Cornea - ARVO

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ARVO 2013 Annual Meeting Abstracts by Scientific Section/Group - Corneamouse. In vitro experiments showed that the loss of NOS2suppressed mRNA expression of TGFb1 and collagen Ia1, but notMCP-1, in ocular fibroblasts. Being inconsistent with the in vivofinding, lacking NOS2 upregulated a-smooth muscle actin mRNA insimple ocular fibroblast culture.Conclusions: NOS2 is required for macrophage invasion andprimary healing of injured corneal stroma folowing incision injury.Appearance of myofibroblasts in the injured corneal stroma wassuppressed by lacking NOS2 in vivo, although the loss of NOS2promoted myofibroblast generation in vitro in monolayer culture.Commercial Relationships: Takayoshi Sumioka, None; YukaOkada, None; Norihito Fujita, None; Masayasu Miyajima, None;Shizuya Saika, NoneProgram Number: 3876 Poster Board Number: D0120Presentation Time: 2:45 PM - 4:30 PMMethod Development for Evaluating Clear Corneal CataractWound IntegrityArthur Driscoll 1 , Suzanne LaScalza 2 , Peter K. Jarrett 1 , MichaelMcGrath 1 , Michael Bassett 1 , Amar S. Sawhney 1 . 1 R&D, OcularTherapeutix, Bedford, MA; 2 Clinical Affairs, Ocular Therapeutix,Bedford, MA.Purpose: To develop a quantitative method simulating forces an eyemay experience during patient manipulation post-clear cornealcataract surgery.Methods: A Dontrix Gauge (GAC International Inc., Bohemia,NY)(Figure 1a), which is a spring gauge used to apply and measureforces in orthodontics, was modified to have a 3 mm atraumatic tip.The resulting Calibrated Force Gauge (CFG) allows application ofcalibrated and quantifiable force to the eye in 0.25 ounce increments(Figure 1b). After in-vitro and in-vivo evaluations, an initial clinicalstudy was conducted using the CFG to apply one ounce of forcetemporal to the limbus in healthy volunteers to examine intraocularpressure (IOP) changes and compare the findings with those in theliterature. After confirming the force simulating ocular surfacemanipulation, the CFG was used to challenge clear corneal incisions(CCIs) which were stromally hydrated (Study 2) or closed with 10-0Nylon suture (3-1-1 with buried knot)(Study 3); the CFG was placed0.5 mm temporal to the incision.Results: In the first study, mean baseline IOP was 17.5 mmHg androse to 43.4 mmHg upon applying 1.0 ounce of force using the CFG.Literature states that application of light and firm digital forces on theeye equate to IOP of 27 and 58 mmHg respectively. As a result, 1.0ounce of force appeared adequate to simulate eye touching, rubbing,or forced blinking. When the CFG was used to challenge CCIs closedwith stromal hydration in Study 2 (n=30), 66.7% of wounds leakedwith ≤ 1.0 ounces of force. In the suture group (Study 3), woundswere challenged prior to and after application of the suture. OnlyCCIs which leaked on the initial challenge were sutured andchallenged with the CFG a second time. Out of these wounds, 23.7%leaked with application of ≤ 1.0 ounces of force (Figure 2).Conclusions: Applying one ounce of force proximal to a CCIappears to be a clinically relevant assessment of wound integrity andpropensity to leak under patient manipulation. Reports in theliterature suggest that wounds which leak have a 44-fold increasedrisk for endophthalmitis. This risk is hypothesized to be related towound gape allowing fluids to travel between the ocular surface andanterior chamber. If a wound leaks under CFG manipulation aftercataract surgery, it may be an indication that the incision architectureis not adequate and closure is necessary to prevent postoperativewound leaks.Commercial Relationships: Arthur Driscoll, Ocular Therapeutix(E); Suzanne LaScalza, Ocular Therapeutix (E); Peter K. Jarrett,Ocular Therapeutix (E); Michael McGrath, Ocular Therapeutix, Inc.(E); Michael Bassett, Ocular Therapeutix (E); Amar S. Sawhney,Ocular Therapeutix (E)Program Number: 3877 Poster Board Number: D0121Presentation Time: 2:45 PM - 4:30 PMEffects of Transforming Growth Factor Beta isoforms (TGFβs)On Diabetic Corneal Wound HealingIlham Bettahi, Feng Wang, HAIJING SUN, Fu-shin X Yu.Ophthalmology, Wayne state university, Detroite, MI.Purpose: Background: Pathological conditions such as diabetesmellitus delay corneal epithelial wound healing frequently,potentially resulting in persistent corneal defects and recurrentcorneal erosion. Transforming growth factor Beta (TGFβs) are keymediators of wound healing. To explore the role(s) of TGFβ isoforms(1, 2 and 3) in corneal epithelial wound healing, we assessed theeffect of TGFβ on epithelial wound closure in cultured porcinecornea in the presence of normal or high glucose concentrations.Methods: Methods: Genome-wide cDNA array was performed usingepithelial cells isolated from normal and diabetic corneas prior to and40 h post epithelial debridement wound. The array results wereverified using RT- and realtime-PCR and immuniohistochemistry. Toassess the effects of TGFβ isforms on corneal epithelial woundhealing, wounded porcine corneas were cultured in high glucose (25mM) and treated with recombinant TGFβ1-3.Results: Results: The expressions of TGFβ1-3 were elevated inresponse to wounding and this elevation for TGFβ3 is dampened indiabetic rat corneas. cDNA array analysis revealed several TGFβtargeted genes were also downregulated in diabetic healing CECs.Immunohistochemistry showed that TGFβ3 is highly expressed inentire migrating epithelial sheet in non-diabetic corneas while only afew cells at the leading edge in diabetic cornea. In cultured corneas,TGFβ3, but not TGFβ1, accelerated high glucose delayed epithelialwound closure.Conclusions: Conclusion: In type II diabetic corneas, the expressionof TGFβ3 but not TGFβ1 response to wound is suppressed byhyperglycemia and TGFβ3, an antifibrosis factor, might be used totreat delayed wound healing in the cornea and potentially in the skinof diabetic patients.Commercial Relationships: Ilham Bettahi, None; Feng Wang,None; HAIJING SUN, None; Fu-shin X Yu, None©2013, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permissionto reproduce any abstract, contact the ARVO Office at arvo@arvo.org.
ARVO 2013 Annual Meeting Abstracts by Scientific Section/Group - CorneaSupport: NIH grants R01 EY017960, EY010869, Midwest EyeBankProgram Number: 3878 Poster Board Number: D0122Presentation Time: 2:45 PM - 4:30 PMNanoparticle Vectored siRNAs Reduce Profibrotic GeneExpression in Wounded Rabbit CorneasSriniwas Sriram 1 , Paulette M. Robinson 2 , Alfred S. Lewin 3 , GregoryS. Schultz 2 . 1 Biomedical Engineering, University of Florida,Gainesville, FL; 2 Ob/Gyn and Opthalmology, University of Florida,Gainesville, FL; 3 Molecular Genetics and Microbiology, Universityof Florida, Gainesville, FL.Purpose: Corneal haze remains a major problem following injury orrefractive surgery. We tested the efficiency of a commerciallyavailable histidine-lysine peptide nanoparticle formulation to deliversiRNAs to a laser ablated cornea, to reduce pro-fibrotic mRNA, andto reduce corneal haze in a rabbit model.Methods: To test the efficacy of siRNA delivery, excimer laserablated rabbit corneas were topically dosed with fluorescently labeledscrambled siRNA sequences complexed with polymeric nanocarriers(22.5 uM). Excised corneas were maintained in organ culture for 8hours then fixed, sectioned, and analyzed via fluorescent microscopy.To test the efficacy of an anti-fibrotic formulation of siRNAsdelivered with these nanoparticles, corneas of nine rabbits wereablated with an excimer laser. One eye was treated with nanoparticlescomplexed with a triple combination of siRNA that targeted majorscarring genes (TGFβ1, TGFβR2 and CTGF), while the other eyereceived empty nanoparticles as a control. To test the molecularefficacy of the siRNAs, corneas of 3 rabbits were excised 24 hourspost-wounding, RNA was extracted and quantified by RT-qPCR.Knockdown percentages of the target genes were compared to thepaired control eyes. To determine therapeutic effect, corneas of 6rabbits were assessed for levels of haze on days 14 and 15 usingdigital photographs, in vivo confocal microscopy, and were gradedfor haze using the standard 0-4 semiquantitative scale.Results: Tissue sections from organ cultured corneas analyzed byconfocal microscopy showed high levels of fluorescence in all layersof the treated cornea when compared to untreated controls. In antifibrotictreated rabbit corneas, the siRNA triple combinationproduced an average knockdown of 57% for TGFB1, 25 % forTGFBR2 and 24% for CTGF. One rabbit had a maximumknockdown of 80% for TGFB1, 57% for TGFBR2 and 46% forCTGF, indicating the siRNA triple combination was effectivelydelivered to the cornea in this animal. Results from haze grading onday 14 showed a decrease in haze formation in three out of the sixtreated rabbits.Conclusions: These results indicate histidine-lysine peptidenanoparticles were effective in delivering siRNAs to all cell layers ofexcimer ablated corneas. With optimization of the dose and deliveryof the triple siRNA combination, this gene targeted therapy may bean innovative treatment to reduce scar formation.Commercial Relationships: Sriniwas Sriram, None; Paulette M.Robinson, None; Alfred S. Lewin, University of Florida (P);Gregory S. Schultz, NoneSupport: US Department of Defense W81XWH-10-1-0917Program Number: 3879 Poster Board Number: D0123Presentation Time: 2:45 PM - 4:30 PMAloe vera: An in-vitro study of effects on corneal wound closureand collagenase activityElizabeth Curto 1 , Amber Labelle 2 , Heather L. Chandler 1 . 1 The OhioState University, Columbus, OH; 2 University of Illinois Urbana-Champaign, Champaign, IL.Purpose: To evaluate the in vitro effects of an aloe vera solution on1) the viability and wound healing response of corneal cells, and 2)the ability to alter collagenase and gelatinase activity.Methods: Primary cultures of corneal epithelial cells and fibroblastswere prepared from grossly normal enucleated canine globes andtreated with an aloe solution (doses ranging from 0.0 - 2mg/mL).Cellular viability was evaluated using a colorimetric assay. A cornealwound healing model was used to quantify cellular ingrowth across adefect made on the confluent surface. Anti-collagenase and antigelatinaseactivity was evaluated by incubating a bacterialcollagenase/gelatinase with aloe solution (doses ranging from 0.0 -500µg/mL) and comparing outcome measures to a generalmetalloproteinase inhibitor, 1, 10-phenanthroline, and canine serum(doses ranging from 0.0 - 100%).Results: None of the concentrations of aloe solution testedsignificantly affected viability of corneal epithelial cells orfibroblasts. Concentrations ≥175µg/mL significantly (p≤0.001)slowed the rate of corneal fibroblast wound closure while aloeconcentrations
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