a newly designed glaucoma drainage implant made of sibs (2) (1)

7/26/2019 A Newly Designed Glaucoma Drainage Implant Made of SIBS (2) (1)

1/8

LABORATORY SCIENCES

A Newly Designed Glaucoma Drainage Implant Madeof Poly(styrene-b-isobutylene-b-styrene)

Biocompatibility and Function in Normal Rabbit Eyes

Ana C. Acosta, MD; Edgar M. Espana, MD; Hideo Yamamoto, MD; Stewart Davis, MD; Leonard Pinchuk, PhD;Bruce A. Weber, MA; Marcia Orozco, MS; Sander Dubovy, MD; Francisco Fantes, MD; Jean-Marie Parel, PhD

Objective:To report clinical evaluation, flow patency,and histopathological findings of a novel glaucoma drain-age implant (GDI) made of poly(styrene-b-isobutylene-b-styrene) (SIBS) in rabbits.

Methods:In 16 normal eyes, the proximal end of theSIBS GDI was inserted into the anterior chamber while

the distal end was placed in the subconjunctival space.A control group underwent implantation of a similarlydesigned silicone GDI. Slitlamp follow-up and intraocu-lar pressure measurements were recorded. Flow patencywas evaluated by injecting 0.01% fluorescein into the an-terior chamber.Immunostaining againstcollagen IV, mac-rophages, and smooth muscle actin was performed.

Results:Slitlamp examination suggested adequate bio-compatibility. A low and diffuse bleb was observed in the

SIBS group. All SIBS tubes were patent 6 months afterinsertion. Immunostaining demonstrated noncontinu-ous collagen deposition. No macrophages or myofibro-blasts were visible around the SIBS tubes. In contrast, sili-cone induced collagen deposition and myofibroblastdifferentiation.

Conclusion:

This new GDI is clinically biocompatiblein the rabbit and maintained 100% patency at 6 months.A remarkable difference was the absence of myofibro-blasts in the surrounding tissue in the SIBS group.

Clinical Relevance: This novelGDI made of SIBS wouldprevent the feared complication of hypotony and will de-crease the amount of subconjunctival fibrosis.

Arch Ophthalmol. 2006;124:1742-1749

DRAINAGE SURGERY TO CON-trol intraocular pressure

(IOP) with different de-vices has limited successbecause of a buildup of

extracellular matrix.1,2 The initial devicesused to drain aqueous were horsehairthreads.3 Other materials including glassrods,4 gold,5 silk,6 and even artificial tra-becular meshworks7,8 were tried withoutsuccess because of subconjunctival scar-ring. New devices including the Ex-PRESS glaucoma implant9 and Wilcoxshunt10 aredescribed in theliterature; how-ever, long-term effectiveness data are notavailable.

Modern glaucoma drainage surgery be-gan with the pioneer work of Molteno inrabbits11 and humans,12 where the aque-ous humor was drained from the anteriorchamber to a plate adjacent to the lim-bus. He later increased the silicone tubelength to allow the drainage of aqueousinto a more posterior area.13 Another modi-fication in glaucoma drainage implants(GDIs) was the introduction of unidirec-tional valve systems to avoid postopera-

tive hypotony.14 Krupin et al15 reportedtheir results with a valved system in 1976,

followed by Coleman et al16

with theAhmed implant. Subsequent designchanges by Molteno17 and Baerveldt18,19

were aimed at increasing the plate area.It is believed that the fibrotic and in-

flammatory reactions induced by bioma-terials are a major determinant of suc-cess.20-22 Other factors such as shape,flexibility, modulus, and texture could alsobe associated with erosion, extrusion, in-flammation, and scarring.20 Hypotheti-cally, selecting a biomaterial and a designthat produces minimal inflammation andfibrosis is a means to increase success.

Poly(styrene-b-isobutylene-b-styrene)(SIBS), a novel synthetic polymer consist-ing of a triblock of polystyrene-polyiso-butylene-polystyrene,23 has been studiedin different medical fields.24,25 Multiple in-vestigators26,27 observed that SIBS has ex-cellent biostability. The lack of biodegra-dation byproducts is believed to be a majorfactor enhancing its biocompatibility. In ad-dition, SIBS can be loaded with differentpharmaceuticalagents.25 These unique ma-

Author Affiliations:Ophthalmic Biophysics Center,Bascom Palmer Eye Institute,University of Miami Miller

School of Medicine (Drs Acosta,Espana, Yamamoto, Orozco,Dubovy, Fantes, and Parel), andDepartment of BiomedicalEngineering, University ofMiami College of Engineering(Drs Orozco and Parel), Miami,Fla; InnFocus LLC, Miami, Fla(Drs Davis, Pinchuk, andWeber); and the University ofLiege, CHU Sart-Tilman, Liege,Belgium (Dr Parel).

(REPRINTED) ARCH OPHTHALMOL/ VOL 124, DEC 2006 WWW.ARCHOPHTHALMOL.COM1742

2006 American Medical Association. All rights reserved.at University of Miami School of Medicine, on December 11, 2006www.archophthalmol.comDownloaded from
http://www.archophthalmol.com/http://www.archophthalmol.com/http://www.archophthalmol.com/http://www.archophthalmol.com/


2/8

terial properties of SIBS are crucial for the fabrication oflife-lastingimplants, as demonstrated by the TAXUS coro-nary stent (Boston Scientific, Natick, Mass). The TAXUSstent uses SIBS as a carrier for the antiproliferative agentpaclitaxel, which is released into the vessel wall to pre-vent the proliferation of smooth muscle cells.28,29

In this article, we report the preliminary results of bio-compatibility, flowpatency, and histopathology of a novelGDI made of SIBS, where the new features include a new

biostable elastomeric polymer, a small and flexible de-sign, and a valveless tube with an inner diameter of 65m.

METHODS

ANIMALS AND MATERIALS

The animals used in the study were 25 normal female New Zea-landwhite rabbits from Harlan Laboratories (Indianapolis, Ind),weighing2.5 to 3.0 kg. All animalswere treated in accordance tothe Association for Researchin Vision andOphthalmology state-ment for the use of animals in ophthalmic research. The Com-mittee and Review Board for Animal Research of the Universityof Miami (Miami, Fla) approved all animal studies. Prior to sur-gery, allanimals were examined to exclude ocular diseases.A Per-

kins tonometer (Clement Clarke, London, England) anda pneu-matonometer (Mentor Inc, Norwell, Mass) were calibrated.Evaluation of the central corneal thickness was performed usingan ultrasonic pachymeter (DGH 500 Pachette; DGH Technol-ogy, Frazer, Pa). The newly designed GDIs were made of SIBS,with 24 mol% styrene (InnFocus LLC, Miami, Fla).

The polydimethylsiloxane tubes, known as silicone, werepurchased (Silastic; Dow Corning, Midland, Mich). The lu-mens of theSIBS tubes were coatedwith glycerol to avoid stick-ing during manipulation. The initial design of the SIBS tubehad a mean inner diameter of 6510 m, and a mean outer di-ameter of 250 10 m(Figure 1A). The silicone rubber tubeshad a mean inner diameter of 30010 m and a mean outerdiameter of 640 15 m (Figure 1C). This designwas later modi-fied by attaching a tab composed of the same materials to the

wall in the middle region of the tube in both the SIBS and sili-cone tubes (Figures 1B and 1D, respectively). A disposable in-serter device with a grip, a 27-gauge slotted needle, and a de-ployment slide were developed to facilitate insertion.

SURGICAL PROCEDURE

The right or left eye of 25 rabbits was randomly assigned forsurgery;the other eye wasusedas a control. Animals were givenan intramuscular injection of a k etamine-xylazine-acepromazine mixture (35 mg/kg, 5 mg/kg, and 0.75 mg/kg,respectively). All surgeries were performed by the same sur-geon (A.C.A.). The surgical area was exposed with a cornealtraction suture. A 90 fornix-based conjunctival peritomy wasmade in the superotemporal quadrant and the subconjuncti-

val space was dissected posteriorly 10 to 14 mm using West-cott scissors. A 27-gauge needle was inserted 2 mm posteriorto the limbus and directed to the anterior chamber. The SIBSGDI waspreloaded into theinserter. Thepreloaded inserter en-tered thesclerafollowing theneedle scleral tract.Once theGDIwas 3 mm into the anterior chamber, the GDI was released byretracting the thumb slide. Flow through the tube was con-firmed by gently pressing the cornea until aqueous came outof the distal end. Thedistal end was then positioned under theconjunctiva. The conjunctiva was suturedwith 7-0 Vicryl (Ethi-con, Somerville, NJ). The silicone GDI was inserted in a simi-lar manner, except that a 23-gauge needlewas used for thescleral

tract. The animals were treated with a subcutaneous injectionof 0.03 mg/kg of buprenorphine after surgery and bacitracin-neomycin-polymyxin ointment and prednisolone acetate 1%

(Allergan Inc, Irvine, Calif) twice a day for 3 days.

SLITLAMP BIOMICROSCOPY, IOPMEASUREMENTS, AND CORNEAL PACHYMETRY

Slitlamp follow-up was performed weekly. After topical anes-thesia,IOP was measuredwith the Perkins tonometer and pneu-matonometer in both operated and nonoperated eyes at 0, 1,3, 14, 21, 60, 120, and 150 days after surgery. Animals wereexamined under general anesthesia at days 7, 28, 90, and 180after surgery.

FLUORESCEIN PATENCY TEST

To evaluate the patencyof the GDI and the passage of aqueoushumor from the anterior chamber to the subconjunctival space,a solution of 0.01% sodium fluorescein (AK-Fluor; Akorn, De-catur, Ill) in a balanced salt solution was injected into the an-terior chamber of 16 eyes in the SIBS group and 6 eyes in thesilicone group. These experiments were performed at 90 and180 days postoperatively. Briefly, theanterior chamber wasen-tered with a 30-gauge needle, and the aqueous humor was al-lowed to drain out from the anterior chamber to avoid exces-sive IOP. A second 30-gauge needle was introduced into theanterior chamber and approximately 0.5 mL of fluorescein wasinjected for 20 minutes. Intraocular pressure wasmonitoreddur-ing the procedure and did not exceed 25 mm Hg. Photographicdocumentation wasacquired using an illuminator paraxial to theoperation microscope (OMS-300; Topcon USA, Paramatta, NJ)and blue dichroic excitation and yellow barrier filters (Y54-653

and NT47-247; Edmond Industrial Optics, Barrington, NJ).

LIGHT MICROSCOPY ANDIMMUNOFLUORESCENT STAINING

Animals were euthanized with 390 mg/ml Euthasol (Del-marva Laboratories Inc, Midlothian, Va). The GDI andthe sur-rounding tissue were dissected, immersed in optimal cuttingtemperature component (Tissue-Tek; Sakura, Torrance, Calif),and snap-frozen in liquid nitrogen. Frozen sections, 5-m-thick, were cut and fixated in acetone for 10 minutes at 20C

B

D

A

C

Figure 1.Scanning electron microscopy shows the differences in tubedimensions. A, Poly(styrene-b-isobutylene-b-styrene) tube with smaller innerdiameter (65 m). B, A tab was attached to prevent migration. C, The siliconetube had a larger inner diameter (300 m). D, A silicone tab was added.




3/8

and blocked with 1% goat serum for 30 minutes. Sections wereincubated overnight with the following antibodies: smoothmuscle actin (-SMA) (monoclonal, 1:100 dilution; DAKO,Carpintera, Calif), macrophages (monoclonal, 1:50 dilution),

and collagen IV (polyclonal that cross-reacts with collagens I,II, and III, 1:100 dilution; Southern Biotechnical, Birming-ham, Ala). Rhodamine-B-isothiocyanateantigoat and fluores-cein-5-isothiocyanateantimouse secondary antibodies(Sigma-Aldrich, St Louis, Mo) were used at 1:100 dilution. The 4,6-diamidino-2-phenylindole mounting media Vectashield wasfrom Vector laboratories (Burlingame, Calif). Some frozen sec-tions were stained with hematoxylin-eosin. Photographs weretaken using a confocal laser scanning microscope (LSM-510;Carl Zeiss, Oberkochen, Germany).

RESULTS

SIBS GDIs AND POSTOPERATIVE HYPOTONY

Surgical time varied between 11 and 18 minutes in bothgroups. The immediate postoperative period was unre-markable in the SIBS group. In contrast, all rabbits in thesilicone group had flat or shallow anterior chambers for2 to 3 days. Hyphema formed in all rabbits in the sili-cone group during the surgical procedure. One rabbit inthis group had blood and fibrin inside the tube and didnot form a bleb. Immediate postoperative IOP readingswere taken only with the Perkins tonometer to avoid thepressure exerted by the pneumatonometer in a shallowchamber. In the SIBS group, the mean IOP taken imme-diately after tube insertion and still under the effect ofgeneral anesthesia was 5.62.1 mm Hg. The lowest IOP

recorded was 3.5 mm Hg. One day postoperatively, themean IOP was 7.91.8 mm Hg in all eyes with SIBS im-plants. In contrast, all controls in the silicone group hadflat anterior chambers with IOP of 0 mm Hg immedi-ately after surgery. No statistically significant differencein IOP reduction was observed between the operatedandnonoperated eyes in the SIBS or silicone groups or be-tween the SIBS and silicone groups 7 days postopera-tively (Figure 2). Taken together, these observationsdemonstrate the advantage of the SIBS tubes in avoidingimmediate postoperative hypotony.

CLINICAL BIOCOMPATIBILITY OF SIBS GDIs

Tubes without a tab (the initial design in both materials)migrated into the anterior chamber. Silicone tubes mi-grated almost entirely within 2 days (Figure 3A), whileSIBS tubesmigrated within2 weeks(Figure3D). Nochangesin central corneal thickness were recorded in any groupafter surgery or during the 6-month follow-up. The meancentral corneal thickness was 3608 m. No tube migra-tion was observedonce a silicone or SIBS tab was attachedto the silicone or SIBS tubes, respectively. No other com-plications were observed in any of the SIBS tubes with anattached tab. In contrast, all silicone tubes produced flatanteriorchambersandhyphemaduring theimmediatepost-operative period (not shown). At the end of follow-up, allanimalsinthesiliconegroup(Figure3B) andthe SIBSgroup(Figure 3E) had deep and quiet anterior chambers. Goni-

oscopy demonstratedthe silicone tubes in a close positionor in contact with the iris (Figure 3C). Without directlycontacting them, SIBS tubes were parallel to the iris or thecornea (Figure 3F). Small blebs were a typical finding dur-ing the first 3 postoperative days in the SIBS group(Figure 4A), compared with very large blebs that slowlyflattened in the silicone group (Figure 4B). One week af-ter surgery, only loose subconjunctival space was noticedat the end of the tube, suggesting the presence of a diffusebleb in both SIBS and silicone groups. In the SIBS group,the bleb was diffuse and vascularized; however, encapsu-lation and neovascularizationwerenever observed aroundthe tube for the duration of the study (Figure 4C). Fi-brous encapsulationandneovascularizationaroundthetube

were clearly observed at 1 month (Figure 4D) in eyes thatunderwent silicone tubes implantation.Twoanimals in thesilicone group were euthanized because of tube extrusionat the limbus area 45 and 109 days postoperatively(Figures 4E and 4F).

SIBS GLAUCOMA DRAINAGE IMPLANTSAFTER 6 MONTHS

Although we observed a low bleb surrounding the tubeduring slitlamp examination and confirmed it with an-

20

15

10

5

0

50 20 40 60 80 100 120 140 160 180 200

Time, d

IOP,

mmH

g

50

40

30

20

5

45

35

25

15

0

10

50 20 40 60 80 100 120 140 160 180 200

Time, d

Operated SIBSControl SIBSOperated SiliconeControl Silicone

A B

Figure 2.Intraocular pressure (IOP) comparison using 2 different tonometers. A, Perkins. B, Pneumatonometer. SIBS indicates poly(styrene- b-isobutylene-b-styrene).




4/8

cillary imaging (Figure 5), fluorescein flow and tubepatency was clearly observed through all tubes in 16 eyesof 16 rabbits evaluated in the SIBS group. Ten of theseanimals had a follow-up of 6 months at the time of thefluorescein assay (Table). After injection of fluoresceininto the chamber, fluorescein began to fill the perilim-bal region and the tube lumen within seconds. Fluores-cein exited from the distal tip of the tube into the sub-

conjunctival space (Figure 6B) and slowly diffusedaround (Figure 6C). Fluorescein continued to diffusethrough the tube into the subconjunctival space to de-fine a 90 to 120 bleb (Figure 6D). In contrast, only 2of 6 silicone tubes were patent at 3 months. The blebswere limited to the area adjacent to the silicone tube anddid not diffuse to the surrounding subconjunctival spaceafter 30 minutes of injection (not shown).

B

D

A C

FE

Figure 3.Slitlamp and gonioscopic examination of the inserted poly(styrene-b-isobutylene-b-styrene) (SIBS) and silicone implants shows the excellentbiocompatibility of both materials in the anterior chamber. Silicone tubes migrated almost entirely within 2 days (A), while SIBS tubes migrated within 2 weeks(D). At the end of follow-up, all animals in the silicone group (B) and the SIBS group (E) had deep and quiet anterior chambers. Gonioscopy demonstrated thesilicone tubes in a close position or in contact with the iris (C, arrow). Without directly contacting them, SIBS tubes were parallel to the iris or the cornea (F).

D E

A B

F

C

Figure 4.A, Low diffuse bleb in the poly(styrene-b-isobutylene-b-styrene) (SIBS) group. B, Giant blebs in the silicone group. C, In SIBS, the bleb was diffuse and

vascularized. D, Encapsulation with silicone. Two animals in the silicone group had tube extrusion (E, F).




5/8

FIBROTIC RESPONSES OF SIBS GDIs

Sections were obtained at different locations along thetube track in the SIBS group at 3 and 6 months and at 3months in the silicone group. Hematoxylin-eosin stain-ing in the SIBS group showedno excessivecollagen depo-sition, lymphocytes, or inflammatory cell infiltration(Figure 7A), even in the area where the tab was lo-cated (not shown). Collagen IV deposition was weak

around the tube and did not surround the entire tube cir-cumference (Figure 7B). Smooth muscle actin did notstain the cells surrounding thetube (Figure 7C). No stain-ing against macrophages was observed (notshown). Simi-

larly, sparse collagen IV deposition was observed aroundthe tab with the absence of a continuous capsule (notshown). No reactivity against-SMA wasobserved aroundthe tab (not shown).

In the silicone GDI, the iris stroma seemed quiet andno stromal inflammatory cell infiltrates were observedat the entrance of the tube into the anterior chamber(Figure 7D) or at a distal region (not shown). Abundantcollagen IV deposition was evident around the tube in

all studied sections (Figure 7E). In contrast to the SIBStubes, -SMA was expressed around the silicone tubes(Figure 7F), and highly deposited areas of collagen wereobserved around the silicone tab (not shown). At 6months, hematoxylin-eosin staining of the SIBS tubes didnot show collagen deposition or cell infiltration aroundthe tube. Interlaminar spaces were clearly observed in thesubconjunctival space suggesting the presence of inter-stitial aqueous humor (Figure 8A). A light depositionof collagen IV completely surrounded the tube(Figure 8B), which was clearly evident at higher magni-fications (Figure 8C). No smooth muscle actin or mac-rophages reactivity were observed in any of the SIBS tubes(Figure 8D) in any time frame.

COMMENT

Drainage implants arevaluable in themanagementof neo-vascular30 and juvenile glaucoma,31 as well as glaucomaassociated with uveitis,32,33 penetrating keratoplasty,34-36

aphakia,37 and failed filtering surgery.38 Despite differ-ent modifications to the material, surgical technique, and

B

D

A

C

Figure 5.Diffuse bleb demonstrated by optical coherence tomography (OCT)imaging (B) compared with a normal subconjunctival space in a nonoperatedcontrol (D). A and C, Location of the OCT scan of the ocular surface.

Table. Summary of Different Variables Studied During the Experiments

AnimalFluorescein

POD Flow

TotalFollow-up,

d

IncreasedVascularizationOver the Tube

TubeEncapsulation

LightMicroscopy Immunofluorescence

NewCollagenPresence

Macrophages/Myofibroblast Complications

SIBS1 210 Yes 320 No No NA NA NA NA No2 180 Yes 230 No No H-E Yes Minimal Minimal No3 90 Yes 130 No No H-E Yes Minimal No No4 90 Yes 130 No No NA NA NA NA No5 90 Yes 95 Minimal No H-E Yes Minimal No No6 90 Yes 95 No No H-E Yes Minimal No No7 90 Yes 95 No No H-E Yes Minimal No No8 60 Yes 110 No No NA NA NA NA No9 365 Yes 400 No No NA NA NA NA No

10 240 Yes 250 Minimal No NA NA NA NA No11 180 Yes 200 No No NA NA NA NA No12 180 Yes 200 No No NA NA NA NA No13 180 Yes 200 No No NA NA NA NA No14 180 Yes 200 No No NA NA NA NA No15 180 Yes 200 No No NA NA NA NA No16 180 Yes 200 No No NA NA NA NA No

Silicone1 90 Yes 109 Yes Yes NA NA NA NA Tube extrusion2 90 No 100 Yes Yes H-E Yes Abundant Abundant No3 60 Yes 110 Yes Yes NA NA NA NA No4 50 No 110 Minimal Yes NA NA NA NA No5 NA NA 45 Yes Yes NA NA NA NA Tube extrusion &

endophthalmitis6 180 No 300 Yes Yes NA NA NA NA No7 120 No 230 Yes Yes NA NA NA NA No8 NA NA 160 Yes Yes NA NA NA NA No9 NA NA 160 Yes Yes NA NA NA NA No

Abbreviations: H-E, hematoxylin-eosin; NA, not applicable; POD, postoperative day; SIBS, poly(styrene-b-isobutylene-b-styrene).




6/8

size and design of implants, the most important cause offailure continues to be the excessive scarring that im-pedes the exit of aqueous.39

Although the biocompatibility of any device is mainlyrelated to the material, other issues, such as design andflexibility, are critical. This new SIBS GDI is made of aninert, soft, andflexible thermoformable material more con-forming to the eye curvature in contrast to silicone con-trols. The thermoset nature of silicone rubber provides

a memory to the tubes, which remain in their originalshape. This straightening may be responsible for the 2extrusions described. The combination of flexibility andconformability, the ability of SIBS to take on a new re-laxed shape, the overall design, the chemical inertness,and the lack of molecules that elute from the material

all contribute to the reduction in microtrauma and in-flammation, therefore decreasing scarring.

The excellent biocompatibility observedclinically withthe SIBS implants was confirmed by histological evalu-ation that showed reduced collagen deposition aroundthe SIBS tubes at 3 and 6 months. Immunofluorescencedemonstrated a modest and discontinuouscollagen depo-sition in the SIBS group, whereas a complete circular col-lagen deposition was observed around the silicone tubes.

To further study the amount of reaction induced by theimplants, the cellular components responsible for scar-ring were characterized. Surprisingly, myofibroblasts inthe tissue surrounding the SIBS deviceseither in areaswhere SIBSwas in contact with the iris, in the area wherethe tab waslocated, or in the subconjunctival space wherethe bleb was formedwere never observed. In contrast,the silicone drainage device always induced the expres-sion of-SMA. This expression was more evident in thearea where the silicone tab was located. These histologi-cal results support the concept that SIBS is indeed a ma-terial that reduces the capsule formation by decreasingthe amount of collagen deposition and the differentia-tion of myofibroblasts. This lack of scarring allows the

outflow of aqueous humor into the subconjunctivalspace.It was a challenge to confirm that there was indeedflow in the aqueous shunts in the long-term in the ab-sence of a discernable bleb and without the ability to vi-sualize direct flow in the healthy rabbit model. For thisreason, we chose to inject fluorescein into the anteriorchamber at 3 and 6 months after surgery. Immediateflowof aqueous was observed with the fluid dispersing intothe subconjunctival space within seconds, with subse-quent enlargement into a diffuse bleb 20 to 30 minuteslater. This experiment confirmed that the tubes thatshowed fluorescein flow were patent. As reported, all (16of 16) SIBS tubes (100%) were patent in the fluoresceinstudy, in contrast to the 2 of 6 (33%) silicone tubes.

B 6 s

10 min2 min D

A

C

Figure 6.Fluorescein injected into the anterior chamber and drainage intothe subconjunctival space to demonstrate patency. A, Immediate preinjectionappearance showing position of the implant. Fluorescein exited from thedistal tip of the tube into the subconjunctival space (B) and slowly diffusedaround (C). D, Fluorescein continued to diffuse through the tube into thesubconjunctival space to define a 90 to 120 bleb.

B

D

A C

FE

Figure 7.Immunofluorescence detection of extracellular matrix deposition and myofibroblasts in the poly(styrene-b-isobutylene-b-styrene) (SIBS) and siliconegroups 3 months after surgical implantation. Hematoxylin-eosin staining in the SIBS group showed no excessive collagen deposition, lymphocytes, orinflammatory cell infiltration (A). Collagen IV deposition was weak around the tube and did not surround the entire tube circumference (B). Smooth muscle actin(-SMA) did not stain the cells surrounding the tube (C). In the silicone glaucoma drainage implant, the iris stroma seemed quiet, and no stromal inflammatorycell infiltrates were observed at the entrance of the tube into the anterior chamber (D). E, Abundant collagen IV deposition was evident around the tube in allstudied sections. In contrast to the SIBS tubes, -SMA was expressed around the silicone tubes (F). Bar represents 150 m.




7/8

The SIBS GDI did not demonstrate postoperative hy-potony, in contrast to the silicone rubber tubes, whichdid. The reason for this disparity is that the lumen of theSIBS tube was significantly smaller than the silicone tube.TheSIBS lumen was designed to be approximately 60 mwith an 11-mm length, as suggested by the Hagen-Poiseuille equation,40 given a flow rate of approximately2.5 L/min and a desired resultant inflow pressure of 5to 10 mm Hg in the absence of a distal resistance to out-flow. However, the effects of a continuous force on theeye or Valsalva maneuvers on eye pressure are un-

known because there is no capsule at the distal end thatlimits the outflow. The 300-m lumen of the silicone tubeextrapolates to negligible pressure by the Hagen-Poiseuille equation at a similar flow rate, as was con-firmed by the hypotony observed in vivo.

Although the argument can be made that the hy-potony, capsule formation, and other factors relating tothe poor performance of the silicone tubes were inher-ent to their design and size, and were perhaps a result ofimmediate hypotony and the spewing of inflammatorycytokines into the subconjunctival space, we are con-vinced that this is not entirely the case, albeit largeamounts of cytokines in the subconjunctival space wouldnot be desirable nor would hypotony, and the SIBS GDIs

were designed appropriately smaller for this reason. Ina previous pilot study,41 0.3-mm-thick discs with a 3-mmdiameter made of SIBS showed minimal inflammationwithout cellular infiltration, neovascularization, infec-tion, or toxic reaction when compared with identicallysized cross-linked poly(dimethylsiloxane) discs that dem-onstrated marked neovascularization and fibrotic reac-tion. These materials were implanted both in the cor-neal stroma and sub-Tenon space of healthy rabbits. Itis noteworthy that in these cases there was no aqueoushumor or other active source of cytokines in contact with

the biomaterials, clearly indicating a local response to thematerial as opposed to the geometry.

Using normal rabbits withoutestablished high IOPmayexplain the similarities in the IOP between the siliconeand the SIBS tubes and between operated and nonoper-ated eyes. Althoughthe SIBS GDIs were patentandformeda flat and extended bleb, no statistically significant dif-ference in IOP between the SIBS and silicone groups wasfound after 7 days. We hypothesize that the pressure simi-

larities between the SIBS and silicone groups relate to theremaining normal drainage system parallel to the shunt.Finally, a major advantage of SIBS is thepossibilityof load-ing the distal end of the GDIs with antiproliferative oranti-inflammatory agents.42,43

Long-term studies in humans will determine whetherthese smallGDIsmade of SIBS areclinicallyuseful in long-term IOP reduction. Hopefully, this novel GDI, with itssimple and quick method of implantation, will avoid andprevent some of the complications observed with the im-plantation of current GDIs. Thesmallsize of theSIBS GDI,as well as ease of removal, if necessary, may provide avaluable tool to treat patients suffering from glaucoma.

Submitted for Publication:October 25, 2005; final re-vision received April 26, 2006; accepted July 2, 2006.Correspondence:Jean-Marie Parel, PhD,OphthalmicBio-physics Center, Bascom Palmer Eye Institute, Univer-sity of Miami Miller School of Medicine, 1638 NW 10Ave, Miami, FL 33136 ([email protected]).Financial Disclosure: Drs Acosta, Espana, Yamamoto,Orozco, Dubovy, Fantes, and Parel are employed at theUniversity of Miami; and Drs Davis, Pinchuk, and We-ber are employed at InnFocus LLC.Funding/Support:This study was supported by FloridaLions Eye Bank; InnFocus LLC; Research to PreventBlindness; Henri and Flore Lesieur Foundation; and Na-tional Institutes of Health Center Grant P30-EY014801.InnFocus LLC and the University of Miami have propri-etary rights to the devices described herein.Acknowledgment: Magda Celdran prepared the tissue forlight microscopy; Eleut Hernandez, LAT, provided dailyanimal care; and Izuru Nose, BS, gave technical assis-tance during the project. John B. Martin and Saul Gott-lieb built the molds and inserters used in this study.

REFERENCES

1. Stanworth A. Conjunctival fibrosis after filtration operations.Trans Opthal Soc

U K. 1958;78:43-55.

2. Tribin-Piedrahita A. Beta therapy in filtering operations for the treatment of

glaucoma.Am J Ophthalmol. 1965;60:140-141.

3. Rollet M. Le drainage au irin de la chamabre anterieure contre lhypertonie et ladouleur.Rev Gen Ophtalmol. 1906;25:481.

4. Bock RH. Subconjunctival drainage of the anterior chamber by a glass seton.

Am J Ophthalmol. 1950;33:929-933.

5. Steffanson J. An operation for glaucoma.Am J Ophthalmol. 1925;8:681-692.

6. Zorab A. The reduction of tension in chronic glaucoma. Ophthalmoscope. 1912;

10:258-261.

7. Helies P, Legeais JM, Savoldelli M, et al. Artificial trabeculum (MESH): clinical

and histological study in the rabbit [in French]. J Fr Ophtalmol. 1998;21:351-

360.

8. Kondo H, Fantes F, Kato H, et al. Synthetic meshwork implant for glaucoma fil-

tering surgery: effectof adjunct heparin andsodium hyaluronate in rabbits. Oph-

thalmic Surg Lasers. 1998;29:669-676.

B

D

A

C

Figure 8.Immunofluorescence detection of extracellular matrix depositionand myofibroblasts in the poly(styrene-b-isobutylene-b-styrene) (SIBS) 6months after surgical implantation. Interlaminar spaces were clearlyobserved in the subconjunctival space, suggesting the presence of interstitialaqueous humor (A). A light deposition of collagen IV completely surroundedthe tube (B, marked by white stars; collagen immunoreactivity was alsoobserved in basement membranes and blood vessels), which was clearlyevident at higher magnifications (C). No smooth muscle actin ormacrophages reactivity were observed in any of the SIBS tubes (D) in any

time frame. Bars represent 150 m.




8/8

9. Nyska A, Glovinsky Y, Belkin M, EpsteinY. Biocompatibilityof theEx-PRESS min-

iature glaucoma drainage implant.J Glaucoma. 2003;12:275-280.

10. Wilcox MJ, Barad JP, Wilcox CC, et al. Performance of a new, low-volume, high-

surface area aqueous shunt in normal rabbit eyes. J Glaucoma. 2000;9:74-82.

11. Molteno AC.New implantfor drainagein glaucoma:animaltrial.Br J Ophthalmol.

1969;53:161-168.

12. Molteno AC.New implant fordrainage in glaucoma:clinicaltrial.Br J Ophthalmol.

1969;53:606-615.

13. Molteno AC, Straughan JL, Ancker E. Long tube implants in the management of

glaucoma.S Afr Med J. 1976;50:1062-1066.

14. Prata JA Jr, Mermoud A, LaBree L, Minckler DS. In vitro and in vivo flow char-

acteristics of glaucoma drainage implants. Ophthalmology. 1995;102:894-

904.15. Krupin T, Podos SM, Becker B, Newkirk JB. Valve implants in filtering surgery.

Am J Ophthalmol. 1976;81:232-235.

16. Coleman AL, Hill R, Wilson MR, et al. Initial clinical experience with the Ahmed

Glaucoma Valve implant.Am J Ophthalmol. 1995;120:23-31.

17. Molteno AC. The optimal design of drainage implants for glaucoma.Trans Oph-

thalmol Soc N Z. 1981;33:39-41.

18. Lloyd MA,BaerveldtG, Heuer DK,et al.Initial clinical experience withthe baerveldt

implant in complicated glaucomas. Ophthalmology. 1994;101:640-650.

19. SiegnerSW, NetlandPA, Urban RC Jr,et al.Clinical experience withthe Baerveldt

glaucoma drainage implant.Ophthalmology. 1995;102:1298-1307.

20. Ayyala RS, Michelini-Norris B, Flores A, et al. Comparison of different biomate-

rials for glaucoma drainage devices: part 2. Arch Ophthalmol. 2000;118:1081-

1084.

21. Jacob JT, Burgoyne CF, McKinnon SJ, et al. Biocompatibility response to modi-

fied Baerveldt glaucoma drains.J Biomed Mater Res. 1998;43:99-107.

22. Pandya AD, Rich C, Eifrig DE, et al. Experimental evaluation of a hydroxylapatite

reservoir tube shunt in rabbits.Ophthalmic Surg Lasers. 1996;27:308-314.23. Kennedy JP, Ivan B.Designed Polymers by Carbocationic Macromolecular En-

gineering: Theory and Practice.Munich, Germany: Hanser; 1992.

24. Pinchuk L, Khan IJ, Martin JB, et al. A new family of thermoplastic elastomers

for ultra-longterm implant basedupon a backbone of alternating quaternaryand

secondary carbons. Paper presented at: 44th Annual Conference ASAIO/CVST;

April 23-25, 1998; New York, NY.

25. Richard RE, Barry JJ, Kamath K, Miller SV, Ranade SV. Polymer technology for

the controlled release of paclitaxel from a vascular compatible matrix: the Tax-

usTM Express paclitaxel-eluting coronary stent. Paper presented at: Biomaterials

in Regenerative Medicine:The Advent of Combination Products; October 16-18,

2004; Philadelphia, Pa.

26. Ranade SV, Miller KM, Richard RE, et al. Physical characterization of controlled

releaseof paclitaxel fromthe TAXUS Express2drug-eluting stent. J BiomedMater

Res A. 2004;71:625-634.

27. PinchukL. Biostable elastomeric polymershavingquaternary carbons.US Patent

5 741 331. April 21, 1998.

28. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in

patients with coronary artery disease. N Engl J Med. 2004;350:221-231.

29. Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-

release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial.

Circulation. 2004;109:1942-1947.

30. Molteno AC, Van Rooyen MM, Bartholomew RS. Implants for draining neovas-

cular glaucoma.Br J Ophthalmol. 1977;61:120-125.

31. Molteno AC, Ancker E, Van Biljon G. Surgical technique for advanced juvenile

glaucoma.Arch Ophthalmol. 1984;102:51-57.

32. Da Mata A, Burk SE, Netland PA, et al. Management of uveitic glaucoma withAhmed glaucoma valve implantation.Ophthalmology. 1999;106:2168-2172.

33. Molteno AC, Sayawat N, Herbison P. Otago glaucoma surgery outcome study:

long-term resultsof uveitis withsecondaryglaucoma drained by Moltenoimplants.

Ophthalmology. 2001;108:605-613.

34. BeebeWE, Starita RJ,FellmanRL, et al.The useof Molteno implant andanterior

chamber tube shunt to encircling band for the treatment of glaucoma in kerato-

plasty patients.Ophthalmology. 1990;97:1414-1422.

35. ArroyaveCP, Scott IU,Fantes FE,et al.Cornealgraftsurvivaland intraocularpres-

sure control after penetrating keratoplasty and glaucoma drainage device

implantation.Ophthalmology. 2001;108:1978-1985.

36. Lee RK,Fantes F. Surgicalmanagement of patientswith combinedglaucomaand

corneal transplant surgery.Curr Opin Ophthalmol. 2003;14:95-99.

37. Heuer DK, Lloyd MA, Abrams DA, et al. Which is better? One or two? A random-

ized clinical trial of single-plate versus double-plate Moltenoimplantationfor glau-

comas in aphakia and pseudophakia.Ophthalmology. 1992;99:1512-1519.

38. Mills RP, Reynolds A, Emond MJ, et al. Long-term survival of Molteno glau-

coma drainage devices.Ophthalmology. 1996;103:299-305.39. Molteno AC, Fucik M, Dempster AG, Bevin TH. Otago Glaucoma Surgery Out-

come Study: factors controlling capsule fibrosis around Molteno implants with

histopathological correlation.Ophthalmology. 2003;110:2198-2206.

40. Geankoplis CJ.Transport Processes and Separation Process Principles (In-

cludes Unit Operations).3rd ed. Upper Saddle River, NJ: Prentice Hall; 1993.

41. AcostaAC, FernandezV, LamarPD, et al.Ocular biocompatibility of Quatromert-

mTM (polystyrene-polyisobutylene triblock polymers)for glaucoma implants. In-

vest Ophthalmol Vis Sci. 2004;45 E-Abstract 2929.

42. Jacob JT, Lacour OJ, Burgoyne CF. Slow release of the antimetabolite 5-fluoro-

uracil (5-FU) frommodifiedBaerveldt glaucomadrainsto prolong drain function.

Biomaterials. 2001;22:3329-3335.

43. Morales J, Kelleher PJ, Campbell D, Crosson CE. Effects of daunomycin im-

plants on filtering surgery outcomes in rabbits.Curr Eye Res. 1998;17:844-

850.


2006 American Medical Association All rights reservedat University of Miami School of Medicine, on December 11, 2006www.archophthalmol.comDownloaded from

a newly designed glaucoma drainage implant made of sibs (2) (1)

Documents