For glaucoma patients with appropriate indication, AM can be transplanted as a secondary adjunct to surgical procedures to replace lost or missing conjunctiva, which can leave the sclera exposed [
4]. AM is known to reduce scarring at the time of the filtering surgery; repair any early or late blebs and act as a protective cover in valve procedures [
43]. When used in conjunction with any glaucoma surgery, AM transplantation is used to protect and cover any exposed sclera to improve both patient outcomes and the rate of complications [
44,
45]. It should be noted that as AM is a human tissue, it can have variable persistence time dependent on the inflammation present at the ocular surface and the method of application. Although literature reports its high tensile strength and ability to be excellent for host-tissue integration [
46]. Table
1 summarises some useful papers on glaucoma.
Table 1
Summary table: Amniotic Membrane (AM) in Glaucoma papers*
| Series of 3 cases | AM on tube exposure of glaucoma tube shunt | 3 | 6 months to 2.5 years | Successful re-epithelialization in all 3 cases |
| Prospective clinical trial | AM covering Ahmend glaucoma valve implantation | 7 | 16.8 ± 4.6 months | Suggests to be a safe and effective procedure. Likely to reduce the risk of bleb encapsulation |
| Prospective clinical trial | Compare AM with conjunctival advancement for glaucoma bleb leaks | 2 groups 15 each | 19 months | Survival Rate AM = 46%, Conjunctival adv. = 100% |
| Randomized controlled trial | AM for leaking glaucoma filtering blebs vs conjunctival advancement | 30 | 80 months | AM was more susceptible to early re-leakage, but can be an alternative to conjunctival advancement |
| Prospective randomized study | Compare trabeculotomy with mitomycin C with vs without AM transplantation | 37 19 with mmc and AM; 18 with mmc alone | 12 months | mmc and AM has lower IOPs and less complications rates than mmc alone |
| Retrospective case series | Evaluation of AM graft in glaucoma shunt surgery | 44 | 22 ± 3 months | AM graft is a good tectonic support and allows visualisation of the underlying tube |
| Systematic Review | Evaluate the safety and effectiveness of trabeculectomy with or without AM transplantation | Varied 67 articles | Varied | Association of AM transplantation shown to be more effective and safer than without it |
| Double-blind Clinical trial | AM transplantation vs Mitomycin C for Ahmed glaucoma Valve | 75 | 12 months | No statistically significant difference |
In conjunction with trabeculectomy
For glaucoma surgeries, the use of AM transplantation in conjunction with trabeculectomy procedures is the most documented glaucoma indication [
4,
13]. First reported by Fujishima et al. [
47] the surgical procedure for AMtransplantation following trabeculectomy is yet to be standardised. Some studies report the placement of the AM below of scleral flap in a ‘inlay-graft’ fashion [
48,
49], however, other studies state that the tissue is placed over the wound in an ‘onlay-graft’ fashion to over the entire exposed scleral bed [
32,
44,
50]. As a whole, data shows the application of AM epithelial-side-down [
2] when placed onto the wound. Although these differences are present, no obvious differences have been noted regarding outcomes dependent on surgical technique. Future research in this area has the potential to define if different surgical methodologies may lead to higher success rates.
In 2015, Wang et al. [
51] conducted a meta-analysis on the data of device modified trabeculectomy procedures for glaucoma conditions. This analysis studied 33 papers that met the inclusion criteria, which included 18 studies utilising AM. These studies reported that tissue transplantation is associated with a lower intraocular pressure at 12 months, compared to trabeculectomy alone [
51]. Although this review was limited by the loss of follow-up in 11/18 studies, but this collation of data presented the benefits of AM as an adjunct to this procedure.
Following this, Shen et al. [
2] ran a meta-analysis of randomised controlled clinical trials that assess the AM assisted trabeculectomy to trabeculectomy alone. Shen et al’s meta-analysis included 174 eyes across 5 studies, the data noted that there was a statistically significant benefit in the intraocular pressure of patients in the AM treatment group at 3 months (
\(p < 0.0003\)) and 12 months (
\(p = 0.02\)). Whilst the complete success of patients’ procedures in the AM group were also significant at 6 months (
\(p = 0.02\)) and 12 months (
\(p = 0.003\)) compared to the trabeculectomy alone group. Additional to this, fewer complications were noted in the AM group. However, no benefit observed differences regarding the number of anti-glaucoma medications; hypotony; encapsulated bleb and choroidal detachment. In conclusion, Shen et al. noted that AM transplantation with trabeculectomy is a safe and efficient treatment compared to trabeculectomy alone.
Studies have researched the use of AM transplantation paired with mitomycin-c application when undergoing trabeculectomy to trabeculectomy and mitomycin-c alone. Sheha et al. [
48] studied 37 eyes in a two-arm comparative study. Complete success at 6 months was noted 93.6% (15/16) of the study eyes, compared to 9/15 (60%) of the trabeculectomy alone control eyes. The AM treatment group saw statistically significantly improved intraocular pressure compared to the control group at 3-months (
\(p = 0.0002\)), 6-months (
\(p < 0.0001\)), 9-months (
\(p < 0.0001\)) and 12-months(
\(p < 0.0001\)). Sheha et al. [
48] noted that the use of mitomycin-c and AM combined in a trabeculectomy with mitomycin-c procedure providers lower intraocular pressure, higher success rates and fewer complications.
Most recently, Roque et al. presented a retrospective study of 51 eyes of 45 glaucoma patients, which compared trabeculectomy with mitomycin-c application to patients who had undergone trabeculectomy with mitomycin-c and amniotic membrane. This study showed no significant difference between the two groups, however, it should be noted that this was not a randomised and controlled cohort of patients due to the retrospective nature of the study [
52].
During glaucoma procedures, mitomycin-c is used to limit scar formation and to improve the bleb formation following trabeculectomy procedures [
53]. However, mitomycin-c can cause the formation of thin-walled blebs, which can lead to over-filtration, hypotony and can form serious complications such as: bleb leaks; bleb infections and endophthalmitis [
53]. Therefore, AM has a potential to improve the success rate and lower the complications rate of trabeculectomies with mitomycin-c even further [
2].
Published clinical data supports the use of AM in conjunction with trabeculectomy procedures, and this also may be supported using mitomycin-c in the procedure too. However, further research is required tos define the most beneficial surgical technique of above or below the scleral flap, as placement as an onlay-graft or inlay-graft.
Trabeculectomy surgeries is known to rely on the availability of mitomicin-C. At the end of 2019, the world experienced an international shortage of this vital medication for glaucoma surgeons [
54,
55]. Taking this into account, studies regarding the AM as a possible substitute for mitomycin-C has an extreme importance to be considered.
Leaking bleb fixture
For patients undergoing AM transplantation to manage a leaking bleb, the tissue is placed over the bare sclera, often epithelial-side-down [
56]. The AM is supported by the corneoscleral limbus with the opposite side being undermined under the healthy conjunctival tissue and secured in place at both areas [
56]. The aim of this treatment is to reduce inflammation, vascularisation and allow for the intraocular pressure of the patient to allow for stabilisation.
A meta-analysis was published by Bochmann et al., in 2012 [
57] that noted the variations of treatments for managing late trabeculectomy bleb leaks. Within the Bochmann et al. analysis, one randomised controlled study of 30 eyes of 30 patients by Budenz et al. [
58] matched the inclusion criteria and was included in the analysis. The study arms compared patients treated with conjunctival advancement to those who underwent AM transplantation. The primary outcome of the study was the sealing of the bleb leak confirmed by a negative Seidel’s test after 1 month, 1 year and 5 years. In the 19.5 ± 6.9 months follow-up period, the cumulative survival rate of the bleb reconstruction was 81% at 6 months and 74% at 1 year for the amniotic membrane group. However, it was at 100% for conjunctival advancement for the follow-up period. Recurrence of the bleb was seen in seven of the AM cases, with two persistent leaks and three that required repeat surgery. However, intra-ocular pressure, visual acuity and the number of glaucoma medications prescribed were comparable between the two groups.
The long-term outcomes (
\(73 \pm 7\) months) of the patient cohort included in the Budenz et al. study were evaluated by Rauscher et al. [
59]. During this analysis, it was noted that there was no significant difference in patients’ intraocular pressure, final visual acuities, or difference in the number of glaucoma medications. Bleb vascularity was significantly lower in the AM group (
\(p = 0.2\)) when comparing failed bleb repair, 7/30 of the AM group failed with 4/30 of the conjunctival advancement group failing (
\(p = 0.44\)), showing no statistically significant difference. Rauscher et al. concluded that although prone to early potential failure, AM may be a suitable alternative to conjunctival advancement in the long-term.
Since the release of Bochmann et al’s meta-analysis, Sethi et al. [
60] published a retrospective case series on patients who underwent sub-conjunctival AM draping to repair leaking cystic blebs. Of the 17 eyes of 16 patients included in the study at a follow-up of
\(21.4 \pm 7.3\) months, a success rate of 88% (15/17 eyes) was noted, patients saw a stabilisation of the intraocular pressure from
\(5.7 \pm 2.8\) mmHg to
\(13.1 \pm 3.4\) mmHg and LogMAR visual acuity improved from
\(0.7 \pm 0.8\) preoperatively to
\(0.1 \pm 0.1\) LogMAR units (
\(p < 0.030\)).
The data regarding the use of AM transplantation as an adjuvant to manage leaking blebs is relatively mixed. Although the technique is viewed as being safe, there are more effective treatment methods available, such as conjunctival advancement. Therefore, this technique may be most viable in patients with a lack of conjunctival tissue, where alternative treatment options are required. Otherwise, further research is required to refine the surgical technique to evaluate if there is a potential for the improvement of AM use in the management of leaking blebs.
Glaucoma valve or shunt implantation
A glaucoma shunt tube or valve will be covered using a range of transplantation materials. This includes: pericardium, donor corneal tissue, sclera, collagen matrixes or AM. The aim of covering the implantation is to avoid erosion, which can cause implantation exposure [
61,
62]. Ainsworth et al. in 2006 [
63] first noted the application of AM to manage exposed tubes following a glaucoma tube shunt surgery in a small case series of 3 patients. In one of these cases, they described a technique using a double AM graft to cover the tube from the glaucoma drainage device (GDD). The GDD tube is first covered by a full thickness scleral patch, sutured with four 9.0 nylon stitches. Then the first AM graft is placed with epithelial side up. The size of this graft is described to be larger than the above conjunctival defect. The conjunctiva is placed above the first AM implant, noticing that between the conjunctiva edges, a gap is kept. Four 10.0 nylon sutures fixate the conjunctiva to the underlying epsclera/AM draft. In sequence the second AM patch is applied over the epithelial defect. This second AM patch is larger than the epithelial defect and is placed with epithelial side down. Finally, four 6.0 nylon sutures are done at the margins of the second AM patch to keep it in the right position.
The use specifically in ahmed glaucoma valve procedure was noted by Amini et al. in 2010 [
64]. The largest study in this area has been conducted by Yazdani et al. in 2016 [
53], a randomised, double-masked 3 arm clinical trial of 75 eyes of 75 patients. The patient arms included ahmed glaucoma valve (AGV) alone compared to AGV with mitomycin-c compared to AGV with AM transplantation. Patients in the AM arm had their AGV wrapped with tissue prior to implantation with the aim to reduce fibrosis and postoperative vascularisation. Regarding intraocular pressure, at 12-weeks no statistically significant difference was noted (
\(p = 0.13\)) between all three arms. Similar to this, there was no difference in the number of glaucoma medications taken by patients in any of the arms (
\(p = 0.22\)). This study is limited by the short follow-up time of 12 months. A longer-term study is required to further assess the benefit of this treatment. Both AM and mitomycin-c have been shown to be safe methods of treatment, however, in this study, neither were associated with improved outcomes within the 12-month follow-up period.
In regard to glaucoma shunt addition, Sheha et al. in 2011 [
3] conducted a retrospective case series of 44 eyes who underwent the implantation of a glaucoma drainage device with an AM graft. The patients had a follow-up of
\(22 \pm 3\) months. Of the cohort, 93% (41/44) of eyes had a successful procedure. The incidence of tube exposure was 2.3%, which is comparable to alternative substrate materials that are applied in these conditions. Sheha et al. [
3] concluded that AM presented good tectonic support and allows for the clinician to have direct visualisation of the implanted shunt through the conjunctiva and tissue graft. Some cases have reported the use of a double layer AM transplantation when protecting a shunt tube to provide additional durability and support, if the AM transplantation were to begin to degrade [
65].
The current body of literature with AM transplantation in glaucoma shunt or valve surgeries is relatively limited and offers the opportunity to be further explored to fully provide data regarding its long-term effectiveness for recipients. The most common reported surgical methodology for applying the AM in shunt procedures is during the primary procedure [
66,
46], however, there is additional reports where AM has been transplanted following an exposed shunt tube, which may or may not have been covered with other transplant materials (i.e. scleral flap or pericardium) [
67].