Biological membranes have been used as grafts since more than one century ago to promote tissue regeneration in cutaneous and mucosal injuries. In particular, the therapeutic use of human placental membranes is ancient. In 1910, J.W. Davis was the first who described and reported the use of the fetal amniotic membrane as a surgical material in skin transplantation. The amniotic membrane was first used in human Ophthalmology in 1940, when De Röth suggested using this membrane in the treatment of an ocular burn wound like a bandage. These first procedures included both fresh amnion and chorion. The treatments were relatively successful, but the use of amniotic membrane then fell out of favor until the mid-1990’s, when with Kim and Tseng, using improved processing and better developed storage techniques. Since then, thousands of ocular surgical procedures have been performed with amniotic membrane as well as more than 700 publications.
n Veterinary Ophthalmology, the literature reports using biological membranes have included, for example, equine pericardium, rabbit renal capsule, canine peritoneum and equine renal capsule. However, in the last few years, and taking note of the extensive advances in human medicine, there have been many successful surgeries with amniotic membrane (amnion) in dogs, cats and horses. The characteristics of the amniotic membrane, including low antigenicity, great antimicrobial potential, promotion of epithelialization, inhibition of fibrosis, relatively ease of production and conservation, as well as the low cost, have led to numerous medical specialties to use this graft as adjuvant therapy. In recent years, a great interest within the field of Veterinary Ophthalmology has been developed, since the properties of amniotic membrane make this tissue an ideal graft to repair defects in the ocular surface. Eye disorders in dog, cat, rabbit and horse have successfully treated with amniotic membrane grafts, both homologous and heterologous, and obtained from the placenta of diverse species (canine, porcine, equine and human). AmnioVet ® is the first product of the market processed from amniotic membrane of bovine, and has demonstrated excellent results in the major domestic species encountered in veterinary medicine.
The amniotic membrane or amnion consists of an epithelium of cuboid cells, a basement membrane whose composition is very similar to that of the conjunctiva and a stromal matrix fully avascular, very rich in collagen and mucopolysaccharides and with few cells, which are mainly some macrophages and fibroblasts. This means that the amnion has a low antigenicity and the immune response against the graft, if it exists, it is certainly light and ineffective.
The mechanisms of action of amniotic membrane graft are histologically explained by:
- an amniotic epithelium that provides large number of growth factors.
- a basement membranel that facilitates the migration of the epithelial cells, reinforces the adhesions of the basal cells, promotes epithelial differentiation and prevents apoptosis, as well as being an ideal substrate for the growth of germinal epithelial cells but keeping their clonal behavior.
- a stromal matrix containing anti-inflammatory proteins, protease inhibitory substances, antiangiogenic proteins and a component which suppresses signaling by TGF-β as well as the proliferation and differentiation of the myofibroblasts. In addition, an antimicrobial effect against a broad spectrum of bacteria has also been demonstrated in vivo.
All these biological properties which the amniotic membrane presents, we can summarize them in a series of clinical effects:
- Facilitates epithelialization, respecting the normal epithelial phenotype
- Reduces inflammation and corneal neovascularization
- Decreases the residual scar after tissue regeneration
AmnioVet® conforms easily to the surface of the defect (can be either glued or sutured to the wound surface) and it serves as a potent facilitator in wound healing by its high concentrations of cytokines and growth factors. The host cells can interact with the bioactive cell-adhesion factors within the basement membrane, serving as a substrate for cellular growth. The membrane is hydrophilic and naturally absorbs the surrounding fluids. As part of the healing process the amnion resorbs into the wound. General literature suggests that the membranes completely resorb into the wound in about 14-21 days.
The amniotic membrane can be used in a large number of ophthalmologic surgical indications, either as graft, as coating, or a combination of both.
When implanted like a graft (or inlay technique) it fills out a defect by replacing the absent stromal matrix and providing a basement membrane that epithelization occurs on it. When applied like patch or overlay technique) the amniotic membrane functions essentially as a cover protecting the ocular surface of possible external insults and providing biological substances that reduce inflammation and promote epithelial regeneration under the implant.
The surgical technique will vary in each case, depending on if it is used as a patch on its epithelial surface or as a graft on the stromal side (adherent). Theoretically, if stroma is directed towards the recipient the implant will incorporate, but if it is the epithelium/basement membrane of the amnion, should fall off. A single layer or multiple folded layers of amniotic membrane can also be applied. In the latter case, another layer of membrane is placed by coating the entire cornea.
Currently, amniotic membrane transplantation is a surgical procedure in expansion in which still there have been established neither the totality of its indications nor the different pathologies that can benefit from it.
In Human Ophthalmology has been used successfully to treat patients in cases of:
- Corneal burns – chemical and physical
- Large conjunctival defects
- Symblepharon/reconstruction of the fornix
- Persistent corneal epithelial defects
- Limbal stem cells deficiency
- Glaucoma (in filtering bleb)
- Stevens-Johnson Syndrome
- Bullous keratopathy (to reduce the pain when keratoplasty is not possible)
On the other hand, some restrictions on the use and effectiveness of amniotic membrane transplantation has also been described: with absence of tear, he transplantation may not restore the ocular surface; and in the presence of an important inflammatory reaction, the amniotic membrane can be quickly reabsorbed (both in case of graft as a patch).
In Veterinary Ophthalmology, there have been published different articles that value the use of amniotic membrane transplantation in cases of corneal ulcers, keratomalacia, dermoids, bullous keratopathy, corneal perforation and excision of corneal-limbal tumors in dogs and horses, or in cases of symblepharon and corneal sequestration in felines.
- DeRoth A., Plastic repair of conjunctival defects with fetal membrane. Arch Ophthalmol 1940;23:522-25
- Bourne G., The Fœtal Membranes. Postgrad Med J. 1962 Apr;38(438):193–201.
- Kim JCI, Tseng SCG., Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit corneas. Cornea 1995;14:473-84.
- Zee SH, Tseng SCG., Amniotic membrane transplantation for persistent epithelial defects with ulceration. Am J Ophthalmol 1997;123:303-12.
- Tseng SC, Prabhasawat P, Barton K, Gray T, Meller D., Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency. Archives of ophthalmology. 1998;116(4):431.
- Blanco AA, Pillai CT, Dua HS., Amniotic membrane transplantation for ocular surface reconstruction. Br J Ophthalmol 1999;83:399-402.
- Tseng SCG, Li D-Q, Ma X., Suppression of transforming growth factor‐beta isoforms, TGF‐β receptor type II, and myofibroblast differentiation in cultured human corneal and limbal fibroblasts by amniotic membrane matrix. Journal of Cellular Physiology. 1999 Jun 1;179(3):325–35.
- Lee S-B, Li D-Q, Tan DT, Meller D, Tseng SC., Suppression of TGF-ß signaling in both normal conjunctival fibroblasts and pterygial body fibroblasts by amniotic membrane. Current eye research. 2000;20(4):325–34.
- Meller D. et al., Amniotic membrane transplantation for acute chemical or thermal burns. Ophthalmology 2000;107:980-90.
- Hui-Kang D, See LC, Zian SB, Tsai RJF., Amniotic membrane graft for primary pterygium: Comparison with conjunctival autograft and topical Mitomycin C treatment. British Journal of Ophthalmology 2000;84:973-78.
- Kim JS, Kim JC, Na BK, Jeong JM, Song CY., Amniotic membrane patching promotes healing and inhibits proteinase activity on wound healing following acute corneal alkali burn. Exp. Eye Res. 2000 Mar;70(3):329–37.
- Solomon A., Suppression of interleukin 1alpha and interleukin 1beta in human limbal epithelial cells cultured on the amniotic membrane stromal matrix. British Journal of Ophthalmology. 2001 Apr 1;85(4):444–9.
- Sippel KC, Ma JJK, Foster CS., Amniotic membrane surgery. Curr Opin Ophthalmol 2001;12:269-81.
- Prabhasawat P, Tesavibul N, Komolsuradej W., Single and multilayer amniotic membrane transplantation for persistent corneal epithelial defect with and without stromal thinning and perforation. Br J Ophthalmol. 2001;85(12):1455–63.
- Baum J., Amniotic membrane transplantation: Why is it effective? Cornea. 2002;21(4):339–41.
- Tseng SCG, Tsubota K., Amniotic membrane transplantation for ocular surface reconstruction. In: Holland EJ, Marris M J, editors. Ocular Surface Diseases: Medical and Surgical Management. New York: springer-Verlag; 2002. p226-31.
- Madhavan HN, Priya K, Malathi J, Joseph PR., Preparation of amniotic membrane for ocular surface reconstruction. Ophthalmology practice. 2002; 50 (3),227-31.
- Solomon A. et al., Amniotic membrane grafts for nontraumatic corneal perforations, descemetoceles, and deep ulcers. Ophthalmology. 2002 Apr;109(4):694–703.
- King A.E. et al., The novel antimicrobial peptide β3-defensin is produced by the amnion: A possible role of the fetal membranes in innate immunity of the amniotic cavity. American Journal of Obstetrics & Gynecology. 2004 Nov;191(5):1678–87.
- Ahn J-I et al., A comparison of lyophilized amniotic membrane with cryopreserved amniotic membrane for the reconstruction of rabbit corneal epithelium. Biotechnology and Bioprocess Engineering. 2005; 10(3):262–9.
- Antimicrobials by Human Placenta and Fetal Membranes. Placenta. 2007. Feb; 28(2–3):161–9.
- Georgiadis NS, Ziakas NG, Boboridis KG, Terzidou C, Mikropoulos DG., Cryopreserved amniotic membrane transplantation for the management of symptomatic bullous keratopathy. Clinical & Experimental Ophthalmology. 2008;36(2):130–5.
- Liu J, Sheha H, Fu Y, Liang L, Tseng SC., Update on amniotic membrane transplantation. Expert Rev Ophthalmol. 2010 Oct;5(5):645–61.
- Riau AK, Beuerman RW, Lim LS, Mehta JS., Preservation, sterilization and de-epithelialization of human amniotic membrane for use in ocular surface reconstruction. Biomaterials. 2010 Jan;31(2):216–25.
- Hsu M, Jayaram A, Verner R, Lin A, Bouchard C., Indications and Outcomes of Amniotic Membrane Transplantation in the Management of Acute Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis. Cornea. 2012 Dec;31(12):1394–402.
- Barros P.S.M. et al., The use of xenologous amniotic membrane to repair canine corneal perforation created by penetrating keratectomy. Vet Ophthalmology 1(2-3):119-123 (1998).
- Barros P.S.M. et al., Amniotic membrane transplantation for the reconstruction of the ocular surface in three cases. Veterinary Ophthalmology 8:3, 189–192. (2005)
- Lassaline Mary E. et al., Equine amniotic membrane transplantation for corneal ulceration and keratomalacia in three horses. Veterinary Ophthalmology 8:5, 311–317. (2005)
- Ollivier F.J. et al., Amniotic membrane transplantation for corneal surface reconstruction after excision of corneolimbal squamous cell carcinomas in nine horses. Veterinary Ophthalmology 9:6, 404–413. (2006)
- Tsuzuki K, Yamashita K, Izumisawa Y, Kotani T., Microstructure and glycosaminoglycan ratio of canine cornea after reconstructive transplantation with glycerin-preserved porcine amniotic membranes. Veterinary Ophthalmology 11, 4, 222–227. (2008)
- Plummer C.E. et al., The use of amniotic membrane transplantation for ocular surface reconstruction: a review and series of equine clinical cases (2002-2008). Veterinary Ophthalmology 12, Suppl 1, 17-24. (2009)
- Kalpravidh M, Tuntivanich P, Vongsakul S, Sirivaidyapong S., Canine amniotic membrane transplantation for corneal reconstruction after the excision of dermoids in dogs. Vet Res Commun. Dec;33 (8):1003-12 (2009)
- Wichayacoop T. et al., Anti-inflammatory effects of topical supernatant from human amniotic membrane cell culture on canine deep corneal ulcer after human amniotic membrane transplantation. Veterinary Ophthalmology 12, 1, 28–35. (2009)
- Kim JY. et al., Effect of bovine freeze-dried amniotic membrane (Amnisite-BATM)on uncomplicated canine corneal erosion. Veterinary Ophthalmology 12, 1, 36-42. (2009)
- Soo Choi UI. et al., Successful treatment of an unusually large corneal epithelial inclusion cyst using equine amniotic membrane in a dog. Vet Ophthalmology 13, 2, 122–125 (2010)
- Barachetti L, Giudice C, Mortellaro C.M., Amniotic membrane transplantation for the treatment of feline corneal sequestrum: pilot study. Vet Ophthalmology 13, 5, 326-330. (2010)
- Huguet E. et al., The use of human amniotic membrane for corneal reparation in dogs: preliminary results. Proceeding ESVO Meeting 2011. Prague, Czech Republic.
- Huguet E, Sanz F, Vergara J, Díaz-Delgado C., Human amniotic membrane graft fixed with corneal adhesive for the treatment of feline corneal secuestrum: 2 clinical cases. Proceeding ECVO Congress 2013. Barcelona, Spain.
- Kang M, Choi S, Cho Lee AR., Effect of freeze dried bovine amniotic membrane extract on full thickness wound healing. Arch Pharm Res. Apr;36(4):472-8 (2013)
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