Several decades after its initial use, amniotic membrane transplantation
has been embraced by many ophthalmologists as a safe, versatile and largely
efficient method of treating ocular surface diseases and other conditions.
Amniotic membrane transplantation is used in conjunction with surgical
procedures involving the cornea, conjunctiva and limbus. It is also used to
support local tissues in glaucoma bleb surgery, strabismus surgery and orbital
Amniotic membrane, or amnion, is the inner layer of the placenta and
comprises a thick basement membrane and avascular stromal matrix. It is
currently available in cryopreserved and freeze-dried forms. It is avascular
and biocompatible with multiple tissue types on the ocular surface.
Amniotic membrane transplantation was first used for ocular surface
reconstruction following chemical injury in the 1940s but yielded inconsistent
results. However, it was virtually rediscovered in the mid-1990s and has since
been used in a growing range of indications. Amnion has largely supplanted
autologous buccal mucosa harvested from the mouth and other allogenic tissue
Amnion can be used as a graft material or bandage contact lens to
promote healing and minimize inflammation, as a scaffold to cultivate stem
cells, or as a structural reinforcement material.
Corneal indications include persistent epithelial defect, recurrent
epithelial erosion, corneal ulcer and perforation, inflammatory and infectious
keratitis, bullous and band keratopathy, limbal stem cell deficiency, high-risk
corneal graft, chemical injury, Stevens-Johnson syndrome and abnormal scarring
after superficial keratectomy.
|Amnion is a user-friendly tissue with great
applicability, according to Kenneth R. Kenyon, MD.
Image: Ashley Brito-New England Eye
Indications in conjunctival reconstruction are pterygium, symblepharon,
conjunctivochalasis and tumors.
For some surgeons, amniotic membrane transplantation has supplanted
conjunctival flaps and autografts as the preferred technique for repairing
defects created by excision of pterygia or conjunctival tumors.
Sutureless grafting techniques, utilizing tissue adhesives, and other
ongoing innovations promise to boost amniotic membrane as a primary and adjunct
treatment in challenging or high-risk cases.
Amniotic membrane is a unique tissue graft that is capable of
promoting wound healing through sophisticated biological pathways,
Scheffer C.G. Tseng, MD, PhD, a leader in the biologics industry, said.
Thomas John, MD, OSN Cornea/External Disease Board Member, said amnion
can be a viable alternative to native tissue in select cases.
There will be a need to ensure coverage when the patients
own conjunctiva is not available or the surgeon prefers not to use that
tissue, Dr. John said. Then, amniotic membrane is a good source to
surgically repair various conditions.
Amnion is versatile and easy to use, Kenneth R. Kenyon, MD, OSN
Cornea/External Disease Editor Emeritus, said.
Mother Nature did a good thing when she gave us amnion. Its
a very user-friendly tissue that has great applicability, Dr. Kenyon
said. Amnion has great utility for major ocular surface applications,
especially in the settings of persistent epithelial defects, noninfectious
corneal ulcers, and as a carrier or overlay for limbal stem cell grafts.
Amnions safety is supported by a 20-year track record, careful
screening protocols and strict quality control measures, Dr. Kenyon said.
The donors are screened with the same rigor as are cornea
donors, he said. The amnion is harvested during cesarean section
and is kept preserved until the mothers testing for hepatitis, HIV and
other communicable disease testing are proven negative before its use. Im
not aware of any case of human disease being transmitted via an amnion graft.
Bottom line, theres no transmissible disease risk, even potentially, with
Dr. Kenyon said he prefers fresh frozen tissue as opposed to
freeze-dried material. He said his enthusiastic use of amnion in non-healing
corneal surface disorders is balanced by his preference for conjunctival
autografts in more straightforward situations, such as pterygia.
Amnion has various biochemical and biomechanical attributes that bolster
its safety and applicability, Amar Agarwal, MS, FRCS, FRCOphth, OSN
Asia-Pacific Edition Board Member, said.
Amniotic membrane is used for its anti-inflammatory and
anti-angiogenic properties as well as its ability to promote epithelial
differentiation, adhesion and migration, Dr. Agarwal said. It also
has antibacterial, wound-protecting, pain-reducing and fibrosis-suppressing
effects. It can be used as a graft where it fills defects and promotes
epithelialization, or it can be used as a patch where it is used for its
anti-inflammatory and anti-angiogenic properties. It may also be used as a
patch-graft simultaneously according to the underlying condition being
Although the biomechanics and chemical composition of amniotic membrane
are largely unknown, it is still highly desirable for a number of reasons, Dr.
It is easily obtainable, is relatively cheap and is easy to
manipulate. Despite being an allograft, it has low immunogenicity and therefore
does not cause rejection, he said.
The cost of amniotic membrane compares favorably with that of other
commercially available tissues, Dr. Tseng said.
Amniotic tissue is more expensive, however, than autologous tissue
such as buccal mucosa, as the amniotic tissue must be processed to follow [U.S.
Food and Drug Administration] regulations as well as to ensure biological
efficacy, he said.
Amnion is eligible for Medicare and other reimbursement in many of its
ocular surface indications, Dr. Kenyon said.
As for the coding aspects, I believe it has been reasonably and
appropriately defined in the U.S., he said.
Cornea and conjunctiva
Amniotic membrane is especially well-suited for use as an overlay graft
or inlay graft, Dr. Kenyon said.
From my perspective, amnion is especially useful as an adjunct to
ocular surface surgery, No. 1 as a large-diameter overlay graft to assist with
limbal allograft or in some cases autograft transplantation, and also as
smaller-diameter inlay grafts in one or more layers to promote the healing of
sterile corneal stromal ulcers and persistent epithelial defects, he
Amniotic membrane has been used for persistent epithelial defects
secondary to neurotrophic corneas, autoimmune disorders and limbal stem cell
deficiency, Dr. Agarwal said.
In these cases, amniotic membrane may act by inhibition of
collagenases while at the same time providing collagen and a basement membrane
for epithelial cells to grow on, he said. The amniotic membrane
also provides growth factors, all of which provide a conducive atmosphere for
epithelial cells to grow on.
Amniotic membrane is used as a graft to fill the defect and replace
stromal matrix loss in small corneal of scleral melts. Necrotic tissue and
loose epithelial tissue are removed from the defect. Larger areas of melt
require additional tissue replacement such as donor scleral patch graft, which
in turn may be covered by amniotic membrane.
This onlay provides anti-inflammatory effects and promotes wound
healing, Dr. Agarwal said.
Amniotic membrane grafts are also used to treat bullous keratopathy
secondary to surgery or Fuchs dystrophy, Dr. Agarwal said.
According to Dr. John, clinicians should seriously consider using
amniotic membrane when appropriate in cases of toxic epidermal necrolysis, a
more severe form of Stevens-Johnson syndrome.
In 2002, Dr. John and colleagues published in Ophthalmology
the first report on the use of amniotic membrane to treat toxic epidermal
necrolysis, showing that a patient with this condition who underwent amniotic
membrane transplant had 20/20 vision and normal tear function after 13 years of
If you never did that, there would be a good chance of losing
vision and even losing the eye, Dr. John said.
Many patients with toxic epidermal necrolysis or Stevens-Johnson
syndrome undergo traditional treatment, which involves application of a
lubricant and breaking of adhesion between the eyelids and the eye.
Youre losing precious time because, after the first 10 to 14
days, you lose the opportunity to actually prevent the ongoing destructive
process over time, Dr. John said.
Amniotic membrane transplantation should be performed within 10 to 14
days of diagnosis, Dr. John said.
Most emergency room physicians, internists and pediatricians who
are in the front lines dont really recognize this, he said.
There are also a lot of ophthalmologists and eye care providers who are
not aware that the timing is so important. This is really huge. To get this
message out is of paramount importance. It is a difference between losing
ones eyesight and preserving ones vision.
Dr. Agarwal said that amniotic membrane has been shown to reduce the
recurrence of pterygia, particularly in patients who lack sufficient
conjunctival tissue for grafting.
Nevertheless, conjunctival autograft has been shown to have a
lower incidence of postoperative inflammation and recurrence than amniotic
membrane transplantation, Dr. Agarwal said.
Dr. Kenyon said that the efficacy of amniotic membrane vs. conjunctival
autograft in pterygium surgery is uncertain.
I realize that there are also schools of thought that like amnion
for pterygium surgery, but having been involved for many years with
conjunctival autograft technique, there is still no study that proves amnion to
be superior, Dr. Kenyon said. Given its significant costs, I think
my opinion is widely shared that conjunctival autografting is economically as
well as clinically superior to amnion.
Glaucoma, strabismus surgery
Amniotic membrane transplantation is used in glaucoma treatment as a
spacer to reduce scarring in trabeculectomy, as a temporary patch or permanent
graft to repair leaking blebs or fill in conjunctival tissue, and as a
conjunctival replacement or tube covering in cases involving glaucoma tube
I have used amnion on occasions to reinforce leaking blebs and to
cover shunt tubes and the like, Dr. Kenyon said. But I must say
that in that scenario, I do not think it is as useful as either conjunctival
bridge and free grafts or as pericardium or preserved lamellar corneal tissue
in reinforcing the thin conjunctival tissues.
The downside is that amnion is neither strong nor durable enough to
serve effectively in these situations that require a permanent structural
reinforcement, Dr. Kenyon said.
Amnion doesnt have much tensile strength and certainly
doesnt have a great deal of staying power, so it is not a great
substitute for settings where you really need to have a durable reinforcement
for conjunctiva, he said.
Dr. Tseng noted that thick membrane options with high tensile strength,
such as AmnioGuard (Bio-Tissue), can be used in glaucoma surgery.
Bleb excision surgery may involve a lack of conjunctival tissue to
construct a conjunctival autograft to cover the bleb excision site, Dr. Agarwal
Excision of the bleb and direct re-suturing, conjunctival
advancement or conjunctival autografts may be used, but these depend on
availability of adequate mobile conjunctiva to cover the defect without
shortening the fornix, he said.
A bleb can be closed with an amniotic membrane graft, although superior
results have been reported with conjunctival advancement.
The amniotic membrane is used to cover the defect after excising
the area of thin, avascular conjunctiva, Dr. Agarwal said.
Dr. Kenyon also expressed mixed feelings about the use of amnion in
Clearly, it does have some role. Some surgeons even use it to wrap
a surgically operated rectus muscle to prevent it from adhering to the
globe, Dr. Kenyon said. Again, I find that conjunctival free
grafting works very well in these situations just for the same reasons that I
find it preferred in pterygium surgery.
Amnion as substrate material
Recent innovations include amniotic membrane being used to cultivate
limbal stem cells, Dr. Kenyon said.
As far as utilization of the grafts, probably the most novel new
application is for ex vivo expansion grafts of limbal stem cells, where amnion
can be used as a substrate for small explants of limbus to be grown out, either
in a tissue culture setting or in an amnion sandwich placed on the
eye with very small explants of limbal autograft tissue that is allowed to
spread between the lamellae of amnion, Dr. Kenyon said. Thats
a very clever way of performing limbal stem cell autografting.
Amnion is safe by virtue of being biologically inert and pliable, Dr.
The amniotic membrane is non-immunogenic and does not contain any
actively replicating cells. It promotes epithelial adhesion and
migration, he said. Hence, it is an ideal substrate for ex vivo
expansion of limbal stem cells obtained via a small biopsy from the
patients eye. Once expanded on the amniotic membrane sheet, this can be
used to transfer the limbal stem cells to the patients eye. It has the
advantage of not leading to iatrogenic limbal stem cell deficiency in the donor
eye, as only a small biopsy is required.
Dr. Tseng said that amnion can be a substrate for the cultivation of
progenitor cells for conjunctival epithelium, corneal epithelium and limbus,
oral mucosa and corneal endothelium.
Currently this composite tissue is being transplanted to restore
vision as well as the structure and the function of damaged ocular surfaces in
humans, Dr. Tseng said. Further investigation should help us
unravel other therapeutic potentials in the fields of reconstruction, tissue
engineering and regenerative medicine.
Tissue-cultured human amniotic epithelial cells are also in use, Dr.
Corneal collagen sheets seeded with amniotic epithelial cells
obtained from human donor placentas are cultured ex vivo and have been used for
treatment of various conditions such as persistent epithelial defects, he
said. The advantage of this technique is that it is repeatable, fast,
easy to perform and does not involve surgery.
Fibrin glue, sutureless grafting
After excision of pterygium or malignant tumors, some surgeons prefer to
affix amniotic membrane grafts with sutures while others prefer fibrin glue.
Generally, smaller conjunctival flaps can be used to cover tumor excision
sites, while amniotic membrane is used to graft larger defects resulting from
the removal of larger tumors. Some surgeons use conjunctival autografts or
advancement flaps with dissolvable sutures to cover pterygium removal sites.
Fibrin glue facilitates adhesion of amnion to the ocular surface, Dr.
It doesnt have a great deal of tensile strength, but
its still adequate, for example, to hold an amnion graft or, for that
matter, a conjunctival graft in place for pterygium surgery or for larger
diameter overlays in ocular surface stem cell grafting, he said.
Sutureless amniotic membrane transplantation is gaining momentum because
of its convenience and efficacy, Dr. Tseng said.
Scheffer C.G. Tseng
There is a growing interest in performing sutureless amniotic
membrane transplantation to decrease tissue manipulation and increase the
surgical efficiency, he said. In this regard, fibrin glue is used
in lieu of sutures to improve the outcome and avoid suture-related
Dr. John said fibrin glue can be used as a means to minimize suturing of
Even at the present time, the combined use of amniotic membrane
with tissue adhesive, I think, will continue to increase in popularity,
Dr. John said. It decreases the number of sutures being used. As you
know, sutures can be a source of inflammation, irritation, discomfort and pain.
Although, in my opinion, you cannot completely eliminate sutures.
One downside to fibrin glue is that edges of the glued area can detach;
a judicious amount of suturing would be warranted in such a case, Dr. John
Having a few sutures will help, he said. The
combination of using amniotic membrane along with tissue adhesives is a good
way to do these procedures. In addition to increasing the patients
comfort, one may want to use a contact lens on the ocular surface. And, of
course, you have to cover with topical antibiotics to prevent any potential
Bandage contact lens, eye drop
The amnion-based product pipeline includes the ProKera bandage contact
lens (Bio-Tissue), which underwent an FDA clinical trial among military
personnel at the Walter Reed Army Medical Center. According to
ClinicalTrials.gov, the device facilitated complete corneal
The ProKera device is comprised of cryopreserved amniotic membrane
clipped into a thermoplastic ring set. Primary indications are corneal
epithelial defects, high-risk corneal transplants, infectious keratitis and
penetrating keratoplasty, according to the companys website.
Dr. Kenyon said that ProKera is easy to insert and precludes the need
[The ProKera amnion] is clever because it allows the amnion to be
slipped in much the way that a large contact lens would be. This obviates the
need for going to the [operating room] for suturing or gluing, Dr. Kenyon
ProKera can be applied in various clinical settings, Dr. Tseng said.
The clinical efficacy of ProKera is highlighted in cases with
severely compromised eyes such as acute chemical burns, acute Stevens-Johnson
syndrome and infectious keratitis, he said. ProKera can also be
used to treat persistent or recurrent epithelial defects and other diseases
where suppression of inflammation and re-epithelialization of the corneal
surface are necessary.
Dr. Kenyon and colleagues at Keera, a biologic/pharmacologic firm in
Italy, have developed lyophilized amnion membrane extract, an amnion-derived
eye drop designed to treat persistent corneal defects secondary to herpes
simplex or zoster, trigeminal nerve defect or diabetes. The product has
successfully undergone clinical trials in Italy and is slated to enter the
market in the European Union in the near future.
Its very exciting work, Dr. Kenyon said. by
Do you glue or suture
amniotic membrane grafts to treat ocular surface disease and tumors?
transplant another achievement for ophthalmic surgeons
- Barton K, Budenz D, Khaw PT, Tseng SCG. Glaucoma filtration surgery
using amniotic membrane transplantation. Invest Ophthalmol Vis
- Gregory DG. Treatment of acute Stevens-Johnson syndrome and toxic
epidermal necrolysis using amniotic membrane: a review of 10 consecutive cases.
- Habot-Wilner, Z, Spierer A, Barequet IS, Greenbaum A. Use of
amniotic membrane graft and corneal transplantation in a patient with bilateral
keratomalacia induced by uncontrolled phenylketonuria. Cornea.
- John T, Foulks GN, John ME, Cheng K, Hu D. Amniotic membrane in the
surgical management of acute toxic epidermal necrolysis.
- Kenyon KR. Amniotic membrane: mothers own remedy for ocular
surface disease. Cornea. 2005;24(6):639-642.
- Miri A, Al-Deiri B, Dua HS. Long-term outcomes of autolimbal and
allolimbal transplants. Ophthalmology. 2010;117(6):1207-1213.
- Resch MD, Resch BE, Csizmazia E, et al. Permeability of human
amniotic membrane to ofloxacin in vitro. Invest Ophthalmol Vis
- Seitz B, Das S, Sauer R, Hofmann-Rummelt C, Beckmann MW, Kruse FE.
Simultaneous amniotic membrane patch in high-risk keratoplasty.
- Strube YN, Conte F, Faria C, Yiu S, Wright KW. Amniotic membrane
transplantation for restrictive strabismus. Ophthalmology.
- Amar Agarwal, MS, FRCS, FRCOphth, can be reached at Dr.
Agarwals Eye Hospital, 19 Cathedral Road, Chennai 600 086, India; fax:
91-44-28115871; email: firstname.lastname@example.org.
- Thomas John, MD, can be reached at 708-429-2223; fax: 708-429-2226;
- Kenneth R. Kenyon, MD, can be reached at Cornea Consultants
International or Eye Health Vision Centers, 51 State Road, Dartmouth, MA 02747;
508-994-1400; fax: 508-992-7701; email: email@example.com.
- Scheffer C.G. Tseng, MD, PhD, can be reached at Ocular Surface
Research and Education Foundation, R&D Department, TissueTech, 7000 SW 97th
Ave., Suite 213, Miami, FL 33173; 305-274-1299; fax: 305-274-1297; email:
- Disclosures: Dr. Agarwal and Dr. John have no relevant financial
disclosures. Dr. Kenyon is involved with Keera, developer of lyophilized amnion
membrane extract. Dr. Tseng is medical director, Ocular Surface Research and
Education Foundation Director, R&D Department, TissueTech. He has a
financial interest in cryopreserved amniotic membrane and in the ProKera
product distributed by Bio-Tissue.