Biodegradable collagen matrix implant for trabeculectomy

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Device Profile
For reprint orders, please contact [email protected]
Biodegradable collagen
matrix implant
for trabeculectomy
Expert Rev. Ophthalmol. 3(6), 613–617 (2008)
Joseph R Zelefsky,
Wei-Cherng Hsu
and Robert Ritch†
Author for correspondence
Einhorn Clinical Research Center,
New York Eye and Ear Infirmary,
310 East 14th Street,
NY 10003, USA
Tel.: +1 212 673 5140
Fax: +1 212 420 8743
[email protected]ink.net
†
The biodegradable collagen matrix implant, marketed initially as OculusGen™ and currently as
Ologen™ and iGen™, is a novel bioengineered implant designed to be used at the time of
trabeculectomy. It consists of a collagen-based scaffold containing thousands of microscopic pores.
The implant is placed directly over the scleral flap and influences the healing process by forcing
fibroblasts and myofibroblasts to grow into the pores and secrete connective tissue in the form of
a loose matrix. This results in decreased scar formation and improved surgical success over
trabeculectomy performed without the adjunctive use of antifibrotic agents. Preliminary studies
have demonstrated that the biodegradable collagen matrix is effective for use in trabeculectomy,
although it may be associated with an increased risk of early postoperative hypotony. Future
randomized, controlled trials should help determine its place in glaucoma surgery.
Keywords : biodegradable collagen • filtering bleb • glaucoma • iGen™ • matrix • microtechnology • OculusGen™
• Ologen™ • tissue bioengineering • trabeculectomy
Trabeculectomy currently remains the ‘gold standard’ for filtration surgery. A disadvantage of this
procedure is postoperative scarring and fibrosis,
leading to bleb failure and elevated intraocular
pressure (IOP) [1] . The development of Tenon’s
cysts, which contain compressed collagen lamellae and lack an epithelial lining, and scarring
at the conjunctiva–Tenon’s–episcleral interface,
may prevent the ability of aqueous humor to
resorb [2] .
Concern over postoperative scarring has led to
the widespread intraoperative use of anti­fibrotic
agents, particularly 5-fluorouracil and mitomycin
C (MMC). These chemotherapeutic agents inhibit
fibroblast activity, reducing post­operative scarring
and increasing surgical success rates [3] . However,
they bring an increased risk for chronic bleb leaks,
hypotony, blebitis and endophthalmitis [4–6] .
The need for a balance between improving
success while reducing complications has led to
the search for an effective method of preventing postoperative fibrosis in a controlled fashion,
without incurring the morbidities and side effects
associated with antifibrotic agents.
Biodegradable collagen matrix implant
One solution to this challenge may have its roots
in the burgeoning field of tissue bio­engineering.
Regenerative medicine, the replacement and
www.expert-reviews.com
10.1586/17469899.3.6.613
improvement of cells, tissues and organs, promises to become the major focus of medicine in
the coming generation. Tissue bioengineering
involves the combination of a polymer scaffold
with a population of proliferating cells. If the
scaffold is biodegradable, it can result in the formation of structures that are remarkably similar
to the normal tissue [7] .
Broadly speaking, nanotechnology deals with
constructs in the order of 100 nm or smaller in
size. Microtechnology deals with structures in
the order of 100–1000 nm (1 µm). Scaffolds are
highly important in tissue bioengineering, drug
release and regenerative medicine. Both the scaffold and the seeded cell population play key roles
in the generation of composite structures. Recent
advances in bioengineering have made it possible
to generate de novo tissue through in vitro constructs, typically consisting of a biodegradable
polymer and stem or progenitor cells. Examples
of bioengineered structures include cartilage,
bone, blood and liver.
The biodegradable collagen matrix (BCM)
implant is marketed, depending on the country, as Ologen™ (Aeon Astron Corporation) or
iGen™ (Life Spring Biotech Company), both
based in Taipei, Taiwan. It takes advantage of
micro­technology and tissue bioengineering by
having a molecular structure that permits the
© 2008 Expert Reviews Ltd
ISSN 1746-9899
613
Device Profile
Zelefsky, Hsu & Ritch
formation of a spongy filtration bleb without the use of antifibrotic agents. The implant is a 3D porous scaffold made of 1%
collagen/C-6-S copolymer with a pore size ranging from 20 µm to
200 µm. It measures 4 × 7 mm and has a cylindrical shape, allowing for easy insertion and manipulation during glaucoma surgery
(Figures 1–3) . The implant encourages the formation of a spongy
meshwork of fibroblasts and connective tissue in a controlled and
organized pattern by forcing fibroblasts and myofibroblasts to
only grow into the pores, during the early post­operative period
and secrete connective tissue in the form of a loose matrix. By
guiding the pattern of cellular migration, it decreases the formation of dense scar tissue. After the polymer scaffold biodegrades, it
leaves a milieu of organized fibroblasts, myofibroblasts and extracellular matrix, with less scar formation than would other­wise
have occurred (Figure 4) [8] . What results is an elevated bleb with
dynamic flow of aqueous humor from the anterior chamber to
the subconjunctival space, without the thin-walled, cystic bleb
associated with antifibrotics (Figure 5) .
The implant also maintains an elevated bleb while the healing
process is underway. In trabeculectomy, early inflammation can
lead to adhesion of the conjunctiva to the episclera. The implant
sits between these two tissue layers, maintaining a prominent
space between them, thus forming a mechanical barrier that may
prevent adhesions between the conjunctiva and episcleral surface
during the early postoperative phase [9] .
In animal studies, the implant minimized wound leaks,
which can result from inadequate conjunctival closure [9] .
Situated between the scleral flap and conjunctiva, the implant
limits the amount of aqueous humor flow through the scleral
flap, in the early postoperative period, and allows the bleb to
maintain an elevated 3D structure as fibroblasts proliferate
and lead to wound healing [9] . Elimination of the thin-walled,
cystic bleb, characteristic of those obtained with antifibrotics,
should also reduce the incidence of late bleb leaks, which are a
serious and difficult problem to deal with. Numerous methods
have been attempted to repair bleb leaks, including amniotic
OculusGen™ implantation
Figure 1. Biodegradable collagen matrix implant positioned
directly above the scleral flap.
614
Figure 2. The biodegradable collagen matrix implant.
membrane grafting [10] , conjunctival grafting [11–13] , conjunctival advancement [14] , fibrinogen glue, application of a bandage
contact lens [15] and collagen shield placement [16] . Despite these
options, bleb leaks remain difficult to manage and frequently
recur after initially successful treatment.
Surgical technique
Implantation of the BCM is easily adapted to the standard trabeculectomy technique. A conjunctival incision (either fornixor limbal-based) is created. After the conjunctiva and Tenon’s
capsule are dissected, a partial-thickness scleral flap is formed. A
sharp blade is used to enter the anterior chamber at the base of the
scleral flap. A sclerostomy is created with a punch or by en bloc
excision, after which the scleral flap is closed with two to four
10–10 nylon sutures. The implant is then placed directly above
the scleral flap and the conjunctiva closed (Figure 6) .
Research
Animal studies
Chen et al. performed trabeculectomy with the BCM implant
in one eye of 17 rabbits and standard trabeculectomy without
antifibrotic agents in the fellow eye as a control [8] . For the first
2 postoperative weeks, IOP was similar in the two groups, then
decreased in the implant group as the matrix dissolved, while IOP
in the control group progressively elevated to preoperative levels.
Another study tested the implant’s ability to minimize bleb
leaks. A total of 30 rabbits undergoing trabeculectomy with the
implant were compared with a control group of six rabbits undergoing trabeculectomy without it. In both groups, the conjunctiva
was incompletely sutured to produce a wound leak. Although
the conjunctival defect sealed equally well in both groups, IOP
was significantly lower in the implant group after conjunctival
healing was complete. The investigators felt that the physical
presence of the implant above the scleral flap limited sudden
fluctuations in aqueous flow through the flap and allowed healing
of the conjunctival defect in a 3D pathway. The control group,
on the other hand, healed in a linear fashion, leading to scarring
of the bleb [9] .
Expert Rev. Ophthalmol. 3(6), (2008)
Biodegradable collagen matrix implant for trabeculectomy
Device Profile
Human studies
The BCM implant is now available in Europe and Asia. Although
the number of clinical studies is still limited, early results are
hopeful. Chen and Hsu reported the preliminary results of their
experience in 12 patients. They found a 64% reduction in IOP 4
months after surgery [17] . The average number of glaucoma medications also decreased from 2 to 0.3. There were no intraoperative
complications and minimal postoperative complications.
Ruokonen et al. reported their experience in 17 patients with
open-angle glaucoma. IOP improved from 30 to 14 mmHg
after 3 months [18] . The average number of glaucoma medications required decreased from 3.3 to 0.2. Four patients required
surgical intervention for hypotony, and two required repositioning of a migrated implant. A total of 11 eyes developed bleb
encapsulation with elevated IOP after 1 month. Of these, some
responded well to needling and two required further surgery
to control IOP. Only two patients required reinstitution of
antiglaucoma medications.
Another study reported the outcomes of 20 consecutive
patients who underwent fornix-based trabeculectomy with
implant placement [19] . After 3 months, mean IOP decreased
from 33.8 to 13.3 mmHg. Seven patients had hypotony (defined
as IOP < 4 mmHg) at some point postoperatively, but only two
developed shallow anterior chambers. A total of 80% of the
subjects achieved either an IOP of less than 21 mmHg without medications, or a 30% reduction in IOP with or without
medications. One patient required a needle revision of the bleb
and another required a repeat trabeculectomy with MMC. All
patients tolerated the implant well and no systemic adverse
effects were noted.
In another clinical trial involving 22 eyes with glaucoma,
11 eyes underwent trabeculectomy with MMC and 11 underwent
trabeculectomy with the implant [20] . Both groups experienced
similar IOP reduction after 30 days. The incidence of shallow
anterior chambers was similar between the two groups.
Figure 4. Randomized collagen (white arrow) deposited in
a prominent bleb (long black arrow) in a rabbit eye that
underwent trabeculectomy with biodegradable collagen
matrix implantation. A 10–10 nylon suture (20–30 µm
diameter, black arrow) is located in the upper right corner.
Reprinted with permission from the Association for Research and
Vision in Ophthalmology.
Researchers in China studied the effects of trabeculectomy with
the implant versus trabeculectomy without antifibrotics. A total of
30 eyes were included in each group. The mean IOP was significantly lower in the implant group after 6 months of follow-up. The
risk of bleb failure was 30% lower in the implant group [21] .
The BCM implant is also being used in cases of cataract
extraction combined with trabeculectomy. Grewal et al. studied
ten patients with primary open-angle glaucoma who were undergoing combined phacoemulsification with trabeculectomy and
implant placement [22] . At 3 months postoperatively, the mean
IOP had improved from 20 to 9 mmHg and the mean number
of topical glaucoma medications needed was reduced from 2.7 to
0.9. No complications were encountered.
Conclusion
Figure 3. Scanning electron micrograph of the
biodegradable collagen matrix implant, demonstrating the
microscopic pores that will control the pattern of scar
tissue formation.
www.expert-reviews.com
The BCM implant invokes the concepts of tissue bioengineering
to promote successful filtration surgery in patients with glaucoma.
The implant induces formation of a diffuse and elevated bleb by
guiding the formation of scar tissue in a physiological pattern.
Animal studies and preliminary results with humans suggest that
trabeculectomy with BCM implant placement may reduce IOP as
well as trabeculectomy with MMC, the current gold standard of
glaucoma surgery. Randomized, controlled prospective trials have
not yet been performed and are necessary. Furthermore, some studies have reported a relatively high incidence of early hypotony after
trabeculectomy with implant placement. Larger-scale clinical trials
and long-term follow-up data will be necessary to better evaluate
its safety and clinical efficacy.
615
Device Profile
Zelefsky, Hsu & Ritch
Figure 5. Postoperative clinical photograph of a patient
who underwent trabeculectomy with biodegradable
collagen matrix implant placement. The bleb is elevated and
spongy, and lacks the thin-walled, ischemic appearance that is
characteristic of antifibrotic usage.
Photograph courtesy of Peter Rieck, MD.
Expert commentary
The early data presented previously suggest that BCM implants
have the potential to play an important role in glaucoma surgery. The past years have seen a tremendous proliferation in
the use of 5-fluoro­u racil and MMC, and this has led to an
increased incidence of several sight-threatening complications
associated with these potent medications. The implant’s ability
to improve bleb survival without incurring the risks associated
with antifibrotic agents will hopefully increase interest in this
device. Randomized, controlled studies will help delineate the
implant’s role in glaucoma surgery. Currently, long-term data are
lacking. Moreover, additional prospective studies are necessary
to confirm the incidence of early postoperative hypotony and, if
substantiated, determine its underlying mechanism.
Figure 6. The surgeon places a biodegradable collagen
matrix implant in the eye of a patient undergoing
fornix-based trabeculectomy.
Photograph courtesy of Henry Shen-Lih Chen, MD.
possible risk of early postoperative hypotony, clinicians who use
the implant should plan accordingly as they care for the patient
during the first few weeks after surgery.
Another factor that will inevitably play a role in the future of
this device is its cost. Currently, it has been estimated that the cost
of the device may range between US$300 and $400. Whether
insurance companies and government-managed healthcare plans
pay for this device remains to be seen.
Due to the lack of current long-term data, one can only speculate whether trabeculectomy with BCM implants alone will be
sufficient to control IOP in patients with advanced glaucoma.
Early data, however, support the concept that microtechnology
and nanotechnology will play increasingly important roles in
ophthalmology.
Financial & competing interests disclosure
Five-year view
As clinicians become familiar with the implant and use it with
greater frequency, we expect to see a decrease in the incidence
of bleb leaks, bleb-related ocular infections and other long-term
complications associated with antifibrotic usage. Given the
Robert Ritch is a consultant to Aeon Astron Corporation. The authors have
no other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Trabeculectomy with antifibrotic agents is the current gold standard for glaucoma surgery and is associated with an increased risk for
chronic bleb leaks, hypotony, blebitis and endophthalmitis compared with trabeculectomy without antifibrotic agents.
• The biodegradable collagen matrix is a collagen-based scaffold containing thousands of microscopic pores and is implanted above the
scleral flap during trabeculectomy in lieu of antifibrotic agents.
• The pores guide the pattern of cellular migration and lead to the development of a milieu of organized fibroblasts, myofibroblasts and
extracellular matrix, as well as decreased scar tissue formation.
• The result is the development of an elevated, spongy bleb without the thin-walled, cystic appearance associated with antifibrotic usage.
• Animal studies and preliminary human results suggest that trabeculectomy with biodegradable collagen matrix implant placement may
be as successful as trabeculectomy with antifibrotic medications.
• Although some preliminary studies in humans report no complications, others reveal an increased incidence of early postoperative
hypotony in patients who underwent trabeculectomy with implant placement.
616
Expert Rev. Ophthalmol. 3(6), (2008)
Biodegradable collagen matrix implant for trabeculectomy
References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1
Arici MK, Demircan S, Topalkara A.
Effect of conjunctival structure and
inflammatory cell counts on intraocular
pressure after trabeculectomy.
Ophthalmologica 213, 371–375 (1999).
•
Publication suggesting that the potential
benefits of the Ologen implant extend
beyond preservation of bleb function.
10
Budenz DL, Barton K, Tseng SCG.
Amniotic membrane transplantation for
repair of leaking glaucoma filtering blebs.
Am. J. Ophthalmol. 130, 580–588 (2000).
11
Buxton JN, Lavery KT, Liebmann JM et al.
Reconstruction of filtering blebs with free
conjunctival autografts. Ophthalmology 101,
635–639 (1994).
12
Schnyder CC, Shaarawy T, Ravinet E et al.
Free conjunctival autologous graft for bleb
repair and bleb reduction after
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2
van Buskirk EM. Cysts of Tenon’s capsule
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3
Lama PJ, Fechtner RD. Antifibrotics and
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Ophthalmol. 48, 314–346 (2003).
•
Well-written and extensive review of
antifibrotic agents and their clinical use in
glaucoma surgery.
13
DeBry PW, Perkins TW, Heatley G et al.
Incidence of late-onset bleb-related
complications following trabeculectomy
with mitomycin. Arch. Ophthalmol. 120,
297–300 (2002).
Wilson MR, Kotas-Neumann R. Free
conjunctival patch for repair of persistent
late bleb leak. Am. J. Ophthalmol. 117,
569–574 (1994).
14
Burnstein AL, WuDunn D, Knotts SL et al.
Conjunctival advancement versus
nonincisional treatment for late-onset
glaucoma filtering bleb leaks. Ophthalmology
109, 71–75 (2002).
15
Blok MD, Kok JH, van Mil C et al. A use of
the Megasoft Bandage Lens for treatment of
complications after trabeculectomy.
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16
Fourman S, Wiley L. Use of a collagen
shield to treat a glaucoma filter bleb leak.
Am. J. Ophthalmol. 107, 673–674 (1989).
17
Chen, Hsu. Initial clinical experience with
biodegradable 3D porous collagenglycosaminoglycan scaffold (OculusGen®)
for treatment of refractory glaucoma.
Presented at: World Ophthalmology Congress.
São Paulo, Brazil, 19–24 February 2006.
4
5
6
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8
Greenfield DS, Liebmann JM, Jee J,
Ritch R. Late-onset bleb leaks after
glaucoma filtering surgery. Arch.
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Soltau JB, Rothman R, Budenz DL et al.
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(2000).
Young MJ, Borràs T, Walte M, Ritch R.
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1725–1731 (2005).
Chen HS, Ritch R, Krupin T, Hsu WC.
Control of filtering bleb structure through
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(2006).
18
Ruokonen P, Rieger R, Berndt S, Mai C,
Rieck P. First experiences with the
OculusGen collagen-matrix-implant in
glaucoma surgery. Presented at: World
Glaucoma Congress 2007. Singapore,
18–21 July 2007.
19
Kaljurand K. Ologen collagen matrix
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2007. Singapore, 18–21 July 2007.
•• First paper published on the Ologen™
implant demonstrating its clinical efficacy
in an animal model.
9
Hsu WC, Ritch R, Krupin T, Chen HS.
Tissue bioengineering for surgical bleb
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www.expert-reviews.com
Device Profile
20
Imtiaz Ali S. Study of the safety and
effectiveness of Ologen™ collagen matrix
implant and MMC in standard glaucoma
filtration surgery. Presented at: World
Ophthalmology Congress 2008. Hong Kong,
28 June – 2 July 2008.
21
Yuan F. Biodegradable 3D-porous
collagen–glycosaminoglycan scaffold for
treatment of refractory glaucoma. Presented
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Hong Kong, 28 June–2 July 2008.
22
Grewal SPS. Adjunctive use of biodegradable porous collage-glycosaminoglycan
implant in phacoemulsification combined
with trabeculectomy for surgical management of primary open-angle glaucoma.
Presented at: World Ophthalmology Congress
2008. Hong Kong, 28 June–2 July 2008.
Affiliations
•
Joseph R Zelefsky, MD
Einhorn Clinical Research Center, New
York Eye and Ear Infirmary, 310 East 14th
Street, NY 10003, USA;
and, New York University Medical Center,
New York, NY, USA;
and, Manhattan Eye Ear and Throat
Hospital, New York, NY, USA
•
Wei-Cherng Hsu, MD
Department of Ophthalmology, Buddhist
Tzu Chi General Hospital Taipei Branch,
Taipei, Taiwan;
and, Department of Ophthalmology,
Tzu Chi University, Hualien, Taiwan
•
Robert Ritch, MD
New York Medical College,
Valhalla, NY, USA;
and, Shelley and Steven Einhorn
Distinguished Chair, Einhorn Clinical
Research Center, New York Eye and Ear
Infirmary, 310 East 14th Street,
NY 10003, USA
Tel.: +1 212 673 5140
Fax: +1 212 420 8743
[email protected]
617
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