Published in Ocular Surface

Cryopreserved Amniotic Membrane Recommendations with Case Report

Debbie Felisha Ali, OD

Debbie Felisha Ali, OD

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Review a case report on cryopreserved amniotic membrane (CAM) for dry eye and pearls for how optometrists can best use CAM to manage refractory DED.

Cryopreserved Amniotic Membrane Recommendations with Case Report
The amniotic membrane, the innermost layer of the placenta, is used extensively in ophthalmology due to its anti-inflammatory, immunomodulatory, anti-scarring, and epithelializing activities.1
Cryopreserved amniotic membrane (CAM) also contains neurotrophic factors that promote the regeneration of corneal nerves, which, when damaged, may complicate the treatment of dry eye disease (DED).2
These qualities make CAM a valuable tool for treating DED, particularly in unresponsive cases where the involvement of nerve damage is suspected.

Overview of cryopreserved amniotic membrane

CAM has the ability to bolster ocular surface health via two main avenues:1,3,4
  1. Decreasing ocular surface inflammation by suppressing pro-inflammatory cytokine activity and releasing anti-inflammatory cytokines.
  2. Inducing corneal epithelial and stromal healing by promoting cellular proliferation.
The only current US Food and Drug Administration (FDA)-approved forms of CAM (e.g., Prokera, AmnioGuard, and AmnioGraft [BioTissue, Miami, FL]) are prepared using the CryoTek process (BioTissue, Miami, FL), which preserves the tissues’ innate biological and structural integrity, and leaves their anti-inflammatory, anti-scarring, and anti-angiogenic properties intact.5
Unlike dehydrated amniotic membrane, cryopreservation is the only process that effectively preserves the heavy chain hyaluronic acid/pentraxin 3 (HC-HA/PTX3) complex thought to be largely responsible for the regenerative healing capabilities of CAM.3-5

The role of inflammation in dry eye disease

DED is a disorder of the ocular surface characterized by abnormal tear film composition and inflammation, which commonly results in symptoms like eye dryness, irritation, foreign body sensation, blurred vision, and photosensitivity.6
Though once considered a disorder of the tear film alone, DED is now understood to be a complex ocular surface disease, involving not only a loss of tear film homeostasis—leading to tear film instability and hyperosmolarity—but also ocular surface inflammation and damage.6
The common thread underlying the signs and symptoms of DED is inflammation, which stimulates the vicious cycle of DED, wherein tear hyperosmolarity induced by desiccating stress initiates proinflammatory cytokine production. This leads to a further cascade of immune responses, exacerbating ocular surface irritation, and ocular surface tissue damage.7
Breaking this complex cycle is difficult because DED is often refractory to treatment, but it is necessary to control the disease before it results in significant damage to the ocular surface.

CAM to manage DED

The anti-inflammatory, pro-healing properties of CAM appear not only at the molecular level, but in clinical trials and real-world data as well.
In a prospective, randomized study of patients with DED, 3 to 5 days of treatment with CAM resulted in significant improvements in:8
  • Dry Eye Workshop (DEWS) score
  • Corneal staining
  • Tear break-up time (TBUT)
  • Corneal nerve density at 1 and 3 months
Meanwhile, patients receiving conventional treatment experienced no significant changes. Additional studies have demonstrated that 5 days of treatment with CAM can improve DED signs and symptoms for up to 6 months post-treatment.9,10
CAM is also effective in the clinical setting—a multicenter, retrospective chart review of patients with refractory DED who received CAM found that after an average (standard deviation) of 5.4±2.8 days of treatment with CAM, mean DEWS scores were significantly reduced at 1 week, 1 month, and 3 months.11
In an additional multicenter, retrospective study, patients with moderate-to-severe DED were treated with self-retained CAM (Prokera Slim) for 2 to 7 days.12 Regardless of treatment duration, CAM treatment led to significantly improved DEWS scores at 1 week, 1 month, and 3 months. Additionally, after only 2 days of treatment with CAM, patients had significant improvements in corneal staining, visual symptoms, and ocular discomfort at all time points.

Data on CAM efficacy: A confirmation of current practice

For me, these clinical and real-world studies of CAM serve as confirmation of what I was already seeing in my practice—clinically meaningful improvements in ocular surface health with CAM in as little as 2 days.
For example, our normal cataract or refractive surgery preparation includes corneal surface optimization to improve the accuracy of biometry measurements, which can be rendered less accurate by ocular surface diseases like DED.13 However, due to the limitations of surgery scheduling, it is sometimes necessary to leave CAM in for only 2 days.
Despite this short treatment duration, we have seen that CAM still improves patients’ pre-surgery measurements. As ocular surface diseases can result in significant irregular astigmatism and higher-order aberrations,13 improving the associated inflammation and healing the ocular surface with CAM.

Integrating CAM into clinical practice

My patients with DED often have durable responses to CAM—sometimes experiencing symptom relief for years—that they were not able to achieve with other treatments. One of my patients with DED, in particular, comes to mind.
Although she was highly adherent, several treatments failed to control her DED symptoms. She constantly needed to use artificial tears, and her symptoms made her miserable—she likened the experience to her eyes being in the Sahara Desert.
After feeling that I had done everything possible to improve her DED, I applied CAM to increase the nerve density and sensitivity of her corneas.6 When DED is unresponsive to classic dry-eye treatments, dryness-induced nerve damage—known as neuropathic corneal pain—may be a contributing factor.2
CAM may be more helpful than traditional treatments in these patients because it contains neurotrophic factors that regenerate corneal nerves damaged in DED.8 Indeed, after one treatment with CAM for 7 days on each eye, the patient’s DED improved to where she now uses serum tears just twice a day and has not needed another round of CAM for 2 years.
She has sent multiple thank you letters and says she will come in first thing if her eyes ever start to feel like the desert again.

Case report: Complete healing of DED with CAM

Another success story I experienced using CAM was with a female patient aged 37 years with treatment-refractory DED. She was in otherwise good health, with no autoimmune conditions or contributory medications.
Despite her 20/20 visual acuity, she experienced mild injection and excessive tearing with blurry vision that worsened throughout the day. Upon examination, she had mild-to-moderate fluorescein staining.
Figure 1: Inferior superficial punctate keratitis visible with fluorescein staining prior to treatment with self-retained CAM (Prokera).
Pretreatment Fluorescein Staining
Figure 1: Courtesy of Debbie Felisha Ali, OD.
Despite trying several treatment regimens, including lifitegrast, cyclosporine, punctal plugs, various ointments, omega-3 supplements, warm compresses, and increased water intake, the patient experienced little improvement. As with many of my treatment-refractory cases of DED, I suspected that CAM would be more effective due to its ability to mitigate the nerve damage that often complicates DED.8
I placed a self-retained CAM (Prokera) for 5 days, resulting in substantial improvements to her superficial punctate keratitis and vision clarity. Now, the patient only requires routine follow-up and maintenance with artificial tears and twice-daily cyclosporine.
Figure 2: Substantial improvement in the inferior superficial punctate keratitis following the administration of self-retained CAM (Prokera).
Post-Prokera Fluorescein Staining
Figure 2: Courtesy of Debbie Felisha Ali, OD.

Key takeaways

These are some of my best success stories; however, when counseling my patients with DED, I typically reference the clinical studies and tell them to expect CAM to improve their DED for about 6 months.8-11
If my patients have had at least some success with other DED treatments, I usually tell them to continue those treatments and to use artificial tears at least twice daily.
I also recommend sleeping with a humidifier and taking omega-3 supplements. However, my biggest takeaway for patients is that there is “no scar left behind” with CAM.
Regardless of the state of a patient’s corneas and the damage they may have incurred, I know the anti-inflammatory and healing benefits of CAM will leave their corneas looking healthy, even if only used for a couple of days.
  1. Chen Z, Lao HY, Liang L. Update on the application of amniotic membrane in immune-related ocular surface diseases. Taiwan J Ophthalmol. 2021;11(2):132-140.
  2. Guerrero-Moreno A, Liang H, Moreau N, et al. Corneal nerve abnormalities in painful dry eye disease patients. Biomedicines. 2021;9(10):1424.
  3. Tan EK, Cooke M, Mandrycky C, et al. Structural and biological comparison of cryopreserved and fresh amniotic membrane tissues. J Biomater Tissue Eng. 2014;(4):379-388.
  4. 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):465-476.
  5. Proprietary technology. BioTissue. Accessed March 28, 2024. https://biotissue.com/technology/proprietary-technology/.
  6. Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol. 2012;130(1):90-100.
  7. Nelson JD, Craig JP, Akpek EK, et al. TFOS DEWS II Introduction. Ocul Surf. 2017;15:269-275.
  8. John T, Tighe S, Sheha H, et al. Corneal nerve regeneration after self-retained cryopreserved amniotic membrane in dry eye disease. J Ophthalmol. 2017;2017:10.
  9. Cheng AM, Zhao D, Chen R, et al. Accelerated restoration of ocular surface health in dry eye disease by self-retained cryopreserved amniotic membrane. Ocul Surf. 2016;14:56-63.
  10. Vendal Z. Management of glaucoma medication induced dry eye disease with self-retained cryopreserved amniotic membrane. J Dry Eye Dis. 2022;5:e28-e34.
  11. McDonald MB, Sheha H, Tighe S, et al. Treatment outcomes in the DRy Eye Amniotic Membrane (DREAM) study. Clin Ophthalmol. 2018;12:677-681.
  12. 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.
  13. He X, Huang AS, Jeng BH. Optimizing the ocular surface prior to cataract surgery. Curr Opin Ophthalmol. 2022;33:9-14.
Debbie Felisha Ali, OD
About Debbie Felisha Ali, OD

Dr. Debbie Felisha Ali is a board-certified optometric physician in multiple states across the country. Dr. Ali completed her undergraduate studies at Nova Southeastern University, where she earned two bachelor’s degrees, one in biology and one in vision science. Following her undergraduate studies, Dr. Ali earned her doctorate degree at NSU College of Optometry in Davie, Florida.

Dr. Ali completed her externship rotations during school, specializing in ocular disease treatment and management at the prestigious Bascom Palmer Eye Institute in South Florida. She also completed training in primary eye care with emphasis on diabetic and glaucoma eye conditions, refractive and cataract surgery co-management, pediatric vision therapy focusing primarily on autistic children, and specialty contact lens fitting.

Dr. Ali is involved locally in the Broward and Miami-Dade County American Optometric Associations, statewide in the Florida Optometric Association, and nationally with the American Optometric Association. She is still connected with her alum at Nova Southeastern University, and lectures throughout the year to students. Dr. Ali is also an ambassador for a female physician group that encourages connecting, promoting, and empowering other female doctors in her field across the board.

When not seeing patients, she loves spending time with her friends and family, traveling around the world, and eating at newly undiscovered restaurants both locally and abroad.

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