The clinical efficacy of a new surgical technique of oral mucosal epithelial transplantation for severe ocular surface disorders

doi:10.21203/rs.3.rs-2244305/v1

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Research Article

The clinical efficacy of a new surgical technique of oral mucosal epithelial transplantation for severe ocular surface disorders

https://doi.org/10.21203/rs.3.rs-2244305/v1

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Journal Publication

published 07 Apr, 2023

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Background

Sever ocular surface disorder was one of the main blinding diseases. Reconstruction work for this kind of ocular surfaces is difficult due to the lack of original tissues. We developed a new surgical technique to reconstruct the ocular surface by using oral mucosal epithelia as the alternative for the limbus in such kind of eyes since 2011, which we called it oral mucosal epithelial transplantation (OMET). The study was designed to analyze the clinical efficacy for OMET in reconstruction of eyes with severe ocular surface disorder.

Methods

Retrospective review of patients with severe ocular surface disorder who underwent OMET during 2011 to 2021 at the Department of Ophthalmology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. Patients who had been followed up for at least 3 months after surgery and had sufficient pre- or postoperative records were included. Surgical efficacy was evaluated by comparing the following pre- and postoperative factors: best-corrected visual acuity, corneal transparency, neovascularization grade and symblepharon grade. Post-operative ocular surface impression cytology results were analyzed to study the morphology of the new corneal epithelial cells.

Results

Forty-eight patients (49 eyes) with a mean age of 42.55 ± 12.40 years (range, 12–66 years) were enrolled. Injuries included chemical burns (30 eyes), thermal burns (16 eyes), explosive injuries (1 eye), Stevens-Johnson syndrome (1 eye), and multiple pterygiums (1 eye). The mean follow-up period was 25.97 ± 22.99 months (range, 3–94 months). After surgery, 29 eyes (59.18%) had improved corneal transparency, and 26 eyes (53.06%) had improved best-corrected visual acuity. Forty-seven eyes (95.92%) had a stable epithelium, with a mean epithelization time of 26.04 ± 26.43 days. Forty-four eyes (89.80%) had a clearly reduced degree of neovascularization. Of 20 eyes with preoperative symblepharon, 15 (75%) were completely corrected, and 5 (25%) were partially corrected. Impression cytological studies showed that the newly transdifferentiated epithelial cells were morphologically different from the corneal or conjunctival epithelial cells and more like the oral mucosal epithelial cells of their origin.

Conclusions

OMET was an effective surgical technique for severe ocular surface disorder reconstruction.

Oral mucosal epithelia

ocular surface disorder

limbal stem cell deficiency

symblepharon

Ocular surface disorders may be caused by various ocular surface diseases, such as chemical or thermal burns, Stevens-Johnson syndrome, pemphigoid, infectious diseases or multiple surgical injuries. In severe damaged cases, the corneal surface is always featured with heavy neovascularization, stromal scarring, recurrent epithelial erosion and chronic inflammation (1–4); and combined with symblepharon which limit ocular motility, cause irregular tear fluid dynamics, cicatricial entropion, and hypophasis (5, 6). Reconstruction work for these kinds of cases is difficult due to the lack of original tissues-limbal stem cells, which maintaining a healthy ocular surface with a clearly separated corneal and conjunctival epithielium.

Various attempts were done to reconstruct the limbus including auto- and allo- limbal graft transplantation (7–9), or ex-vivo cultivated limbal stem cells (10, 11). For severe ocular surface disorders, autologous tissue was rare and the donor site was under the risk of limbal deficiency, while allografts were accompanied by high risk of rejection (12–14).Cultivated oral mucosal epithelial sheet transplantation (COMET) was recently developed which using oral mucosal epithelial stem cells as the alternative of corneal limbal stem cells, and had shown good efficacy in clinical use (15–17) comparing to some other sources such as mesenchymal stem cells (18–19), hair follicle stem cells (20), and human pluripotent stem cells (21). Nevertheless, the complexities of the cultivation techniques limited it to be widely used. To avoid such kind of disadvantages, a direct transplantation of oral mucosal graft was performed in total limbal stem cell deficiency eyes to reconstruct the limbus and had demonstrate good clinical efficacy (22, 23). A study for single oral mucosal epithelial transplantation in rabbits also showed complete success in restore the limbus (24). There were no further studies and clinical application reports for this ever since.

On these bases, we improved the oral mucosal graft transplantation technique and performed it on cases with severe ocular surface disorders. This study was then designed to analyze the clinical efficacy for this modified surgery in ocular surface reconstruction works.

Ethical Compliance

This retrospective study was approved by the ethics committee of Sir Run Run Shaw Hospital. Informed consent was provided to each patient. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki

Patients

We retrospectively reviewed patients who had severe ocular surface disorder and undergone oral mucosa epithelial transplantation (OMET) surgery from 2011 to 2021 and been followed up for at least 3 months after surgery. In this study, severe ocular surface disorder was defined as total limbal stem cell deficiency (LSCD) with or without symblepharon, or more than half of the limbal stem cells were destroyed combined with symblepharon. We analyzed data from the medical records. Patients with insufficient pre- or postoperative records were excluded.

A total of 48 patients with a mean age of 42.55 ± 12.40 years (range, 12–66 years) were enrolled in the study. Of them, 45 were male, and 3 were female. This patient cohort provided 49 injured eyes with etiologies including chemical burns (30 eyes), thermal burns (16 eyes), explosive injuries (1 eye), Stevens-Johnson syndrome (1 eye), and multiple pterygiums (1 eye). Thirty-three eyes had total LSCD, and 17 had partial LSCD. The diagnosis of LSCD was confirmed by impression cytology that showed the invasion of conjunctival epithelial cells and goblet cells on the corneal surface (25–27). Besides LSCD, 20 eyes had different degrees of symblepharon, 9 had persistent epithelial defects (PEDs), and 25 had previous ocular surface reconstruction surgery without OMET (Table 1). Before surgery, any ocular surface inflammation was controlled as far as possible. All patients were well-informed and consented to participate in the study.

Table 1

Preoperative ocular surface status
Variables	No. of eyes	LSCD scale		Ocular surface surgery history	PEDs	Symblepharon
Variables	No. of eyes	Total	Partial	Ocular surface surgery history	PEDs	Symblepharon
Chemical burns	30	26	4	12: AMT (n = 7), PKP (n = 2), LK (n = 1), KLAL (n = 2)	7	11
Thermal burns	16	5	11	11: AMT (n = 8), LK (n = 2), Deb (n = 1)	1	7
Explosion	1	1		1 (PKP)
SJS	1	1		No	1
MP	1		1	1 (Deb)		1
Total	49	33	16	25	9	20

LSCD, limbal stem cell deficiency; PEDs, persistent epithelial defects; AMT, amniotic membrane transplantation; PKP, penetrating keratoplasty; LK, lamellar keratoplasty; KLAL, kerato-limbal allograft; Deb, debridement of corneal surface invasion tissue; SJS, Stevens-Johnson syndrome; MP, multiple pterygiums.

The Surgical Procedures Of Omet

All surgeries were performed by one surgeon. The procedure was carried out under general anesthesia, keeping the endotracheal tube to one side of the mouth to allow for the harvesting of the oral mucosa graft. Normal saline was injected subconjunctiva to detach the epithelium and fibroblast connective tissue (Fig. 1A). In eyes with severe symblepharon, a traction suture was made to expose the operating area. The extent of the peritomy was determined by the degree of LSCD. Subconjunctival fibrovascular tissue was extensively removed to bare the sclera and corneal stroma. The conjunctival epithelium was retained as much as possible, especially in eyes with severe symblepharon (Fig. 1B).

The cleared ocular surface was then smoothly covered by a sheet of cryopreserved amniotic membrane (cryo-AM) as a basement membrane, which would be extended to the deep fornix area.

In all cases, the cryo-AM was sewn along the limbus with a circle and then interruptedly sutured in the fornix area, using 10 − 0 nylon (Fig. 1C). A 1.5 to 2 mm-wide oral mucosa graft was harvested from the lower lip (next to the gum) (Fig. 1D), and the subepithelial tissue was shaved off as much as possible (Fig. 1E). The length of the graft was determined by the degree of LSCD. The oral mucosal epithelial graft was sutured at the limbus area above AM (Fig. 1F-H). Finally, interruptedly sutured the middle of the eyelids by 5 − 0 nylon wire (Fig. 1I). OMET was combined with autologous conjunctival transplantation in the eyes with grade III and grade IV symblepharon (n = 3).

Postoperative Management

All patients were given systemic antibiotics and steroids for 3 days. Topical antibiotics, steroids, and artificial tear fluids were used throughout the recovery period. Both the oral and eyelid sutures were removed in the second week (10 to 12 days) after surgery. Bandage contact lenses were used according to the condition of the ocular surface epithelization. Patients were asked to follow up regularly.

Once epithelization was completed and stable, impression cytology was performed routinely in all patients to study the morphology of the new epithelial cells on the ocular surface. We followed Tseng’s method (28) for impression cytology, using cellulose acetate filter paper (millipore filter paper, 0.22µm pore size) and periodic acid Schiff (PAS) staining photographed under a light microscope.

Evaluation Of Efficacy

Surgical efficacy was evaluated by comparing the following pre- and postoperative factors:

I. Best-corrected visual acuity and corneal transparency.

Visual acuity was evaluated by standard logarithmic visual acuity chart. Visual acuity lower than 1/100 would be evaluated by finger counting and hand motion. The best-corrected result was recorded. Corneal transparency was recorded using slit-lamp photography.

II. Epithelization status.

Complete and stable epithelization was defined as the patient having no epithelial defects on the cornea or the conjunctival surface and remaining so throughout the follow-up period. In patients with recurrent epithelial defects, the epithelization time was recorded as the time when epithelization was complete, and no further defects occurred. Those with persistent epithelial defects whose epithelization was not complete at the last follow-up visit were recorded as patients with PEDs. The thickness of epithelium was examined with the Cirrus high-resolution optical coherence tomography system (Zeiss, Oberkochen, Germany).

III. Neovascularization grading.

Evaluation of ocular surface neovascularization (NV) was blindly graded by an experienced ophthalmologist using the slit-lamp photography results and according to Yoshiyuki Satake’s method (16). The following grades were awarded according to the extent of the NV: grade 0, no invasion of the cornea; grade 1, peripheral invasion of cornea 1 to 2 mm inside the limbus; grade 2, mid-peripheral invasion, greater than grade 1 but not involving the pupillary area; and grade 3, invasion of entire cornea, extending to the pupillary area (Fig. 2).

IV. Symblepharon grading.

The severity of the symblepharon was graded according to the length of the remaining conjunctiva, including the tarsal conjunctival depth and the bulbar conjunctival depth. Grades were awarded as follows: grade I if the remaining conjunctiva was equal to or longer than the length of the normal palpebral conjunctiva in that area, grade II if it was shorter than the normal palpebral conjunctiva but equal to or longer than the normal tarsus in that area, grade III if it was shorter than the normal tarsus, and grade IV if it was close to zero (ankyloblepharon) (Fig. 3) (5).

Statistical analysis

Data analysis was performed using SPSS software (version 23.0, IBM Corporation, USA). Normal distribution test for continuous variables was done before analyzing. We use Student t-test to analyze the normal distribution data, and Wilcoxon rank-sum test to analyze the non-normal distribution data. We used the Spearman’s rank correlation method to analyze the relationship between ordinal categorical variables. We use the Wilcoxon signed-rank test to analyze the compared ordinal categorical variables. A P value of less than 0.05 (two-sided) was considered statistically significant.

Surgery was successful in all cases. The average postoperative follow-up time was 25.97 ± 22.97 months (range, 3–94 months). Thirty-two eyes (65.31%) were followed up for over 1 year, and among them, 22 eyes were followed up for over 2 years.

After excision of the fibroconnective tissues and re-epithelization of the corneal surface, 26 cases (53.06%) had improved best-corrected visual acuity, and 29 eyes (59.18%) had better corneal transparency than before.

Forty-seven eyes (95.92%) completed epithelization in a mean time of 26.04 ± 26.43 days. Only 2 eyes had a tiny area of persistent epithelial defects. Age, etiology, preoperative surgery history, preoperative PEDs and LSCD scale were analyzed weather be related to the postoperative epithelization time. As to the statistical analysis results, it showed that postoperative epithelization time was related to LSCD scale (partial or total) and preoperative PEDs (R = 0.52 and 0.39, respectively; P < 0.01). Epithelization took less time to complete in patients with partial LSCD than patients with total LSCD (12.19 ± 5.90 days VS 32.80 ± 30.41 days, P < 0.05). Patients with preoperative PEDs took longer time than those without (53.71 ± 34.35 days VS 21.20 ± 21.93 days, P < 0.05).

After surgery, the oral graft was thick and edema under slit lamp examinations and anterior segment OCT examinations during the early stage. It would become thinner and smoother in later postoperative stages (Fig. 4).

The new corneal surface epithelia were thicker than normal corneal epithelia and were less transparent than normal corneal epithelia. When stained by fluorescein, the cornea surface was smooth, with abundant clusters of mucins which could be washed away by artificial tear fluid. One year after surgery, the epithelia were still changing, becoming thinner and more transparent than in earlier postoperative stages. (Fig. 5).

Impression cytology was performed in 47 patients (47 eyes), whose surface epithelium was complete and stable. The impression cytological study area covered the whole mucosa graft and a 3–4 mm corneal area. The results showed that the newly transdifferentiated epithelial cells were morphologically different from the corneal or conjunctival epithelial cells and more like the oral mucosal epithelial cells of their origin. Cells near the graft area were small, with a high ratio of nucleus to cytoplasm. They were irregular in shape, had multiple layers, and were darkly stained by PAS staining. During the migration into the central corneal area, they become larger and more regular in shape, their ratio of nucleus to cytoplasm decreased, they were more lightly stained, and had fewer layers. No conjunctival or goblet cells were detected above the corneal surface in the examined cases. (Fig. 6)

The degree of postoperative NV clearly decreased in 44 eyes (89.80%). There were 12 eyes (24.49%) with grade 0 NV, 27 (55.10%) with grade 1, 9 (18.37%) with grade 2, and only 1(2.04%) eye with 3 after OMET. This contrasts with preoperative NV assessment results: 0 eyes with grade 0 NV, 2 eyes (4.08%) with grade 1, 10 eyes (20.41%) with grade 2, and 37 eyes (75.51%) with grade 3. The rest 5 eyes had the same neovascularization invasion grade as preoperative’s (Table 2). The difference between pre- and postoperative NV was significant (P < 0.01).

There were 20 eyes with symblepharon before surgery, including 13 (65%) eyes with grade I symblepharon, 4 (20%) with grade II, 1 (5%) with grade III, and 2 (10%) with grade IV. After surgery, 15 eyes (75%) were completely released, 5 (25%) were partially released (2 changed from grade II to grade I, 1 changed from grade III to grade I, and 2 changed from grade IV to grade II) (Table 3). The difference between pre- and postoperative symblepharon was significant (P < 0.01).

Table 2

Neovascularization grading before and after surgery
Neovascularization grade	Preoperatively (eyes)	Postoperatively (eyes)
Grade 0	0	12
Grade 1	2	27
Grade 2	10	9
Grade 3	37	1

Table 3

Symblepharon grading before and after surgery
Symblepharon grade	Preoperatively (eyes)	Postoperatively (eyes)
Grade 0	0	15
Grade I	13	3
Grade II	4	2
Grade III	1	0
Grade IV	2	0

There were no complications during the operations. Postoperative follow-up showed that the oral mucosal epithelial grafts were well survived in all patients and no rejection reaction was observed. Eighteen eyes developed a mild hematocele under the amniotic membrane but recovered in 10 to 45 days without any sequelae. The donor sites in the lower lips healed in 9 to 12 days, and only 1 patient complained of stabbing pain during the first month. No other complications were observed during the whole follow-up period.

Severe ocular surface disorder is still a challenging disease to the ophthalmologists. The lack of limbal stem cells was the major problem of the reconstruction work. For limbus reconstruction, current management including autologous or allogenic limbal stem cell transplantation (7, 8), ex vivo expansion of limbal epithelial stem cells (10, 11), and alternative sources of corneal epithelial cells transplantation (15–21). Autologous tissue is limited in severe damaged patients, and complications such as conjunctival encroachment, graft dislodging and progressive conjunctivalization were also reported during the post-operative period (13). While allogenic limbal stem cell transplantation is associated with incidences of immune reactions, and the use of systemic immunosuppression had its own adverse effects (12, 29, 30). Alternative stem cell sources as aforementioned, including oral mucosal epithelial cells (15, 16), mesenchymal stem cells (18, 19), hair follicle stem cells (20), and human pluripotent stem cells (21). Among them, cultivated oral mucosal epithelial sheet transplantation (COMET) was used relatively frequently and verified to be effective (15–17, 31–33). Others were seldom applied in clinical uses and lack of evaluations. However, due to the specific techniques and experimental equipment requirements, COMET was limited in popularization, especially in undeveloped area, where such kind of eye disease was common be seen caused by chemical or thermal burns (34).

Liu J first reported that using the free oral mucosal graft which harvested from the inferior labial surface to reconstruct the limbus had received good results in 7 total LSCD patients (22). Although some of the NV remained recurrent and post operative epithelium showed opaque than normal corneal epithelium, it demonstrated that direct oral mucosal transplantation was useful in limbus reconstruction. Compared to COMET, this kind of surgery presented to have more advantages than it. The surgery skill was easy to operate, and the donor graft was abundant, safe and easy to harvested.

In this study, we modified the surgery procedures in attempts to get better results. We took the whole epithelium layer of the oral mucosal (including the stem cell layer and some sub-epithelium tissue) as a graft and transplanted them onto the amniotic membrane in the limbal stem cell deficient area. All the conjunctival epithelium was retained and sutured the to the outer side of the oral graft. The inner side of the oral graft remained free, Once the graft survived, new epithelial cells were generated by the stem cells and spread continuously to the cornea until the whole surface was epithelized. The amniotic membrane acted as the basement membrane, providing a smooth and firm surface for the epithelial cells to grow on and migrate across from the limbus area to the centra of the cornea surface. Different from Liu’s surgery, the oral graft we harvested was thinner, and post operative expansion of the stem cells was single side only to the cornea surface. According to the impression cytological study, the post-operative cornea surface epithelium was thicker at early stage and kept on changing for quite a long time after surgery. Some of them turned out to be a close to transparent outlook which was mimic to normal cornea epithelium. Several researchers had reported that ex vivo cultivated oral mucosal stem cells could be induced to differentiate into a new cell type, which was similar to the normal cornea epithelia (31–33, 35, 36). One research on animal showed that after two weeks of oral mucosal graft transplantation, a K3 positive and K13 negative stratified epithelium was covered on the cornea surface (37). Whether in vivo transplantation would induce the stem cells of the oral epithelial graft to change in human was unknown. Results in our study were encouraging, and the characteristics of the new epithelial cells and their functions are worthy of further study.

Analysis of the epithelization time suggested that the existence of preoperative PEDs was closely related to recovery time. A PED may indicate an inflammatory process and a poor ability of the ocular surface to self-heal. Postoperative epithelization took longer to complete in this kind of eye. The 2 eyes with postoperative PEDs in this study had had recurrent epithelial defects for years before surgery. Lid margin keratinization, entropion and trichiasis would be responsible. Correction of such lid margin pathologies before OMET would achieve a better result. We also inferred that a healthier preoperative ocular surface status would receive a shorter post-operative epithelization time. This hypothesis was supported by the fact that the group of patients with partial LSCD had a shorter epithelization time than those with total LSCD. Another interesting observation in the patients with partial LSCD was that the NV around cornea limbus in no surgery areas also diminished after surgery (Fig. 3, A1–2). The recession of these vessels may have been due to the healthier surface environment after OMET, with less inflammation and a completed epithelium leading to a stable environment.

We also found that the pre- and postoperative corneal surface NV were different. After surgery, there were large, looped vessels in the oral graft area. Small, tiny blood vessels branched out vertically from the loop and extended onto the corneal surface within the new epithelium or deeper in the front stroma, without conjunctival or fibroconnective tissue ingrowth. The density and ingrowth of the NV were related to the epithelization process. The defection of the epithelium would call in extra NV invasion. When the corneal surface epithelization was completed and became stable, the NV became looser and smaller in diameter, or even absence of blood.

Another encouraging result was that OMET was also effective in patient with Stevens-Johnson syndrome. These patients often have severe vision loss and discomfort due to persistent inflammation and NV of the ocular surface and no effective management other than corticosteroids and immunosuppressors (38, 39). And cultivated oral mucosal epithelial transplantation allows successful and sustained restoration of ocular surface anatomy with functional improvement (40). In our study, we found that although epithelization took over 2 months and was accompanied by intensive NV in SJS patient, in the later postoperative stages, the corneal surface became smooth and with less vessel invasion (Fig. 4B-C), which was encouraging to a consequent optical keratoplasty to improve the visual acuity.

The longest follow-up time in this study was over 90 months for 2 eyes whose ocular surface remained smooth and without any complications. The shortest follow-up time was 3 months for 3 eyes. For more systematic and reliable results, longer follow-up is required for all cases.

In conclusion, this study demonstrated that OMET surgery can be a viable technique for severe ocular surface disorder reconstruction, especially in those bilateral damaged or allogeneic tissue transplantation has failed eyes. A stable and completed corneal epithelium, decreased neovascularization, symblepharon lysis, improved corneal clarity and enhanced best-corrected visual acuity would be achieved after the surgery. The grafts were abundant and easy to get, and the surgery skills were easy to learn and implement. This technique has great potential in use and is worth further study.

OMET: Oral Mucosal Epithelial Transplantation, COMET: .Cultivated Oral Mucosal Epithelial Sheet Transplantation, LSCD: Limbal Stem Cell Deficiency, PED: Persistent Epithelial Defects, NV: Neovascularization, cryo-AM: cryopreserved Amniotic Membrane

Ethics approval and consent to participate

The study was approved by the ethics committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and informed consent was taken from all the patients.All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available because we are not able to permit any possibility of identifying persons from treatment history regardless of data anonymity, but data are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the Health Commission of Zhejiang Province (No. 2021KY-723, 2019ZD040 and WKJ-ZJ-1905), the Science and Technology Department of Zhejiang province (No. LGF21H120004 ), and the National Natural Science Foundation of China (U20A20387).

Authors’ contributions

Yuanfang Zhu: Data collection and assemble, Data analysis and interpretation, Manuscript writing. Wenya Qiu: Data collection and assemble, Provision of study materials or patients, Manuscript modification. Yesheng Xu: Provision of study materials or patients, Manuscript modification. Yufeng Yao: Conceptualization, Supervision, Administrative support, Manuscript modification. The authors read and approved the final manuscript:

Acknowledgements

Not applicable.

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No competing interests reported.

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The clinical efficacy of a new surgical technique of oral mucosal epithelial transplantation for severe ocular surface disorders

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Ethical Compliance

Patients

The Surgical Procedures Of Omet

Postoperative Management

Evaluation Of Efficacy

Statistical analysis

Results

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1