Historical overview
The use of amniotic membranes in ophthalmology, though seemingly a recent advancement, actually saw its initial inception shortly after the beginning of World War II. In 1940, Andrew de Rötth treated an ocular surface burn with fetal birth tissue that included both amnion and chorion as a graft for conjunctival surface reconstruction.1 Shortly thereafter, Albert Louis Brown proposed the use of rabbit peritoneum as a temporary patch to cover an acutely burned ocular surface, in an effort to promote healing and prevent the spread of necrosis.2
For a long period of time—save for some studies in the mid-60s—the use of amniotic membrane largely disappeared from Western literature. In the mid-90s, however, the topic reemerged when Jae Chan Kim and Scheffer Tseng demonstrated (in a rabbit model) that ~40% of corneas with total limbal deficiency could be completely cleared with no vascularization by replacing the conjunctivalized surface with a preserved human amniotic membrane.3
Amniotic membrane designated for ophthalmic purposes is typically derived from the innermost layer of the placenta (donated by consenting mothers) and consists of thick basement membrane with devitalized amniotic epithelial cells and an avascular stromal matrix.4 (Figure 1) Because the membrane lacks immunologic markers, the chances of rejection by the potential host are greatly diminished. One of the most medically relevant properties of amniotic tissue is that it can prompt wound healing without promoting scar tissue, offering tremendous benefit for the ocular surface and particularly the cornea, wherein scarring could significantly impact vision.5
Figure 1. Pictorial representation of the placenta in utero, demonstrating the source of amniotic tissue.
Though amniotic membrane has been utilized in ophthalmology historically and provided some benefit as a wound covering, only BioTissue's advanced proprietary CryoTek® cryopreservation method is recognized by the FDA for preserving the natural tissue's anti-inflammatory and anti-scarring benefits, its ability to promote epithelial healing on the ocular surface, and for its inherent angio-modulatory properties as well.4,6 By virtue of these factors, CAM therapies, such as Prokera, occupy a great role in the treatment of punctate keratitis, filamentary keratitis, neurotrophic keratitis, persistent corneal epithelial defects, and dry eye disease. Moreover, many eyecare professionals are now employing this therapeutic option earlier in the treatment protocol than ever before.7,8
How the Prokera CAM platform is unique within amniotic membrane technology
Prokera biologic corneal bandages are the only FDA-cleared CAM products available in the US. Unlike “dry” amniotic membranes that are processed using heat dehydration – which can destroy crucial biologic components – BioTissue’s proprietary CryoTek® cryopreservation process maintains these vital elements, including a key extracellular complex known as heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3).9 HC-HA/PTX3 represents a unique matrix component known for its anti-inflammatory and anti-scarring potential, and for its role in helping to orchestrate healing within the human fetal environment.10-14 The CryoTek preservation technology devitalizes resident living cells to minimize the risk of an immune reaction while preserving other key components of the extracellular matrix, including:9,15
- Collagen (types I, III, IV, V, and VI)
- Hyaluronic Acid
- Proteoglycans
- Growth Factors
Additionally, the structural integrity of Prokera biologic corneal bandages has been shown to be equivalent to fresh tissue.9,16
Studies show that the technology underlying Prokera supports the eyes' natural healing processes with a favorable safety profile, having been validated in hundreds of peer-reviewed research publications to date, with investigations delving into: (1) healing of wounds and damage to the ocular surface; (2) modulating inflammation; and (3) minimizing corneal scarring.3,17-19
Additionally, clinical results show that the use of Prokera:
- Improves corneal nerve regeneration and accelerates ocular surface health recovery7,19
- Significantly improves both corneal nerve density and sensitivity7,19
- Facilitates faster re-epithelialization17
Figure 2. Evidence of corneal nerve density before and after Prokera
Utilizing Prokera in clinical practice
The use of Prokera is indicated for eyes “in which ocular surface cells are damaged or the underlying stroma is inflamed or scarred.“20 Similar in appearance to a large contact lens, the Prokera device acts as a self-retaining biologic corneal bandage. It is suitable for use in most patients, although it may be contraindicated in eyes with glaucoma drainage devices or a filtering bleb, as well as in patients with a history of drug reactions to ciprofloxacin, amphotericin B, glycerol, and/or Dulbecco's Modified Eagle Medium (DMEM), as these agents are found in Prokera’s storage media.20
Doctors throughout the US are currently utilizing Prokera successfully across a wide range of applications, typically for moderate-to-severe cases of potentially vision-threatening disorders. An assortment of these conditions is shown in the accompanying graphic (Figure 3).
Despite the numerous indications, many eyecare professionals believe that Prokera is appropriate for an even broader variety of conditions, including recalcitrant dry eye disease and pre-surgical ocular surface disease management (e.g., refractive and/or cataract surgeries). Early intervention with Prokera may likely reduce inflammation, improve corneal health, and optimize long-term outcomes.7,8,21 Moreover, Prokera creates an environment that is supportive of regenerative healing, helping to modulate ocular surface inflammation, promote ocular surface cell recovery, and even regenerate damaged or dysfunctional corneal nerves.7,8
Figure 3. Conditions commonly managed with amniotic membrane therapy.
The link between dry eye disease and Neurotrophic Keratitis (NK)
Increasingly, as doctors explore the link between dry eye and NK, awareness is building regarding the need for earlier intervention. Inflammation from dry eye disease can induce damage to the corneal epithelium, and its underlying nerve plexus responsible for regulating corneal sensitivity, the blink reflex, tear production, and even epithelial regeneration.22 This cycle of deterioration can lead to corneal nerve dysfunction, ultimately resulting in the clinical picture we know as NK. Many of us have seen at least one patient with significant punctate keratopathy, presumably due to dry eye disease, and initiated treatment only to encounter one failed therapeutic response after another. Over time, we come to find that these patients are actually manifesting the earliest stages of NK, and hence do not respond to conventional dry eye treatment. Performing routine corneal sensitivity testing on all individuals with dry eye disease is one way to avoid this dilemma.
While NK is specifically caused by damage to the trigeminal nerve, whereas dry eye disease is a multifactorial disorder, both conditions display a similar spectrum of corneal pathologies, including inflammation and epithelial disruption, which can progress to persistent epithelial defects and vision-threatening stromal ulceration in severe instances.23 Because dry eye is chronic and progressive, it’s important to treat the signs and symptoms aggressively, before the disease can advance and cause damage to the corneal nerves.
In a recent clinical study, Thomas John, MD and colleagues investigated whether Prokera biologic corneal bandages could restore nerve density and improve corneal sensitivity in patients with dry eye disease, as compared to other targeted therapies including artificial tears, cyclosporine A, serum tears, antibiotics, steroids, and non-steroidal anti-inflammatory medications.7 At 1 month and 3 months post-treatment, the researchers found a statistically significant increase in corneal nerve density and corneal sensitivity in the Prokera group versus the control group; they concluded that Prokera is a promising therapy for corneal nerve regeneration and accelerated recovery of ocular surface health in patients with dry eye disease.
The use of Prokera in these cases can accelerate regenerative healing that can’t typically be replicated with conventional therapies, such as drops, corticosteroids, or bandage contact lenses. While there are many effective dry eye treatments on the market, it is nearly impossible to replicate the human body’s capacity to prevent scarring within the fetal environment. The Prokera CAM device harnesses the properties and mechanisms of action that heat dehydrated amniotic membrane have been shown to lose.9-14,16,17
Challenges with conventional treatments
DREAM Study Demonstrates Prokera’s Efficacy and Optimal Treatment Duration
The 2018 Dry Eye Amniotic Membrane Study set out to evaluate the efficacy of Prokera in reducing signs and symptoms of dry eye disease in a large patient population.8 A retrospective chart review at 10 clinical sites was conducted on patients with refractory dry eye who received Prokera and completed at least 3-months of follow-up. Data collection included: demographics; medical history, including previous and current ocular treatments; diagnoses; clinical presentations; comorbidities; duration and frequency of treatment with Prokera; and concomitant medications. The primary outcome measure was the change in Dry Eye WorkShop (DEWS) score, graded from 1 (mild) to 4 (severe) after treatment.
Ultimately, the study concluded that Prokera is a promising treatment to enhance recovery of ocular surface health and reduce signs and symptoms in patients with moderate to severe dry eye disease.8
The study also found:
- Single placement of Prokera for 5.4±2.8 days resulted in a significant improvement of dry eye disease signs and symptoms with an overall reduction in DEWS scoring from 3.25±0.5 (baseline) to 1.44±0.6 at 1-week, 1.45±0.6 at 1-month, and 1.47±0.6 at 3-months.
- This improvement was associated with restoration of corneal surface health as evidenced by resolution of corneal punctate staining and improvement of visual symptoms.
A follow-up study published in 2023 suggests that a single placement of Prokera for 2-days can significantly improve signs and symptoms of dry eye disease with a lasting benefit observed for up to 3-months.29
Early intervention may reduce vision loss caused by NK
Even in those instances where the patient may have progressed to NK, Prokera can play a significant role in corneal rehabilitation. Because impaired corneal innervation leads to breakdown of the corneal epithelium, with the potential for subsequent ulceration, melting, and perforation,30,31 early treatment is crucial to prevent further damage and potential vision loss.32-34 In addition to serving as a biological corneal bandage, Prokera’s capacity to help regenerate corneal nerves targets the underlying cause of NK.7
Advantages of cryopreserved vs. dehydrated amniotic membranes
Because the Prokera device is manufactured with CAM, it is able to promote ocular wound healing and repair.35 As stated earlier, many of the crucial biologic components are lost during a standard heat dehydration processing method, which limits the application of membranes prepared in this fashion.16 Hence, dehydrated amniotic tissue is relegated to simple wound covering rather than regenerative healing.
It can also be reassuring to know that Prokera is manufactured according to quality standards:
- BioTissue is accredited by the American Association of Tissue Banks (AATB)
- BioTissue’s facilities and Quality Management Systems are inspected by the FDA, AATB, and an international certification body performing ISO 13485:2016 and Medical Device Single Audit Program (MDSAP) certification
- Prokera has been used in more than 300,000 successful transplants
- Alternatively, dehydrated amniotic membrane solutions often lack crucial biologic components9,12
Figure 4. Advantages of Prokera cryopreserved biologic corneal bandage
While dehydrated membranes may play a role in some cases, Prokera remains unique, and the FDA recognizes this by means of its 510(k) clearance.
The process of inserting a Prokera device is workflow-friendly
While the placement of a Prokera device is not a technically challenging exercise, the timing is crucial, as the limitations imposed can have substantial impact on patients’ daily routines. While acute conditions such as infectious keratitis or injury warrant immediate treatment, use of the device for chronic conditions can often be accommodated to the patient’s individual needs. One important caveat that patients must acknowledge is that their vision during treatment with the Prokera device may be impaired, limiting their ability to drive, work, attend school, or perform other important tasks. Therefore, it’s important to communicate with patients to find the best time for the procedure, so as to limit the potential impact on activities of daily living.
Fortunately, because it only takes a few minutes to prepare the Prokera for use, and even less time to insert, it can easily be scheduled during a typical office visit. Convenient on-site storage in a (designated) refrigerator or freezer allows for easy access, even in the case of acute presentations. The manufacturer advises rinsing the device thoroughly with buffered saline solution to avoid any irritation from the storage fluid. A “tape tarsorrhaphy” can be beneficial for increased comfort following insertion, and patients should ideally have a driver to take them home, as their vision will be blurry following application of the device. While CAMs have a reputation for being uncomfortable with some patients, the Prokera device is usually well tolerated after a brief adjustment period. Most doctors insert the device themselves and allow the patient to acclimate in the exam chair for about 10 minutes. (Figure 5) If you suspect a patient may be apprehensive, have high anxiety, or some other challenge with Prokera, it’s crucial to identify such factors before placing the device. Similarly, if a patient has any superficial alteration of their eyelids, including scarring or an atypically narrow palpebral fissure, that should be considered as well.
Corneal dystrophies: Prokera vs. Bandage Contact Lenses
Epithelial basement membrane dystrophy (EBMD) is the most common corneal dystrophy encountered in clinical practice. It’s characterized by an abnormal basement membrane which may result in defective adhesions and corneal epithelial breakdown. When intervention becomes necessary due to EBMD progression, it’s important to first remove the poorly adherent, irregular epithelium using a debridement procedure, such as Superficial Keratectomy (SK), to promote healthy corneal reepithelialization. While this procedure is beneficial to the patient, it can potentially cause significant discomfort and/or delayed healing.36
Unlike a bandage contact lens, Prokera can be extremely effective in these cases and has already demonstrated superior outcomes vs. bandage contact lenses.17 As a result, Prokera can accelerate healing after debridement procedures and provide patients with pain relief not currently available with other conventional therapies.
Prokera prior to surgery may lead to better visual outcomes
A 2017 clinical survey by the American Society of Cataract and Refractive Surgery (ASCRS) revealed that ocular surface disease which is present prior to surgery can significantly affect the postoperative visual quality of patients undergoing keratorefractive and phacorefractive procedures.36 Additionally, while it’s easy to identify patients who have symptomatic dry eye disease, the multicenter Prospective Health Assessment of Cataract Patients' Ocular Surface (PHACO) observational study found that many asymptomatic patients undergoing these procedures have undiagnosed ocular surface disease. In the study, about 60% of routine cataract patients reported having no foreign body sensation, but 50% displayed central corneal staining, indicating damage to the ocular surface that could potentially impact surgical outcomes.37 In another prospective study, more than 80% of scheduled cataract surgery patients showed signs of OSD, even though most were asymptomatic, while 40% displayed an abnormal tear osmolarity or MMP-9 level.38 The results of these studies underscore the need for more rigorous screening prior to surgery, including corneal staining and/or MMP-9 diagnostic testing. Furthermore, they support the argument for optimizing the ocular surface in all surgical candidates. By consensus, the ASCRS Corneal Clinical Committee recommends that doctors consider a more aggressive, multifaceted approach to treating ocular surface disease pre-surgically in order to maximize outcomes and minimize scheduling delays. Tactics may include:
- Prescription medications
- Use of amniotic membranes
- Other procedural interventions
In cases where patients have visually significant dry eye disease and/or are failing to respond to conventional therapies, introducing Prokera prior to surgery can be extremely beneficial to both patients and their surgeons. Moreover, because Prokera can demonstrate efficacy after just 2 to 5 days, it’s an ideal choice for patients with a surgical deadline.
Consequences of failing to optimize the ocular surface before surgery
If ocular surface disease is not addressed prior to keratorefractive or phacorefractive surgeries, potential consequences may include:
- IOL calculation errors
- Unsatisfactory post-surgical visual outcomes
- New or persistent signs and symptoms of ocular surface disease
- Reduced retinal image quality
Pre-existing dry eye disease that reduces the quality of vision can be exacerbated by cataract surgery.39 The ASCRS Corneal Clinical Committee defines visually significant ocular surface disease in the cataract population as any combination of:37
- Fluctuating vision that improves with blinking or lubrication
- Highly elevated osmolarity and MMP-9
- Irregular or fluctuating topography and/or aberrometry
- Increases in the interblink interval
- Irregular astigmatism from corneal epithelial abnormalities
- Significant corneal staining
How to bill for Prokera using CPT code 65778
Because Prokera is considered a medical device, its classification increases the chances of appropriate reimbursement. Such fees always depend on the payor, but providers can anticipate remuneration within the range of $1,000 to $1,800 per treatment.
To ensure appropriate reimbursement, physicians must utilize the appropriate medical coding and billing practices. The CPT code for Prokera is 65778, defined as "placement of amniotic membrane on the ocular surface; without sutures." Specific ICD-IO codes that may be applicable to 65778 are listed in Figure 3. Modifiers may be appropriate also, depending upon the situation:
• -RT (Right) and -LT (Left) may be used to specify which eye received the treatment. Laterality is often a crucial element for accurate billing, and these modifiers can help to avoid claim denials.
• -50 (Bilateral Procedure) is not a commonly used modifier with 65778. although it may be required in some instances. -50 indicates amniotic membrane placement on both eyes during the same operative session.
• -59 (Distinct Procedural Service) is another rarely used modifier, indicating that the procedure was distinct or independent from other services performed on the same day, e.g., a comprehensive examination.
• -79 (Unrelated Procedure or Service by the Same Physician During the Postoperative Period) may be appropriate if the placement of the amniotic membrane is conducted during the postoperative period of another unrelated procedure, and the procedures are performed by the same physician.
Most eyecare professionals hold the view that practicing at the top of our license means always offering patients our best options. When Prokera is a part of a recommended treatment plan, a few things can make the reimbursement process go more smoothly, including:
• Thorough documentation. including corneal sensation, and any persistent epithelial defects
• All tried and failed therapies, duration, and results observed
• Results from diagnostic testing and exam findings
• Diagnosis-related patient history
• Results expected from the Prokera treatment
• Appropriate ICD-10 diagnosis coding
It should also be noted that BioTissue has an excellent Customer Service Team eager to help eyecare professionals should any complications arise.
Different treatment options available
BioTissue recognizes that each patient demands a unique solution for healing. With four options to choose from, you can select the Prokera device that enables the best possible outcome for your patient.
Clinical pearls for optimal outcomes with Prokera
- Utilize staff as much as possible to help patients learn about Prokera and become comfortable with the procedure. Having more educated staff to answer patient’s questions and address concerns allows the doctor to be more efficient in practice.
- While most eyecare professionals insert the Prokera device themselves, staff often prepare and rinse the device prior to insertion, as well as prepare and deliver educational materials.
- Reiterate to patients that, anecdotally among eyecare providers, only 4% of patients were intolerant of Prokera.35
- The majority of eyecare providers opt to use an anesthetic drop prior to the insertion of Prokera. It can be helpful to let patients know that they will be most uncomfortable immediately after insertion, much like a contact lens. After placing the device, allow patients to acclimate for several minutes in the chair, and let them know that the discomfort will diminish over time. Most patients find the device to be easily tolerable after about 10 minutes.
- Ensure patients have a driver or other means of transportation following the procedure.
