Amniotic membranes, and birth tissue-derived products in general, have quickly established themselves as essential platform technologies in the burgeoning realm of regenerative medicine thanks to their ability to offer fast healing in a variety of clinical contexts. In ophthalmology, this tissue possesses biological properties that make it an ideal scaffold for corneal epithelial differentiation and healing. In this article, we’ll look at the available amniotic membranes and explain how they differ in their methodologies, as well as broadly discuss the evolving regulatory landscape and its potential impact on reimbursement.

CRYOPRESERVED AMNIOTIC MEMBRANE

Cryopreserved amniotic membranes (CAM) like BioTissue’s Prokera, AmnioGuard and AmnioGraft have proven to serve as a delivery vehicle for key biologics with anti-inflammatory, anti-fibrotic and anti-angiogenic properties — creating a favorable environment for adhesion, growth and differentiation of ocular surface cells.¹ The pioneering work of Scheffer C.G. Tseng, MD, PhD, on CAM laid the foundation for expansive exploration in the field, fostering greater understanding of the broad clinical applications and the gateway for other entrants into the amniotic membrane arena.

Amniotic membrane products currently in the market differ in their processing methodologies, which can have significant impacts on the structural and biochemical composition of the tissue. Cryopreservation is the only tissue processing method that has been shown to retain the native architecture of the amniotic membrane’s extracellular matrix and preserve key biological molecules, such as high molecular weight hyaluronic acid (HA), heavy chain (HC)-HA complex and pentraxin-3.¹ An ample number of studies demonstrate the HC-HA/PTX3 molecular complex orchestrates the many downstream therapeutic benefits.^2,3 Dehydration processing, on the other hand, has been shown to compromise the survival and permanence of these key anti-inflammatory and anti-scarring properties, suggesting reduced healing capability and lessened clinical efficacy.^1,3,4

DECELLULARIZED, DEHYDRATED AMNIOTIC MEMBRANE

Recently, Verséa Ophthalmics debuted BIOVANCE 3L Ocular, a decellularized, dehydrated amniotic membrane (DAM) with a triple-layer, acellular matrix. Based on results of the company’s benchtop study, Verséa suggests that the tissue not only acts as a suitable scaffold for epithelial cell migration, but that the decellularization process prevents a host-mediated immune response and promotes dynamic interactions between the matrix and host cells. Initial findings indicate significant increase in cell viability on the surface of decellularized membrane on Day 4. However, further analysis reveals no significant differences in cell viability, adhesion and migration by Day 7 vs CAM.⁵

This study is unique in its comparison of ocular cell activity on three commercially available tissues; however, further in vivo research will be required to ascertain how this translates clinically. We eagerly anticipate future studies that delve into the wound healing response of this new tissue product, its clinical application and their outcomes.

In addition to the DAM produced from Verséa, many other dehydrated membrane products are currently available on the market.

CASE STUDY

A 61-year-old myopic presbyope came in for surgical evaluation with the desire for spectacle independence at all ranges. Examination revealed the presence of subtle central epithelial basement membrane dystrophy (A) in one eye with significant, albeit irregular, astigmatism (2.4 D) on topography (see area of irregular steepening superiorly) (B). An unsuspecting surgeon may have recommended a toric IOL based solely on the biometry and keratometry. Surgeons would be well justified in avoiding any recommendation for presbyopia-correcting IOLs in a patient with such corneal findings.

Instead of proceeding with cataract surgery, “Prokera-tectomy” was performed — superficial keratectomy followed by placement of Prokera Slim (BioTissue) for 5 days. (C) After 1 month, allowing for epithelial remodeling, all measurements were repeated. Significant improvement in regularity of keratometry (Sim K = 44.87 D), reduction of irregular astigmatism (0.39 D) and improved HOA profile were observed (D).

A refractive lens exchange (RLE) was then performed using a diffractive multifocal IOL. The patient was able to achieve her desired refractive goal with 20/20, J2 UCVA, and was so satisfied that she referred three other patients for RLE.

 

 

ADDRESSING INFLAMMATION

Controlling, mitigating or modifying the inflammatory cascade underlying wound healing remains the central focus of research and development. Over the past 30 years, more than 300 peer-reviewed publications have entered the literature regarding the clinical and biological activity of CAM. In a landmark 2014 study, Cooke et al observed that IL-10, a key anti-inflammatory cytokine, was eight times higher in cryopreserved membranes than in dehydrated membranes. Additionally, IL-12, a known pro-inflammatory cytokine, was seven-fold less prevalent in CAM.¹ This underscores the advantage of cryopreservation for the permanence of valuable anti-inflammatory properties and their relevance in clinical applications.

In a study conducted by Verséa Ophthalmics, Mao et al observed higher expression of IL-6, IL-8 and TNF, notably pro-inflammatory cytokines, in cells cultured on decellularized, dehydrated membranes in the first 24 hours. Verséa purports that this initial inflammatory response might prevent a prolonged inflammatory response in the corneal epithelial cells.⁵ Though there is no published peer-reviewed data on this theorized effect at this time, we eagerly await translational clinical studies to allow us to discover the impact of this unique platform on clinical outcomes.

Amniotic membrane has become a valuable tool in ophthalmology for the management of ocular surface disease (OSD), encompassing a range of conditions such as dry eye syndrome, corneal ulcers, neurotrophic keratitis and even mechanical dry eye (conjunctivochalasis). Ophthalmologists are increasingly turning to amniotic membrane as a safe and effective treatment option that can improve patient outcomes and quality of life.⁶

OCULAR SURFACE OPTIMIZATION

It is now well understood that a poor ocular surface is one of the leading causes of refractive surprise following cataract surgery and a common limitation to surgeons’ confidence in offering advanced technology IOLs. In the landmark study by Dr. William B. Trattler, up to 76.8% of patients presenting for cataract surgery had some form of OSD.⁷ A number of studies demonstrate that corneal surface irregularities can lead to inaccurate IOL selection, misguided astigmatism correction and aberrated wavefront analyses.^8,9

Since 2014, our practice implemented a formal protocol — co-written by Neel R. Desai, MD, and Gary Wörtz, MD, and again restated by the ASCRS Cornea Clinical Committee in 2019 — for ocular surface optimization prior to refractive cataract surgery.^10,11 We found that, by following this protocol, average Ks changed by at least 1 D in 50% of patients and up to 2 D in 19%. Additionally, BCVA improved 1-2 lines, suggesting that performing cataract surgery without surface optimization would have resulted in a certain refractive miss. Utilization of CAM in this context not only improves outcomes but allows surgeons to confidently expand their offerings of refractive opportunities to a greater number of patients.¹²

BROAD APPLICATIONS

Numerous studies establish that cryopreserved biologics promote limbal stem cell expansion, corneal nerve regeneration and overall improvement in visual acuity.^1,13,14 Some studies suggest that CAM has a high concentration of substance P, which may modify the pain pathway while promoting regenerative healing.¹³

By contrast, the few clinical studies related to DAM-facilitated wound healing suggests that it may prolong the healing process of controlled surgical wounds (ie, PRK) or corneal epithelial defects by as long as 2-5 weeks, even when the membrane is successfully retained beyond Day 8 under a contact lens.^15,16

All amniotic membranes are not equivalent, as it is the biologics preserved and conveyed by them that makes all the difference in clinical outcome and efficacy.¹⁷ Furthermore, the preservation process can affect structural and histological integrity, which can affect intraoperative workability for surgical applications. Cryopreserved tissue uniquely retains tissue resiliency and consistency of conjunctiva, making it ideal for surgical applications that conventionally require the sacrifice of healthy conjunctiva to harvest an autograft. Cryopreserved tissue can be manipulated, tucked and positioned to provide restoration and regeneration of functional anatomy without autograft.^18,19

Outcomes of pterygium surgery, for instance, are equally dependent on technique as well as type of amniotic membrane product. We recently reported on outcomes of our novel “Tissue Tuck Technique” that has produced excellent outcomes with low recurrence rates (0.7%) and efficiency of operative time, producing a significant health economic benefit.^19-21

We also utilize AmnioGraft, BioTissue’s CAM, in the treatment of another common, but previously under-recognized and inadequately treated condition of mechanical dry eye. In an effort to reconstruct the inferior fornix and tear reservoir, obtaining a sufficiently large autograft would be detrimental, if not impossible. This approach with CAM biologics also fosters other significant benefits in the OSD patient — increased goblet cell density, corneal nerve regeneration, restoration of tear reservoir mechanics, improvement in dry eye symptoms, visual stability and overall ocular health.^17,20,22

For patients seemingly recalcitrant to conventional dry eye therapies, the use of CAM offers often miserably symptomatic patients a real and near immediate chance for relief.

EVOLVING LANDSCAPE FOR REIMBURSEMENT

In 2011, CMS recognized BioTissue’s work on CAM by creating a specific CPT code for Prokera placement (65778; placement of self-retaining amniotic membrane on the ocular surface without sutures). Subsequently, CPT codes for single-layer placement and multilayer placement of amniotic membrane were created for intraoperative applications. Since that time, clinicians have utilized these codes for placement of any amniotic membrane product without distinction, even while the FDA uniquely recognized wound-healing indications for CAM but not for DAM. Margins when using DAM were far greater than with CAM due to higher processing, manufacturing and product costs for CAM, leaving some clinicians struggling to balance margin against proven clinical efficacy.

In our personal view, the long-term economic benefit for patients and practices of faster and better healing far outweighs the short-term profit margin.

In recent years, however, the FDA has provided all companies in the birth-product industry warnings and guidance over its increased level of scrutiny for all biologics. After a 3.5-year compliance grace period, the FDA’s new regenerative medicine guidelines went into effect in May 2021, requiring companies to apply for “BLA-certification” as biologics, regulated by Section 351, rather than simply minimally-manipulated human tissue products (Section 361).^23,24 BioTissue, perhaps uniquely, appears to be most prepared to achieve the FDA designations for its ophthalmic, orthopedic and wound-care products.

The ability of companies and their products to comply with these stricter compliance requirements will have a predictable and distinguishing impact on coding and reimbursement for biologic products, including CAM vs DAM and other products going forward. It is highly likely that new codes will have to be introduced for non-certified products at lower reimbursement rates. Doing that which is best and most effective for patients should, is and will always remain to be, most highly rewarded.

BEYOND THE OCULAR SURFACE

The myriad benefits bestowed by biologics and birth-tissue products provide great transformative promise for the field of regenerative medicine. After all, there is not a single field of medicine or surgery that isn’t in pursuit of faster, better-quality restorative healing, with the avoidance of inflammation, fibrosis, scarring, angiogenesis, pain or functional deficit. The future of regenerative medicine is very bright not just within ophthalmology but, indeed, in wound care, orthopedics, dermatology, plastics and beyond. We look forward to the development of innovative human birth tissue-based products to treat an ever-broadening array of clinical conditions. OM

References

1. Cooke M, Tan EK, Mandrycky C, He H, O’Connell J, Tseng SC. Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. J Wound Care. 2014;23(10):465-476.
2. Badylak SF. Regenerative medicine and developmental biology: the role of the extracellular matrix. Anat Rec B New Anat. 2005;287(1):36-41.
3. Zhang S, Zhu YT, Chen SY, He H, Tseng SC. Constitutive expression of pentraxin 3 (PTX3) protein by human amniotic membrane cells leads to formation of the heavy chain (HC)-hyaluronan (HA)-PTX3 complex. J Biol Chem. 2014;289(19):13531-13542.
4. Desai NR, McDevitt T. Histological and Biochemical Characterization of Commercially Available Cryopreserved and Dried Amniotic Membrane. Invest Ophthalmol Vis Sci. 2012;53(14):4225.
5. Mao Y, Protzman NM, John N, et al. An in vitro comparison of human corneal epithelial cell activity and inflammatory response on differently designed ocular amniotic membranes and a clinical case study. J Biomed Mater Res B Appl Biomater. 2023;111(3):684-700.
6. Trattler WB, Shulman M, Montenegro D, Gupta P. Clinical Utility of Amniotic Membranes. Ophthalmology Management. 2020; 24: 34-36.
7. Trattler WB, Majmudar PA, Donnenfeld ED, McDonald MB, Stonecipher KG, Goldberg DF. The Prospective Health Assessment of Cataract Patients’ Ocular Surface (PHACO) study: the effect of dry eye. Clin Ophthalmol. 2017;11:1423-1430. Published 2017 Aug 7.
8. Venkateswaran N, Luna RD, Gupta PK. Ocular surface optimization before cataract surgery. Saudi J Ophthalmol. 2022;36(2):142-148. Published 2022 Aug 29.
9. Gupta PK, Drinkwater OJ, VanDusen KW, Brissette AR, Starr CE. Prevalence of ocular surface dysfunction in patients presenting for cataract surgery evaluation. J Cataract Refract Surg. 2018;44(9):1090-1096.
10. Desai NR, Wortz GN. A Protocol for Ocular Surface Optimization Prior to Refractive Cataract Surgery. BioTissue. Medical Advisory Board. 2015 April.
11. Starr CE, Gupta PK, Farid M, et al. An algorithm for the preoperative diagnosis and treatment of ocular surface disorders. J Cataract Refract Surg. 2019;45(5):669-684.
12. Desai NR. The OSD opportunity: Hard facts and a protocol for cataract patients. Ophthalmology Times. https://www.ophthalmologytimes.com/view/osd-opportunity-hard-facts-and-protocol-cataract-patients . Published January 11, 2019. Accessed April 19, 2023.
13. Lockington D, Cooney J, Lewis A, Agarwal P, Caslake M, Ramaesh K. Substance P concentration in human amniotic membrane. Arch Ophthalmol. 2012;130(4):522-523.
14. 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.
15. Moore, M, Connolly, SY, Wang, MX. Amniotic Membrane Contact Lens: Effectiveness in Treating Persistent Keratoepithelial Defects Due to Wide Range of Ocular Surface Diseases. Cornea, Pterygium, Adhesives, Medications Paper Session 3C. ASCRS 2014 Annual Conference.
16. Gris O, del Campo Z, Wolley-Dod C, et al. Amniotic membrane implantation as a therapeutic contact lens for the treatment of epithelial disorders. Cornea. 2002;21(1):22-27.
17. Tighe S, Mead OG, Lee A, Tseng SCG. Basic science review of birth tissue uses in ophthalmology. Taiwan J Ophthalmol. 2020;10(1):3-12. Published 2020 Mar 4.
18. Brocks D, Mead OG, Tighe S, Tseng SCG. Self-Retained Cryopreserved Amniotic Membrane for the Management of Corneal Ulcers. Clin Ophthalmol. 2020;14:1437-1443. Published 2020 May 26.
19. Desai NR, Adams B. Cryopreserved Amniotic Membrane Using the TissueTuck Technique: A Sutureless Approach for Pterygium Surgery. Cornea. 2023;42(2):181-185.
20. Desai NR, Adams B. Outcomes of the TissueTuck Surgical Technique for Recurrent Pterygium [published online ahead of print, 2023 Feb 16]. Cornea. 2023;10.1097/ICO.0000000000003255.
21. Desai NR, Adams B. Use of Cryopreserved Amniotic Membrane During Pterygium Excision: Health Economic Analysis. Clin Ophthalmol. 2023;17:1137-1146
22. Cheng AM, Yin HY, Chen R, et al. Restoration of Fornix Tear Reservoir in Conjunctivochalasis With Fornix Reconstruction. Cornea. 2016;35(6):736-740.
23. Food and Drug Administration, Center for Biologics Evaluation and Research. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products—Guidance for Industry and FDA Staff. https://www.fda.gov/media/109176/download . Published July 2020. Accessed May 5, 2023.
24. Marks, Peter. Innovative Regenerative Medicine Therapies—Patient Safety Comes First. FDA Voices. https://www.fda.gov/news-events/fda-voices/innovative-regenerative-medicine-therapies-patient-safety-comes-first . Published June 3, 2021. Accessed May 5, 2023.

Bryan Adams, BS, is a graduating medical student at Nova Southeastern University and incoming resident, Ophthalmology, HCA Healthcare/USF Morsani College of Medicine in Tampa, Fla. Dr. Adams reports no financial disclosures.

Neel R. Desai, MD, is director of Cornea, Cataract, and Refractive Services at The Eye Institute of West Florida; medical director, Lions Eye Institute for Transplant and Research; and president and CEO, Clarity Visionary Consulting. Disclosure: Dr. Desai is a speaker, consultant and shareholder for BioTissue Inc.