Introduction

Glaucoma is the leading cause of irreversible blindness in the United States and worldwide, with primary open-angle glaucoma (POAG) the most common subtype, affecting an estimated 80 million individuals [1]. Despite more than a century of research, intraocular pressure (IOP, pressure exerted from within the eye) remains the only modifiable risk factor demonstrated to slow or stop disease progression. Therefore all glaucoma treatments, whether medical or surgical, aim to reduce IOP — mainly by either reducing aqueous humor production or enhancing aqueous drainage via the uveoscleral or trabecular outflow pathways [2]. Reducing IOP alleviates tension on the optic nerve head (ONH) and slows or stops the progressive neurological degeneration responsible for progressive and permanent vision loss.

Surgical access to the uveoscleral pathway was first introduced in 1905 by Heine with the development of the cyclodialysis procedure, which creates a supraciliary conduit for internal aqueous drainage [3]. Although cyclodialysis was a mainstay surgical technique for many years, it was eventually replaced by trabeculectomy and trans-scleral aqueous drainage implants, which provided more predictable and durable results [4].

Recent advances in surgical instrumentation and implantable materials, have led to a resurgence of uveoscleral-based surgical approaches [3]. One method for enhancing aqueous outflow involves supraciliary drainage devices for internal stenting and sustained outflow support, though they carry the drawbacks of implantable foreign intraocular hardware. More recently, hardware-free methods, such as the bio-interventional cyclodialysis technique originally described by Ianchulev et al.[5], have emerged as more bio-compatible alternatives. This approach combines a micro-interventional ab-interno cyclodialysis with reinforcement using a micro-trephined allogeneic bio-scaffold. The bio-tissue stabilizes the filtration cleft and supports sustained uveoscleral outflow [6–8].

This study provides 12-month real-world evidence evaluating the hypothesis that standalone bio-interventional cyclodialysis, followed by cleft reinforcement with acellular allogenic scleral tissue for IOP reduction in eyes with OAG inadequately controlled on medical therapy, including those with prior glaucoma procedures, would lower IOP safety and durably. Safety reporting from this study confirms the compatibility of the world’s first acellular scleral allograft implant, contributing favorable data for future investigations of extracellular matrix (ECM) biomaterials.

Materials and methods

Participants

Recruitment started on 08/17/2022 and was planned to end on 12/31/2025. Participants were recruited within each investigator’s clinical practice or via the investigator’s referral network. All eyes in this analysis had investigator-confirmed OAG with open-angle gonioscopy findings and evidence of glaucomatous optic neuropathy, with or without visual field defects. Most eyes had previously undergone ocular surgery for cataract or glaucoma and were inadequately controlled on medical therapy. A CONSORT Diagram is provided in Fig 1.

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Fig 1. CONSORT 2025 flow diagram.

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Procedure

Following administration of topical anesthesia with optional intracameral lidocaine, sub-tenon, or peribulbar block, gonioscopic visualization of the angle was obtained. A 2 mm temporal corneal incision and subsequent 1.5 mm paracentesis is performed for ab-interno access, followed by stabilization of the anterior chamber (AC) with viscoelastic.

The cyclodialysis procedure is performed using a microsurgical cyclodialysis cannula (CycloPen, Iantrek, Inc, White Plains, New York, USA). A 1–2 clock-hour cyclodialysis cleft is created by carefully disinserting the ciliary body from the scleral spur. Viscocycloplasty (augmentation of the cleft with viscoelastic) is then performed to expand the supraciliary filtration reservoir.

The scleral reinforcement procedure is subsequently performed using micro-trephined processed allogeneic bio-tissue (AlloFlo, Iantrek, Inc, White Plains, New York, USA). An elongated 5 mm x 500-micron acellular scleral allograft bio-scaffolding construct is prepared and introduced into the AC under gonio-visualization (Figs 2 and 3). The reinforcing spacers are deployed at the endoscleral surface bilaterally and adjacent to the edges of the cyclodialysis. The treating surgeon has discretion to use either one or two allograft spacers, depending on patient physiology. Components do not protrude into the AC, and AC-clear placement is confirmed under direct visualization with the bio-tissue spacers deployed “flush” with the iris root. Any residual viscoelastic is evacuated with irrigation or irrigation/aspiration. Patients were prescribed a surgeon’s choice of postoperative regimen of topical antibiotics and corticosteroids.

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Fig 2. Placement of allograft cleft reinforcement.

(Top) Bio-interventional cyclodialysis with the allograft spacer fully deployed to maintain a durable uveoscleral outflow conduit. (Lower-left) processed micro-trephined scleral bio-scaffold made of porous, acellular, hydrophilic, collagenouc sterile matrix. (Lower-right) Sleeved interventional deployment with a cyclodialysis cannula. Reprinted from Iantrek, Inc. under a CC BY license, with permission from Iantrek, original copyright 2024.

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Fig 3. In-situ images of allogenic implant.

Clockwise from upper-left: (1) Gonioscopy view of the allogenic bio-spacer during intraocular implantation. (2) Post-implantation 90-day corneal optical coherence tomography (OCT) section of the cyclodialysis with the in-situ allograft reinforcement demonstrating the homologous biologic nature of the tissue in lieu of conventional implantable hardware. (3) Post-implantation 90-day longitudinal OCT imaging of the uveoscleral outflow enhancing bio-scaffold designed to maintain a durable aqueous conduit and filtration reservoir and prevent re-stenosis of the cyclodialysis. (4) External transluminating image demonstrating the visible allograft spacers with the additive reinforcement at 90 days after the procedure. Reprinted from Iantrek, Inc. under a CC BY license, with permission from Iantrek, original copyright 2024.

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Results

Patient demographics and baseline disease characteristics

A total of 41 eyes in 38 patients underwent the standalone uveoscleral outflow procedure with 12-month postoperative follow-up (Table 1). Most eyes (66%) were considered refractory because they had uncontrolled IOP despite maximally tolerated medication therapy (MTMT) or previous incisional surgery or cilioablative procedure. Additionally, most eyes had undergone at least one prior glaucoma procedure: 37% had prior trabecular MIGS, 37% had prior SLT, and 27% had prior incisional glaucoma surgery (e.g., tube shunt, trabeculectomy, gel stent, or cyclophotocoagulation). Among the four eyes classified as having secondary open-angle glaucoma, two had pigmentary glaucoma, one had pseudoexfoliation glaucoma, and one had glaucoma associated with prior ocular trauma. The single eye classified as having angle closure glaucoma was pseudophakic at baseline with a patent laser peripheral iridotomy; the angle was adequately visualized gonioscopically at the time of surgery, no peripheral anterior synechiae required synechiolysis, and no intraoperative modification of the standard technique was needed. This eye had severe baseline visual field loss (mean deviation −18.2 dB) and best corrected distance visual acuity (BCDVA) of 20/20 at baseline. Because CREST Cohort 2 includes only eyes that underwent standalone cyclodialysis, most already were pseudophakic and had received cataract surgery prior to the study procedure: only 1 eye (2.4%) was phakic, and in 2 eyes (4.9%) preoperative lens status was not recorded. The rest (38 [92.3%]) were pseudophakic at baseline. The mean (± SD) baseline IOP was 21.6 ± 5.0 mmHg with 2.8 ± 1.3 glaucoma medications.

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Table 1. Patient demographics and baseline disease characteristics.

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IOP and medication outcomes

At 12 months after the study procedure, eyes had a 31% reduction in mean IOP, reduced from a mean (± SD) of 21.6 ± 5.0 mmHg at baseline to 14.7 ± 6.9 mmHg (p < 0.001; Table 2). Eyes also had a 32% reduction in glaucoma medications, reduced from a mean (± SD) of 2.8 ± 1.3 agents at baseline to 1.9 ± 1.6 (p < 0.001). Importantly, 71% of eyes had a clinically relevant (≥ 20%) IOP reduction from baseline (a clinically meaningful benchmark established by the FDA as an endpoint in glaucoma device clinical trials [9]), and approximately half of eyes (53%) achieved this target without increasing medication.

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Table 2. Effectiveness outcomes.

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Because the standard deviation of the mean IOP change was of similar magnitude to the mean, distributional statistics are also reported. The median IOP change from baseline to 12 months was −6.0 mmHg (interquartile range [IQR] −9.0 to −1.0 mmHg); the median percentage change in IOP within individual eyes was −26% (IQR −39% to −9%). Among the 29 eyes with both baseline and 12-month medication counts recorded, 12 (41.4%) had a net decrease in medication burden, 12 (41.4%) had no change, and 5 (17.2%) had an increase. The median medication count in these eyes was 3 (IQR 2–4; range 1–5) at baseline and 2 (IQR 1–3; range 1–5) at 12 months, for a median within-eye change of 0 medications (IQR −2–0; range −3 to +2). Results were consistent in a prespecified sensitivity analysis restricted to one study eye per patient (N = 38 eyes): mean IOP decreased from 21.5 ± 5.8 mmHg at baseline to 15.1 ± 4.9 mmHg at 12 months (mean change −6.0 ± 6.3 mmHg, p < 0.001), with 67% of eyes (24/36) achieving a ≥ 20% IOP reduction.

Corrected distance visual acuity was maintained or improved through 12 months of follow-up. Mean logMAR CDVA was 0.30 at baseline (approximately Snellen 20/40; median 0.18 [20/30]; N = 35), 0.27 at 1 month (N = 35), 0.21 at 6 months (N = 26), and 0.16 at 12 months (approximately Snellen 20/29; median 0.10 [20/25]; N = 33). The proportion of eyes with CDVA of 20/40 or better increased from 51% (18/35) at baseline to 60% (21/35) at 1 month, 73% (19/26) at 6 months, and 79% (26/33) at 12 months. Among the 29 eyes with paired baseline and 12-month measurements, CDVA was stable (within ± 0.1 logMAR, corresponding to approximately one Snellen line) in 15 eyes (52%), improved by ≥ 2 Snellen lines in 8 eyes (28%), and decreased by ≥ 2 Snellen lines in 2 eyes (7%); the mean change in logMAR within individual eyes was statistically significant (p = 0.04, paired two tailed test).

IOP reductions were consistent among eyes that had undergone trabecular MIGS or SLT prior to uveoscleral outflow enhancement and cleft reinforcement (Table 3). In eyes with prior MIGS (N = 10), mean (± SD) IOP decreased 6.5 mmHg (from 21.3 ± 2.9 mmHg at baseline to 14.4 ± 0.8 mmHg). In eyes with prior SLT (N = 11), mean (± SD) IOP decreased 6.1 mmHg (from 21.3 ± 5.2 mmHg at baseline to 14.8 ± 4.9 mmHg.

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Table 3. Effectiveness outcomes by prior procedure.

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Safety outcomes

The procedure demonstrated a favorable safety profile, with no reported cases of device migration, no persistent or severe postoperative inflammation, no adverse events related to the allogenic bio-scaffold, no implant rejection, and no hyphema or vision-threatening complications (Table 4). There was a single case of same-day anteriorization of the implant, which was also seen on postoperative day 1 and subsequently corrected with proper deployment and good postoperative stability.

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Table 4. Post-surgical safety.

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The need for subsequent incisional glaucoma surgery was low: only 3 eyes (7.3%) required incisional surgery through the 12-month follow-up, all due to inadequate IOP control, which included one patient whose IOP increased ≥ 10 mmHg from baseline. A Kaplan-Meier analysis estimated the 12-month probability of surgical success as 26.1% (95% CI: 13.1%, 41.2%; Fig 4). No subsequent surgeries were due to complications of the index procedure. There were no reports of clinically significant hypotony; the two transient episodes of IOP < 6 mmHg were mild and asymptomatic, with no associated anterior chamber shallowing, choroidal effusion, maculopathy, or visual disturbance, and both resolved spontaneously without medical or surgical intervention. The single case of visual field worsening occurred in an eye with well controlled postoperative IOP and was attributed by the treating investigator to progression of baseline glaucomatous optic neuropathy rather than to the study device or procedure. Postoperative IOP elevation ≥ 10 mmHg from baseline occurred in 7 eyes (17%), most of which (4 of 7) occurred within 30 days of the procedure and resolved spontaneously with conservative medical therapy, no requiring incisional surgery. One of these eyes received subsequent SLT on Day 44. The other three cases occurred > 90 days after surgery — one did not lead to subsequent surgery, one led one led to ciliary body ablation at Month 3, and one led to implantation of a tube shunt at Month 12.

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Fig 4. Kaplan-Meier estimate of surgery-free survival after index procedure.

Note: The curve displays the cumulative probability that an eye remained free of subsequent incisional glaucoma surgery (e.g., tube shunt, trabeculectomy, gel stent, or cyclophotocoagulation) among the 41 treated eyes. 100% of eyes remained free of subsequent surgery through 6 months, 97% at 229 days, 94% at 359 days, and 91% at the end of follow-up (388 days). All 41 treated eyes contributed follow-up time to the analysis; eyes lost to follow-up prior to an incisional surgery event were censored at the date of their last available postoperative visit; tick marks indicate censoring events.

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Discussion

This study results demonstrate statistically significant and clinically meaningful IOP lowering after standalone bio-interventional uveoscleral outflow enhancement in patients who are inadequately controlled with topical medication therapy, previous glaucoma procedures, or both. Reduction in mean IOP and number of IOP lowering medications was immediate and sustained over the entire 12-month follow-up period across primary and secondary efficacy outcomes. As a standalone treatment, allograft-reinforced cyclodialysis achieves a clinically meaningful and durable augmentation of uveoscleral outflow with a favorable interventional risk-benefit profile, significantly reducing the need for more invasive, bleb-forming surgeries (e.g., trabeculectomy and tubes).

The magnitude of IOP reduction was notable: 31% mean IOP reduction with 82% of eyes achieving responder status through 12 months. Moreover, the need for escalation to filtering or tube-based procedures was significantly reduced. While 66% of eyes were surgical candidates at baseline due to uncontrolled IOP on maximal medical therapy, only 7.2% required further incisional intervention through the 12-month follow-up. In addition, nearly 80% of eyes achieved IOP control (defined as < 21 mmHg) without increasing medications.

These findings are consistent with prior reports of bio-interventional cyclodialysis performed in combination with cataract surgery. However, the present study isolates the IOP-lowering effects of the procedure alone, eliminating the confounding hypotensive effect of phacoemulsification after cataract surgery, as described in previous reports. The results also parallel those of other uveoscleral-targeting approaches, such as suprachoroidal stents, which have demonstrated high drainage potential and sustained efficacy.

These results of bio-interventional uveoscleral outflow enhancement compare favorably with published results of stented trabecular outflow enhancement with iStent and Hydrus in stand-alone cases [10]. In the COMPARE standalone trial, there was only 1.1 and 1.7 mmHg IOP reduction from medicated baseline for iStent and Hydrus at 12 months, respectively, compared to 6.7 mmHg with the uveoscleral outflow procedure. Change in mean IOP lowering medication burden at 12 months was 1.0 and 1.6 for iStent and Hydrus, respectively, compared to 1.0 for the uveoscleral procedure — from similar pre-operative baselines of 2.5–2.7 medications.

The rate of secondary incisional surgery in the COMPARE trial was 2.6% in the iStent group, compared with 7.2% in the CREST cohort. CREST enrolled a population with higher baseline treatment burden than COMPARE, with a baseline medicated IOP of 21.6 mmHg versus 19.1 mmHg and a higher proportion of eyes with prior glaucoma surgery; however, visual field mean deviation was not reported for the COMPARE cohort, so a direct comparison of glaucomatous disease severity by perimetric criteria is not possible and the two populations should be compared with this caveat in mind.

Furthermore, uveoscleral outflow enhancement results compare favorably with the iStent infinite trial where three iStents are implanted in patients with advanced OAG [11]. There was a mean IOP reduction of 5.5 mmHg at 12 months from a medicated baseline of 23.5 mmHg compared to the reduction in this cohort of 6.7 mmHg from a medicated baseline of 21.6 mmHg. The rate of secondary surgical intervention for IOP control in the iStent study was 4.2%.

Overall, the safety of newer interventional procedures for uveoscleral outflow enhancement seems to be closing the gap by demonstrating canal MIGS-like safety profile, while tapping the higher therapeutic index of the uveoscleral drainage pathway. This provides a natural next-generation technological advancement of the glaucoma interventional paradigm to raise the efficacy bar similar to the pharmacologic treatment parallel where uveoscleral outflow drugs represent the mainstay category with the highest efficacy. A recent meta-analysis confirms the surgical parallel of superior uveoscleral outflow biologic effect over trabecular outflow enhancement: at 24 months, there was a greater reduction in IOP from baseline in the uveoscleral interventional group vs trabecular stenting (two iStents; −9.57 vs. −4.92 mmHg, p = 0.03). The change from baseline in mean medication use was −1.00 medications with MINIject and −0.56 medications with iStent [12].

The clinical utility of uveoscleral intervention can be significant, as millions of glaucoma patients have already exhausted the canal interventional option with stents or goniotomy and canaloplasty and are facing waning efficacy with the prospects of highly invasive bleb-forming surgery. Uveoscleral intervention can open the second native/endogenous outflow pathway of higher outflow capacity to delay or diminish the need for more invasive bleb-based procedures, such as trabeculectomy or tubes. Currently, less than 10% of trabecular outflow canal-based MIGS procedures, such as iStent and Hydrus, are used for standalone glaucoma intervention outside being an adjunct to cataract surgery due to the limited efficacy of the trabecular outlow pathway. Even with three iStent implants, the Infinite pivotal trial reported only 23% IOP reduction (5.5 mmHg) using [13], whereas the single uveoscleral intervention in the present study demonstrated 32% reduction (6.7 mmHg).

Safety outcomes were favorable and consistent with those reported for other minimally invasive interventions. Only three eyes (7.2%) required subsequent incisional glaucoma intervention, and IOP spikes ≥ 10 mmHg occurred in only 17% of cases, predominantly during the postoperative steroid taper period. Given the known steroid sensitivity in up to one-third of glaucomatous eyes [14] these elevations were expected and largely manageable; nearly half resolved spontaneously without surgical or pharmacologic escalation. This incidence is comparable to rates reported for other procedures, including 17% with gonioscopy-assisted transluminal trabeculotomy (GATT), 21.5% with Xen Gel Stent, and 32% with trabeculotomy [15–17]. The postoperative safety results are not dissimilar to the standalone results reported with iStent Infinite, in which 22% of eyes had significant postoperative IOP increase and 11.1% underwent secondary glaucoma surgery [13].

No cases of scaffold migration, extrusion, or persistent tissue-related complications were observed. Mild hyphema occurred in only 4.9% of eyes, resolving spontaneously without clinical intervention. The favorable safety profile is likely attributable to the implant’s biologic, acellular composition and the intra-cleft deployment that avoids contact with the corneal endothelium. The collagenous matrix is engineered to mimic native scleral biomechanics while promoting aqueous permeability and minimizing inflammation, fibrosis, or immune reaction.

This study is one of the few to provide clinical outcomes from standalone interventional glaucoma treatment. Nevertheless, the study is limited in scope and duration with only 41 eyes and 12-month outcomes. The relatively small sample size limits subgroup analyses and generalizability. As a real-world evidence investigation, it reports true real-world effectiveness and safety, rather than effectiveness in a rigid and selective protocol design. Because of this, there is inherent variability in treatment and patient selection which captures the standard of care clinical paradigm. There was no prescribed medication re-introduction procedure and there was no medication wash-out. Post-surgical medication regimen was also non-standardized and physician specific. Because the enrolled cohort included multiple eyes from a small number of patients (three patients contributed both eyes), statistical inference at the eye level did not formally account for the correlation between fellow eyes in the same patient; given the small number of bilateral cases, the impact on the reported estimates is expected to be minimal, but this remains a limitation of the analysis. Endothelial cell density (ECD) was not required to be measured and is not assessed as part of routine glaucoma care; although no clinically apparent corneal decompensation was observed, the absence of quantitative ECD data is a safety data gap, and prospective ECD assessment is planned in future studies of the procedure. Dedicated anterior segment imaging for fibrosis, cleft remodeling, or supraciliary lake morphology at the 12 month visit was also not prespecified in the protocol and therefore is not reported.

While the study is real-world evidence, unlike passive retrospective registries, the postoperative follow-up was prospective, monitored, and consistent with Good Clinical Practice (GCP) where patients were consented, and investigators followed the investigational protocol for safety and efficacy outcomes. There was minimal attrition in patient follow-up, and the study was inclusive of a high-risk, real-world glaucoma population, including patients with prior failed surgical interventions.

Conclusions

Standalone bio-interventional cyclodialysis reinforced with an allogeneic scleral scaffold offers a safe and effective method for sustained IOP reduction in patients with open-angle glaucoma. The procedure may delay or reduce the need for more invasive filtering or tube surgeries, particularly in cases where prior trabecular MIGS have failed.

Supporting information