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. Related emerging strategies include tissue-engineered oral mucosal grafts (TEOMG), extracellular vesicles and organoid systems, which 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 main limitation of DVIU, its high recurrence rate: the AUA reports failure rates above 80% for another endoscopic procedure in strictures previously treated with dilation or DVIU.[24] LBMG aims to provide a biological substrate that promotes re-epithelialization with healthy mucosa instead of fibrotic scar.[1][2]
Preparation of liquid BMG
- 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).
- Mechanical mincing. The harvested tissue is mechanically minced into micrografts containing epithelial cells, basement membrane, and lamina propria.
- Suspension. In the original rabbit LBMG protocol, minced tissue was suspended in fibrin glue. Gaur's modified human protocol centrifuged the minced graft, suspended the buccal-cell-containing supernatant in fibrinogen, and added thrombin only after endoscopic delivery.[1][3]
- 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]
- Standard direct vision internal urethrotomy (DVIU) is performed to incise the stricture.
- Deliver the graft preparation onto the urethrotomy bed after DVIU. In Gaur's modified human pilot, a 12 Fr Foley was placed and an 11 Fr scope advanced beside it; after stopping irrigation and aspirating residual fluid, the surgeons instilled approximately 2 mL of buccal-cell-containing supernatant in fibrinogen through a 5 Fr catheter under direct vision, then added thrombin to set the scaffold in situ. Foley traction and gentle perineal pressure were maintained for 10 minutes.[3]
- In the rabbit LBMG protocols, fibrin glue held tissue micrografts against the urethrotomy bed. Gaur's human modification delivered cell-containing supernatant and set the fibrin scaffold in situ.[1][2][3]
- In Gaur's human pilot, the Foley placed before graft delivery remained in situ until postoperative day 5.[3]
- Rabbit tissue micrografts demonstrated histologic engraftment; whether the cells delivered in Gaur's human modification implant, re-epithelialize the urethrotomy site and prevent recurrence remains unproven.[1][2][3]
Preclinical evidence
The foundational LBMG studies used rabbit stricture models. Subsequent early human work is discussed below.
| Study | Phase | n | Design | Results |
|---|---|---|---|---|
| Nikolavsky 2016 (proof of concept)[1] | Phase 1 feasibility; Phase 2 efficacy | Phase 1: 3 rabbits; Phase 2: 9 rabbits (6 treated, 3 controls) | DVIU + LBMG vs DVIU + fibrin glue only | Phase 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 and controls showed fibrosis/chronic inflammation, but only 1/3 had a persistent stricture on RUG/cystoscopy |
| Scott 2020 (validation)[2] | Single-phase validation | 26 rabbits induced; outcomes reported for 12 treated and 13 controls | Randomized DVIU + LBMG vs DVIU + fibrin glue only; blinded radiographic + histologic assessment | 8/12 (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. Both studies found that mechanically minced buccal mucosa micrografts can engraft in the rabbit urethra when delivered endoscopically in fibrin glue (6/6 and 8/12 treated animals).[1][2]
- Histology. 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]
- Follow-up. Engraftment was present at 24 weeks, the longest time point assessed.[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]
Current status
The field has progressed to early human feasibility studies, while remaining investigational. A 2025 uncontrolled pilot (Gaur) enrolled 30 men with author-defined primary bulbar strictures <2 cm; recurrent, penile and posterior strictures and unavailable oral donor sites were excluded.[3] The authors defined success as AUA symptom score <7, Qmax >12 mL/s and PVR <100 mL, with cystoscopy for suspected recurrence.[3] Among 30 enrolled men, they reported success rates of 93.3% at 12 months, 83.3% at 24 months and 76.6% at 30 months; seven recurred and 16 completed 30 months of follow-up.[3] The patient-level table also labels several men as successes despite scores outside the stated criteria and lists three recurrence times beyond recorded follow-up.[3] After cold-knife urethrotomy, the investigators instilled buccal-cell-containing supernatant in fibrinogen and then added thrombin to form the scaffold in situ.[3] Only 16 completed that follow-up interval. A nonrandomized single-center analysis pooled Gaur's 30-patient pilot with additional MBGEU cases from a protocol allowing prior failed urethrotomy and bulbar strictures up to 4 cm, and compared the pooled group with a separate cultured-cell cohort.[28] The authors reported six-month success in 54/60 MBGEU and 22/30 cultured-cell patients, with postoperative sepsis in two cultured-cell patients.[28] It included neither a DVIU-only nor an open-urethroplasty arm.[28]
Related minimally invasive approaches
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, with 95% (42/44) of patients patent at mean 36-month follow-up in a single-institution retrospective series of fossa navicularis and distal urethral strictures.[5]
- Endoscopic BMG with suturing device. The 2023 membranous-stricture case was patent at six months.[6] A subsequent single-surgeon retrospective series reported a traversable urethra at four months in 23/28 men (82%; 24 had prior radiation), with median follow-up of eight months; 16/28 later received an AUS.[27] Three of the 28 men later underwent cystectomy with diversion for radiation-related disease, including one with a delayed urosymphyseal fistula amid extensive radionecrosis. The authors advise careful selection when substantial necrosis or calcification is present.[27]
Tissue-Engineered Oral Mucosal Grafts (TEOMG / MukoCell®)
Tissue-engineered oral mucosal grafts are the most clinically advanced form of expanded 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 cm² buccal mucosa biopsy is taken from the patient’s cheek and sent to a laboratory. Over approximately 3 weeks, cells are expanded on a collagen matrix scaffold to produce an engineered graft for standard urethroplasty; the cited comparative cohort used a predetermined 3.8 × 2.8 cm MukoCell sheet.[8][9][11]
Key advantages over native BMG
- Less oral morbidity in one comparison. MukoCell® manufacture used a 0.5 cm² cheek biopsy rather than an intraoperative native graft harvest. In a nonrandomized 77-versus-76 patient comparison using a nonvalidated questionnaire, oral symptoms were less frequent at 3 weeks and none were reported in the TEOMG group at 6 or 12 months.[9][11]
- Operative time. MukoCell required no intraoperative oral-graft harvest; in a nonrandomized comparison, median surgery duration was 104 min with TEOMG versus 182 min with native BMG (p <0.001), and graft-placement techniques differed between groups.[11]
- Oral biopsy remains necessary. MukoCell manufacture requires an available 0.5 cm² oral mucosa biopsy. The EAU guideline strongly recommends against use outside a clinical trial.[4]
Clinical outcomes
| Study | n | Design | Success | Follow-up | Findings |
|---|---|---|---|---|---|
| Ram-Liebig 2017 (multicenter prospective)[8] | 99 | Prospective observational; 8 centers | 67.3% at 12 mo and 58.2% at 24 mo (conservative Kaplan–Meier estimates using a post hoc recurrence assessment of investigator rating, spontaneous voiding and Qmax after the prespecified criterion could not be applied consistently); evaluable-patient proportions 46/65 (70.8%) at 12 mo and 30/39 (76.9%) at 24 mo | 24 mo | Success ranged 85.7% (high experience) to 0% (low experience); 64/83 (77.1%) with available history had ≥2 prior surgeries; mean Qmax was 8.3 mL/s preoperatively (n = 57) and 25.4 mL/s after catheter removal (n = 51) |
| Barbagli 2018 (multicenter retrospective)[9] | 38 | 4 techniques (ventral onlay, dorsal onlay, dorsal inlay, combined); recurrent strictures, median length 5 cm; lichen sclerosus and failed hypospadias excluded | 84.2% (32/38) | median 55 mo | No adverse reactions to engineered material; success 80–100% across techniques |
| Karapanos 2021 (single center)[10] | 77 | Retrospective | 68.8% | median 38 mo | All recurrences in patients with prior surgery / dilations; one urethrocutaneous fistula (1.3%) requiring reoperation; otherwise no reported oral-urethral adverse events related to MukoCell® |
| Karapanos 2023 (comparative)[11] | Same 77 TEOMG recipients as 2021 row vs 76 native BMG recipients | Observational comparison with longer TEOMG follow-up | 68.8% vs 78.9% (p = 0.155, NS) | 52 mo (TEOMG); 53.5 mo (native BMG) | Overall difference was not statistically significant; no equivalence analysis. Success after >10 prior dilations was lower with TEOMG (full-text table: 5/16 [31.3%] vs 10/12 [83.3%], p = 0.006; the abstract contains inconsistent comparator and p values); At 3 weeks, RUG showed extravasation in 7/77 TEOMG patients (9.1%) versus 5/76 native-BMG patients (6.6%); six TEOMG cases resolved with prolonged catheterization and one required revision. Median OR time and reported oral morbidity were lower with TEOMG |
Critical observations
- In one observational MukoCell® cohort, success ranged from 85.7% with high surgical experience to 0% with low surgical experience.[8]
- After repeated urethral dilations, TEOMG success was lower (31.3% vs 81.3% in the abstract, p = 0.003; the full text gives 5/16 (31.3%) vs 10/12 (83.3%), p = 0.006).[11]
- The multicenter TEOMG cohort reported 58.2% conservative Kaplan–Meier success at 24 months, and the single-center cohort reported a 68.8% recurrence-free rate at median 38 months; these separate outcomes are below the 80–90% perceived native-BMG success reported by surgeons in a GURS member survey.[8][10][23] The MukoCell series included many multiply operated patients and centers with varying experience.[8][10][23]
Biological Rationale — Oral Mucosal Wound Healing
Oral mucosa generally heals with less scarring than skin.[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. 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 2025 Science Translational Medicine study in mice identified that murine OMFs use Growth Arrest Specific-6 (GAS6) – AXL receptor signaling to suppress fibrosis-related mechanosignaling through focal adhesion kinase (FAK). Inhibition of AXL in murine oral mucosa resulted in fibrotic wounds, stimulation of AXL by exogenous GAS6 in murine facial skin yielded regenerative healing, and rare human oral scars showed decreased GAS6 and AXL expression.[13]
- Rapid re-epithelialization. Keratinocytes in uninjured human oral mucosa show proliferation- and metabolism-associated transcriptomic signatures that may contribute to rapid repair; this tissue comparison did not measure wound closure.[14]
- Favorable inflammatory profile. Compared with skin wounds, oral wounds have a shorter inflammatory response, fewer profibrotic mediators and less wound-induced neovascularization, even though uninjured oral mucosa is more vascular than skin dermis.[15][16]
- Controlled fibroblast action. Tightly regulated collagen deposition and organization prevent excessive fibrosis.[7][16]
These mechanisms support further research.
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. In the first human series of this construct, five patients with lichen sclerosus strictures received a graft of autologous keratinocytes and fibroblasts cultured on de-epidermized donor dermis, with follow-up of 32–37 months (mean 33.6).[26] All grafts initially took, but one patient required complete excision of the grafted urethral segment and one required partial excision, both for graft fibrosis and hyperproliferation; the remaining three retained a patent urethra with the graft in situ, though all three required some form of instrumentation.[17][26] A later report of these five men found four with an engineered graft in situ and a patent urethra at nine years after additional treatment.[18]
- Buccal mucosa cells on collagen matrix showed similar early results.[17]
- Urothelial cells on a synthetic substrate also performed well in the early studies reviewed.[17]
- Acellular biomaterials alone commonly led to fibrosis when used for long urethral defects in animals. In clinical use a non-seeded matrix appears suited only to onlay grafts, and a cell-seeded construct appears more beneficial for tubularized substitution.[17][18] The EAU 2026 guideline weakly recommends against cell-free tissue-engineered grafts in extensive spongiofibrosis, after failed prior urethroplasty, or for strictures >4 cm.[4]
- 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 an animal urethral defect model, with no urethral stricture or scar formation at 4 weeks.[22]
- A preclinical review describes EV-mediated fibrosis prevention and regeneration in orofacial soft tissues without live cell transplantation.[21]
- Clinical translation requires manufacturing standardization and cost reduction.[7]
Organoid systems
Organoid systems are three-dimensional mucosal cultures being explored as a future source of tissue for urethral reconstruction; production of clinically usable grafts remains unestablished.[7]
Comparison of Approaches
| Approach | Graft Source | Delivery | Clinical Stage | Success | Advantage | Limitation |
|---|---|---|---|---|---|---|
| Native BMG (standard)[23][24] | 5–7 cm buccal harvest | Open surgical placement | Standard of care | Surgeon-reported 80–90% | Extensive clinical experience | Donor-site morbidity; limited graft size |
| Liquid / Minced BMG[1][2][3] | Small buccal harvest → tissue micrografts (rabbit) or centrifuged cell-containing supernatant (human) → fibrin scaffold | Endoscopic injection | Preclinical and early human feasibility | Animal engraftment and small uncontrolled human outcomes | Endoscopic delivery | No robust comparative clinical evidence |
| TEOMG (MukoCell®)[4][8][9][10][11] | 0.5 cm² biopsy → lab expansion (3 wk) | Open surgical placement | National German authorization; EAU recommends trial-only use | 58.2% Kaplan–Meier at 24 mo (99 enrolled; 98 included in the analysis); 84.2% (32/38) at median 55 mo in a separate cohort | Minimal oral morbidity; shorter OR time | Lower success than native oral mucosa graft after >10 prior dilatations in one observational comparison; experience-dependent; 3-wk manufacturing delay |
| Transurethral ventral inlay BMG[5] | Standard BMG harvest | Minimally invasive transurethral | Clinical (single center) | 95% at mean 36-mo follow-up (n = 44) | Same-day discharge; no perineal incision | Limited to fossa navicularis / distal strictures |
| Endoscopic BMG (suturing device)[6][27] | Standard BMG harvest | Endoscopic graft placement with suturing device | Case report plus single-surgeon retrospective series | 2023 case: viable graft at 10 wk and no recurrence reported at 6 mo; 2025 series: 23/28 (82%) passed a 17 Fr cystoscope at 4 mo, median follow-up 8 mo | Avoids open urethral exposure | Short follow-up; outcomes from a selected, mostly radiated cohort |
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]
- Extracellular vesicles, organoids and 3D bioprinting are separate investigational approaches to urethral tissue engineering. Evidence is insufficient to determine whether they will supply clinically usable grafts or avoid donor tissue harvest.[7][21][22][29]
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