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COVER FOCUS
AMNIOTIC MEMBRANES FOR
OCULAR SURFACE DISEASE
These tissues can be helpful adjuncts to treat difficult ocular surface conditions.
BY JEFFREY R. VARANELLI, OD, FAAO, AND NICHOLAS COLATRELLA, OD, FAAO
The amniotic membrane is
an avascular, acellular tissue
that promotes epithelialization, suppresses inflammation, inhibits scarring, inhibits angiogenesis, and contains
neurotrophic factors. The
amniotic membrane tissue,
harvested from consenting donors during planned cesarean section, has inherent properties that make it effective
in reducing ocular inflammation while helping to stimulate
growth factors. Sutureless or self-retained amniotic membranes have been shown to improve the corneal surface
in patients with keratoconjunctivitis sicca, as well as other
types of ocular surface disease (OSD), such as recurrent
corneal erosions, chemical burns, and persistent epithelial
defects.
Use of these treatment modalities allows eye care practitioners to manage OSD in ways far different from those
used in the past. The aim of this article is to give a general
overview of indications and of the membranes available,
as well as to discuss the clinical benefits possible with this
therapeutic approach.
HISTORY
Amniotic membranes have been used in the treatment
of wound repair for more than 100 years. In the early days,
when a child was born with its fetal membranes (caul)
intact, it was considered lucky.1 In the 1940s, deRotth used
fetal membranes for the treatment of conjunctival defects;
this work helped to substantiate their clinical effectiveness.2 Several years later, Sorsby and Symons noted the
intrinsic benefits of this tissue in the treatment of acute
chemical injuries.3,4
Nonetheless, the abundant clinical applications and
benefits of amniotic membranes did not become widely
recognized and accepted until the 1990s, after Batlle and
Padermo reintroduced their use for treatment of ocular
surface disorders.5 Subsequently, Kim and Tseng used
amniotic membranes to reconstruct the ocular surface in
rabbits, confirming their clinical effectiveness.6 Since that
time, amniotic membranes have become an extremely
important component of the management of OSD.
SCIENCE
The structural, biochemical, and physiologic properties
of sutureless amniotic membranes are what convey their
clinical benefits and make them useful adjuncts in the
treatment of OSD. The human amniotic membrane is the
innermost of the three layers forming the fetal membranes.
This translucent membrane is composed of an inner layer
of epithelial cells that rests on a basement membrane,
which in turn is connected to a thin connective tissue
membrane by filamentous strands.7
TABLE. SUTURELESS AMNIOTIC MEMBRANES
Product
Company
Diameters (mm)
Procurement and Processing
Supplied
AlphaVision
Amniotic Therapies
8, 10, 12, 15
Proprietary
Dehydrated
AmbioDisk
Katena/IOP
9, 12, 15
Purion
Dehydrated
Aril
SeedBiotech
8, 10.5, 15
Novel decellularization
Dehydrated
BioDOptix
BioD
9, 12, 15
DryFlex
Dehydrated
Prokera
Bio-Tissue
21.6 in thermoplastic ring set
CryoTek
Cryopreserved
RenovoAT
RegenMed
9, 12, 15
DryFlex
Dehydrated
VisiDisc
Skye Biologics
9, 10, 15
HydraTek
Dehydrated
46 ADVANCED OCULAR CARE | MAY/JUNE 2016
Case report illustrates the power of this therapeutic option for corneal healing.
BY NATHAN ROCK, OD, FAAO
COVER FOCUS
CRYOPRESERVED AMNIOTIC MEMBRANE OFFERS
ADVANTAGES
Practicing at a cataract and LASIK center with
A DIFFICULT COURSE
corneal specialists allows me the opportunity to
At that time, our office was using only dehydrated AMCLs.
care for numerous patients with corneal patholWhen the patient returned, we obtained his informed consent and
ogies. I had the pleasure of caring for a 70-yearplaced a dehydrated AMCL under a soft scleral lens OS. We also
old man with a chief complaint of severe vision
placed a 3-month extended duration collagen punctal plug in his
blur in his left eye. He was seeking a second
left lower punctum to promote optimal hydration.
opinion regarding a non-healing corneal ulcer in
We started the patient on a mild steroid twice daily (loteprednol
his left eye. He reported mild foreign body sensa- [Lotemax; Bausch + Lomb]), a nonsteroidal antiinflammatory drug
tion but no pain and said that this had been an ongoing problem four times daily (bromfenac [Prolensa; Bausch + Lomb]) and a
for 1 year.
prophylactic antibiotic three times daily (trimethoprim/polymyxin
This patient was being treated by a cornea specialist who had
B ophthalmic solution). We elected against use of our typical fluoexhausted all of his treatment options and had referred him to
roquinolone antibiotic because the patient reported a systemic
another provider for a lateral tarsorrhaphy, an option which the
allergy to ciprofloxacin. He was directed to wear the AMCL for 2
patient understandably wanted to avoid. His drop regimen at the weeks and return for removal and follow-up.
time was artificial tears six times daily OU. His medical history was
At follow-up, the patient reported that he felt like the AMCL
significant for hypertension, arthritis, hypercholesterolemia, previ- had fallen out 4 days prior. The lens had indeed fallen out, and
ous stroke, and type 2 diabetes. His diabetes was being treated
although his UCVA had improved to 20/50, his anterior segment
with two oral agents, and he reported that his blood sugar was
was still significant for a 3-mm central epithelial defect. We added
poorly controlled with a range of 200 to 240 mg/dL and his A1C
oral doxycycline 100 mg twice daily and discussed with him the
was between 7% and 8%.
option of another AMCL. We placed the AMCL under a soft scleral
The patient’s UCVA was 20/100 OD and 20/400 OS. BCVA
lens with the goal of 2 weeks of wear.
was 20/30 OD and 20/200 OS. Anterior segment examination
was significant for 1+ inferior punctate keratitis OD and 3+
inferior punctate keratitis and a central 3.5-mm corneal epithelial defect with underlying anterior stromal haze OS (Figure).
Posterior segment examination revealed moderate cataracts OU,
mild diabetic retinopathy with several scattered dot and blot
hemorrhages, and no macular edema OU.
The diagnosis was neurotrophic keratopathy secondary to
poorly controlled diabetes OS, severe dry eye disease OU, visually
significant cataracts OU, and mild diabetic retinopathy OU. To
reduce the risk of retinopathy progression and promote optimal
corneal healing, we encouraged diligent blood sugar control and
recommended that the patient see an endocrinologist. We also
recommended that he start cyclosporine (Restasis; Allergan) OU
twice daily and preservative-free artificial tears every 2 hours OU.
We directed the patient to return for placement of an amniotic membrane contact lens (AMCL) OS. We told him that we Figure. Neurotrophic keratopathy: central 3.5-mm corneal
would monitor his cataracts until his cornea was stable.
epithelial defect with underlying anterior stromal haze.
MAY/JUNE 2016 | ADVANCED OCULAR CARE 47
COVER FOCUS
TABLE. COMPARISON OF AMCL TYPES
Attribute
Cryopreserved AMCL
Dehydrated AMCL
Stability
Unlikely to fall out, so full
duration of treatment is
generally maintained
May fall out, which
may not allow the
full duration of
treatment
Coverage
Drapes uniformly over the May be decentered
entire cornea
and cover only part
of the cornea
Biochemistry1 Crucial cytokines and
Not all cytokines
growth factors maintained and growth factors
maintained
The patient returned 2 days later and reported that the lens had
fallen out. We replaced it with a soft bandage contact lens. We
continued to follow him over a period of 6 months, during which
his UCVA remained overall stable but the epithelial defect persisted and would not heal. Throughout this time we continued to
discuss the option of tarsorrhaphy and we tried a series of similar
treatments including bandage contact lenses and additional dehydrated AMCLs. We employed strategies such as tape tarsorrhaphy
and nighttime Fox eye shield, which allowed some of the AMCLs
to stay in for the desired time, although some continued to fall out
prior to the planned removal.
The patient continued on the same drop and oral medication
regimen, and we maintained collagen punctal plugs to promote
ocular surface hydration. Throughout, despite our encouragement
and the patient’s best efforts, including seeing an endocrinologist,
his blood glucose was suboptimally controlled. This cycle was frustrating for patient and provider alike, and we were strongly leaning
toward referral for a lateral tarsorrhaphy.
CRYOPRESERVED OPTION
As noted, our clinic had previously used only dehydrated
AMCLs. At the end of this difficult period, our clinic began using
Prokera cryopreserved AMCLs (Prokera Slim 15 mm; Bio-Tissue).
The device consists of an amniotic membrane graft wrapped
around a PMMA ring, and it is applied to the eye directly without
need for an additional contact lens. We educated the patient
regarding the potential for foreign body sensation. I placed the
AMCL without difficulty and applied a small piece of surgical tape
on his upper eyelid to induce a mild ptosis to promote comfort.
He continued on the same drop and oral regimen. He wore the
lens for 2 weeks and tolerated it well.
When he returned, the Prokera ring was still in place over the
sclera, but the membrane itself had been consumed, which is often
the case with this duration of wear. His anterior segment looked
48 ADVANCED OCULAR CARE | MAY/JUNE 2016
fantastic. The epithelial defect had fully healed, and there was only
minimal diffuse punctate keratitis. He still had central haze, which
had been present when we first saw him, but his UCVA had again
improved to 20/50, and to 20/40 with pinhole, even with his moderate cataract.
We removed the Prokera ring and followed the patient closely,
initially maintaining hydration and tapering off all the drops and
oral medications other than preservative-free artificial tears and
cyclosporine. Six months and more after the successful resolution,
the epithelium has remained healed and UCVA stable. We are
holding off on cataract surgery until his visual symptoms increase,
but from an ocular surface standpoint he is all ready for this when
he desires to proceed.
OCULAR SURFACE HEALING
We typically have satisfactory results with all AMCLs, but in this
case, we found the Prokera device particularly useful for ocular
surface healing. The ring sits nicely tucked under the superior and
inferior eyelids, keeping the ring in place and ensuring coverage of
the amniotic membrane over the entire cornea.
The cryopreservation process for Prokera involves rapidly freezing
the tissue with the goal of maintaining the structural integrity of the
amniotic membrane. Histology confirms that this method maintains
the architecture of the extracellular matrix, which contains crucial
cytokines and growth factors. Biochemistry studies indicate that
heavy chain hyaluronic acid and pentraxin 3 (HCHA/PTX3) are also
maintained in cryopreserved tissues. The HCHA/PTX3 complex has
been shown to downregulate pro-inflammatory cytokines and to
upregulate anti-inflammatory cytokines, which has been hypothesized to play an integral role in the amniotic membrane healing
response. The extracellular matrix and HCHA/PTX3 complex do not
appear to be maintained in dehydrated tissues (Table).1
CONCLUSION
When it comes down to it, although they generally provide satisfactory clinical results, all AMCLs are not created equal. Prokera
provides advantages with regard to stability, coverage, and biochemistry which can result in improved clinical outcomes. n
1. 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):465-474.
Nathan Rock, OD, FAAO
Consultative Optometrist and Clinical Study Coordinator,
Wang
Vision 3D Cataract and LASIK Center, Nashville, Tennessee
n [email protected]; (615) 321-8881, ext 116
n Financial disclosure: past member of the Bio-Tissue advisory board
n
The amniotic membrane, like both the corneal and conjunctival basement membranes, contain collagen types IV,
V, and VII, as well as fibronectin and laminin.8 These similarities are what make the use of amniotic membranes in
conjunctival and corneal disease so successful.
In eyecare, amniotic membranes have been shown to
promote epithelialization by acting as a suitable substratum for epithelial cell migration, preventing apoptosis,
reinforcing the adhesion of basal epithelial cells, and
promoting cell proliferation.8 They can also suppress
inflammation by inhibiting proinflammatory matrix metalloproteinases, and they can prevent scarring by inhibiting
the transduction of transforming growth factor beta in
conjunctival and corneal fibroblasts. Other clinical benefits
include antiangiogenic activity and the ability to reduce
pro-inflammatory cytokines while releasing anti-inflammatory cytokines such as interleukin-10.9
Although amniotic membranes have also been shown
to have antimicrobial properties, it is believed that they
do not contain these properties inherently, but rather
that they reside solely in the membranes’ ability to adhere
closely to the underlying substrate and simply block microbial penetration.8
INDICATIONS AND FOLLOW-UP
The term OSD can be used to describe any anomaly that
affects the lids, conjunctiva, tear film, or cornea. Amniotic
membranes are extremely effective for treating OSD and a
wide variety of other conditions. Many ocular surface conditions that are encountered routinely, including keratitis
secondary to blepharitis and meibomian gland dysfunc-
COVER FOCUS
Figure 1. Prokera Classic disc on the eye. These
cryopreserved membranes are supplied frozen and attached
to a thermoplastic ring set. They are applied directly onto
the eye and sit under the lids.
tion, have been shown to benefit from treatment with
amniotic membranes. These membranes can also be used
for patients with recalcitrant dry eye disease, recurrent corneal erosion, and filamentary keratitis. We have also seen
clinical improvement in patients with exposure keratitis,
chemical burns, persistent epithelial defects, and neurotrophic defects after application of amniotic membrane.
Depending upon the indication and on the circumstances surrounding the insertion (whether including debridement or not), patients should always be treated postoperatively with a topical broad spectrum antibiotic. Topical
corticosteroids are also often used to help keep inflammation controlled while the membrane is in place.
The rate at which the amniotic membrane will dissolve
depends on the amount of inflammation present, but the
average is typically 4 to 7 days. Patients should be followed
closely during the first week, and closer monitoring should
be used for those whose ocular surface is more greatly
compromised. It is important to note that the use of amniotic membranes should be considered an additive and
synergistic treatment, and the mainstays of therapy for the
underlying indication should be used in conjunction with
amniotic membranes.
AVAILABLE MEMBRANES
Over the past several years, there has been tremendous
growth in the availability of amniotic membranes. At the
time of publication, there are seven brands of sutureless
amniotic membranes (Table). In general, sutureless amniotic membranes are divided into two distinct varieties:
cryopreserved and dehydrated. Each type is applied in a
different manner, and each may be better suited for certain
patients or clinical conditions.
Figure 2. AmbioDisk placement. Dehydrated membranes
should be applied using a lid speculum.
MAY/JUNE 2016 | ADVANCED OCULAR CARE 49
COVER FOCUS
WATCH IT NOW
Drs. Varanelli and Colatrella demonstrate their four-step
dehydrated amniotic membrane insertion process.
bit.ly/varinelli_0516
Drs. Varanelli and Colatrella show the insertion and
removal of cryopreserved amniotic membrane.
bit.ly/varinelli2_0516
The cryopreserved membranes are supplied frozen and
attached to a thermoplastic ring set. They are applied
directly onto the eye and sit under the lids (Figure 1). The
ProKera line of amniotic membranes (BioTissue) is the only
ophthalmic cryopreserved membrane, and these products
are available in several different parameters with differing
ring heights. All ProKera membranes must remain refrigerated and frozen throughout the shelf life of the tissue until
they are ready for use. After insertion, the ring may create
minor discomfort, and it is not uncommon to have to use
a “tape-sorraphy” to relieve this minor irritation. Once the
membrane dissolves, the ring must be removed.
Dehydrated membranes are available in varying disc
diameters and have shelf lives of 3 to 5 years when stored
at room temperature. There are now several dehydrated
50 ADVANCED OCULAR CARE | MAY/JUNE 2016
options available, including AmbioDisk (IOP Ophthalmics),
BioDOptix (BioD), Aril (SeedBiotech), and others. All
should be applied using a lid speculum (Figure 2), and
all are kept in place with a bandage contact lens. Each
manufacturer has several diameters available, but the 10to 12-mm diameter membranes are generally the most
practical.
Insertion of an amniotic membrane using a speculum
may be new to some practitioners. We have developed
a simple, four-step process that easily allows insertion in
2 minutes (see Watch It Now).
If you are just getting started in amniotic membrane
therapy, we recommend creating a standard routine, and
we suggest developing a consent form to be reviewed and
signed by each patient prior to insertion.
CONCLUSION
Treatments for OSD have evolved significantly over the
past several years. Sutureless amniotic membranes are
easy to insert in the office, and they give practitioners the
ability to monitor healing without interfering with the
penetration of ophthalmic medications. With their ability to reduce inflammation, prevent scarring, and enhance
epithelial proliferation, these therapeutic tissues should be
considered as adjunctive approaches for managing patients
with OSD. n
1. Trelford JD, Trelford-Sauder M. The amnion in surgery, past and present. Am J Obstet Gynecol. 1979;134:833-845.
2. de Rotth A. Plastic repair of conjunctival defects with fetal membranes. Arch Ophthalmol. 1940;23:522-525.
3. Sorsby A, Haythorne J, Reed H. Further experience with amniotic membrane grafts in caustic burns of the eye. Br J
Ophthalmol. 1947;31:409-418. 4. Sorsby A, Symmons HM. Amniotic membrane grafts in caustic burns of the eye (burns of second degree). Br J
Ophthalmol. 1946;30:337-345.
5. Batlle JF, Perdomo FJ. Placental membranes as a conjunctival substitute. Ophthalmology. 1993;100:107.
6. Kim JC, Tseng SC. Transplantation of preserved human amniotic membrane for surface reconstruction in severely
damaged rabbit corneas. Cornea. 1995;14:473-484.
7. Danforth DN, Hull RW. The microscopic anatomy of the fetal membranes with particular reference to the detailed
structure of the amnion. Am J Obstet Gynecol. 1958;75:536-550.
8. Aplin JD, Campbell S, Allen TD: The extracellular matrix of human amniotic epithelium: ultrastructure, composition
and deposition. J Cell Sci. 1985;79:119-136.
9. Hao Y, Ma DH, Hwang DG. Identification of antiangiogenic and antiinflammatory proteins in human amniotic
membrane. Cornea. 2000;19:348-352.
Nicholas Colatrella, OD, FAAO, Dipl AAO, ABO, ABCMO
djunct professor of optometry at Illinois College of Optometry
A
Medical director of PineCone Vision Center in Sartell, Minnesota
n (320) 258-3915; [email protected]
n Financial disclosure: honoraria from Allergan, BioDLogics, BioTissue, IOP Ophthalmics
n
n
Jeffrey R. Varanelli OD, FAAO, Dipl ABO, ABCMO
ptometrist at Simone Eye Center in Warren, Michigan
O
(586) 558-2981; [email protected]
n Financial disclosure: honoraria from Allergan, BioDLogics, BioTissue, Vistakon, IOP Ophthalmics
n
n