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Review
. 2021 Jul:83:100917.
doi: 10.1016/j.preteyeres.2020.100917. Epub 2020 Nov 17.

Aqueous outflow regulation - 21st century concepts

Murray Johnstone  1 , Chen Xin  2 , James Tan  3 , Elizabeth Martin  4 , Joanne Wen  5 , Ruikang K Wang  6
Affiliations
Review

Aqueous outflow regulation - 21st century concepts

Murray Johnstone et al. Prog Retin Eye Res. 2021 Jul.

Abstract

We propose an integrated model of aqueous outflow control that employs a pump-conduit system in this article. Our model exploits accepted physiologic regulatory mechanisms such as those of the arterial, venous, and lymphatic systems. Here, we also provide a framework for developing novel diagnostic and therapeutic strategies to improve glaucoma patient care. In the model, the trabecular meshwork distends and recoils in response to continuous physiologic IOP transients like the ocular pulse, blinking, and eye movement. The elasticity of the trabecular meshwork determines cyclic volume changes in Schlemm's canal (SC). Tube-like SC inlet valves provide aqueous entry into the canal, and outlet valve leaflets at collector channels control aqueous exit from SC. Connections between the pressure-sensing trabecular meshwork and the outlet valve leaflets dynamically control flow from SC. Normal function requires regulation of the trabecular meshwork properties that determine distention and recoil. The aqueous pump-conduit provides short-term pressure control by varying stroke volume in response to pressure changes. Modulating TM constituents that regulate stroke volume provides long-term control. The aqueous outflow pump fails in glaucoma due to the loss of trabecular tissue elastance, as well as alterations in ciliary body tension. These processes lead to SC wall apposition and loss of motion. Visible evidence of pump failure includes a lack of pulsatile aqueous discharge into aqueous veins and reduced ability to reflux blood into SC. These alterations in the functional properties are challenging to monitor clinically. Phase-sensitive OCT now permits noninvasive, quantitative measurement of pulse-dependent TM motion in humans. This proposed conceptual model and related techniques offer a novel framework for understanding mechanisms, improving management, and development of therapeutic options for glaucoma.

Keywords: Aqueous outflow pump; Elastance; Glaucoma; Intraocular pressure regulation; Pulsatile aqueous outflow; Schlemm's canal valves.

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Figures

Fig. 1.
Fig. 1.. Cardiac-induced pulsatile aqueous outflow mechanisms.
Cardiac source of (a) pulsatile aqueous outflow and (b) resultant pulsatile flow into the aqueous veins. During systole, the left ventricle contracts, which initiates a pulse wave that causes the choroidal volume to expand, thus increasing intraocular pressure (IOP). Increased IOP causes the trabecular meshwork (TM) to move into the lumen of Schlemm’s canal (SC), narrowing it. TM movement that narrows the SC lumen increases pressure in SC. Reduced space and increased pressure in SC favor the pulsatile flow of aqueous from SC into aqueous and episcleral veins (ESV). Movement creates an aqueous pulse wave and increases aqueous vein pressure (AVP) during systole. During diastole, choroidal volume decreases, and IOP falls. The TM recoils, releasing the potential energy stored during systole. TM recoil reduces pressure in SC, favoring aqueous flow from the AC into SC through SC inlet valves, (b) Various manifestations of oscillatory pulsatile flow into the episcleral veins are synchronous with the ocular pulse. Pressure in the aqueous veins falls as SC pressure decreases during diastole. Episcleral venous pressure (EVP) is then transiently higher than aqueous vein pressure (AVP) resulting in oscillatory blood entry into aqueous veins. The next systolic wave causes the AVP to be higher than EVP. From: Johnstone M, Aqueous Veins, The Glaucoma Book. New York: Springer, 2010:65–78. Video - Pulsatile Aqueous Vein Flow 1-s2.0-S1350946220300896-mmc1.mp4).
Fig. 2.
Fig. 2.. Path of aqueous flow from the anterior chamber to collector channels.
The blue arrows depict the passage of aqueous from the anterior chamber through passages within the trabecular lamellae that lead into the juxtacanalicular space. From the juxtacanalicular space, aqueous passes through the lumen of the Schlemm’s canal (SC) inlet valves, where it flows into SC. From SC, aqueous enters a collector channel (CC) entrance through an open SC inlet valve. SC endothelium (SCE) is continuous with the SC inlet valve. The SC inlet valve connections link the TM to the hinged, mobile SC outlet valve. Illustration conceived and developed by Antonio Moreno-Valladares (University Hospital of Albacete, Spain) and Manuel Romera (www.ilustracionmedica.es). Video – SC Inlet Valve Aqueous Flow 1-s2.0-S1350946220300896-mmc2.mp4).
Fig. 3.
Fig. 3.. Aqueous pulse wave distance and velocity profile vs. intraocular pressure.
Fig. 1 demonstrates the source of the oscillatory pulse waves found in the aqueous veins. Aqueous veins show oscillatory aqueous discharge into episcleral veins. Increased stroke volume increases aqueous outflow, (a, b, c, d) Stroke volume responses in a 59-year-old Caucasian male after an increase in intraocular pressure (IOP) following a water-drinking test. Outflow medications that reduce IOP have a similar initial increase in the pulsatile flow until IOP falls to a new lower setpoint, (a) Baseline IOP: velocity (V) is low. The aqueous pulse wave travels a short distance (D) with each stroke. Oscillation of a standing transverse wave results in a systolic discharge of aqueous fluid into a small venous tributary (ST), (b) Increased distance traveled by the oscillatory aqueous pulse wave, (c) A further increase in velocity and travel of the aqueous pulse wave. At each systole, a lamina of clear aqueous discharges into an episcleral vein, (d) Additional velocity increase and increased travel of the pulse wave. Continuous oscillating laminar flow now occurs in a more distal episcleral vein. Two hours after drinking water, IOP was again 10 mm Hg, and stroke volume returned to the appearance in (a). Illustrations from: Johnstone M, The Glaucoma Book. New York: Springer, 2010:65–78. Vessel Images from Johnstone M, Aqueous Veins, J Glaucoma 13, 421 438, 2004. Video – Stroke Volume Control of IOP 1-s2.0-S1350946220300896-mmc3.mp4.
Fig. 4.
Fig. 4.. Pulsatile aqueous flow from Schiemm’s canal into collector channels.
Pulsatile aqueous flow from SC into collector channels and more distal intrascleral channels in a human subject. Parallel white lines above the trabecular meshwork depict the course of the flow of blood-tinged aqueous (white arrows). A-C are sequential video frames encompassing one systolic pulse wave. (Gonioscopic video courtesy of R. Stegmann) From Grehn, H., Stamper, R., Essentials in Ophthalmology: Glaucoma II. Springer, Heidelberg, 2006.
Fig. 5.
Fig. 5.. Pulsatile aqueous flow from the anterior chamber into Schiemm’s canal.
Pulsatile aqueous flow through a Schiemm’s canal (SC) inlet valve in synchrony with the ocular pulse. Blood reflux into SC creates a red background that is visible through the transparent trabecular meshwork (TM). The stable background of blood contrasts with the propagating wave of clear aqueous moving through the SC inlet valve with each cardiac pulse wave. The aqueous always moves along a constrained path, indicating that the surrounding tissues determine the course of flow. Dimensions of the aqueous-defined pathway correspond to those of the aqueous inlet valves seen in laboratory studies. Cyclic enlargement of the aqueous filled funnel (F) then proceeds to collapse of the funnel as the propagating aqueous wave moves into the enlarging cylindrical region (C). The propagation of the pulse wave into the tube-area continues, followed by the closure of the tube-like area as a stream of clear aqueous is propelled into SC. Ejection of the propagating aqueous stream into SC results in swirling eddies of aqueous and blood mixing (M) in SC. (Gonioscopic video courtesy of R. Stegmann) From Johnstone M, An Aqueous Outflow Pump and its failure in glaucoma, Essentials in Ophthalmology: Glaucoma II. Springer, Heidelberg, 2006. Video Flow to SC Through SC Inlet Valves 1-s2.0-S1350946220300896-mmc2.mp4).
Fig. 6.
Fig. 6.. Synchrony of color-encoded trabecular meshwork and cardiac pulse.
(A) Representative structural image captured by OCT. (B) Heartbeat signals obtained from a digital pulsimeter shows the frequency domain positions (red markings). The trabecular meshwork (TM) motion signal is the filtered frequency domain TM motion (black trace, synchronized with the heartbeat signal. (C) Color-encoded instantaneous velocity is overlaid on the structural image. Red indicates anterior tissue movement toward the probe above the scleral surface. Blue indicates posterior tissue movement toward the anterior chamber. Tissue source: Human subject. From Xin C, Pulse-dependent TM motion in normal humans using phase-sensitive OCT. Invest Ophthalmol Vis Sci 59, 3675–3681, 2018.
Fig. 7.
Fig. 7.. Cataract surgery changes outflow system vector forces, favoring improved outflow.
(A) High-resolution MRI of a 74-year-old. The crystalline lens is present in the right image, but in the fellow eye of the left image, an artificial lens replaces the crystalline lens. Note the posterior shift of the ciliary body after cataract surgery. The haptic is perpendicular to the image and appears black. (B) In vivo composite image showing that life-long lens growth displaces the uvea anteriorly. Backward movement of the ciliary body induces vector forces pulling the scleral spur both posteriorly and inward. (C) Intraocular pressure (IOP) before and after cataract surgery in the Ocular Hypertension Treatment Study. Month 0 is the study visit that the participant reported cataract surgery, or a randomly selected, corresponding date in the control group. Error bars are ± two standard errors of the mean. (D) Final IOP changes in combined postoperative years following cataract surgery grouped by presurgical IOP (PO is postoperative) (The 8th, 9th, and 10th year pooled data represents the 144 patients.) (A), (B) and (D) from Poley B, IOP after cataract surgery in open-angle glaucoma. J Cataract Refract Surg 35,1946–1955, 2009, (C) from Mansberger S, IOP after cataract surgery, Ophthalmology 119, 1826–1831, 2012.
Fig. 8.
Fig. 8.. Pressure-dependent configuration of the trabecular meshwork, and scleral spur.
Images (A), (B), (C) depict the tissue configuration with intraocular pressure (IOP) & episcleral venous pressure (EVP) as indicated. (D) Primate eye fixed in vivo at IOP of 25 mm Hg and normal EVP. (E) Fellow eye of (D) fixed in vivo with an IOP of 0 mm Hg and normal EVP. White arrow in (E) indicates the SC inlet valve suspended in the canal with the valve connections to the TM and external wall identified in serial sections. These experiments were the first to recognize IOP as the cause of “giant vacuoles” that deform not only SC inner wall endothelial cells but also the trabecular meshwork (TM) lamellae. The scleral spur (SS) and ciliary body (CB) undergo marked changes in configuration, moving outward as IOP increases. Cellular connections, depicted in (A) between the TM, juxtaeanalieular cells, and SC endothelium, provide tethering of SC inner wall to prevent it from collapsing into SC. Tissue source of (D) and (E): Primate, Macaca mulatto. Adapted from Johnstone M and Grant M, Pressure-dependent changes in structure of the aqueous outflow system. Am. J. Ophthalmol 75, 365–383, 1973.
Fig. 9.
Fig. 9.. Connections attach the Schlemm’s inner wall to the trabecular lamellae.
(A) Cytoplasmic processes (black arrows) of juxtaeanalieular cells (asterisks) in the juxtaeanalieular space (JCS) link Schlemm’s canal endothelium (SCE) to the underlying trabecular beams of the trabecular meshwork (TM). (B) Arrows depict the source of the pressure gradient originating from the anterior chamber (AC). SCE cell cytoplasmic processes attach to juxtaeanalieular cell processes. Juxtaeanalieular cell processes also attach to cytoplasmic processes arising from the endothelium covering the trabecular lamellae. This arrangement provides a mechanism anchoring the inner wall endothelium of Schlemm’s canal to the lamellae. Intertrabecular cytoplasmic processes also maintain contact between adjacent lamellae. The continuous pressure gradient between the AC and SC permits the cytoplasmic attachments to tensionally integrate the structural elements of the trabecular meshwork, providing tissue and cellular prestress. (A) Tissue source: Human. From Johnstone M. The aqueous outflow system as a mechanical pump: evidence from examination of tissue and aqueous movement in human and non-human primates. From: (A) J Glaucoma 13, 421–438.
Fig. 10.
Fig. 10.. Outflow system response to ciliary muscle tension: Motion observations.
Ciliary body tension on outflow pathways in a radial limbal segment (~2 mm thickness). Forceps tension moves the ciliary body (CB) posteriorly to simulate ciliary muscle contraction on the scleral spur (SS), and trabecular meshwork (TM). Green arrows indicate A) no CB tension, B) moderate CB tension, and C) increased CB tension. Concurrent phenomena demonstrate a highly interconnected system with structures moving in synchrony. As tension increases, the CB-TM tendon interface moves posteriorly, (dotted red outline). The scleral spur also rotates posteriorly and inward toward the AC. TM lamellae attached to both the scleral spur and the ciliary body move posteriorly and elongate (double-headed red arrows). The TM lamellae are anchored anteriorly to Schwalbe’s line. The lamellae move inward with a fan-like motion enlarging the more posterior intertrabecular spaces with minimal movement near SL (double-headed green arrows). Intertrabecular spaces between the parallel layers of the TM lamellae communicate directly with the face of the ciliary muscle and the TM-CB tendons. Oscillatory TM lamellar excursions, more substantial in the posterior than anterior spaces of the lamellae, will ensure constant oscillatory aqueous movement toward and away from the ciliary tendons and muscle. Translucent cylindrical structures, the SC inlet valves, arise from SC inner wall and cross SC (white arrowheads) to a septum at the SC external wall (red arrow). As CB tension increases, the septum moves toward SC, becoming progressively more curved (green arrow). The septum movement enlarges the lumen of a circumferentially oriented deep scleral plexus (CDSP) (black arrow). The release of forceps tension results in a rapid recoil from the configuration in C to that of A. Ciliary body tendinous attachments to the trabecular lamellae cause them to elongate and remain in a constant state of tensional prestress in vivo. Tension on the SC inlet valves also places tension on the septa and flaps at CDSP. The ciliary body tension maintains prestress of trabecular lamellae, SC inlet valves and septa. The prestress determines the lumen size of SC, CC, and CDSP. The optimized stresses and lumen size permit the TM to distend and recoil, enabling changes in stroke volume in response to ocular transients. Normal ciliary muscle tone and loading forces are absent in ex vivo preparations. – Tissue source: primate, Macaca nemestina. From Johnstone M, Intraocular pressure control through linked trabecular meshwork and collector channel motion. Glaucoma Research and Clinical Advances: 2016 to 2018. Kugler Publications, Amsterdam 2016. Ciliary Muscle Effect on Outflow Pathways 1-s2.0-S1350946220300896-mmc6.mp4.
Fig. 11.
Fig. 11.. Conduits cross Schlemm’s canal to hinged collector channel flaps.
(A) Scanning electron microscopy image after Schlemm’s canal (SC) dilation with viscoelastic and fixation. The inner wall of SC rests against several layers of adjacent collapsed trabecular meshwork (TM) lamellae. Nuclear bulges of endothelial cells are visible along the SC inner wall. A Schlemm’s canal inlet valve arises from SC inner wall endothelium and crosses SC to the external wall. The lumen of the inlet valve is continuous with the juxtacanalicular space of the TM. The SC inlet valve lumen thus provides a conduit for aqueous passage from the juxtacanalicular space to SC. (B) Anterior segment of the eye perfused with 500 nm green fluorescent microspheres followed by Schlemm’s canal dilation with viscoelastic. Confocal microscopy labeling is with DAPI (blue) for nuclei and CD31 (red) for vascular endothelium. The CD31 label identifies continuity of SC inner wall and SC inlet valve endothelial surfaces. Microspheres fill the intertrabecular spaces. A Schlemm’s canal inlet valve labeled with CD31 originates from SC inner wall endothelium and crosses SC to a collector channel entrance (CCE). Microspheres fill the SC inlet valve lumen from its origin at SC inner wall to its attachment at a CCE at SC external wall. Passage of microspheres provides evidence that the SC inlet valves can function as a conduit for aqueous. (C) Confocal microscopy - native fluorescence, SC viscoelastic dilation. An SC inlet valve initially forms a funnel (FNL) arising from the TM, develops a cylindrical conduit area, then attaches to the tip of a hinged collagen flap (HCF) at SC external wall. A Schlemm’ canal inlet valve has a direct opening to SC (OTC). The OTC is adjacent to a CCE at the entrance to a circumferential deep scleral plexus (CDSP). Tissue source: Primates, Macaca nemestrina. From Johnstone Glaucoma Lab, University of Washington.
Fig. 12.
Fig. 12.. Schlemm’s canal inlet valve attachments to SC external wall at collector channel entrances.
Scanning electron microscopy images (A, B) are from an eye with an IOP of 4 mm Hg during fixation. An SC inlet valve has a funnel shaped (FNL) region as it joins the trabecular meshwork (TM). The funnel region leads to a cylindrical area that crosses SC to attach at collector channel entrances (CCE). The section in (A) bisects the SC inlet valve lumen of the conduit-like pathway (CLP), revealing the lumen connection between the funnel-shaped juxtaeanalieular space and collector channel entrance. Internal structural features are like those of the juxtaeanalieular space. (B) A view of the funnel region of a Schlemm’s inlet valve with a plane of section revealing its surface features as it courses across the canal from the TM to SC external wall at the entrance of a collector channel. (C) Viscoelastic dilated Schlemm’s canal (SC) before fixation. The image reveals the conduit-like pathway (CLP) of the Schlemm’s canal inlet valve as it arises from the TM and attaches to a hinged collagen flap (HCF) at SC external wall. The inlet valve is bisected, revealing an open distal end in communication with a collector channel entrance (CCE). Aqueous can flow freely into SC and CCE through the lumen of the conduit-like pathways. Tissue source: Primate, Macaca nemestrina. From the Johnstone Glaucoma Lab, University of Washington.
Fig. 13.
Fig. 13.. Schlemm’s canal inlet valves – transient compression between Schlemm’s canal walls.
Left panel. Following in vivo fixation at 25 mm Hg, radial serial sections track a Schlemm’s (SC) inlet valve as it courses circumferentially in SC over a distance of 70 μm. (A) Illustration of Schlemm’s canal inlet valve discharging aqueous into the canal adjacent to a collector channel. (B) Compression of the same valve in regions of its course along SC. The pressure-dependent trabecular meshwork (TM) comes into proximity with the SC external wall causing varying degrees of compression and valve lumen closure throughout the valve length. The lumen of the inlet valve is at times open as in (A-B), and other times closed as in (C–D). White arrows identify areas of compression. Frequent closure of SC lumen is an expected finding in vivo as a result of pressures caused by normal ocular transients (Section 3.8.2) Tissue source: Primate, Macaca mulatta. Right Panel (1) Transient IOP increase from blinking, eye movement, lid squeezing, or experimental in vivo steady-state IOP of 25 mm Hg results in the configuration of Panel A (C–D). A TM elastance abnormality may result in persistent SC closure and elevated IOP. (2) Pump-conduit configuration at homeostatic IOP. (3) Pressure reversal results in SC dilation and blood reflux. IOP: Intraocular Pressure, EVP: Episcleral Venous Pressure, SC: Schlemm’s Canal, SCE: SC Endothelium, TM: Trabecular Meshwork, CC: Collector Channel, JCS: Juxtacanalicular Space, SIV: SC Inlet Valve, SOV: SC Outlet Valve. Left Panel from Poley B J Cataract Refract Surg 35, 1946–1955, 2009. Right Panel by Antonio Valladares and Manuel Romera. Video – TM Motion Closes SC 1-s2.0-S1350946220300896-mmc4.mp4.
Fig. 14.
Fig. 14.. Red blood cell tracers fill the lumen of Schlemm’s canal inlet valves.
Avian red blood cells (arbc) introduced into the anterior chamber (AC) as a tracer in living Macaca mulatto, monkey eye. (1) The arbc enter and fill a Schlemm’s canal (SC) inlet valve. (2) Gradual reduction of intraocular pressure (IOP) to 0 mm Hg in vivo causes SC to dilate and blood refluxes into the canal, because IOP is lower than episcleral venous pressure. Dilation of SC causes straightening and stretching of SC valves between SC walls enabling single radial sections to capture their full length. (3) Illustration of serial radial sections along a Schlemm’s canal inlet valve length. (4) From left to right: (A–D) are representative serial histologic sections encompassing the entire width of a Schlemm’s canal inlet valve depicted in (3). The endothelial lining (ET) of the SC valve is continuous with SC inner wall endothelium. The SC inlet valve spans across SC to attach to the corneoscleral wall (CSW). Avian red blood cells are present in the trabecular meshwork, and the juxtacanalicular space. In a central section through a Schlemm’s canal inlet valve, red cells fill the length of the lumen, as shown in C. In 4B and 4C, note the two collagenous supporting structures at the SC valve distal end with a narrow space where they meet. From Johnstone M, The aqueous outflow system as a mechanical pump, J Glaucoma 13, 421–438, 2004.
Fig. 15.
Fig. 15.. Schlemm’scanal outlet valve hinged flaps and trabecular meshwork connections.
(a–f) A cannula inserted into the Schlemm’s canal (SC) lumen attaches at its other end to a reservoir controlling hydrostatic pressure within the lumen. A laboratory-developed high-resolution SD-OCT system permits a detailed examination of the TM, SC, and collector channels (CC). Images result from orienting the tissue volume to optimally view the hinged collagen flaps (red asterisks) at the CC entrances. A reservoir maintains a height providing SC lumen with a steady-state pressure of 50 mm Hg. The hinged collagen flaps provide mobile valved leaflets at the collector channels entrances. The hinged flaps attach to the TM by the SC inlet valve appearing as thin cylindrical attachment structures (CAS) (black arrows) spanning SC. Note that despite SC dilation, the oblique orientation of the SC inlet valves persists (black arrows). Some sections through the CAS reveal the Schlemm’s canal inlet valve lumen (green arrows) consistent with the dual role as conduits and connections between the TM and the SC outlet valves. Tissue source: Primate, Macaca nemestrina. From Xin C, Mechanical Properties of the TM and Collector Channels, PLoS One 11, e0162048, 2016.
Fig. 16.
Fig. 16.. Synchronous lumen dimension changes of Schlemm’s canal and collector channels.
(A) Representative 3-D reconstruction of the entire length of a limbal Schlemm’s canal (SC) region obtained from stitching five tangential sections together. The image plane is perpendicular to the canal circumference. The SC inlet valves appear as structures spanning between the walls of SC (yellow arrows). Purple and green arrows show collector channel ostia (CCO). Blue arrows show entrances of circumferentially oriented deep scleral plexus. Asterisks mark septa that divide SC from the circumferentially oriented deep scleral plexus (CDSP) parallel to SC. The tilted section shows different levels in the height of SC, thus exhibiting differing relationships. (B) Representative two-dimensional (2-D) structural OCT and scanning electron microscopy (SEM) images from the limbal region of an eye. (a) OCT image with the cannula inside SC (arrow). (b) At a location, ~150 μm away from the cannula tip before infusion of perfusate to raise pressure. Arrows identify SC as a potential space with no lumen, (c) shows the maximally dilated appearance at the same location resulting from a bolus of aqueous. Images (d) and (e) are representative SEM images from the limbal region. The SEM and OCT images mirror each other in illustrating the structural features of the outflow system. Original SEM images: 337× magnification. The image in (d) shows a collector channel entrance or ostia (CCO). A septum present at the CCO is attached to the TM by a Schlemm’s canal inlet valve, which is labeled here as a cylindrical crossing structure (CAS). Image (e) is the adjacent section from the same segment showing the transition from the region of a CCO in (d) to the circumferentially oriented deep scleral plexus (CDSP). The CDSP is labeled as a collector channel in (d), (e), (f) because publication of these figures was before recognition of CDSP as unique entities. The image in (f) is a 2× enlargement of (c). CM, ciliary muscle. (C) Enlarged view of (f) in image (B) identifying the location of measurements in D. (D) Progressive increase in the height of SC, CC, and CAS with time during SC filling with a bolus of aqueous from a reservoir. SC (black curve), CC (red curve), Schlemm’s canal inlet valves (here labeled as CAS) (blue curve). Tissue source: Primates, Macaca nemestrina. From Hariri S, Pressure dependent TM motion with high-resolution OCT, J Biomed Opt 19,106013 1–10601311, 2014. Video - Linked TM and CC Motion 1-s2.0-S1350946220300896-mmc5.mp4.
Fig. 17.
Fig. 17.. Schlemm’s canal outlet valves: Pressure-dependent appearance.
In vivo fixation, while maintaining an IOP in (A) of 0 and (B1–B3) of 25 mm Hg. Images in serial sections of (B1–B3) illustrate the transition from a collector channel entrance to a circumferentially oriented deep scleral plexus (CDSP). Hinged collagen flaps (HCF) at collector entrances (CCE) are free at one end. The HFC can move freely in response to TM movement induced by pressure changes, thus permitting them to have a pressure-dependent valve-like function at CCE. In (B2 and B3), a long septum (S) separates SC from a circumferentially oriented deep scleral plexus (CDSP). In (A and C), a HCF is far from the corneoscleral wall (CSW) of SC. The next serial section, not shown but depicted in C, contains a transcanalicular attachment extending from the TM to the tip of the HCF. In image (B1), the hinged collagen flap at the entrance to a CCE is in apposition (App) to the CSW. Collagen fibers at the base of the hinge in (B1–B3) are circular running orthogonal to the plane of section, but are parallel in the hinged septum, providing a pivot point for motion. Septa dividing SC from CDSP are collagenous structures and differ from the aqueous valves that are transcanalicular endothelial-lined conduits spanning SC. Features of images (C and D), derived from (A) and (B), are color-coded as follows: Red, blood, blue, aqueous; green, hinged collagen flap; yellow, cylindrical attachments connecting to TM. Note blood in (B1) and (D) distal to the HCF. The apposition of the HCF to SC external wall prevents blood from entering the canal. (E) Ex vivo fixation of human eye at IOP of 50 mm Hg with TM distending or herniating into SC at a CC entrance at a fusiform dilation (FD) of SC external wall. A long HCF is present at the CC entrance. Tissue source: Primate, Macaca mulatto. From Johnstone, Howe Laboratory of Ophthalmology, Harvard Medical School 1972. Video - CC Open and Close 1-s2.0-S1350946220300896-mmc7.mp4.
Fig. 18.
Fig. 18.. Circumferentially oriented deep scleral plexus visualization.
A microvascular cast of the outflow system. (A). The trabecular meshwork (TM) is between the black curved line and the orange Schlemm’s canal (SC) cast. White arrows indicate the location of collector channels (CC) arising from SC and connecting to a circumferentially oriented deep scleral plexus (CDSP), as is indicated by a thin dashed red line. The CDSP forms a relatively continuous communicating ring adjacent and parallel to SC. Intraseleral vessels exit the CDSP and pass through the sclera (blue arrows) to the surface of the eye where episcleral and aqueous veins are visible. Between SC and CDSP are long, thin layers of collagenous tissue that appear as septa in histologic and OCT sections. OCT and direct observation at the dissecting microscope reveal that the thin septa move in response to ciliary body tension and pressure gradient changes within SC. Septa movement causes the lumen of the CDSP to open and close, thus functioning as a pressure-dependent compressible chamber. (B) Schematic illustration from the microscope view through the cut corneal surface that reveals the uniform angle of exit of the CC from SC. A view of casts from the surface of the corneoscleral interface does not provide a view perpendicular to the sites where CC exit SC. The view looking along the axis of the exit sites inadvertently gives the impression that the collector channels course directly from SC to the episcleral veins. By looking through the cut corneal surface (C), the view is perpendicular to the CC exit sites as in (D), which is the orientation shown in the microvascular cast in (A). The orthogonal view (E) makes the typical CC connections with the CDSP apparent. Tissue Source 78-year-old Caucasian male. From Johnstone Glaucoma Laboratory, University of Washington. Review Video in Fig. 16 – CDSP Open and Close 1-s2.0-S1350946220300896-mmc5.mp4.
Fig. 19.
Fig. 19.. Aqueous pump model incorporating valves and compressible chambers.
From the resting state in diastole, systole induces an intraocular pressure (IOP) rise, causing an ocular pulse wave in the anterior chamber (AC). The trabecular meshwork (TM) distends as IOP rises. TM distention causes Schlemm’s canal (SC) to narrow, reducing its volume, and forcing fluid through the collector channel (CC) entrances into the circumferentially oriented deep scleral plexus (CDSP). The SC outlet valve entrances close, followed by septa movement outward forcing aqueous out of the CDSP. During TM recoil in the next diastole, aqueous flows into the intertrabecular spaces, into SC through the conduits of the SC inlet valves and into CDSP. The cycle then repeats. The proposed anatomic relationships and pressure-dependent sequences are provisional and warrant further study. From Johnstone Glaucoma Laboratory, University of Washington.
Fig. 20.
Fig. 20.. Ciliary muscle tension, intraocular pressure (IOP) and TM removal: Impact on outflow facility.
(A) Crystalline lens backward movement dilates Schlemm’s canal (SC) and reduces resistance. The upper panel is with no lens depression. The trabecular meshwork (TM) is in extensive apposition to SC external wall (EW), causing the closure of SC lumen (arrow). In the lower panel, with depression of the crystalline lens, the ciliary body (CB) and scleral spur (SS) rotate posteriorly, pulling the TM attachments away from SC external wall. The TM distends, and SC lumen is large. The black arrow demonstrates the SC inlet valve extending from the TM to a hinged flap at a collector channel entrance. (B) The corneal perfusion fitting contains a lens-depression device. The CB and SS move backward with lens depression resulting in the opening of SC. As the lens moves backward, causing CB tension, resistance falls by over 50%. (C1) No iridectomy. Anterior chamber perfusion forces the lens backward, resulting in a reverse pupillary block phenomenon. Backward movement increases zonular tension that transmits to the ciliary body, scleral spur (SS), and TM tendons. The tension and vector forces cause the scleral spur and TM to move posteriorly and inward. In (C2) with an iridectomy, pressure gradients equalize between the anterior and posterior chamber eliminating posterior lens movement, so no tension is exerted on the ciliary body. (D) Outflow facility experimentally controlled at a series of steady-state intraocular pressures. The blue curve is outflow facility with no ciliary body tension, as shown in the C2 protocol. The orange curve is outflow facility with ciliary body tension resulting from the protocol, as shown in Cl. Pressures in the abscissa need to be adjusted upward by 8 mm Hg to reflect transtrabecular in vivo pressure gradients because of the lack of episcleral venous pressure in the ex vivo setting. Ellingsen and Grant determined reduction of outflow resistance from TM removal at each of the pressures noted in the blue curve of C2. As indicated by the boxed data, an effective IOP of 13, 18, and 33 mm Hg, trabeculotomy reduces resistance (R) by 14%, 27%, and 75%, respectively. The upward-pointing blue arrow and asterisk indicate the conditions of Grant’s initial 1958 and 1963 studies. With simulated ciliary muscle tension as in condition C-2, the outflow facility is initially higher than under condition (C-1). The facility of outflow remains high despite increasing IOP. The authors conclude that it is an apposition of the TM to SC external wall that causes increased resistance with pressure. They also reach the conclusion that ciliary muscle tension prevents SC wall apposition and a decrease in outflow facility. (A) From Van Buskirk M, Anatomic correlates of changing outflow facility. Invest Ophthalmol Vis Sci 22, 625–632, 1982. (B) From Johnstone, Pump failure in glaucoma. Essentials in Ophthalmology: Glaucoma II. Springer, Heidelberg, 2006. C) From Ellingsen and Grant, IOP and aqueous outflow, Invest Ophthalmol 10: 430–437, 1971.
Fig. 21.
Fig. 21.. Provisional 2D outflow model for regulation of homeostasis.
(A), (B), and (C) depict cross-sections through the outflow system while (D), (E) and (F) show global motion in three dimensions (3-D). Aqueous passes through the TM to the juxtacanalicular space (JCS). From the JCS, aqueous flows through the Schlemm’s canal (SC) inlet valves into SC. SC outlet valves (SOV), consisting of hinged collagen flaps, control collector channel entrance (CCE) dimensions. As Intraocular pressure (IOP) increases from low in (A-D) through the setpoint (B-E) to high in (C-F), the intertrabecular spaces and JCS enlarge, and SC narrows. In a 3-D view, the SIV, attached both to the TM and SOV, are oriented circumferentially in SC. Outward movement thus pulls the SOV open. (B-E) envisions an IOP of 16 mm Hg as an ideal homeostatic setpoint configuration. As IOP increases in (C-F), the TM moves outward. The SIV experience increased tension, resulting in increased stress on the SOV, causing it to open the CCE further. The CCE enlargement causes increased aqueous flow; IOP then falls with an associated inward movement of the TM, restoring it to the setpoint of (B-E). At a low IOP as in (A-D), the CCE is closed, reducing flow. Reduced flow increases IOP causing the TM to distend, thereby returning tension to the setpoint in (B-E). IOP generates forces causing TM tissues to deform and distend into SC. TM elastance properties balance the distending or loading force of IOP. TM tissues at the homeostatic setpoint are in an IOP-induced, prestressed, equilibrium state of deformation. Under homeostatic conditions of IOP > SCP > EVP, gradients favor closure of the HCF because SCP is higher than EVP. TM tension on the SOV, causes them to enlarge and optimizes CCE dimensions. Blue arrows in CCE depict changes in the rate of flow. Black arrow points to CCE. The proposed model is offered for consideration but is unproven, and its premises are subject to modification or rejection as new evidence emerges. From Johnstone M, IOP control through linked trabecular meshwork and collector channel motion. Glaucoma Research and Clinical Advances: 2016 to 2018. Kugler Publications, Amsterdam.
Fig. 22.
Fig. 22.. Trabecular meshwork elastance curve.
OCT imaging quantifies the relationship of Schlemm’s canal (SC) pressure and volume over a range from 0 of 50 mmHg. (a) A composite cross-sectional image permits visualization of ~8 mm of a limbal segment while maintaining a perfusion pressure of 50 mm Hg. The perfusion pressure dilates SC along its entire length. A cannula is visible in SC at the right edge of the image. The trabecular meshwork (TM) is superior to the canal. OCT images (b1-b4) are radial cross-sections through SC. Images demonstrate progressive dilation of the canal as pressure increases from 0 to 50 mm Hg. (c) Curves represent SC instantaneous volume and pressure measured at 10 μm intervals along the 2 mm limbal segment with pressures as indicated, (d) Plotting the pressure increase against the SC volume generates an elastance curve. The curve captures the elastic energy increase resulting from an increase in SC volume. The increase in potential energy distributes between further TM tissue deformation and the rise in pressure. The elastance curve provides a means of assessing the ability of the TM tissues to store elastic energy. Elastance and stiffness are synonymous terms. Tissue source: Human Eye. From Xin C, Mechanical Properties of the TM and Collector Channels, PLoS One 11, e0162048, 2016.
Fig. 23.
Fig. 23.. Synchronous pressure-dependent cytoplasm and nucleus deformation enabled by tethering.
(A) Images are from transmission electron microscopy following in vivo fixation at an intraocular pressure (IOP) of 25 mm Hg with normal episcleral venous pressure (EVP). Schlemm’s canal (SC) endothelial cell cytoplasmic projections (arrowheads) join cytoplasmic processes of subendothelial cells (sec) bodies in the subendothelial space (SES). The terms subendothelial cell and juxtacanalicular cell are synonyms. The terms subendothelial space and juxtacanalicular space are also synonyms. Nuclei and cytoplasm of the SC endothelial cells distend into the SC lumen. The periphery of these distended, flattened nuclei taper (arrows). Nuclei frequently deform into a hollow-hemisphere shape and are tilted into many planes, resulting in frontal sections as illustrated by the plane through AB in the lower-left panel. A corresponding section (AB) in the upper right panel is a cylindrical nuclear profile surrounding the subendothelial space. The hollow circular nuclear profile is analogous to the appearance in the areas of cytoplasm that are referred to as “giant vacuoles.” Cytoplasmic processes originating beneath the nucleus of the endothelial cells join cone-shaped nuclear projections that appear as an inverted triangle in cross-sections (np). A cytoplasmic process from an endothelial cell (cpe) traverses the subendothelial space to join a cytoplasmic process (cps) of a subendothelial cell. f. 4650.) Tissue source: Primate, Macaca mulatto. (B) SC inner wall endothelial lining mirrors the appearance seen in the lower panel of (A). It illustrates the cytoplasmic processes that tether SC endothelium to the trabecular lamellae (TL) through cytoplasmic process connections of subendothelial cells. (A) from Johnstone M, Pressure-dependent changes in Nuclei, Ophthalmol. & Vis. Sci. 18, 44–51, 1979. Illustration from Johnstone Glaucoma Lab, University of Washington.
Fig. 24.
Fig. 24.. Tethering of Schlemm’s canal endothelium to the meshwork permits cell deformation.
Images from non-human primate eyes following in vivo fixation. Image (A) and (C) represent the configuration with a positive IOP of 2525 mm Hg. Image group in (B) is the configuration with zero IOP but normal episcleral venous pressure. The reversed transtrabecular pressure gradient of 8 mm Hg results in TM collapse, Schlemm’s canal (SC) dilation, and altered cellular configuration. (A) Light microscopy. Upper image. Nuclei of Schlemm’s canal (SC) inner wall endothelium are flattened and elongated, tapering peripherally toward cytoplasmic elongations. At the origins of endothelial cell cytoplasmic processes (cp), the cytoplasm and nucleus (np) of the lining deform toward the subendothelial space (SES), creating a triangular projection in the two-dimensional image. The SES and juxtacanalicular space are synonyms. In the lower-left and right images of (A), elongated nuclei (n) have the same shape as the cytoplasm, forming a partial circular profile. Distal ends of the nuclei taper, resulting in crescent-shaped structures in section. Sections through portions of the distended cells that do not include the nucleus result in cytoplasmic vacuole-like (V) structures. Triangular-shaped cytoplasmic processes of SC inner wall endothelial cells extend into the subendothelial space (SES). Depressions are present on the cytoplastic surface facing Schlemm’s canal (asterisk) opposite the origin of cytoplasmic processes consistent with tension exerted on the cell walls at cytoplasmic process attachment sites. A subendothelial cell (sec) is also known as a juxtacanalicular cell, (scale bar = 5 μm; ah ×2000.) In image (C), left panel, scanning electron microscopy demonstrates an endothelial cell (e), forming a hemispherical profile. A cytoplasmic process (fe) originates from the endothelial cell and attaches to a subendothelial cell. A second process (ft) arises from another surface of the same subendothelial cell and joins a trabecular lamella (tl). In image (C) right panel, a cone-shaped area (cp) of the undersurface of the endothelial cell becomes a cylindrical cytoplasmic process (fe) as it extends to the subendothelial cell, (scale bar = 0.5 μm; left panel (×10,000); right panel, (×12,000). (B) Reversed transtrabecular pressure gradient of ~8 mm Hg. Transmission electron microscopy. Nuclei of the endothelial cells (ec) are rounded and bulge prominently into Schlemm’s canal lumen. Subendothelial cells are generally round. The nuclei have many deep nuclear folds (nf) and notches (nn); Endothelial cell junction (cj). (scale bar = 2 μm; ×4650.) (D) Schematic illustration of an endothelial cell (ec) lining Schlemm’s canal. The SC endothelial cell with its cytoplasmic processes attaches to a subendothelial cell (sec), which in turn attaches to a trabecular lamella (tl) via cytoplasmic processes. From Invest. From Johnstone M, Pressure-dependent changes in Nuclei, Ophthalmol. & Vis. Sci. 18, 44–51, 1979.
Fig. 25.
Fig. 25.. Tethering enables sensory signaling through cell deformation.
Cellular connections link the structural elements of the trabecular meshwork (TM). The cytoplasmic process tethering function permits Schlemm’s canal endothelial cell deformation. Left Panel Schlemm’s canal endothelial cells (SCE) have processes (SCP) that project into the juxtacanalicular space and attach to juxtacanalicular cell processes (JCP). JCP attach to trabecular lamellae endothelial cell processes (TIP), linking SCE to the trabecular lamellae. Trabecular lamellae endothelial cell cytoplasmic processes connect to adjacent trabecular lamellae cell processes. SC endothelial cell bodies, nuclei, and cytoplasmic processes undergo progressive deformation in response to progressive lOP-induced loading forces. The tethered trabecular lamellae limit SC inner wall endothelium distention by countering lOP-induced SCE loading forces. Spaces between the resisting trabecular tissues progressively increase as lOP increases. At physiologic pressures (baseline lOP), tensional integration is present throughout the trabecular tissues. IOP loading forces presented to SCE distribute throughout the TM lamellae as a result of the tethering cytoplasmic processes. The tensioned network allows finely graded responses to transient increases in lOP. Such force-dependent mechanotransduction mechanisms are like those elsewhere in the vasculature. Right Panel Detail of SC inner wall endothelium shown in panel one. The images in (A), (B), (C) depict alterations in cell surface membranes, organelles, nuclear envelope, nuclear intermediate filaments, and chromatin resulting from physiologic changes in IOP. The prestressed, tensionally-integrated chromatin permits instantaneous sensing of IOP changes at the genomic level. Pressure-dependent deformation of the cytoplasm, nucleus, and chromatin thus provides mechanotransduction signals to restore homeostatic setpoints (Section 5). The left panel is from “Aqueous Outflow Overview, Diagnosis and Therapy of the Glaucomas. Mosby, St. Louis, 22–46, 2009”. Right panel from Johnstone Glaucoma Lab, University of Washington.
Fig. 26.
Fig. 26.. Elastic energy equilibrium: Focal point for vascular homeostasis.
During differentiation, each cell type establishes unique, evolutionally optimized cellular stresses that determine internal structure and responses to external stimuli. The stresses establish and define an optimized elastic energy setpoint or equilibrium (Section 5.). The elastic energy setpoint provides a governing framework for the way the twin sensory stimuli of cellular deformation and shear stress interact, thus coordinating mechanotransduction events that maintain homeostasis. (A) Vascular endothelial cells sense changes in their lumen volume by force-induced deformation of their shape; (B) the same cells sense flow changes by monitoring shear stress on their walls. The aqueous outflow system behavior illustrates how cell deformation and shear stress provide feedback loops in the vasculature that maintain volume and flow homeostasis. Increased pressure induces instantaneous increases in cellular deformation that act as a sensory signal. Cellular deformation or strain causes the cell membrane, cytoskeletal elements, organelles, nuclear membrane, nuclear intermediate filaments, and attached chromatin to all alter their configuration. Cell and tissue constituents respond to the signal by adjusting the tissue and cellular elastance. The altered elastance restores the elastic energy equilibrium that ensures appropriate tissue distension and recoil. Shear stress detects flow. With a constant volume flowing through a vessel, narrowing of the lumen increases flow, resulting in higher shear stress; the increase initiates responses in cells, contiguous extracellular matrix, and muscle in the vessel walls that lead to enlargement of the lumen. Lumen enlargement restores the lumen dimensions and linked shear stress to an equilibrium. Volume changes that induce cell wall deformation and shear responses work in unison to achieve the same homeostatic cell and vessel wall endpoint. From Johnstone Glaucoma Lab, University of Washington, Adapted from Johnstone M, The aqueous outflow system as a mechanical pump: J Glaucoma 13, 421–438.
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