A Novel 8-mm Schlemm's Canal Scaffold Reduces Outflow Resistance in a Human Anterior Segment Perfusion Model

2013 ◽  
Vol 54 (3) ◽  
pp. 1698 ◽  
Author(s):  
Vikas Gulati ◽  
Shan Fan ◽  
Cassandra L. Hays ◽  
Thomas W. Samuelson ◽  
Iqbal Ike K. Ahmed ◽  
...  
Keyword(s):  
Anterior Segment ◽  
Outflow Resistance ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Perfusion Model

scholarly journals Pharmacological regulation of outflow resistance distal to Schlemm’s canal

2018 ◽  
Vol 315 (1) ◽  
pp. C44-C51 ◽  
Author(s):  
Fiona McDonnell ◽  
W. Michael Dismuke ◽  
Darryl R. Overby ◽  
W. Daniel Stamer
Keyword(s):  
Dynamic Range ◽  
Smooth Muscle Actin ◽  
Anterior Segment ◽  
Physiological Model ◽  
Outflow Resistance ◽  
Schlemm’S Canal ◽  
Outflow Facility ◽  
Schlemm's Canal ◽  
Anterior Segments ◽  
Outflow Pathway

The trabecular meshwork (TM) and Schlemm’s canal generate the majority of outflow resistance; however, the distal regions of the conventional outflow pathway account for 25–50% of total resistance. Sections of distal vessels are surrounded by α-smooth muscle actin-containing cells, indicating that they may be vasoregulated. This study examined the effect of a potent vasodilator, nitric oxide (NO), and its physiological antagonist, endothelin-1 (ET-1), on the regulation of outflow resistance in the distal regions of the conventional outflow pathway. Using a physiological model of the conventional outflow pathway, human and porcine anterior segments were perfused in organ culture under constant flow conditions, while intrachamber pressure was continually monitored. For porcine anterior segments, a stable baseline outflow facility with TM intact was first achieved before anterior segments were removed and a trabeculotomy was performed. For human anterior segments, a trabeculotomy was immediately performed. In human anterior segments, 100 nM ET-1 significantly decreased distal outflow facility from 0.49 ± 0.26 to 0.31 ±  0.18 (mean ± SD) µl·min−1·mmHg, P < 0.01. Perfusion with 100 µM diethylenetriamine-NO in the presence of 1 nM ET-1 immediately reversed ET-1 effects, significantly increasing distal outflow facility to 0.54 ± 0.35 µl·min−1·mmHg, P = 0.01. Similar results were obtained in porcine anterior segment experiments. Therefore, data show a dynamic range of resistance generation by distal vessels in both the human and the porcine conventional outflow pathways. Interestingly, maximal contraction of vessels in the distal outflow tract of trabeculotomized eyes generated resistance very near physiological levels for both species having an intact TM.

A Novel Schlemm's Canal Scaffold Increases Outflow Facility in a Human Anterior Segment Perfusion Model

2012 ◽  
Vol 53 (10) ◽  
pp. 6115 ◽  
Author(s):  
Lucinda J. Camras ◽  
Fan Yuan ◽  
Shan Fan ◽  
Thomas W. Samuelson ◽  
Ike K. Ahmed ◽  
...  
Keyword(s):  
Anterior Segment ◽  
Schlemm’S Canal ◽  
Outflow Facility ◽  
Schlemm's Canal ◽  
Perfusion Model

scholarly journals Morphological changes in the trabecular meshwork and Schlemm’s canal after treatment with topical intraocular pressure-lowering agents

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji-Hye Park ◽  
Hyun Woo Chung ◽  
Eun Gyu Yoon ◽  
Min Jung Ji ◽  
Chungkwon Yoo ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Trabecular Meshwork ◽  
Morphological Changes ◽  
Open Angle Glaucoma ◽  
Anterior Segment ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Before And After ◽  
Treatment Naïve ◽  
Aqueous Outflow

AbstractGlaucoma treatment is usually initiated with topical medication that lowers the intraocular pressure (IOP) by reducing the aqueous production, enhancing the aqueous outflow, or both. However, the effect of topical IOP-lowering medications on the microstructures of the aqueous outflow pathway are relatively unknown. In this retrospective, observational study, 56 treatment-naïve patients with primary open-angle glaucoma were enrolled. Images of the nasal and temporal corneoscleral limbus were obtained using anterior segment optical coherence tomography (AS-OCT). The conjunctival vessels and iris anatomy were used as landmarks to select the same limbal area scan, and the trabecular meshwork (TM) width, TM thickness, and Schlemm’s canal (SC) area were measured before and after using the IOP-lowering agents for 3 months. Among the 56 patients enrolled, 33 patients used prostaglandin (PG) analogues, and 23 patients used dorzolamide/timolol fixed combination (DTFC). After 3 months of DTFC usage, the TM width, TM thickness, and SC area did not show significant changes in either the nasal or temporal sectors. Conversely, after prostaglandin analog usage, the TM thickness significantly increased, and the SC area significantly decreased (all P < 0.01). These findings warrant a deeper investigation into their relationship to aqueous outflow through the conventional and unconventional outflow pathways after treatment with PG analogues.

Trabecular Bypass: Effect of Schlemm’s Canal and Collector Channel Dilation

2004 ◽  
Author(s):  
Jianbo Zhou ◽  
Gregory T. Smedley
Keyword(s):  
Intraocular Pressure ◽  
Second Order ◽  
Polynomial Equations ◽  
Outflow Resistance ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Elevated Intraocular Pressure ◽  
Order Polynomial ◽  
Trabecular Bypass

An ocular outflow model is proposed to theorize the effect of Schlemm’s canal (SC) and/or collector channel (CC) dilation combined with a trabecular bypass on elevated intraocular pressure (IOP) in glaucomatous eyes. The dilated height of the elliptic SC is largest at the bypass and linearly deceases to the non-dilated height over the dilated circumferential length. The CC dilation is modeled with a reduced outflow resistance of second order polynomial. Equations governing the pressure and flow in SC are solved numerically. The model predicts that the IOP is reduced substantially with moderate dilation from the normal 20 μm to 40 μm at the bypass. SC dilation is more effective for eyes with smaller SC. The dilation of CC can also significantly lower the IOP. With the trabecular bypass alone, the elevated IOP is expected to drop to the mid-to-high teens. The IOP can be further reduced by another 3 to 6 mmHg with moderate SC and CC dilation.

scholarly journals Anterior Segment Optical Coherence Tomography Signs of Local Dilatation Effect of a Micro-Stent on Schlemm’s Canal

2018 ◽  
Vol 10 (2) ◽  
pp. 184-187
Author(s):  
Kevin Gillmann ◽  
Giorgio Enrico Bravetti ◽  
Kaweh Mansouri ◽  
André Mermoud
Keyword(s):  
Optical Coherence Tomography ◽  
Trabecular Meshwork ◽  
Anterior Segment ◽  
Optical Coherence ◽  
Schlemm’S Canal ◽  
New Device ◽  
Schlemm's Canal ◽  
Canal Diameter ◽  
Trabecular Bypass

Introduction: The iStent inject® (Glaukos Corporation, CA, USA) is a relatively new device designed to be implanted ab-interno through the trabecular meshwork. This is, to the best of our knowledge, the first in-vivo description of a trabecular bypass device visualised with anterior segment optical coherence tomography (AS-OCT), and report of its structural effect on Schlemm’s canal. Case Report: A 74 year-old female patient suffering from long-standing primary open-angle glaucoma and nuclear sclerosis underwent cataract surgery combined with the implantation of two iStent injects®. Surgery was uncomplicated and achieved intraocular pressure (-1 mmHg) and medication (-2 molecules) reduction at 6 months. Under AS-OCT (Spectralis OCT, Heidelberg Engineering AG, Germany) the stent appears as a 300 μm long hyper reflective hollow device within the trabecular meshwork. Approximately a third of it protruded into the anterior chamber. Profound OCT signal loss was notable within the shadow of the device. A second AS-OCT section 500 μm beside the microstent shows a markedly dilated Schlemm’s canal, with a major diameter of 390 μm. Discussions: This report confirms that AS-OCT is a suitable technique to assess microstent positioning, and provides a first report on the in-vivo appearance of a functioning stent. It also indicates that iStent injects® could have a tangible effect on adjacent portions of Schlemm’s canal with, in this case, a 220% increase in canal diameter compared to the observed average (122 μm). This suggests the IOP-lowering effect of trabecular bypass devices could rely on a  dual mechanism involving Schlemm’s canal dilatation.

scholarly journals Suture Distension of Schlemm’s Canal in Canaloplasty: An Anterior Segment Imaging Study

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Livia M. Brandao ◽  
Andreas Schötzau ◽  
Matthias C. Grieshaber
Keyword(s):  
Intraocular Pressure ◽  
Anterior Segment ◽  
Imaging Study ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Anterior Segment Imaging ◽  
The Difference ◽  
Cup To Disc Ratio

Purpose. The object of this study was to investigate the role of the suture stent regarding its impact on reduction of intraocular pressure (IOP) in canaloplasty based on the distension of the inner wall of Schlemm’s canal.Methods. Nineteen glaucoma patients who underwent canaloplasty with successful positioning of the tensioning suture were included. The measurements were analyzed using linear mixed models, with the means adjusted to IOP, age, cup-to-disc ratio, and time of follow-up.Results. Mean follow-up time was 27.6 months (SD 10.5). Mean intraocular pressure (IOP) was 24.6 mmHg (SD 5.29), 13.8 (SD 2.65), and 14.5 (SD 0.71) before surgery, at 12 months, and at 36 months after surgery, respectively. 57.9% of patients had no medication at last evaluation. Differences and variations of measurements between the devices over a time of 12 months were not significant (p= 0.15 to 0.98). Some angles of distension associated with the suture stent inside SC were predictive for IOP reduction (p< 0.03 to < 0.001), but not for final IOP (p= 0.64 to 0.96).Conclusion. The angles of the inner wall of Schlemm’s canal generated by the suture stent were comparable between OCT and UBM and did not change significantly over time. There was a tendency towards a greater distension of Schlemm’s canal, when the difference was larger between pre- and postoperative IOP, suggesting the tensioning suture may contribute to IOP reduction.

scholarly journals Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy

2021 ◽  
Author(s):  
Michael P. Vincent ◽  
Trevor Stack ◽  
Amir Vahabikashi ◽  
Guorong Li ◽  
Kristin M. Perkumas ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Endothelial Cells ◽  
Targeted Drug Delivery ◽  
Surface Engineering ◽  
Vision Loss ◽  
Open Angle Glaucoma ◽  
Anterior Segment ◽  
Schlemm’S Canal ◽  
Schlemm's Canal ◽  
Targeted Drug

Primary open-angle glaucoma is associated with elevated intraocular pressure (IOP) that damages the optic nerve and leads to gradual vision loss. Several agents that reduce the stiffness of pressure-regulating Schlemm's canal endothelial cells, in the conventional outflow pathway of the eye, lower IOP in glaucoma patients and are approved for clinical use. However, poor drug penetration and uncontrolled biodistribution limit their efficacy and produce local adverse effects. Compared to other ocular endothelia, FLT4/VEGFR3 is expressed at elevated levels by Schlemm's canal endothelial cells and can be exploited for targeted drug delivery. Here, we validate FLT4 receptors as a clinically-relevant target on Schlemm's canal cells from glaucomatous human donors and engineer polymeric self-assembled nanocarriers displaying lipid-anchored targeting ligands that optimally engage this receptor. Targeting constructs were synthesized as lipid-PEGX-peptide, differing in the number of PEG spacer units (x), and were embedded in micelles. We present a novel proteolysis assay for quantifying ligand accessibility that we employ to design and optimize our FLT4-targeting strategy for glaucoma nanotherapy. Peptide accessibility to proteases correlated with receptor-mediated targeting enhancements. Increasing the accessibility of FLT4-binding peptides enhanced nanocarrier uptake by Schlemm's canal cells while simultaneously decreasing uptake by off-target vascular endothelial cells. Using a paired longitudinal IOP study in vivo, we show this enhanced targeting of Schlemm's canal cells translates to IOP reductions that are sustained for a significantly longer time as compared to controls. Histological analysis of murine anterior segment tissue confirmed nanocarrier localization to Schlemm's canal within one hour after intracameral administration. This work demonstrates that steric effects between surface-displayed ligands and PEG coronas significantly impact targeting performance of synthetic nanocarriers across multiple biological scales. Minimizing the obstruction of modular targeting ligands by PEG measurably improved the efficacy of glaucoma nanotherapy and is an important consideration for engineering PEGylated nanocarriers for targeted drug delivery.

Differential P1-purinergic modulation of human Schlemm's canal inner-wall cells

2005 ◽  
Vol 288 (4) ◽  
pp. C784-C794 ◽  
Author(s):  
Mike O. Karl ◽  
Johannes C. Fleischhauer ◽  
W. Daniel Stamer ◽  
Kim Peterson-Yantorno ◽  
Claire H. Mitchell ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Aqueous Humor ◽  
Adenosine Receptors ◽  
Outer Wall ◽  
Outflow Resistance ◽  
Schlemm’S Canal ◽  
Adenosine Receptor Agonists ◽  
Schlemm's Canal ◽  
Aqueous Humor Flow

Intraocular pressure is directly dependent on aqueous humor flow into, and resistance to flow out of, the eye. Adenosine has complex effects on intraocular pressure. Stimulation of A1and A2Aadenosine receptors changes intraocular pressure oppositely, likely through opposing actions on the outflow of aqueous humor. While the cellular sites regulating outflow resistance are unknown, the cells lining the inner wall of Schlemm's canal (SC) are a likely regulatory site. We applied selective adenosine receptor agonists to SC cells in vitro to compare the responses to A1and A2Astimulation. Parallel studies were conducted with human inner-wall SC cells isolated by a novel enzyme-assisted technique and with cannula-derived mixed inner- and outer-wall SC cells. A1agonists increased whole cell currents of both inner-wall and cannula-derived SC cells. An A2Aagonist reduced currents most consistently in specifically inner-wall SC cells. Those currents were also increased by A2B, but not consistently affected by A3, stimulation. A1, A2A, and A3agonists all increased SC-cell intracellular Ca2+. The electrophysiological results are consistent with the possibility that inner-wall SC cells may mediate the previously reported modulatory effects of adenosine on outflow resistance. The results are also consistent with the presence of functional A2B, as well as A1, A2A, and A3adenosine receptors in SC cells.

scholarly journals Mechanical responsiveness of the endothelial cell of Schlemm's canal: scope, variability and its potential role in controlling aqueous humour outflow

2011 ◽  
Vol 9 (71) ◽  
pp. 1144-1155 ◽  
Author(s):  
E. H. Zhou ◽  
R. Krishnan ◽  
W. D. Stamer ◽  
K. M. Perkumas ◽  
K. Rajendran ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Endothelial Cell ◽  
Aqueous Humour ◽  
Open Angle Glaucoma ◽  
Primary Cultures ◽  
Cell Stiffness ◽  
Donor Strain ◽  
Outflow Resistance ◽  
Schlemm’S Canal ◽  
Schlemm's Canal

Primary open-angle glaucoma is associated with elevated intraocular pressure, which in turn is believed to result from impaired outflow of aqueous humour. Aqueous humour outflow passes mainly through the trabecular meshwork (TM) and then through pores formed in the endothelium of Schlemm's canal (SC), which experiences a basal-to-apical pressure gradient. This gradient dramatically deforms the SC endothelial cell and potentially contributes to the formation of those pores. However, mechanical properties of the SC cell are poorly defined. Using optical magnetic twisting cytometry and traction force microscopy, here we characterize the mechanical properties of primary cultures of the human SC cell, and for the first time, the scope of their changes in response to pharmacological agents that are known to modulate outflow resistance. Lysophosphatidic acid, sphingosine-1-phosphate (S1P) and thrombin caused an increase in cell stiffness by up to 200 per cent, whereas in most cell strains, exposure to latrunculin A, isoproterenol, dibutryl cyclic-AMP or Y-27632 caused a decrease in cell stiffness by up to 80 per cent, highlighting that SC cells possess a remarkably wide contractile scope. Drug responses were variable across donors. S1P, for example, caused 200 per cent stiffening in one donor strain but only 20 per cent stiffening in another. Isoproterenol caused dose-dependent softening in three donor strains but little or no response in two others, a finding mirrored by changes in traction forces and consistent with the level of expression of β 2 -adrenergic receptors. Despite donor variability, those drugs that typically increase outflow resistance systematically caused cell stiffness to increase, while in most cases, those drugs that typically decrease outflow resistance caused cell stiffness to decrease. These findings establish the endothelial cell of SC as a reactive but variable mechanical component of the aqueous humour outflow pathway. Although the mechanism and locus of increased outflow resistance remain unclear, these data suggest the SC endothelial cell to be a modulator of outflow resistance.

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