Cryopreserved Amniotic Membrane Promotes Tissue Repair and Remodeling

This therapeutic treatment plays an integral role in my ocular surface disease treatment protocol.

By Jeremy Z. Kieval, MD

Amniotic membrane tissue has a rich and lengthy history in ophthalmology starting in 1940 with its first reported use as a biological dressing for the management of conjunctival defects.¹ Since then, amniotic membrane transplantation (AMT) has expanded throughout eyecare and is now used for the treatment of all forms of cornea involved ocular surface anomalies from defect-based conditions to inflammation-induced diseases. AMT plays an integral role in my ocular surface disease treatment protocol, but to be clear I rely exclusively on a specific type of AM tissue known as cryopreserved amniotic membrane. This article will clarify why that distinction is important, and detail how I use this versatile biologic therapeutic in my practice.

Currently, there are two types of AM available for ophthalmic purposes: cryopreserved and dehydrated. The main differentiator is that cryopreserved amniotic membrane (CAM) promotes regenerative wound-healing.^2-4 This wound-healing capability is maintained in cryopreservation but lost in dehydration.⁵

CAM’s wound-healing ability is possible because the CRYOTEK cryopreservation process allows CAM to retain an extra cellular matrix (ECM) of growth factors: heavy chain peptide (HC), hyaluronic acid (HA), and pentraxin-3 (PTX3). The hyaluronic acid that is retained in the cryopreservation process inhibits pro-inflammatory cells, suppresses T-cell activation, controls matrix metalloproteinases (MMP) production, and prevents scar formation. The overall extracellular matrix is responsible for CAM’s anti-inflammatory and healing properties, such as tissue repair and remodeling.^2-7

 Important Distinctions

Prokera, AmnioGraft, and AmnioGuard (BioTissue, Miami, FL) are the only CAM products commercially available for ophthalmic use. AmbioDisk (IOP Ophthalmics/Katena) and BioDOptix (DermaSciences) are among several dehydrated amniotic membrane (DAM) allografts available for ophthalmic use. It is possible — and unfortunately common — to inadvertently conflate the capabilities of cryopreserved with dehydrated AM.

Because of the way they are preserved, the capabilities and clearances of cryopreserved and dehydrated amniotic membranes are very different. CAM has been cleared by the FDA as a Class II medical device, and product claims designated by the FDA include protective wound healing and anti-inflammatory effects. FDA approved claims for dehydrated AM are limited to wound coverage.⁸

My exclusive use of CAM is due to its wound healing capabilities. I previously used DAM, but I have seen wounds worsen with it and I have had three patients experience severe fibrosis and corneal haze as a result of treatment with DAM. In one of those cases, the patient developed irregular astigmatism and was ultimately relegated to a rigid gas permeable contact lens.

I will no longer use DAM because, in my experience, CAM is superior in safety and efficacy. Some of my peers rely on DAM, and their primary reason is cost because DAM is less expensive. I trust CAM based on my experience with both types of AM, and because using CAM is in the best interest of patients.

How Does it Work?

Prokera is a contact-lens-like self-retained AM graft that is intended for use in eyes in which ocular surface cells are damaged or underlying stroma is inflamed or scarred. I find that a major advantage is that it allows for topical therapeutic agents to be applied over the device when active infection is present, and it is safe to use with a fluorescein stain to monitor efficacy.

Treatment of persistent epithelial defects and neurotrophic keratitis are the primary reasons I use CAM, but I find that it is also of great value to patients who have ocular surface disease of any kind, including moderate-to-severe dry eye disease and epitheliopathies, such as anterior basement membrane dystrophy and Salzmann’s nodules. Ultimately, any case requiring re-epithelialization is an ideal use of CAM. The literature demonstrates that Prokera is associated with expedited healing and reduced risk of corneal haze and/or infection, and these findings are borne out in my own anecdotal experience.⁷

With Prokera, as the ocular surface disease heals, the cryopreserved membrane dissolves leaving the conformer ring behind for removal at the follow-up visit. I typically leave it in the eye for under a week, depending on the particular etiology. The membrane may dissolve faster in someone with neurotrophic keratitis or more inflammatory ocular surface disease, but in the majority of cases, I follow up in 5-to-6 days. The more inflammatory the eye disease — especially stages 2 and 3 neurotrophic keratitis — the more likely a second or even third graft may be needed.

AmnioGraft and AmnioGuard are more like traditional grafts in that they are ideal for ocular surface reconstruction, and they are sutured or glued into place. AmnioGraft is indicated for band keratopathy, bullous keratopathy, chemical burns of the ocular surface, conjunctival defects, conjunctivochalasis (See Case Study), corneal epithelial defects, corneal ulcers, high-risk corneal transplants, trabeculectomy in conjunction with superficial keratectomy, pterygium, Stevens-Johnson Syndrome, symblepharon, and fornix reconstruction. My rationale for including CAM when performing surgery on a patient with, for instance, severe band keratopathy is that it is an effective and efficient way to optimize success.

Managing Patient Expectations

Understanding and managing patient expectations can improve patient satisfaction in all aspects of healthcare, including AMT. Some patients experience moderate discomfort from the Prokera conformer ring. When I first started using this product, I did not advise patients of this possibility, and invariably I would get phone calls from them complaining of discomfort. Once I understood this, I began to approach it similarly to PRK or corneal crosslinking by advising the patient that they could expect 2 or 3 days of discomfort. Those phone calls completely ceased after I began explaining that the procedure provided rehabilitation of the ocular surface to treat and cure the disease and that some discomfort would accompany the process. I use the analogy of breaking in a shoe, explaining that when you wear new shoes, they are often not comfortable, but after a few days there’s no problem. It’s all about managing their expectations.

Practice, Patient, Provider Benefits

Using CAM provides benefits for the patient, the practice, and the provider. Most patients who undergo AMT with CAM have vision-threatening conditions, and this biologic intervention enables me to save or restore visual acuity. Using CAM is helpful for the practice because amniotic membrane is almost always covered by insurance, and there are rarely roadblocks as far as preauthorization or coverage of any kind. Furthermore, use of CAM cuts down on patient visits because I know that once I apply a Prokera or AmnioGuard, there is something continuous at work on the corneal surface, and I can be confident that it is doing what it is supposed to do in between visits. We always worry when a patient has a stage-3 neurotrophic ulcer, but I worry a bit less that it might perforate between the CAM application on Monday and the follow-up visit on Friday – and that is a boon for me and the patient.

Conclusion

Cryopreserved AM tissue offers an effective and efficient way to treat cornea involved ocular surface anomalies, from defect-based conditions to inflammation-induced diseases. These conditions are often sight-threatening, so if we are going to implement AM therapy, it behooves us to abide by what’s been validated in the literature and choose CAM because it is the only AM tissue for ophthalmic purposes that promotes wound healing.

Jeremy Z. Kieval, MD: Cornea, cataract, and refractive surgeon, Lexington Eye Associates, Lexington, MA. Email: [email protected]

Disclosure: Dr Kieval has no financial interest in the products mentioned in this article.

References

1. de Rötth A. Plastic repair of conjunctival defects with fetal membranes. Arch Ophthalmol. 1940;23(3):522-525. doi:10.1001/archopht.1940.00860130586006
2. Tseng SCG. HC-HA/PTX3 Purified from amniotic membrane as novel regenerative matrix: insight into relationship between inflammation and regeneration. IOVS. 2016;57(5):ORSFh1-ORSFh8. doi:10.1167/iovs.15-17637.
3. 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.
4. Rock T, Bartz-Schmidt KU, Landenberger J, et al. Amniotic membrane transplantation in reconstructive and regenerative ophthalmology. Ann Transplant. Mar 6 2018;23:160-165.
5. Cooke M, Tan EK, Mandrycky C, et al. Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. J Wound Care. 2014;23(10):465-74, 476.
6. Watson CT, Breden F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease. Genes Immun. 2012;13(5):363-73. doi:10.1038/gene.2012.12.
7. John T, Tighe S, Sheha H, et al. Corneal nerve regeneration after self-retained cryopreserved amniotic membrane in dry eye disease. J Ophthalmol. 2017. doi:10.1155/2017/6404918
8. Mcgaughy AG, Gupta PK. In-office use of amniotic membrane. EyeNet. 2015;31-32. https://www.aao.org/eyenet/article/in-office-use-of-amniotic-membrane.