Structural Confirmation of Lymphatic Outflow from Subconjunctival Blebs of Live Humans

Lee, Jong Yeon; Heilweil, Gad; Le, Phuc Van; Saraswathy, Sindhu; Hong, Young‐Kwon; Girkin, Christopher A.; Huang, Alex S.

doi:10.1016/j.xops.2021.100080

Cited by 10 publications

(12 citation statements)

References 43 publications

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“… 19 , 20 Similar results were seen in human patients who received subconjunctival anesthetic injection (mixed with a fluorescent tracer) prior to clinically indicated intravitreal drug injection for the treatment of retinal diseases. 17 In these cases, the bleb-related outflow pathways of human patients showed irregular sausage-shaped pathways that also contained OCT-visualized valves.…”

mentioning

confidence: 83%

“…Human case series with inadvertent (traumatic subconjunctival hemorrhage) or advertent subconjunctival tracer application have shown that subconjunctival blebs give rise to irregular sausage-shaped outflow pathways. 15 – 17 These pathways are distinct from classic Y-shaped ocular surface episcleral veins or corkscrew conjunctival blood vessels. 17 , 18 Subsequent study in post-mortem porcine eyes in the laboratory isolated these pathways, and they demonstrated immunopositivity for PROX-1 and podoplanin (lymphatic makers) but not CD31 (a blood vessel endothelial marker).…”

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confidence: 99%

“… 15 – 17 These pathways are distinct from classic Y-shaped ocular surface episcleral veins or corkscrew conjunctival blood vessels. 17 , 18 Subsequent study in post-mortem porcine eyes in the laboratory isolated these pathways, and they demonstrated immunopositivity for PROX-1 and podoplanin (lymphatic makers) but not CD31 (a blood vessel endothelial marker). 19 Structural evaluation using optical coherence tomography (OCT) in postmortem porcine eyes showed that these bleb-related outflow pathways contained intraluminal valves, a lymphatic hallmark.…”

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confidence: 99%

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Subconjunctival Lymphatics Respond to VEGFC and Anti-Metabolites in Rabbit and Mouse Eyes

Lee

Liu

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose To characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes. Methods Rabbits received subconjunctival injections of trypan blue or fixable fluorescent dextrans. Bleb-related outflow pathways were quantified. Immunofluorescence for vessel-specific markers (lymphatics [podoplanin and LYVE-1] and blood vessels [CD31]) were performed in native rabbit conjunctiva and after fixable fluorescent dextran injection. Vascular endothelial cell growth factor-C (VEGFC) was injected subconjunctivally in rabbits. mRNA and protein were assessed for the above markers using RT-PCR and Western blot. Alternatively, mouse studies used Prox1-tdTomato transgenic reporter mice. Subconjunctival injection conditions included: no injection, balanced salt solution (BSS), VEGFC, 5-fluorouracil (5FU) and two concentrations of mitomycin-C (MMC). Two mouse injection protocols (short and long) with different follow-up times and number of injections were performed. Mouse eyes were enucleated, flat mounts created, and subconjunctival branching and length assessed. Results Rabbit eyes demonstrated clear bleb-related subconjunctival outflow pathways that were distinct from blood vessels and were without nasal/temporal predilection. Immunofluorescence against vessel-specific markers showed lymphatics and blood vessels in rabbit conjunctiva, and these lymphatics overlapped with bleb-related subconjunctival outflow pathways. Subconjunctival VEGFC increased lymphatic ( P = 0.004–0.04) but not blood vessel ( P = 0.77–0.84) mRNA or protein in rabbits. Prox1-tdTomato transgenic reporter mice demonstrated natively fluorescent lymphatics. Subconjunctival VEGFC increased murine lymphatic branching and length ( P ≤ 0.001–0.004) while antimetabolites ( P ≤ 0.001–0.043) did the opposite for the long protocol. Discussion Subconjunctival lymphatics are pharmacologically responsive to both VEGFC and antimetabolites in two animal models studied using different methodologies. These results may be important for bleb-forming glaucoma surgeries or ocular drug delivery.

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confidence: 83%

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confidence: 99%

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confidence: 99%

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Subconjunctival Lymphatics Respond to VEGFC and Anti-Metabolites in Rabbit and Mouse Eyes

Lee

Liu

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…our simulations like done by Gardiner and co-workers [15]. The reason for this is that, in a glaucomatous eye and when a glaucoma drainage device is implanted, most aqueous humor drains through the glaucoma implant into the bleb, which represents the easiest fluidic pathway [19]. It is hypothesized in the literature that only 10% of the aqueous humor drains through the natural outflow pathways after trabeculectomy is performed [20].…”

Section: Plos Onementioning

confidence: 98%

“…The sclera was not included in our model. Although it is reported in the literature that some aqueous humor flowing into the bleb after glaucoma filtration surgery is reabsorbed by the episcleral vasculature, tracer-based studies have proved that the conjunctival blood vessels and conjunctival lymphatic system are the main structures involved in removing the excess interstitial subconjunctival fluid (aqueous humor) [8,[19][20][21]. Taking this into account, we have decided to not include the absorption of aqueous humor by the episcleral vasculature in our model and only consider the conjunctival route of absorption.…”

Section: Geometrymentioning

confidence: 99%

A model for designing intraocular pressure-regulating glaucoma implants

et al. 2022

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Glaucoma is a group of eye conditions that damage the optic nerve, the health of which is vital for vision. The key risk factor for the development and progression of this disease is increased intraocular pressure (IOP). Implantable glaucoma drainage devices have been developed to divert aqueous humor from the glaucomatous eye as a means of reducing IOP. The artificial drainage pathway created by these devices drives the fluid into a filtering bleb. The long-term success of filtration surgery is dictated by the proper functioning of the bleb and overlying Tenon’s and conjunctival tissue. To better understand the influence of the health condition of these tissues on IOP, we have developed a mathematical model of fluid production in the eye, its removal from the anterior chamber by a particular glaucoma implant–the PRESERFLO® MicroShunt–, drainage into the bleb and absorption by the subconjunctival vasculature. The mathematical model was numerically solved by commercial FEM package COMSOL. Our numerical results of IOP for different postoperative conditions are consistent with the available evidence on IOP outcomes after the implantation of this device. To obtain insight into the adjustments in the implant’s hydrodynamic resistance that are required for IOP control when hypotony or bleb scarring due to tissue fibrosis take place, we have simulated the flow through a microshunt with an adjustable lumen diameter. Our findings show that increasing the hydrodynamic resistance of the microshunt by reducing the lumen diameter, can effectively help to prevent hypotony. However, decreasing the hydrodynamic resistance of the implant will not sufficiently decrease the IOP to acceptable levels when the bleb is encapsulated due to tissue fibrosis. Therefore, to effectively reduce IOP, the adjustable glaucoma implant should be combined with a means of reducing fibrosis. The results reported herein may provide guidelines to support the design of future glaucoma implants with adjustable hydrodynamic resistances.

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Unconventional Aqueous Humor Outflow

Huang,

Johnson

2024

Reference Module in Neuroscience and Biobehavioral Psychology

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Structural Confirmation of Lymphatic Outflow from Subconjunctival Blebs of Live Humans

Cited by 10 publications

References 43 publications

Subconjunctival Lymphatics Respond to VEGFC and Anti-Metabolites in Rabbit and Mouse Eyes

Subconjunctival Lymphatics Respond to VEGFC and Anti-Metabolites in Rabbit and Mouse Eyes

A model for designing intraocular pressure-regulating glaucoma implants

Unconventional Aqueous Humor Outflow

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