A history of amniotic membrane use in eye care

Image credit: AdobeStock/Juiy

The modern use of biological materials in ocular surface eye care is growing, particularly with the use of amniotic membrane tissue (AMT).¹ It may be surprising to learn that AMT has been used in health care for some time. AMT was first utilized for skin grafting in 1910, and its first applications in eye care began in the 1940s when it was utilized as a conjunctival substitute.² AMT harvested from the innermost layer of the placental sac after birth confers unique biological properties with widespread clinical applications, including in dermatology, plastic surgery, and regenerative medicine. In 2003, the FDA approved the use of a self-retained, cryopreserved AMT, which began a period of widespread use in eye care.³

Unique healing properties

The healing capabilities of fetuses in utero are drastically different than those of postbirth humans. Reports in the literature indicate that fetuses can undergo surgery in utero without scar formation because of their cellular ability to regenerate and heal damaged tissue.⁴ The cellular capabilities of adults, in contrast, form a reactionary environment in which scars are formed preferentially to protect the organism from infection.⁵ Through AMT donation, however, it is possible to retain and utilize the properties of the fetal environment for their anti-inflammatory, antiangiogenic, antifibrotic, and antimicrobial capabilities.⁶ The internal lining of the placental tissue can be harvested after an elective cesarean delivery to preserve these properties for clinical applications.⁶

The structural components of AMT contribute to its unique biological functions, as AMT contains collagens, fibronectin, laminin, proteoglycans, and growth factors.⁷ Because of the regenerative properties of these components, cryopreserved AMT promotes wound healing, beneficial cellular migration, and epithelial adhesion.⁸ For example, when reepithelialization is needed to establish a healthy epithelium over the cornea, as in cases of injury, infection, ocular surface disease, and inflammation, AMT is an excellent choice.

Clinical utility

Whenever the eye’s anterior surface needs restoration, AMT presents an opportunity for healing. Unlike bandage contact lenses, cryopreserved AMT is antimicrobial and can be used during infective processes.⁶ A bandage contact lens should not be used over a herpetic lesion, for example, because it could exacerbate the infection. During antiviral therapy, cryopreserved AMT can be placed on top of a herpetic dendrite or pseudodendrite.⁹

Cryopreserved AMT is also capable of nerve regeneration.^10,11 Although it can be used at any stage of neurotrophic keratitis (NK), it is especially helpful in the early stages in preventing progression. Early NK often resembles dry eye disease but with reduced corneal sensitivity and, often, a history of corneal nerve damage from infection, injury, or surgery. For stage 2 NK or above, I find it helpful to use the nerve factor cenegermin-bkbj between 2 self-retained, cryopreserved AMTs, as described in a clinical observation by Damon Dierker, OD, FAAO.

Patients with any disruptions to the ocular surface also benefit from AMT. If a patient presents with a corneal abrasion needing quick reepithelialization, cryopreserved AMT can facilitate wound healing.¹² I treated one patient with an overly aggressive upper eyelid blepharoplasty that left about 3 mm of the ocular surface exposed at night. The patient could not figure out why her eyes were so red, so she began using an over-the-counter drop, preserved with benzalkonium chloride, about 8 times daily. When I treated her with AMT, it helped resolve not only the drop toxicity but also the exposure, with benefits to the cornea lasting several months.

Overall, AMT is uniquely helpful in patients who need quick results, such as those approaching scheduled travel or even cataract surgery. I recently treated a patient with stage 1 NK who had an upcoming cataract surgery evaluation that included biometric measurements in just 5 days. Her NK had flared up after she contracted viral conjunctivitis, so her cornea was extremely irritated with grade 4 superficial punctate keratitis. As her imminent evaluation did not allow sufficient time to treat her with topical steroids, and a bandage contact lens could not be used because of the risk of residual viral infection, AMT was the best option. I placed a self-retained, cryopreserved AMT on the surface of her eye, and 2 days later, her cornea had completely healed. She then proceeded to have biometric readings taken for the upcoming cataract surgery.

AMT preservation techniques

Several methods are available to preserve AMT so that it can be stored successfully and to prevent the risk of infection that could be created by using fresh tissue.² Cryopreservation is the only method that retains AMT’s natural structural and biological characteristics. This is because cryopreservation retains heavy chain hyaluronic acid/pentraxin 3 (HC‑HA-PTX3), a molecule with anti-inflammatory, antiangiogenic, and wound-healing properties, which is why only cryopreserved AMT is approved by the FDA for wound healing.^2,13

To cryopreserve AMT, fresh amniotic tissue is prepared with glycerol or dimethyl sulfoxide and frozen at –80° C, which helps to retain the soft pliability.¹⁴ Because the tissue is so soft and pliable, it must be stretched over a polymethylmethacrylate ring to remain in place,¹⁵ which may cause discomfort in some patients. A recently-released product (CAM360 AmnioGraft; BioTissue) maintains cryopreservation’s anti-inflammatory, antiscarring, and antiangiogenic properties and does not require a ring.¹⁶

In contrast, AMT dehydrated by freeze-drying precludes the use of a ring.² This dehydration process involves freezing, sublimating, and irradiating the tissue, resulting in a thin, dry membrane.² Because of its texture, I find that freeze-dried AMT should be rubbed into the ocular surface or the back of a contact lens to adhere to the ocular surface properly; the cornea must be dried out before applying the AMT, necessitating a lid speculum or a second person to hold the eye open during placement. Lyophilized membranes have been shown to maintain their original histological structure, but the preparation method eliminates HC-HA-PTX3, which may reduce certain fibroblast growth factors.²

A third preservation method of note is dehydration, involving a process that eliminates the moisture of AMT with heat.⁸ A sugar protectant is added during evaporation to replace the lost intracellular water and prevent disruption of internal cellular structures. However, some biological properties, including the presence of HC-HA-PTX3 and the anti-inflammatory, antiangiogenic, wound-healing benefits, may be lost in heat-dried AMT.¹⁷

Evidence supports AMT

Because of a wide range of published clinical research in ophthalmic AMT applications, I prefer self-retained, cryopreserved AMT (CAM). For example, I followed the DREAM study in which CAM was used on the ocular surface for about 5 days,¹⁸ but even when the CAM had to be removed early—after only 2 days—it still provided healing benefits. A more recent study showed that only 2 days of CAM use can result in up to 3 months of relief for patients with dry eye.¹⁹ There is also evidence supporting the unique capability of CAM to regenerate corneal nerves and reactivate limbal stem cells.^10,20

I have had mixed results with noncryopreserved AMT. Although I prefer CAM in my patients, I have found that lyophilized AMT is most helpful in patients not suited for self-retained CAM. A few of my patients have had adverse reactions to dehydrated AMT, though, so I do not use that as often. However, dehydrated AMT can be useful when storage is limited or when freezing is not possible, as freezing is a storage requirement for CAM.

Impact on clinical practice

My practice has acclimated to using AMT, and we have come to rely on its acceleration of healing time. Although any treatment strategy that utilizes AMT’s healing capabilities must address the root cause of the ocular damage, the differentiating factor of AMT over other products is the ability of cryopreserved AMT to markedly restore the ocular surface in days rather than weeks. Regardless of the indication for which it is being used, AMT offers the opportunity for strong induction therapy and possible salvation of sight.

References:

1. Tas MD, Devebacak A, Palamar M, et al. Demographic data and trends in use of amniotic membrane transplant during the past decade at a tertiary eye center. Exp Clin Transplant. 2024;22(6):451-454. doi:10.6002/ect.2023.0254

2. Walkden A. Amniotic membrane transplantation in ophthalmology: an updated perspective. Clin Ophthalmol. 2020;14:2057-2072. doi:10.2147/OPTH.S208008

3. Chiu HI, Tsai CC. Self-retained, sutureless amniotic membrane transplantation for the management of ocular surface diseases. J Clin Med. 2023;12(19):6222. doi:10.3390/jcm12196222

4. Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg. 2010;126(4):1172-1180. doi:10.1097/PRS.0b013e3181eae781

5. Marshall CD, Hu MS, Leavitt T, Barnes LA, Lorenz HP, Longaker MT. Cutaneous scarring: basic science, current treatments, and future directions. Adv Wound Care (New Rochelle). 2018;7(2):29-45. doi:10.1089/wound.2016.0696

6. Jirsova K, Jones GLA. Amniotic membrane in ophthalmology: properties, preparation, storage and indications for grafting-a review. Cell Tissue Bank. 2017;18(2):193-204. doi:10.1007/s10561-017-9618-5

7. Dadkhah Tehrani F, Firouzeh A, Shabani I, Shabani A. A review on modifications of amniotic membrane for biomedical applications. Front Bioeng Biotechnol. 2021;8:606982. doi:10.3389/fbioe.2020.606982

8. Baig IF, Le NT, Al-Mohtaseb Z. Amniotic membrane transplantation: an updated clinical review for the ophthalmologist. Ann Eye Sci. 2023;8:5. doi:10.21037/aes-22-56

9. Cheng AMS, Tseng SCG. Self-retained amniotic membrane combined with antiviral therapy for herpetic epithelial keratitis. Cornea. 2017;36(11):1383-1386. doi:10.1097/ICO.0000000000001316

10. John T, Tighe S, Sheha H, et al. Corneal nerve regeneration after self-retained cryopreserved amniotic membrane in dry eye disease. J Ophthalmol. 2017;2017:6404918. doi:10.1155/2017/6404918

11. Mead OG, Tighe S, Tseng SCG. Amniotic membrane transplantation for managing dry eye and neurotrophic keratitis. Taiwan J Ophthalmol. 2020;10(1):13-21. doi:10.4103/tjo.tjo_5_20

12. Devries DK, Karpecki PM, Nanda S. Guideline redefines amniotic membrane’s role in ocular surface disease. Optometry Times. October 15, 2021. Accessed March 14, 2025. https://www.optometrytimes.com/view/guideline-redefines-amniotic-membrane-s-role-in-ocular-surface-disease

13. Tighe S, Mead O, Lee A, Tseng S. Basic science review of birth tissue uses in ophthalmology. Taiwan J Ophthalmol. 2020;10. doi:10.4103/tjo.tjo_4_20.

14. Jaiswal AN, Vagga A. Cryopreservation: a review article. Cureus. 2022;14(11):e31564. doi:10.7759/cureus.31564

15. Nair S, Vanathi M, Mukhija R, Tandon R, Jain S, Ogawa Y. Update on ocular graft-versus-host disease. Indian J Ophthalmol. 2021;69(5):1038-1050. doi:10.4103/ijo.IJO_2016_20.

16. BioTissue introduces CAM360 AmnioGraft regenerative therapy for dry eye and ocular surface disease. Eyewire. Press release. Published June 3, 2024. Accessed March 14, 2025. https://eyewire.news/news/biotissue-introduces-cam360-amniograft-regenerative-therapy-for-dry-eye-and-ocular-surface-disorders?c4src=article:infinite-scroll

17. Cooke M, Tan EK, Mandrycky C, He H, O’Connell J, Tseng SCG. Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. J Wound Care. 2014;23(10):465-474, 476. doi:10.12968/jowc.2014.23.10.465

18. McDonald MB, Sheha H, Tighe S, et al. Treatment outcomes in the DRy Eye Amniotic Membrane (DREAM) study. Clin Ophthalmol. 2018;12:677-681. doi:10.2147/OPTH.S162203

19. McDonald M, Janik SB, Bowden FW, et al. Association of treatment duration and clinical outcomes in dry eye treatment with sutureless cryopreserved amniotic membrane. Clin Ophthalmol. 2023;17:2697-2703. doi:10.2147/OPTH.S423040

20. Liang L, Sheha H, Li J, Tseng SCG. Limbal stem cell transplantation: new progresses and challenges. Eye (Lond). 2009;23(10):1946-1953. doi:10.1038/eye.2008.379