No eyes had postoperative adverse events such as endophthalmitis, hypotony, IOP elevation, or retinal or choroidal reactions; no rejection of the hAM implanted in the subretinal space was reported after more than 1 year of follow-up.
Human amniotic membrane has been used in superficial ocular pathologies since 1940. Although hAM reduces inflammation and scarring and facilitates epithelialization, there are still uncertainties regarding the integration of the graft and the mechanisms through which it exerts its long-term effects.
Recently, the interest of authors has been directed toward the interactions of the hAM with retinal structures and in particular with the RPE. Amniotic membranes induce RPE cell proliferation and differentiation.
In vivo transplantation of the hAM to repair a choroidal wound has already been performed in one case, and good integration of the plug to the suprachoroidal structures was observed.23
More recently, the Seprafilm Adhesion Barrier (Sanofi, Bridgewater, NJ), a bioreabsorbable translucent membrane composed of sodium hyaluronate and carboxymethylcellulose, was developed to prevent pathological adhesions after abdominal and pelvic surgery. It was used with success to repair retinal breaks in retinal detachment in four cases.24
Haruta et al applied laser retinopexy around the retinal breaks and used the seprafilm sheet to cover the breaks to avoid intravitreal dispersion of proliferating retinal pigment epithelial cells. In our cases, we did not apply laser retinopexy. We implanted the hAM plug in the subretinal space to maximize its interaction with the RPE, to stimulate tissue proliferation and retinal breaks closure. After 3 months, we decided to remove the silicone oil in all the cases of retinal detachment. Preoperative and intraoperative OCT showed a thin retinal substrate over the plug of hAM, which covered the previous retinal break. The repaired retina seemed organized in normal layers as well as the original retina, and it adhered well to the underlying hAM. The results led us to conclude that hAM plugs stimulate retinal proliferation and organization in layers, which can virtually recover the original retinal function.
The treatment of recurrent macular holes is still a challenge for a retinal surgeon. The failure rate of primary surgery in idiopathic macular hole is less than 10%. It may be due to residual epiretinal traction, insufficient gas tamponade, poor compliance by the patient in keeping prone position, or no obvious cause. In recent years, many management options have been proposed, such as laser treatment,25 a second operation with transforming growth factor-beta 2 application,26 or autologous platelet concentrate27 inserted inside the macular hole to achieve its closure.
Some authors have tried alternative endotamponades such as semifluorinated alkane F6H8,28 standard silicone oils,29 or heavy silicone oils30–32 to induce macular hole closure.
Modern approaches to recurrent macular holes are the use of a plug of ILM peeled from the periphery of the posterior pole and inserted into the macular hole,33 a neurosensory retinal free flap,34,35 or capsular lens fragments.36,37
The above mentioned procedures have gained from 60% to 90% of anatomical success and a BCVA improvement of 80% in the case of anatomical success.
In our series, the recurrent macular hole was resolved during the first week after the operation in all the cases. After the gas endotamponade disappeared, the OCT scan demonstrated the macular hole closure without glial process but with a fully stratified retinal layer over the hAM patch. During the follow-up period, the neuroretina over the hAM plug differentiated to form retinal layers, in particular in the outer layer such as the external limiting membrane and ellipsoid zone. This process can probably be associated with the visual acuity improvement found during the follow-up.
Some authors have described retinal fibrosis and pigment epithelium dystrophy in the macular area, after internal limiting membrane autologous transplantation for recurrent macular hole, which can affect final visual recovery.38 The OCT analysis on our patients did not show these pathological findings (Figure 9).
In conclusion, we have described a new technique that uses a subretinal placement of a hAM plug in patients with recurrent macular hole and complex retinal detachment with posterior breaks and PVR.
Anatomical success was reached in all cases. The amniotic membrane stimulated a retinal ingrowth in all cases. The new retina showed a time-dependent external layer differentiation that in the macular hole group can be associated with the visual acuity improvement. In the retinal detachment group, we did not observe PVR development even in the case of complex recurrent retinal detachment.
Some authors proposed the possibility of amniotic membrane rejection when implanted in the subretinal space,20 but Rosenfeld et al. did not report any visible signs of rejection or retinal disorganization in a rabbit model.19
Our study has mid-term follow-up, but we do not report any complications such as hAM rejection, retinal detachment, or PVR.
Several studies have demonstrated that hAM is an optimal substrate for conjunctival growth and corneal re-epithelization probably because amniotic stroma can secrete growth factors or express adhesion molecules17,18; recently some studies have demonstrated that hAM is an adequate support to RPE growth and plays an important role in facilitating RPE integration into the subretinal space.19–22
We believe that these hAM characteristics can play a role even in retinal repair. The growth factors that are secreted can induce retinal growth and differentiation with retinal activity increase.
Human amniotic membrane patches are easy to obtain from the tissue bank, and rather than other substrates used to close macular holes, such as ILM plugs, autologous retinal plugs, or capsular lens fragments, they are also easier to manipulate inside the eye. Further studies are necessary to determine the efficacy of this new technique, and more intraoperative and postoperative analyses would be useful to understand the interaction between the amniotic membrane and the retina. Inducing retinal ingrowth and stimulating regeneration of the retinal inner layers, the external limiting membrane, and the ellipsoid zone is a new frontier for vitreoretinal surgery.
We believe that this technique could be a starting point, and we will extend it to other retinal pathologies.
1. Van Herendael BJ, Oberti C, Brosens I. Microanatomy of the human amniotic membranes. A light microscopic, transmission, and scanning electron microscopic study. Am J Obstet Gynecol 1978;131:872–880.
2. De Roth A. Plastic repair of conjunctival defects with fetal membranes. Arch Ophthalmol 1940;23:522–525.
3. Lavery W. Lime burns of conjunctiva and cornea treated with amnioplastin graft. Trans Ophthalmol Soc UK 1946;66:668–671.
4. Sorsby A, Haythorne J, Reed H. Amniotic membrane grafts in caustic soda burns. Br J Ophthalmol 1947;31:401–404.
5. Lee SH, Tseng SC. Amniotic membrane transplantation for persistent epithelial defects with ulceration. Am J Ophthalmol 1997;123:303–312.
6. Azuara-Blanco A, Pillai CT, Dua HS. Amniotic membrane transplantation for ocular surface reconstruction. Br J Ophthalmol 1999;83:399–402.
7. Letko E, Stechschulte SU, Kenyon KR, et al. Amniotic membrane inlay and overlay grafting for corneal epithelial defects and stromal ulcers. Arch Ophthalmol 2001;119:659–663.
8. Tseng SC. Amniotic membrane transplantation for ocular surface reconstruction. Biosci Rep 2001;21:481–489.
9. Kim JS, Kim JC, Hahn TW, Park WC. Amniotic membrane transplantation in infectious corneal ulcer. Cornea 2001;20:720–726.
10. Pires RT, Tseng SC, Prabhasawat P, et al. Amniotic membrane transplantation for symptomatic bullous keratopathy. Arch Ophthalmol 1999;117:1291–1297.
11. Anderson DF, Prabhasawat P, Alfonso E, Tseng SC. Amniotic membrane transplantation after the primary surgical management of band keratopathy. Cornea 2001;20:354–361.
12. Tseng SC, Prabhasawat P, Barton K, et al. Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency. Arch Ophthalmol 1998;116:431–441.
13. Meller D, Pires RT, Mack RJ, et al. Amniotic membrane transplantation for acute chemical or thermal burns. Ophthalmology 2000;107:980–989; discussion 990.
14. Ucakhan OO, Koklu G, Firat E. Nonpreserved human amniotic membrane
transplantation in acute and chronic chemical eye injuries. Cornea 2002;21:169–172.
15. Gomes JA, dos Santos MS, Cunha MC, et al. Amniotic membrane transplantation for partial and total limbal stem cell deficiency secondary to chemical burn. Ophthalmology 2003;110:466–473.
16. Tsubota K, Satake Y, Ohyama M, et al. Surgical reconstruction of the ocular surface in advanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Am J Ophthalmol 1996;122:38–52.
17. Grueterich M, Tseng SC. Human limbal progenitor cells expanded on intact amniotic membrane ex vivo. Arch Ophthalmol 2002;120:783–790.
18. Meller D, Dabul V, Tseng SC. Expansion of conjunctival epithelial progenitor cells on amniotic membrane. Exp Eye Res 2002;74:537–545.
19. Rosenfeld PJ, Merritt J, Hernandez E, et al. Subretinal implantation of human amniotic membrane
: a rabbit model for the replacement of Bruch's membrane during submacular surgery. Invest Ophthalmol Vis Sci 1999;40.
20. Capeans C, Pineiro A, Pardo M, et al. Amniotic membrane as support for human retinal pigment epithelium (RPE) cell growth. Acta Ophthalmol Scand 2003;81:271–277.
21. Ohno-Matsui K, Ichinose S, Nakahama K, et al. The effects of amniotic membrane on retinal pigment epithelial cell differentiation. Mol Vis 2005;11:1–10.
22. Kiilgaard JF, Scherfig E, Prause JU, la Cour M. Transplantation of amniotic membrane to the subretinal space in pigs. Stem Cell Int 2012:716968.
23. Zhu D, Jin X, Zhou J. Transplantation of amniotic membrane for choroidal hole to treat suprachoroidal silicone oil migration. Acta Ophthalmol 2017;95:e522–e523.
24. Haruta M, Arai M, Sueda J, et al. Patching retinal breaks with Seprafilm for treating retinal detachments in humans: 9 years of follow-up. Eye (Lond) 2017;31:776–780.
25. Ohana E, Blumenkranz MS. Treatment of reopened macular hole after vitrectomy
by laser and outpatient fluid-gas exchange. Ophthalmology 1998;105:1398–1403.
26. Ie D, Glaser BM, Thompson JT, et al. Retreatment of full-thickness macular holes persisting after prior vitrectomy
. A pilot study. Ophthalmology 1993;100:1787–1793.
27. Korobelnik JF, Hannouche D, Belayachi N, et al. Autologous platelet concentrate as an adjunct in macular hole healing: a pilot study. Ophthalmology 1996;103:590–594.
28. Jonas JB, Jager M. Perfluorohexyloctane endotamponade for treatment of persisting macular hole. Eur J Ophthalmol 2003;13:103–104.
29. Oz O, Akduman L. Successful surgical repair and good visual outcome of a recurrent macular hole
of seven years duration. Eur J Ophthalmol 2003;13:588–589.
30. Rizzo S, Genovesi-Ebert F, Vento A, et al. Heavy silicone oil (Densiron-68) for the treatment of persistent macular holes: Densiron-68 endotamponade for persistent macular holes. Graefes Arch Clin Exp Ophthalmol 2009;247:1471–1476.
31. Saeed MU, Heimann H, Wong D, Gibran SK. Heavy silicone oil tamponade after failed macular hole surgery with perfluoropropane (C3F8): a report of five cases. Graefes Arch Clin Exp Ophthalmol 2009;247:707–709.
32. Lappas A, Foerster AM, Kirchhof B. Use of heavy silicone oil (Densiron-68) in the treatment of persistent macular holes. Acta Ophthalmol 2009;87:866–870.
33. Morizane Y, Shiraga F, Kimura S, et al. Autologous transplantation of the internal limiting membrane for refractory macular holes. Am J Ophthalmol 2014;157:861–869 e1.
34. Grewal DS, Mahmoud TH. Autologous neurosensory retinal free flap for closure of refractory myopic macular holes. JAMA Ophthalmol 2016;134:229–230.
35. Thomas AS, Mahmoud TH. Subretinal transplantation of an autologous retinal free flap for chronic retinal detachment
with proliferative vitreoretinopathy
with and without macular hole. Retina 2017;38:S121–S124.
36. Chen SN, Yang CM. Lens capsular flap transplantation in the management of refractory macular hole from multiple etiologies. Retina 2016;36:163–170.
37. Peng J, Chen C, Jin H. Autologous lens capsular flap transplantation combined with autologous blood application in the management of refractory macular hole. Retina [Epub Ahead of Print October 17, 2017].
38. Lee SM, Kwon HJ, Park SW, et al. Microstructural changes in the fovea following autologous internal limiting membrane transplantation surgery for large macular holes. Acta Ophthalmol 2018;96:e406–e408.
recurrent macular hole; retinal detachment; proliferative vitreoretinopathy; vitrectomy; human amniotic membrane
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