Wall Of Schlemm's Canal Research Articles

Clinical application of the CO2 laser in Ab externo Schlemm's canal surgery.

PurposeThis study aimed to investigate the clinical application of laser as a knife in Ab externo Schlemm's canal (SC) surgery and compare the efficacy and safety of the CO2 laser with the conventional procedure using a surgical knife.MethodsPatients who underwent either canaloplasty or trabeculotomy with CO2 laser system which was used to locate and ablate the outer wall of SC at the time interval between May 2020 and May 2021 were identified, their medical files were reviewed, and their results were compared with conventional surgery group who underwent canaloplasty or trabeculotomy with conventional surgical knife at the same time period. The following datas were conducted and compared: age, sex, intraocular pressure (IOP), number of drugs, best-corrected visual acuity (BCVA), mean deviation and pattern standard deviation of visual field examination, SC opening related complications.ResultsA total of 49 patients (49 eyes) were included in this study, including 23 in the Laser surgery group and 26 in the conventional surgery group. Time for SC opening was 49.33 ± 25.23 s and 116.50 ± 31.79 s for laser surgery group and conventional surgery group, respectively. This difference between the two groups was statistically significant (P < 0.01). Hemorrhage occurred in five eyes during ablation for the laser surgery group and in 24 eyes for the conventional surgery group. In addition, anterior chamber penetration occurred in two cases for the laser surgery group and in six cases for the conventional surgery group. The success rate of identifying and opening outer wall of SC was 91.30% (21 eyes) for the laser surgery group and 76.92% (20 eyes) for the conventional surgery group. The difference between preoperative and postoperative intraocular pressure for each group was statistically significant (P < 0.01), and there were no statistically significant differences across the two groups in terms of postoperative IOP (P = 0.238) and BCVA (P = 0.389).ConclusionCompared with the conventional procedure using a surgical knife, CO2 laser-assisted ablation of the outer wall of SC was less time-consuming and less technically challenging. CO2 laser-assisted ablation also resulted in fewer complications. Furthermore, it had a shorter learning curve and a higher success rate of identifying and opening SC.

Eight-year follow-up of excimer laser trabeculostomy alone and combined with phacoemulsification in patients with open-angle glaucoma.

To describe the 8-year results of excimer laser trabeculostomy (ELT) alone and ELT in conjunction with phacoemulsification (phaco). University hospital. Retrospective review. 308 nm excimer laser energy delivered through an intraocular fiber-optic probe created channels through the inner wall of Schlemm canal. 2 groups were studied: ELT alone and ELT + phaco. Inclusion criteria were adult patients with open-angle glaucoma or ocular hypertension on 1 or more intraocular pressure (IOP)-lowering medications and, in the ELT + phaco group, presence of visually significant cataract. Primary outcome measures were change of IOP from baseline and number of IOP-lowering medications. 164 eyes in 2 groups, ELT alone (n = 90) and ELT + phaco (n = 74), were followed up for 8 years. Baseline IOP was 22.17 ± 7.0 mm Hg and 21.9 ± 6.44 mm Hg in the ELT alone and the ELT + phaco groups, respectively. IOP in the ELT alone group decreased to 16.84 ± 5.2 mm Hg at 1 year (n = 69) and remained at 15.9 ± 3.5 (n = 19) at 8 years. IOP in the ELT + phaco group was 14.04 ± 4.1 mm Hg at 1 year (n = 63) and 13.7 ± 2.8 mm Hg at 8 years (n = 13). The number of IOP-lowering medications at baseline in the ELT alone group was 1.85 ± 0.8 and decreased to 1.19 ± 1.10 at 1 year and 1.4 ± 1.4 at 8 years. In the ELT + phaco group, it was 1.58 ± 0.8 at baseline and decreased to 0.97 ± 0.95 at 1 year and 1.85 ± 0.7 at 8 years. ELT demonstrated long-term IOP lowering and decrease in the number of IOP-lowering medications. Benefits of this laser-based implant-free microinvasive glaucoma surgery procedure included a high safety profile and long-term efficacy.

Modified viscocanalostomy in the Chinese population with open angle glaucoma: a 10-year follow-up results.

To study the long-term efficacy and safety of modified viscocanalostomy in Chinese people with open angle glaucoma (OAG). This retrospective study included a total of 100 eyes from 100 Chinese patients with medically uncontrolled OAG. All the patients underwent modified viscocanalostomy with injection of viscoelastic material in the surgically created ostia of Schlemm's canal (SC). The modifications included peeling of the inner wall of SC and the juxtacanalicular meshwork, use of mitomycin C, and loosely suturing the superficial scleral flap. Intraocular pressure (IOP), visual acuity, number of medications, laser goniopuncture data and complications were recorded. The definition of complete (qualified) success was an IOP equal to or lower than 21, 18, 16 mm Hg without (with or without) anti-glaucoma medications. The mean IOP was 33.5±9.9 mm Hg before surgery, 15.2±3.6 mm Hg (mean IOP reduction of 51%) at 5y after surgery, and 15.6±2.8 mm Hg (mean IOP reduction of 49.9%) at 10y after surgery (P<0.001). The number of anti-glaucoma medications dropped from 2.39±0.5 preoperatively to 0.47±0.8 at 5y and 0.67±0.8 at 10y postoperatively (P<0.001). The follow-up period was 104.5±37.0mo. The qualified success rate for an IOP of 21, 18 or 16 mm Hg or less was 84% [95% confidence interval (CI): 0.80-0.88], 73% (95%CI: 0.68-0.78), and 59% (95%CI: 0.52-0.66) after 5y, and 80% (95%CI: 0.76-0.84), 69% (95%CI: 0.64-0.74), 51% (95%CI: 0.44-0.58) after 10y, respectively. There was a relationship between age, preoperative IOP and success rate (P<0.01, P<0.05). A total of 31 eyes (31.3%) in 31 patients underwent laser goniopuncture, decreasing the IOP from 22.9±4.3 mm Hg to 16.3±2.5 mm Hg (P<0.01). Neither blebitis nor endophthalmitis occurred. Modified viscocanalostomy could be performed to lower IOP, decrease multiple anti-glaucoma drops use as well. It's a safe procedure with less complications over 10y in Chinese individuals with OAG.

Mathematical Modeling of Outflow Facility Increase With Trabecular Meshwork Bypass and Schlemm Canal Dilation.

To mathematically model the conventional aqueous humor outflow system with trabecular meshwork (TM) bypass and Schlemm canal (SC) dilation. The SC was modeled as a rectangular channel with the TM modeled as a permeable membrane. The collector channels (CCs) were modeled as fluid sinks distributed along the outer wall of SC. Two different implants were investigated in this study. The Hydrus Microstent (scaffold) was modeled with a TM bypass and a dilated region in SC that was 7 or 15 mm long and approximately 5-fold larger than the normal height of SC (h0). The iStent trabecular microbypass was modeled with a similar structure except that the dilated region in SC was 1 mm long and 25% larger than h0. Creation of a TM bypass structure would increase the pressure in the surrounding regions inside the SC and make it close to the intraocular pressure. SC dilation would increase the pressure more uniformly in the dilated region. The pressure increase led to higher flow rates in SC and CCs, and subsequently increased outflow facility (C). If CCs were uniformly distributed, the increase in C was the smallest after implantation of 1 microbypass, compared with that after implantation of 2 microbypasses or 1 scaffold. If CCs were nonuniformly distributed, the magnitude of increase in C was sensitive to the location of implant, and the sensitivity was higher for the microbypass than the scaffold. The study showed that creation of TM bypass and SC dilation significantly increased outflow facility, and the amount of increase correlated with the length of dilated regions in SC.

Aqueous Humor Outflow: Dynamics and Disease

This review summarizes the goals and outcomes of the eighth annual ARVO/Pfizer Ophthalmic Research Institute conference that was held on May 4th and 5th, 2012, at the Embassy Suites Fort Lauderdale, Fort Lauderdale, Florida. This conference series has been funded by the ARVO Foundation for Eye Research with the help of a generous grant from Pfizer Ophthalmics. Funding from the ARVO/Pfizer Ophthalmics Research Institute has allowed a series of “think tanks” for the leading experts on various subspecialties of ophthalmology research. These meetings have helped to define various challenges and potential solutions to issues relevant to the field of ophthalmology. In 2012, the emphasis of the conference was on the physiological role of the conventional outflow pathway in aqueous humor dynamics in normal and glaucomatous eyes. In particular, clinical observations associated with aqueous humor outflow in health and disease, animal models in the understanding of aqueous outflow, role of mechanosensing in aqueous humor fluid flow, and new paradigms in cell and extracellular matrix crosstalk within the conventional outflow pathway were discussed. The primary goal of the conference was to bring together a diverse group of experts who are pioneers in conventional outflow biology and related nonocular areas of research with the hope of utilizing the group's knowledge and experience to evaluate the current understanding of aqueous outflow regulation and problems thereof. The invited group consisted of 29 investigators directly involved in conventional outflow research. Also present were three invited outside experts in cellular mechanics and cytoskeleton structures (Jeffrey Fredberg, PhD, Harvard School of Public Health, Boston, MA, USA), molecular mechanisms of cell adhesion and mechanosensing (Benjamin Geiger, PhD, Weizmann Institute of Science, Rehovot, Israel), and murine genetics (Richard Libby, PhD, University of Rochester Medical Center, Rochester, NY, USA). In addition, the conference was attended by 27 observers who participated in discussion of key topics at the end of each presentation. Together, the group was tasked with reviewing the current scientific dogma regarding aqueous outflow diseases and identifying the most pressing research questions and needs in the current funding environment. Above all, the group was asked to think “outside the box” to develop future research directions. The conference generated a list of highly relevant but currently unanswered questions with the hope that solutions to these issues would improve understanding of the role of the conventional outflow pathway in normal and glaucoma eyes. The meeting was organized into four sessions: (a) clinical insights into conventional outflow dysfunction, (b) the use of mice as model systems for conventional outflow, (c) mechanosensing within the conventional outflow pathway, and (d) the role of the extracellular matrix and signaling in conventional outflow dynamics. Speakers presented their thoughts on the preselected topics and provided key research goals that have been addressed or need to be addressed in the near future. The sessions were followed by discussion aimed at summarizing and interpreting the current knowledge as well as identifying unique research questions that were as yet unanswered. Anatomy and Physiology of the Conventional Aqueous Humor Outflow Pathway The conventional outflow pathway is mainly a pressure-driven system. Under homeostatic conditions, this pathway regulates the drainage of aqueous humor from the anterior chamber of the eye, thereby maintaining a constant intraocular pressure (IOP).1 Relevant tissues of the anterior segment that are anatomically involved in IOP control include the ciliary muscles, trabecular meshwork (TM), Schlemm's canal (SC), collector channels, and aqueous veins. The ciliary muscle is composed of smooth muscle fibers that have a true elastic net of tendons that anchor into the choroid posteriorly and the scleral spur, TM, and inner wall of SC anteriorly.2,3 It is widely accepted that contraction of the ciliary muscle causes expansion of the TM and opening of SC, which subsequently increases the conductivity of aqueous humor (AH) through the TM. All these, along with reports of nerve innervation in the TM, indicate that the TM is a self-regulating tissue with both afferent and efferent nervous components responsible for controlling its functions.2,4

Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction.

Ocular hypertension in glaucoma develops due to age-related cellular dysfunction in the conventional outflow tract, resulting in increased resistance to aqueous humor outflow. Two cell types, trabecular meshwork (TM) and Schlemm's canal (SC) endothelia, interact in the juxtacanalicular tissue (JCT) region of the conventional outflow tract to regulate outflow resistance. Unlike endothelial cells lining the systemic vasculature, endothelial cells lining the inner wall of SC support a transcellular pressure gradient in the basal to apical direction, thus acting to push the cells off their basal lamina. The resulting biomechanical strain in SC cells is quite large and is likely to be an important determinant of endothelial barrier function, outflow resistance and intraocular pressure. This review summarizes recent work demonstrating how biomechanical properties of SC cells impact glaucoma. SC cells are highly contractile, and such contraction greatly increases cell stiffness. Elevated cell stiffness in glaucoma may reduce the strain experienced by SC cells, decrease the propensity of SC cells to form pores, and thus impair the egress of aqueous humor from the eye. Furthermore, SC cells are sensitive to the stiffness of their local mechanical microenvironment, altering their own cell stiffness and modulating gene expression in response. Significantly, glaucomatous SC cells appear to be hyper-responsive to substrate stiffness. Thus, evidence suggests that targeting the material properties of SC cells will have therapeutic benefits for lowering intraocular pressure in glaucoma.

Schlemm's canal: more than meets the eye, lymphatics in disguise.

Schlemm's canal (SC) is a unique vascular structure that functions to maintain fluid homeostasis by draining aqueous humor from the eye into the systemic circulation. The endothelium lining the inner wall of SC has both blood and lymphatic vascular characteristics, thus prompting exploration of the development and regulation of this unique channel. In this issue of the JCI, back-to-back papers by Aspelund et al. and Park et al. detail the mechanisms of SC development, which includes a lymphatic reprogramming that is necessary to maintain proper function. Furthermore, both groups exploit the lymph-like qualities of this canal: they identify VEGF-C as a potential therapeutic for glaucoma and suggest that expression of PROX1, a marker of lymphatic fate, could also serve as a biosensor for monitoring SC integrity. These studies provide substantial insight into the molecular and cellular pathways that govern SC development and reveal that ocular pathology is associated with deregulation of the lymph-like characteristics of SC.

The structure of the trabecular meshwork, its connections to the ciliary muscle, and the effect of pilocarpine on outflow facility in mice.

To determine the connections between the ciliary muscle (CM), trabecular meshwork (TM), and Schlemm's canal (SC) and their innervations that allows CM contraction (by pilocarpine) to influence conventional outflow in mice. Sequential sections and whole mounts of murine corneoscleral angles were stained for elastin, α-smooth muscle actin (αSMA), vesicular acetylcholine transporter (VAChT), neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide (VIP), and tyrosine hydroxylase (TH). Elastic (EL) fibers between the CM, TM, and SC were examined in ultrathin, sequential sections from different planes. The effect of pilocarpine (100 μM) on conventional outflow facility was measured by perfusion of enucleated mouse eyes. The mouse TM contains a three-dimensional (3D) net of EL fibers connecting the inner wall of SC to the cornea anteriorly, the ciliary body (CB) internally and the choroid and CM posteriorly. The CM bifurcates near the posterior TM, extending outer tendons to the juxtacanalicular tissue and inner wall of SC and internal connections to the lamellated TM and CB. Ciliary muscle and lamellated TM cells stain with αSMA and are innervated by VAChT-containing nerve fibers, without TH, VIP, or nNOS. Pilocarpine doubled outflow facility. Mouse eyes resemble primate eyes not only by their well developed SC and TM, but also by their 3D EL net tethering together the TM and SC inner wall and by the tendinous insertion of the CM into this net. The increase in outflow facility following cholinergic stimulation in mice, as in primates, supports using mice for studies of aqueous humor dynamics and glaucoma.

Effects of a Schlemm canal scaffold on collector channel ostia in human anterior segments

This study evaluates the morphologic effect of the implantation of two different sizes of the Hydrus microstent on the outer wall of Schlemm's canal (SC) and collector channel (CC) ostia. Twelve human eyes were dissected at the equator removing the iris, lens, ciliary body and vitreous. The cornea was excised with a corneal trephine exposing a direct view of the angle while leaving the trabecular meshwork (TM) intact. The Hydrus delivery system was used to deliver microstents of 8 mm and 15 mm in length into SC. Following delivery, the tissues were immediately immersed in fixative. After tissue fixation, the microstents were gently lifted out of SC through the TM leaving a small slit opening in the TM. The slit opening was widened by gently dissecting the entire TM. Control eyes underwent dissection before fixation by gently removing the TM exposing the outer wall of SC. The tissues were prepared for scanning electron microscopy (SEM). The external wall of SC was imaged using SEM and were reviewed with particular attention focused on the distribution of irregular particulate matter (IPM), the shape of the CC ostia and the health of the SC endothelium. Three eyes received the 8 mm microstent, two the 15 mm microstent and 6 eyes served as controls. Five of the controls had reported histories of glaucoma while all other eyes were normal. All eyes showed evidence of removal of the trabecular meshwork revealing the external wall of SC. CCs were regularly visible in all eyes and were not obstructed, compressed or their margins disrupted. Nuclear profiles were oriented circumferentially in SC except at regions of CC ostia where they assumed a radial configuration oriented toward the lumen of the CC. The area of microstent contact with SC external wall was examined with SEM and a comparison made between the 8 and 15 mm microstent showing a smaller area of indentation with the 8 mm microstent. The indentations were generally free of particulate debris, were smooth and were devoid of nuclear profiles. In bridged areas adjacent to areas of microstent contact, CCs were identified, appearing patent and intact like those of the control eyes. The eyes receiving 8 mm and 15 mm Hydrus microstents both maintained CC ostia patency but a smaller area of external wall contact was evident from insertion of the 8 mm microstent.

Pigment Epithelium-Derived Factor Decreases Outflow Facility

Pigment epithelium-derived factor (PEDF) regulates blood-retinal barrier function. As a constituent of aqueous humor, the role of PEDF in conventional outflow function is unknown. The goals of the study were to examine the effects of PEDF on barrier function of cultured Schlemm's canal (SC) endothelia and outflow facility in mouse eyes in situ. To model the inner wall of SC, transendothelial electrical resistance (TEER) of human SC and porcine angular aqueous plexus (AAP) cells was monitored. To examine an intact conventional outflow pathway, enucleated eyes from culled C57BL/6 mice were perfused with PEDF using a computer-controlled system. Purified PEDF (0.1 and 1 μg/mL) was perfused at four different pressure steps (4, 8, 15, 20 mm Hg), measuring flow to determine outflow facility (slope of flow/pressure relationship). Pigment epithelium-derived factor increased TEER of porcine AAP cells in a dose-dependent fashion (0.3-3 μg/mL), and 1 μg/mL recombinant PEDF or conditioned media from pigmented retinal pigment epithelial monolayers stabilized TEER of human SC monolayers over time (0-48 hours). In perfusion experiments, we observed a 43.7% decrease in outflow facility (0.016 vs. 0.029 μL/min/mm Hg, P = 4.5 × 10⁻⁵) in eyes treated with 1 μg/mL PEDF compared to vehicle-perfused controls, and a 19.9% decrease (0.021 vs. 0.027 μL/min/mm Hg, P = 0.003) at 100 ng/mL PEDF. Pigment epithelium-derived factor increased barrier function in both the in vitro and in situ models of the inner wall of SC. Modification of PEDF signaling in SC cells may be therapeutically exploited to increase outflow facility in people with ocular hypertension or decrease outflow facility in those with hypotony.

A Potential Application of Canaloplasty in Glaucoma Gene Therapy

Canaloplasty, a recently developed non-penetrating glaucoma surgical approach, may restore physiological outflow routes in primary open-angle glaucoma with less risk of severe postoperative complications than trabeculectomy. Since the inner wall of Schlemm's canal (SC) is directly in contact with the trabecular meshwork (TM) for 360 degrees and the catheter device used in canaloplasty allows viscoelastic to be injected into the entire length of SC, canaloplasty might also be used to perform SC/TM-targeted delivery of transgene vectors for glaucoma gene therapy. This hypothesized new method for transgene delivery may give the transgene access to the entire inner wall of SC and the whole juxtacanalicular region of the TM and allow the transgene to be expressed in both the TM and SC without affecting the cornea, iris and ciliary body. Further, this strategy might have a greater trabecular outflow resistance-decreasing effect than either the genetic or surgical approach alone.

In Situ Autofluorescence Visualization of Human Trabecular Meshwork Structure

To characterize the three-dimensional (3-D) structure of the human trabecular meshwork (TM) by two-photon excited (TPEF) autofluorescence (AF) and optical sectioning without conventional histologic embedding and sectioning. Viable human ex vivo explants of the anterior chamber angle containing the aqueous humor drainage tissue in situ were imaged by TPEF to localize AF and Hoechst 33342 nuclear fluorescence. An autofluorescent marker in Schlemm's Canal (SC) aided SC situ visualization. En face and orthogonal views of the TM were generated. In the innermost uveal TM, AF signals outlined an intricate 3-D network of fine branching beams with large openings between the beams. In the adjacent corneoscleral TM, beams were thicker and coalesced as plate-like structures with pore-like openings. Linear and coiled AF fibers were visible on the background AF of beams. Deeper, in the external TM, this organization changed to fine fiber arrays orientated in the tissue's longitudinal axis, reminiscent of the cribriform plexus of the juxtacanalicular TM (JCT). In the outermost JCT, AF of fine fibers was sparse, then undetectable as optical sections approached the inner wall of SC. Cell nuclei were closely associated with the TM structural extracellular matrix. We have used TPEF and optical sectioning to exploit AF as a useful method to visualize the structure of the human conventional aqueous drainage pathway in situ. Ancillary nuclear staining allowed cell association with the AF structures to be seen. This approach revealed a unique 3-D perspective of the TM that is consistent with known TM structural characteristics.

Ex Vivo Optical Coherence Tomography Imaging of Collector Channels with a Scanning Endoscopic Probe

To achieve high-fidelity optical coherence tomography (OCT) imaging of ex vivo collector channels (CCs) exiting Schlemm's canal (SC) using a paired-angle rotating scanning endoscopic probe. An endoscopic probe was developed to guide an OCT laser beam onto human cadaver eye tissue samples to detect CCs. The prototype probe consisted of two gradient-index (GRIN) lenses that were housed in two stainless steel needles, respectively. The probe scanned the laser beam across a fan shape area by rotating the two GRIN lenses. The authors built a swept source OCT system to provide the depth scans. Human cadaver eye tissue was prepared for imaging. OCT images were acquired while the wall of SC was scanned. After successfully locating the opening of a CC on the SC wall from the OCT images, the authors applied scanning electron microscopy (SEM) to image the sample for comparison. The prototype probe focused the laser beam to a working distance of approximately 1.4 mm (in air), with spot sizes ranging from 12 to 14 μm. The fan shape scan area had a radius of 3 mm and an arc angle of approximately 40°. Acquired OCT images clearly showed a CC opening on the wall of SC with the channel going into the sclera, from which quantitative measurements were made. Results from OCT and SEM show good agreement with each other. The resolving power of the scanning endoscopic probe is sufficient to locate CCs and to observe their shape.

S1P2 receptor regulation of sphingosine-1-phosphate effects on conventional outflow physiology

Elevated intraocular pressure is the main risk factor in primary open-angle glaucoma, involving an increased resistance to aqueous humor outflow in the juxtacanalicular region of the conventional outflow pathway which includes the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC). Previously, sphingosine-1-phosphate (S1P) was shown to decrease outflow facility in porcine and human eyes, thus increasing outflow resistance and intraocular pressure. Owing to S1P's known effect of increasing barrier function in endothelial cells and the robust expression of the S1P₁ receptor on the inner wall of SC, we hypothesized that S1P₁ receptor activation promotes junction formation and decreases outflow facility. The effects of subtype-specific S1P receptor compounds were tested in human and porcine whole-eye perfusions and human primary cultures of SC and TM cells to determine the receptor responsible for S1P effects on outflow resistance. The S1P₁-specific agonist SEW2871 failed to both mimic S1P effects in paired human eye perfusions, as well as increase myosin light chain (MLC) phosphorylation in cell culture, a prominent outcome in S1P-treated SC and TM cells. In contrast, the S1P₂ antagonist JTE-013, but not the S1P₁ or S1P₁,₃ antagonists, blocked the S1P-promoted increase in MLC phosphorylation. Moreover, JTE-013 prevented S1P-induced decrease in outflow facility in perfused human eyes (P < 0.05, n = 6 pairs). Similarly, porcine eyes perfused with JTE-013 + S1P did not differ from eyes with JTE-013 alone (P = 0.53, n = 3). These results demonstrate that S1P₂ , and not S1P₁ or S1P₃, receptor activation increases conventional outflow resistance and is a potential target to regulate intraocular pressure.

Sphingosine-1-Phosphate Enhancement of Cortical Actomyosin Organization in Cultured Human Schlemm's Canal Endothelial Cell Monolayers

Perfusion of sphingosine-1-phosphate (S1P) in whole eye organ culture models decreases outflow facility, whereas S1P promotes stress fiber formation and contractility in cultured trabecular meshwork (TM) cells. Because of S1P's known effect of increasing barrier function in endothelial cells, the authors hypothesized that Schlemm's canal (SC) cells in culture respond to S1P by increasing actomyosin organization at the cell cortex. Using primary cultures of human SC cells, the authors determined S1P activation of the GTP-binding proteins, RhoA and Rac (1,2,3). Time- and dose-dependent myosin light chain (MLC) phosphorylation in response to S1P and total expression of MLC were determined. Immunocytochemistry after S1P treatment was used to monitor filamentous actin (F-actin) and phospho-MLC organization and the localization of β-catenin, a component of adherens junctions. TM and human umbilical vein endothelial cell monolayers were used as controls. S1P (1 μM) activated RhoA and Rac after 5- and 30-minute treatments. S1P increased MLC phosphorylation with a similar time- and dose-dependent response in SC (EC(50) = 0.83 μM) compared with TM (EC(50) = 1.33 μM), though MLC expression was significantly greater in TM. In response to 1 μM S1P treatment, phospho-MLC concentrated in the SC cell periphery, coincident with cortical actin assembly and recruitment of β-catenin to the cell periphery. Results obtained in this study support the hypothesis that S1P increases actomyosin organization at the SC cell cortex and promotes intercellular junctions at the level of the inner wall of SC to increase transendothelial resistance and in part explains the S1P-induced decrease of outflow facility in organ culture.

Morphological and hydrodynamic correlates in monkey eyes with laser induced glaucoma

This study investigated the relationship between decreased outflow facility (C) and changes in hydrodynamic aqueous humor outflow patterns and morphology in cynomolgus monkey eyes with unilateral chronically elevated intraocular pressure (IOP). Argon laser photocoagulation burns to the trabecular meshwork (TM) were made in one eye of each monkey (N = 3), leaving the contralateral eye as a normotensive control. IOPs were followed by pneumatonometry for 16–70 months. C was measured by fluorophotometry before sacrifice. To label the hydrodynamic patterns of outflow, the eyes were enucleated and perfused with fluorescent microspheres (0.5 μm; 0.002%) at the last pressure measured before death minus 7 mmHg. The eyes were perfusion-fixed at the same pressure. Confocal images were taken along the inner wall (IW) of the Schlemm's canal (SC). The total length (TL) and the filtration length (FL) of the IW decorated by tracers were measured in frontal sections. The average percent effective filtration length (PEFL = FL/TL) was calculated for each eye. Sections exhibiting SC were processed and examined under light and electron microscopy. The average IOP was significantly higher in laser-treated eyes (mean ± SD = 61.33 ± 4.16 mmHg) than controls (22.67 ± 4.16 mmHg, P = 0.002). The average C was 13-fold lower in laser-treated eyes (0.03 ± 0.02 μl/min/mmHg) than controls (0.39 ± 0.17 μl/min/mmHg, P = 0.057). By confocal microscopy, in control eyes, SC was open and a segmental distribution of microspheres was found in the TM with a greater concentration near the collector channel (CC) ostia. Much less tracer labeling was seen along SC in laser-treated eyes than control eyes. The average PEFL in controls (47.47 ± 10.79%) was 6-fold larger than in laser-treated eyes (8.40 ± 4.81%, P = 0.048). The average distance between the inner and outer wall of SC was 5-fold greater in control eyes (18.99 ± 6.03 μm) than in laser-treated eyes (3.47 ± 0.33 μm, P = 0.048). By light microscopy, there was extensive pigmentation throughout the TM, denser extracellular matrix in the JCT region, and most of SC collapsed with focal herniations of the IW and JCT protruding into the CC ostia in laser-treated eyes. By electron microscopy, few or no microspheres were observed in laser-treated areas and the areas with SC collapse. More microspheres were observed near the CC ostia area in non-lasered areas. In conclusion, in the laser-induced glaucoma model, laser damage results in a reduction in the available area for outflow across the IW of SC which contributes to the decrease in C and thus elevation of the IOP. Constriction of SC, caused by the chronic elevation of IOP, further decreases the available area for outflow across the IW which decreases C even more in a vicious cycle. This study suggests that the available area for aqueous humor outflow across the IW of SC may play a role in regulating outflow resistance and maintaining IOP.

Canaloplasty: Circumferential viscodilation and tensioning of Schlemm canal using a flexible microcatheter for the treatment of open-angle glaucoma in adults: Two-year interim clinical study results

Purpose To evaluate 2-year postsurgical safety and efficacy of canaloplasty (circumferential viscodilation and tensioning of the inner wall of Schlemm canal) to treat open-angle glaucoma (OAG). Setting Multicenter surgical sites. Methods This international prospective study comprised adult OAG patients having glaucoma surgery or combined glaucoma–cataract surgery. Qualifying preoperative intraocular pressure (IOP) was at least 16 mm Hg and historical IOP, at least 21 mm Hg. The full circumference of the canal was viscodilated and a trabecular tensioning suture placed with a microcatheter. Primary outcome measures included IOP and glaucoma medication use. Results At 24 months, all 127 eyes (127 patients) had a mean IOP of 16.0 mm Hg ± 4.2 (SD) and mean glaucoma medication use of 0.5 ± 0.8 (baseline values 23.6 ± 4.8 mm Hg and 1.9 ± 0.8 medications). Eyes with canaloplasty alone had a mean IOP of 16.3 ± 3.7 mm Hg and 0.6 ± 0.8 medications (baseline values 23.2 ± 4.0 mm Hg and 2.0 ± 0.8 medications). Eyes with combined glaucoma–cataract surgery had a mean IOP of 13.4 ± 4.0 mm Hg and 0.2 ± 0.4 medications (baseline values 23.1 ± 5.5 mm Hg and 1.7 ± 1.0 medications). The IOP and medication use results at all time points were statistically significant versus baseline ( P Conclusion Canaloplasty was safe and effective in reducing IOP in adult patients with OAG.

Combined cataract extraction and trabeculotomy by the internal approach for coexisting cataract and open-angle glaucoma: Initial results

To provide an update of the short-term results of combined phacoemulsification and trabeculotomy by the internal approach with a follow-up to 21 months. Universities and private practices in the United States. This prospective interventional case series comprised 304 consecutive eyes with open-angle glaucoma and cataract having combined phacoemulsification and trabeculotomy with a Trabectome (NeoMedix Inc.). The Trabectome is designed to open a direct pathway for aqueous to flow from the anterior chamber into Schlemm canal collector channels. Under gonioscopic control, bipolar cautery was applied by a purpose-designed footplate to ablate the trabecular meshwork and inner wall of Schlemm canal. The main outcome measures were intraocular pressure (IOP), glaucoma medication use, and complications. The mean IOP was 20.0 mm Hg+/-6.3 (SD) preoperatively, 14.8+/-3.5 mm Hg at 6 months, and 15.5+/-2.9 mm Hg at 1 year. There was a corresponding drop in glaucoma medications from 2.65+/-1.13 at baseline to 1.76+/-1.25 at 6 months and 1.44+/-1.29 at 1 year. Subsequent secondary glaucoma procedures were performed in 9 patients. The only frequent complication, blood reflux in 239 patients (78.4%), resolved within a few days. Combined phacoemulsification and trabeculotomy by the internal approach using the Trabectome lowered IOP and medication use in the majority of patients. Complications were minimal and comparable to those in an earlier series of Trabectome-only procedures.

Circumferential viscodilation and tensioning of Schlemm canal (canaloplasty) with temporal clear corneal phacoemulsification cataract surgery for open-angle glaucoma and visually significant cataract: One-year results

To evaluate the safety and efficacy of circumferential viscodilation and tensioning of the inner wall of Schlemm canal, a new nonpenetrating surgical procedure (canaloplasty) to treat open-angle glaucoma (OAG), combined with clear corneal phacoemulsification and posterior chamber intraocular lens (IOL) implantation. Multicenter surgical sites. This international multicenter prospective study comprised adult patients with OAG having combined glaucoma and cataract surgery. Patients with qualifying treated preoperative intraocular pressure (IOP) of at least 21 mm Hg or higher and open angles were eligible. Evaluation was performed at baseline and 1 day, 1 week, and 1, 3, 6, and 12 months postoperatively. Intraoperative and postoperative high-resolution ultrasound imaging was used to assess Schlemm canal and anterior segment angle morphology, including distension of the trabecular meshwork due to the tensioning suture. Data from 54 eyes that had combined glaucoma and cataract surgery performed by 11 surgeons at 9 study sites were analyzed for this interim analysis. The mean baseline IOP was 24.4 mm Hg+/-6.1 (SD) with a mean of 1.5+/-1.0 medications per eye. In all eyes, the mean postoperative IOP was 13.6+/-3.8 mm Hg at 1 month, 14.2+/-3.6 mm Hg at 3 months, 13.0+/-2.9 mm Hg at 6 months, and 13.7+/-4.4 mm Hg at 12 months. Medication use dropped to a mean of 0.2+/-0.4 per patient at 12 months. Surgical complications were reported in 5 eyes (9.3%) and included hyphema (n=3, 5.6%), Descemet tear (n=1, 1.9%), and iris prolapse (n=1, 1.9%). Transient IOP elevation of more than 30 mm Hg was observed in 4 eyes (7.3%) 1 day postoperatively. Circumferential viscodilation and tensioning of Schlemm canal combined with clear corneal phacoemulsification and posterior chamber IOL implantation was a safe and effective procedure to reduce IOP in adult patients with OAG.

Ab Interno Trabeculotomy With the Trabectome Surgical Device

iven the historically high complication rates of tra- ditional incisional glaucoma surgery, surgeons are always looking forward to new techniques that would im- prove our patient outcomes. Antimetabolite-enhanced trabeculectomy carries a 1% per year risk of endophthal- mitis 1 and yet has a success rate of roughly only 80% in most recent published series. 2 The Trabectome surgical device was developed to address the outflow resistance problems in open-angle glaucoma, while attempting to minimize the risks typically associated with other filter- ing procedures (Fig. 1). The Trabectome device was Food and Drug Administration approved last year for the treatment of adult and juvenile glaucoma. The device is a microelectrocautery and aspiration unit that ablates a strip of trabecular meshwork and the inner wall of Schlemm canal, allowing direct access of the aqueous into the canal and the aqueous collector channels down- stream (Fig. 2). This technique therefore reestablishes the eye's physiological outflow pathway, which is thought to be the defective in a large portion of primary open-angle glaucoma. The potential advantages of this procedure are numer- ous. Firstly, this technique of trabeculotomy does not in- volve manipulation of the conjunctiva, Tenon, or external eye wall, and hence does not put the patient at risk for bleb