After decades of trabeculectomy and tubes, glaucoma surgical options have dramatically increased with minimally invasive glaucoma surgery (MIGS). Most MIGS are constrained, however, to only trabecular interventions as an adjunct to cataract surgery, as their effect is boosted by the intraocular pressure (IOP) lowering effect of phacoemulsification.¹ In standalone glaucoma surgical interventions, where advanced glaucoma is addressed and the intraocular surgical risk is independent of cataract surgery, trabecular MIGS are rarely used due to their limited IOP lowering potential. A surgical procedure that could provide a safety profile permitting combination with phacoemulsifcation and have a robust IOP effect to justify standalone interventions could expand the current MIGS surgical paradigm. Perhaps this could be achieved by unlocking the potential of another route of outflow: the uveoscleral/suprachoroidal pathway. Until recently, surgical access to this space has remained elusive.

The supraciliary and suprachoroidal (SC) spaces form a continuum within a potential space. The supraciliary space is an anterior physiologic route for aqueous humor outflow between the outer surface of the ciliary body and the internal surface of the sclera. It continues posteriorly into the SC space, which extends toward the pars plana and posteriorly.^2,3 The SC space has 2 key physiologic attributes that are distinctly advantageous for aqueous outflow. First, the colloid osmotic pressure gradient created by the 3-fold higher concentration of albumin in the plasma compared to the choriocapillaris promotes fluid outflow from the SC space. Studies have revealed outflow via the SC space to be 1.1 to 1.5 μL/min and scleral outflow to be 4.3 μL/min, demonstrating a natural direction of fluid egress from the eye. Secondly, there is a downward gradient of hydrostatic pressure from the anterior segment to the posterior segment. The fluid from the anterior chamber (AC) is pulled via the supraciliary space toward the SC space, which has lower hydrostatic pressure, after which it exits the eye.⁴ For these reasons, the supraciliary and SC spaces have garnered interest as possible targets for new glaucoma drainage devices.

CyPass

The first-generation SC implantable MIGS device to go through clinical development, pivotal studies, FDA approval, and market launch was the CyPass Glaucoma Micro-Stent (Alcon). Other technologies have been developed, but none were appropriate for ab interno MIGS classification. CyPass is a polyimide implant that received CE mark in 2008 and FDA approval in 2016. It proved that IOP could be lowered in a sustained manner by increasing outflow and shunting aqueous to the SC space without need for a bleb or conjunctival dissection, and this was achieved with an ab interno approach through a clear corneal incision.^5,6 The device was approved in conjunction with phacoemulsification.

CyPass is a fenestrated biocompatible polyimide microstent that is 6.35 mm long, with an inner diameter of 300 μm and outer diameter of 510 μm. When properly implanted, CyPass was intended to allow outflow of aqueous from the AC through and around the fenestrated lumen and distal end of the tube into the SC space via the uveoscleral pathway. It was deployed in the supraciliary space and had retention features for postimplantation stability. The stent was designed to create a durable and augmented outflow pathway for SC drainage.⁷

The COMPASS trial, a randomized, multicenter study conducted at 24 US sites, demonstrated the effectiveness of the device in lowering IOP in combination with phacoemulsification. At 2 years, 77% of patients had at least a 20% lower unmedicated IOP compared with 60% of controls. In addition, 85% of patients remained unmedicated after 24 months.⁷ These data were pivotal for the device’s FDA approval.

The long-term COMPASS XT safety study enrolled 480 patients who completed the COMPASS trial and followed them for up to 60 months. Patients were distributed in an almost 4-to-1 ratio between microstent and control, respectively. A total of 253 patients completed the COMPASS XT trial. After 48 months, it was found that the endothelial cell density (ECD) in the CyPass group continued to decline compared to the stable ECD in the phaco-only group. After 60 months, 27.2% of patients experienced an ECD loss of >30%, in contrast to 10.0% of patients in the control group, with the majority of the loss attributable to anteriorized hardware whose vertical orientation, proximity, and angle of impact to the corneal endothelium led to the persistent endothelial erosion.^8,9 The CyPass device was subsequently voluntarily recalled by the manufacturer from the market in 2018, removing access to the only commercially available SC MIGS device.^10,11 Despite the ECD loss and recall, there were no reports of corneal transplantation due to the device.⁹ Although the CyPass recall exposed challenges to SC surgery, the surgical experience and outcomes were otherwise favorable and highly appreciated by surgeons who saw the benefit of SC access.

iStent Supra

Following in the footsteps of CyPass was the iStent Supra (Glaukos). The iStent Supra was similarly designed for ab interno placement into the SC space to increase aqueous outflow via the uveoscleral pathway. Each iStent Supra came preloaded on a single-use inserter, much like the CyPass. Unlike the CyPass, however, it was slightly shorter at 4 mm in length and made of polyethersulfone and titanium, with a heparin-coated lumen roughly 165 µm in diameter.¹²

The device received CE Mark in Europe in 2010. In a study of 42 patients with open-angle glaucoma on 2 medications with a preoperative IOP of 20.4±2.4 mmHg, 98% achieved a 20% IOP decrease and reduction of 1 medication after 12 months combined with postoperative travoprost administration.¹³

In a later prospective study, 80 patients with refractory open-angle glaucoma, defined as IOP ≥18 mmHg after trabeculectomy and concomitant use of 1 to 3 IOP-lowering medications, received 2 iStent trabecular microbypass stents, 1 iStent Supra SC stent, and travoprost postoperatively. The study showed promising results. In patients who did not receive additional medications or surgeries, such as cataract extraction, 91% had an IOP lowering of >20% over 4 years. There were cases of transient hypotony, which resolved, as well as incidence of cataract. No data were reported for ECD.¹² Limited recent data exist on the Supra. The pivotal FDA investigational device exemption trial is listed as “complete” on ClinicalTrials.gov as of 2020, but no results have been published or reported on the site.¹⁴

MINIject

The second-generation flexible MINIject SC stent (iSTAR Medical) is a supraciliary MIGS drainage device that consists of approximately 200,000 interconnected, hollow spheres. It is implanted via an ab interno approach to reestablish the alternate physiologic SC drainage pathway. The device is made of porous flexible implant-grade silicone and is of significantly larger cross-section than other stents, measuring 1,100 µm by 600 µm with a length of 5 mm.¹⁵ The company claims that the silicone porosity allows for a natural flow of aqueous humor and no CyPass-like lumen is necessary for long-term drainage efficacy. The material is also designed to conform to the eye’s anatomy and integrate with surrounding tissue to ensure the device remains in place and functions effectively.¹⁶

Similarly to CyPass, implantation uses a clear corneal ab interno approach, but unlike CyPass, deployment is achieved with a sleeve rather than a guidewire.¹⁶ In a study of standalone implantation, the device was successfully deployed in 29 eyes. Twelve months after implantation, MINIject lowered IOP by 38% and decreased the number of medications needed.¹⁷

Unlike the CyPass and iStent Supra, there are no retention rings to prevent anterior migration. However, in the study, the implants remained stable in their location with no migration after 12 months. So far, no migration has been documented, although only a maximum of 2-year follow-up has been reported,¹⁷ in contrast to the 5 years of the COMPASS XT trial. The MINIject device received CE approval in late 2021 and is in an FDA premarket approval study. Future trials may explore its use in combination with cataract surgery and in more advanced cases.¹⁸

CycloPen

A new entry into the next generation SC interventional space is the CycloPen cyclodialysis system (Iantrek, Inc). It is designed for the ab interno construction of a cyclodialysis cleft followed by allograft scleral biotissue reinforcement to maintain the cleft and aqueous outflow. No extrinsic hardware is used, only homologous allograft tissue, which is native to the supraciliary space. It is highly permeable,¹⁹ flexible, and conforming to the endoscleral wall, and it has a low fibrotic index — these are all important attributes to minimize fibrosis and local tissue reaction.^20-22 In addition, the lack of rigid protruding hardware is a critical feature concerning ECD loss. The CycloPen cyclodialysis system provides a streamlined surgical deployment using a microincisional depth-controlled ab-interno approach.

Twelve-month data on the novel MIGS approach were recently published in the British Journal of Ophthalmology with early results showing a 40% IOP lowering from baseline into the low to mid teens with no serious adverse events. The IOP lowering may be greater, because the cohort of patients in this study had on average the same medicated mean IOP as the unmedicated mean IOP of studies from similar SC technologies. The study demonstrated ECD stability as well, with the same expected 11% ECD loss of phaco-MIGS combination surgery seen in other devices in the MIGS space.^23-25 Study results also revealed a reduced ocular hypotensive medication dependence, no cases of hypotony or increased IOP postoperatively, and excellent visual outcomes.²³ Iantrek is pursuing further testing.

CID

Multiple SC technologies have been tried, and more still are in development, even targeting the SC space from different approaches. Although most novel MIGS have an ab interno approach, Ciliatech has developed the Cilio-Scleral Inter-positioning Device (CID), which has an implantation technique more like a traditional ab externo surgery. It is a one-piece 26% hydrophilic acrylic plate that is 6 mm long, 4 mm wide, and 200 µm thick. The device is stated to improve outflow from the AC without entering the chamber itself.²⁶ The procedure involves incisions in the conjunctiva, tenons, and 2 radial full-thickness scleral incisions into the SC space. The space is expanded with viscoelastic, and the CID plate is pulled inside via the full-thickness scleral incisions until it is seated subsclerally. The incisions are then sutured closed.²⁷

Some purported benefits are no ECD loss (because it does not enter the AC), no bleb, and the potential to treat patients with narrow-angle glaucoma. Preliminary internal unpublished data reveal that after 24 months 85% of patients were using 0.3 medications from a baseline of 1.7, and 79% of patients had an IOP of ≤18 mmHg. These findings appear to be from 14 patients who were followed for 24 months and are the result of a combination of data from studies (SAFARI 1 and SAFARI 2) including 1 and 2 device implants, respectively.²⁶ Ciliatech aims to obtain CE marking and FDA approval for this technology by 2025.²⁸

Conclusion

The SC space has been an area of interest since 1868 when Knapp observed cyclodialysis cleft formation during cataract surgery²⁹ and in 1900 when Fuchs described it as a possible pressure-dependent pathway.³⁰ There have been numerous attempts at developing this additional outflow pathway in the past, and while some devices, like CyPass, came close, the field of glaucoma is now entering an age where SC outflow may finally be realized as a long-term viable option for patients with glaucoma. GP

Gautam Kamthan, MD, is an assistant professor of ophthalmology at the New York Eye and Ear Infirmary and Icahn School of Medicine of Mount Sinai. He is also the assistant director of ophthalmic innovation and technology and the associate director for cataract surgical training at the New York Eye and Ear Infirmary of Mount Sinai. He is the medical director of Iantrek, Inc. Reach Dr. Kamthan at gautamkamthanmd@gmail.com.

Sean Ianchulev, MD, MPH, is a professor of ophthalmology at the New York Eye and Ear Infirmary and Icahn School of Medicine of Mount Sinai, and director of ophthalmic innovation and technology at the New York Eye and Ear Infirmary of Mount Sinai. He reports he is the founder and inventor of Iantrek, Inc.

References

1. Mansberger SL, Gordon MO, Jampel H, et al. Reduction in intraocular pressure after cataract extraction: the Ocular Hypertension Treatment Study. Ophthalmology. 2012;119(9):1826-1831. doi:10.1016/j.ophtha.2012.02.050
2. Emi K, Pederson JE, Toris CB. Hydrostatic pressure of the suprachoroidal space. Invest Ophthalmol Vis Sci. 1989;30(2):233-238.
3. Alm A, Nilsson SF. Uveoscleral outflow — a review. Exp Eye Res. 2009;88(4):760-768. doi:10.1016/j.exer.2008.12.012
4. Figus M, Posarelli C, Passani A, et al. The supraciliary space as a suitable pathway for glaucoma surgery: Ho-hum or home run? Surv Ophthalmol. 2017;62(6):828-837. doi:10.1016/j.survophthal.2017.05.002
5. Hoeh H, Vold SD, Ahmed IK, et al. Initial clinical experience with the CyPass Micro-Stent: safety and surgical outcomes of a novel supraciliary microstent. J Glaucoma. 2016;25(1):106-112. doi:10.1097/IJG.0000000000000134
6. Hoeh H, Ahmed II, Grisanti S, et al. Early postoperative safety and surgical outcomes after implantation of a suprachoroidal micro-stent for the treatment of open-angle glaucoma concomitant with cataract surgery. J Cataract Refract Surg. 2013;39(3):431-437. doi:10.1016/j.jcrs.2012.10.040
7. Vold S, Ahmed II, Craven ER, et al. Two-year COMPASS trial results: supraciliary microstenting with phacoemulsification in patients with open-angle glaucoma and cataracts. Ophthalmology. 2016;123(10):2103-2112. doi:10.1016/j.ophtha.2016.06.032
8. Reiss G, Clifford B, Vold S, et al. Safety and effectiveness of CyPass Supraciliary Micro-Stent in primary open-angle glaucoma: 5-year results from the COMPASS XT study. Am J Ophthalmol. 2019;208:219-225. doi:10.1016/j.ajo.2019.07.015
9. Lass JH, Benetz BA, He J, et al. Corneal endothelial cell loss and morphometric changes 5 years after phacoemulsification with or without CyPass Micro-Stent. Am J Ophthalmol. 2019;208:211-218. doi:10.1016/j.ajo.2019.07.016
10. Griswold A. Alcon's voluntarily withdrawal of the CyPass microstent updated to class 1 recall. American Academy of Ophthalmology. December 3, 2018. Accessed February 26, 2023. https://www.aao.org/education/headline/recall-cypass-microstent-withdrawn-amid-concerns
11. ASCRS CyPass Withdrawal Task Force. Cypass withdrawl. September 28, 2018. Accessed April 27, 2023. https://ascrs.org/news/ascrs-news/cypass-withdrawl
12. Myers JS, Masood I, Hornbeak DM, et al. Prospective evaluation of two iStent trabecular stents, one iStent Supra suprachoroidal stent, and postoperative prostaglandin in refractory glaucoma: 4-year outcomes. Adv Ther. 2018;35(3):395-407. doi:10.1007/s12325-018-0666-4
13. Kammer JA, Mundy KM. Suprachoroidal devices in glaucoma surgery. Middle East Afr J Ophthalmol. 2015;22(1):45-52. doi:10.4103/0974-9233.148348
14. Multicenter investigation of the Glaukos suprachoroidal stent model G3 in conjunction with cataract surgery. ClinicalTrials.Gov identifier: NCT01461278. Updated May 19, 2022. Accessed April 27, 2023. https://clinicaltrials.gov/ct2/show/study/NCT01461278
15. Elhusseiny AM, Abdelnaem S, Aref AA, et al. Suprachoroidal devices. December 25, 2022. Accessed April 28, 2023. https://eyewiki.aao.org/Suprachoroidal_Devices#Design_6
16. iSTAR Medical. MINIject MIGS. Accessed February 23, 2023. https://www.istar-medical.com/treatments/miniject-migs/
17. Denis P, Hirneiß C, Durr GM, et al. Two-year outcomes of the MINIject drainage system for uncontrolled glaucoma from the STAR-I first-in-human trial. Br J Ophthalmol. 2022;106(1):65-70. doi:10.1136/bjophthalmol-2020-316888
18. AbbVie. AbbVie and iStar Medical announce strategic alliance for treatment of glaucoma. January 7, 2020. Accessed April 28, 2023. https://news.abbvie.com/news/press-releases/abbvie-and-istar-medical-announce-strategic-alliance-for-treatment-glaucoma.htm .
19. Prausnitz MR, Noonan JS. Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87(12):1479-1488. doi:10.1021/js9802594
20. Blakney AK, Swartzlander MD, Bryant SJ. The effects of substrate stiffness on the in vitro activation of macrophages and in vivo host response to poly(ethylene glycol)-based hydrogels. J Biomed Mater Res A. 2012;100(6):1375-1386. doi:10.1002/jbm.a.34104
21. Ayyala RS, Michelini-Norris B, Flores A, Haller E, Margo CE. Comparison of different biomaterials for glaucoma drainage devices: part 2. Arch Ophthalmol. 2000;118(8):1081-1084. doi:10.1001/archopht.118.8.1081
22. Carnicer-Lombarte A, Chen ST, Malliaras GG, Barone DG. Foreign body reaction to implanted biomaterials and its impact in nerve neuroprosthetics. Front Bioeng Biotechnol. 2021;9:622524. doi:10.3389/fbioe.2021.622524
23. Ianchulev T, Weinreb RN, Kamthan G, Calvo E, Pamnani R, Ahmed IK. Biotissue stent for supraciliary outflow in open-angle glaucoma patients: surgical procedure and first clinical results of an aqueous drainage biostent. Br J Ophthalmol. 2023;bjo-2022-322536. doi:10.1136/bjo-2022-322536
24. Fea AM, Consolandi G, Pignata G, et al. A comparison of endothelial cell loss in combined cataract and MIGS (Hydrus) procedure to phacoemulsification alone: 6-month results. J Ophthalmol. 2015;2015:769289. doi:10.1155/2015/769289
25. Arriola-Villalobos P, Martínez-de-la-Casa JM, Díaz-Valle D, et al. Mid-term evaluation of the new Glaukos iStent with phacoemulsification in coexistent open-angle glaucoma or ocular hypertension and cataract. Br J Ophthalmol. 2013;97(10):1250-1255. doi:10.1136/bjophthalmol-2012-302394
26. Ciliatech. Ciliatech — transforming glaucoma surgery. Accessed April 25, 2023. https://www.cilia.tech/
27. Ciliatech. Ciliatech implant glaucoma. September 1, 2022. Accessed April 27, 2023. https://vimeo.com/user184304869
28. Ciliatech presents new concept in glaucoma implants first to bypass opening anterior eye chamber. November 4, 2020. Accessed February 23, 2023. https://eyewire.news/news/ciliatech-presents-new-concept-in-glaucoma-implants-first-to-bypass-opening-anterior-eye-chamber
29. Rycroft BW. Choroidal detachment. Br J Ophthalmol. 1943;27(7):283-291. doi:10.1136/bjo.27.7.283
30. Fuchs E. Ableosung der aderhaut nach staaroperation. Albrecht Von Graefes Arch Ophthalmol. 1900;51:199e224