Carol Toris
Love your color-coded images. As we get older do you think that the SC septa might grow and start to get in the way of outflow? Do you see differences in SC morphology with aging?
Good questions. The collagenous septa may enlarge with age, but I am not aware that anyone has studied the issue. The septa’s ECM material likely develops an altered composition with age as occurs in vessel walls elsewhere. The composition change is likely to cause stiffening, reducing the ability to respond to pressure gradient changes, just as occurs in systemic vessels’ walls. Autopsies are uncommon now, so the older literature is probably the best source for exploring changes in the distal pathways. The work of Dvorak-Theobald and Teng and Paton shows marked alterations in the region of the septa and distal pathways in eyes with advanced glaucoma.
- Dvorak-Theobald, G., Kirk, H.Q., 1956. Aqueous pathways in some cases of glaucoma. Am J Ophthalmol 41, 11-21.
- Teng, C.C., Paton, R.T., Katim, H.M., 1955. Primary degeneration in the vicinity of the chamber angle; as an etiologic factor in wide-angle glaucoma. Am J Ophthalmol 40, 619-631.
- Chi, H.H., Katzin, H.M., Teng, C.C., 1957. Primary degeneration in the vicinity of the chamber angle; as an etiologic factor in wide-angle glaucoma. Ii. Am J Ophthalmol 43, 193-203.
John R. Samples
Do all the circumferential and radial channels have a similar relationship or do they vary i.e. some areas with a lot of radial channels and thick vascular endothelium and some that are thin? Do you always find a hinged flap or are there some ostia without them?
We have examined the canal’s circumference in several human eyes and two species of non-human primates using microvascular casting. Our impression is that the circumferential channels are consistently present with the radial channels regularly arising from the circumferential channels. We have not recognized differences in appearance in the different quadrants. These studies are difficult because slight changes in orientation of the tissue cause considerable variability in appearance. Because of the innate variability associated with orientation, it would require a relatively large number of eyes to characterize differences effectively, so the fact that we have not recognized differences does not mean that they are absent. We find hinged flaps consistently present at CC ostia when looking with the dissecting microscope, microvascular casting, SEM, and OCT. However, these relationships have been recently recognized, and the question needs further study. We cannot assess the endothelial thickness with microvascular casting and have not identified a difference with SEM.
Ross Ethier
Murray, great talk. Have you ever looked in a mouse eye and seen any similar structures? Also, how circumferentially uniform are these structures?
We have not looked at mouse eyes, but that is an excellent question. Orientation is key to recognizing the relationships because it is necessary to obtain a view perpendicular to the collector channels’ exit sites from the sclera. It would be great if someone explored the issue in mice with your question and the need to maintain appropriate orientation in mind. The question of circumferential uniformity is relevant from both a mechanistic and clinical standpoint. John Samples raised the subject as well. Please refer to my response to John’s question in the previous query related to the issue.
John R. Samples
In a few minutes we will hear from Janice on zonal perfusion changes. Do you think these structures you have shown have zonal variation?
As both you and Ross pointed out in your questions above, variation in location or character is an important issue both from a mechanistic and therapeutic standpoint. I understand your wish to emphasize the questions importance and I have attempted to provide an answer in your initial query listed above.
Susannah Waxman
Thank you for your talk! Have changes in collector channel motion been investigated in response to not only IOP, but pharmacological stimuli?
An excellent question. Your work showing dimension changes of the distal channels with nitric oxide agents makes the issue salient. We have not explored the effects of pharmacologic stimuli, but such experiments would be very informative, as your question implies. We obtain and immediately initiate experiments in non-human primate eyes in our laboratory setting. We have explored pharmacologic responses following pilocarpine exposure and have demonstrated the ciliary body, TM, and distal channels marked motion using videomicroscopy. From these observations, we know that the tissue retains its ability to respond to pharmacologic agents, so such studies should be feasible. We have the means to analyze the real-time movement of the distal outflow channels with agents such as nitric oxide donors and inhibitors with our ex vivo high-resolution OCT setup.
Shahinur Tayab
Which OCT device was used for the collector channel and trabecular meshwork?
The setup we use for the ex vivo work is a laboratory-developed system on an optical bench that uses SD-OCT with a probe facing the TM surface with a short working distance that provides high resolution.
We use reservoirs to control pressure in SC. By switching between reservoirs at two different heights, we can change SC pressures while monitoring TM and distal pathway configuration changes with OCT. A reference describing the OCT device and setup is below and is available on ResearchGate.
- Hariri, S., Johnstone, M., Jiang, Y., Padilla, S., Zhou, Z., Reif, R., Wang, R.K., 2014. Platform to investigate aqueous outflow system structure and pressure-dependent motion using high-resolution spectral domain optical coherence tomography. J Biomed Opt 19, 106013 1-10601311.
Shantha Balekudaru
Where are the majority of the collector channels located? Isn’t this important for I Stent surgery?
You are right; the location of the collector channels is an important consideration for MIGS surgery. Several studies have shown that the collector channels are relatively uniformly distributed around the Schlemm’s canal circumference. (See below) With the microvascular casting of the entire limbus, we also find relatively uniform distribution.
- Ashton N. Anatomical study of Schlemm’s canal and aqueousveins by means of neoprene casts. Part I. Aqueous veins. Br J Ophthalmol. 1951;35:291–303.
- Dvorak-Theobald G. Further studies on the canal of Schlemm. Its anastomoses and anatomic relations. Am J Ophthalmol. 1955;39:65–89.
- Rohen JW, Rentsch FJ. Uber den Bau des Schlemmschen Kanals und seiner AbfluBwege beim Menschen. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1968;176:309–329.
- Bentley, M.D., Hann, C.R., Fautsch, M.P., 2016. Anatomical variation of human collector channel orifices. Invest Ophthalmol Vis Sci 57, 1153-1159.
Thomas Read
Nice images Murray. I wonder about the composition of the septae, if they might have a muscular component?
Yes, it seems reasonable to consider the septa as having a muscular component that is a factor in modulation of flow. An endothelium with significant contractile properties lines the collector channel entrances and associated septa. In addition, there is smooth muscle in the adjacent walls of the lumen of these channels, as is illustrated by James Tan’s group’s work. Although IOP and tension from the TM appear to create a tensionally integrated mechanism to regulate flow, there are likely to be multiple interactive control mechanisms at play. The muscular component may well play an important role.
- Gonzalez, J.M., Ko, M.K., Hong, Y.-K., Weigert, R., Tan, J.C.H., 2017. Deep tissue analysis of distal aqueous drainage structures and contractile features. Scientific reports 7, 17071.
Sahil Thakur
As these hinge collagen valves are moving structures constantly near blood, do you think they undergo stiffening with aging and potential lipid and plaque deposition that hampers their function like valves in major vessels? Could potentially explain why POAG has association with CKD, HTN, CVD and possibly hyperlipidemia.
Yes, it seems likely that the distal moving collagen valves and septa undergo stiffening with age. As you point out, extensive cardiovascular physiology and biomechanics literature describes age-related stiffening of vessel walls. Since the outflow system’s distal pathways are an extension of the systemic vasculature, it seems reasonable to think the outflow system vasculature is subject to the same considerations as vessels elsewhere.
Shear stress needs to be maintained within a relatively narrow range to provide signals that optimize vessel wall properties. In the presence of abnormal shear stress, either too high or too low, there are alterations in signaling that lead to cytokine release, inflammatory changes, and overall vessel wall remodeling that can reduce lumen dimensions.
There is considerable evidence that the TM comes into chronic apposition with SC external wall in glaucoma, even herniating into collector channel entrances. Chronic apposition of the TM to SC outer wall will prevent flow that induces normal shear stress in the distal pathways.
If the distal outflow system vascular responds like vasculature elsewhere, we can expect eventual occlusion of collector channel entrances, the circumferential channels, and the distal radially oriented pathways. Such changes are well documented in advanced glaucoma by Dvorak-Theobald, Teng, and Chi.
- Dvorak-Theobald, G., Kirk, H.Q., 1956. Aqueous pathways in some cases of glaucoma. Am J Ophthalmol 41, 11-21.
- Teng, C.C., Paton, R.T., Katim, H.M., 1955. Primary degeneration in the vicinity of the chamber angle; as an etiologic factor in wide-angle glaucoma. Am J Ophthalmol 40, 619-631.
- Chi, H.H., Katzin, H.M., Teng, C.C., 1957. Primary degeneration in the vicinity of the chamber angle; as an etiologic factor in wide-angle glaucoma. II. Am J Ophthalmol 43, 193-203.