site morbidity; limited graft size
Liquid / Minced BMG[1][2][3]Small buccal harvest → minced → fibrin glueEndoscopic injectionPreclinical and early human feasibilityAnimal engraftment and small uncontrolled human outcomesEndoscopic deliveryNo robust comparative clinical evidence
TEOMG (MukoCell®)[8][9][10][11]0.5 cm biopsy → lab expansion (3 wk)Open surgical placementNational German authorization; EAU recommends trial-only use58–84%Minimal oral morbidity; shorter OR timeLower success in dilated patients; experience-dependent; 3-wk manufacturing delay
Transurethral ventral inlay BMG[5]Standard BMG harvestMinimally invasive transurethralClinical (single center)95% at 36 mo (n = 44)Same-day discharge; no perineal incisionLimited to fossa navicularis / distal strictures
Endoscopic BMG (suturing device)[6]Standard BMG harvestEndoscopic with suturing deviceCase report1 patient, patent at 6 moFully endoscopic; no open incisionSingle case; very early data

Key Takeaways​

  • Liquid / minced BMG has animal proof-of-concept and early human feasibility data. It remains investigational; larger comparative trials are needed before routine adoption.[1][2][3]
  • MukoCell® reduces the amount of oral tissue harvested, but comparative durability and cost effectiveness remain uncertain. Follow the EAU recommendation for use within a clinical trial.[4][8][11]
  • GAS6–AXL signaling and oral fibroblast biology are mechanistic research findings, not validated predictors of human urethroplasty success.[13]
  • The field is moving toward cell-free and organoid-based approaches (extracellular vesicles, 3D bioprinting) that may eventually provide unlimited graft material without any donor-site harvest, though clinical translation remains years away.[7][21][22]

References​

  1. Nikolavsky D, Manwaring J, Bratslavsky G, et al. Novel concept and method of endoscopic urethral stricture treatment using liquid buccal mucosal graft. J Urol. 2016;196(6):1788-1795. doi:10.1016/j.juro.2016.05.028.
  2. Scott KA, Li G, Manwaring J, et al. Liquid buccal mucosa graft endoscopic urethroplasty: a validation animal study. World J Urol. 2020;38(9):2139-2145. doi:10.1007/s00345-019-02840-5.
  3. Gaur AS, Tarigopula V, Mandal S, et al. Modification of minced buccal mucosal graft endourethral urethroplasty: a pilot study. Indian J Urol. 2025;41(2):131-136. doi:10.4103/iju.iju_519_24.
  4. European Association of Urology. EAU Guidelines on Urethral Strictures: Tissue Transfer. 2026. Guideline.
  5. Sterling J, Daneshvar M, Nikolavsky D. Transurethral ventral inlay buccal mucosa graft urethroplasty: technique and intermediate outcomes. BJU Int. 2023;132(1):109-111. doi:10.1111/bju.16007.
  6. Ungerer G, Kemble J, Sischka M, Balzano FL, Warner JN. Endoscopic urethroplasty using buccal graft for male membranous urethral stricture. Urology. 2023;181:e200-e203. doi:10.1016/j.urology.2023.05.059.
  7. Sterling J, Hecksher D, Hayden C, et al. Buccal mucosa — a narrative review: how does it work, how is it used, what is coming next. Urology. 2026:S0090-4295(26)00169-X. doi:10.1016/j.urology.2026.03.015.
  8. Ram-Liebig G, Barbagli G, Heidenreich A, et al. Results of use of tissue-engineered autologous oral mucosa graft for urethral reconstruction: a multicenter, prospective, observational trial. EBioMedicine. 2017;23:185-192. doi:10.1016/j.ebiom.2017.08.014.
  9. Barbagli G, Akbarov I, Heidenreich A, et al. Anterior urethroplasty using a new tissue engineered oral mucosa graft: surgical techniques and outcomes. J Urol. 2018;200(2):448-456. doi:10.1016/j.juro.2018.02.3102.
  10. Karapanos L, Akbarov I, Zugor V, et al. Safety and mid-term surgical results of anterior urethroplasty with the tissue-engineered oral mucosa graft MukoCell — a single-center experience. Int J Urol. 2021;28(9):936-942. doi:10.1111/iju.14606.
  11. Karapanos L, Knorr V, Halbe L, et al. Comparison of oral morbidity and mid-term efficacy of anterior urethroplasty using an autologous tissue-engineered graft (MukoCell®) versus native oral mucosa graft. Int J Urol. 2023;30(11):1000-1007. doi:10.1111/iju.15247.
  12. Pereira D, Sequeira I. A scarless healing tale: comparing homeostasis and wound healing of oral mucosa with skin and oesophagus. Front Cell Dev Biol. 2021;9:682143. doi:10.3389/fcell.2021.682143.
  13. Griffin MF, Cook J, Morgan A, et al. Growth arrest specific-6 and angiotoxin receptor-like signaling drive oral regenerative wound repair. Sci Transl Med. 2025;17(805):eadk2101. doi:10.1126/scitranslmed.adk2101.
  14. Shi Y, Feng T, Hou D, et al. Single-cell transcriptomic analysis reveals distinct cellular and molecular signatures of human oral mucosa and skin. Cell Mol Life Sci. 2026. doi:10.1007/s00018-025-06007-x.
  15. Overmiller AM, Sawaya AP, Hope ED, Morasso MI. Intrinsic networks regulating tissue repair: comparative studies of oral and skin wound healing. Cold Spring Harb Perspect Biol. 2022;14(11):a041244. doi:10.1101/cshperspect.a041244.
  16. Glim JE, van Egmond M, Niessen FB, Everts V, Beelen RH. Detrimental dermal wound healing: what can we learn from the oral mucosa? Wound Repair Regen. 2013 Sep-Oct;21(5):648-60. doi:10.1111/wrr.12072.
  17. Osman NI, Hillary C, Bullock AJ, MacNeil S, Chapple CR. 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.
  18. de Kemp V, de Graaf P, Fledderus JO, Ruud Bosch JL, de Kort LM. Tissue engineering for human urethral reconstruction: systematic review of recent literature. PLoS One. 2015;10(2):e0118653. doi:10.1371/journal.pone.0118653.
  19. Habibizadeh M, Mohammadi P, Amirian R, Moradi M, Moradi M. Engineered tissues — a bright perspective in urethral obstruction regeneration. Tissue Eng Part B Rev. 2025;31(3):209-220. doi:10.1089/ten.TEB.2024.0124.
  20. Buhl M, Jundziłł A, Dąbrowski P, et al. Exploring the differentiation potential of adipose tissue-derived mesenchymal stromal/stem cells and progenitor buccal epithelial cells into urothelial cells. Front Bioeng Biotechnol. 2025;13:1687541. doi:10.3389/fbioe.2025.1687541.
  21. Wang Z, Knight R, Stephens P, et al. Stem cells and extracellular vesicles to improve preclinical orofacial soft tissue healing. Stem Cell Res Ther. 2023;14(1):203. doi:10.1186/s13287-023-03423-3.
  22. Wang L, Cheng W, Zhu J, et al. Electrospun nanoyarn and exosomes of adipose-derived stem cells for urethral regeneration: evaluations in vitro and in vivo. Colloids Surf B Biointerfaces. 2022;209(Pt 2):112218. doi:10.1016/j.colsurfb.2021.112218.
  23. Berg C, Singh A, Hu P, et al. Current trends in the use of buccal grafts during urethroplasty among Society of Genitourinary Reconstructive Surgeons. Urology. 2024;191:139-143. doi:10.1016/j.urology.2024.06.019.
  24. Wessells H, Morey A, Souter L, Rahimi L, Vanni A. Urethral stricture disease guideline amendment (2023). J Urol. 2023;210(1):64-71. doi:10.1097/JU.0000000000003482.
  25. Paul-Ehrlich-Institut. Tissue engineered products with a valid marketing authorisation: MukoCell. Regulatory listing.