Suprachoroidal injection is a method of directly administering drugs into the suprachoroidal space (SCS), a potential space between the sclera and choroid. It enables precise and targeted drug delivery to the retina, retinal pigment epithelium (RPE), and choroid.
The SCS extends anteriorly near the scleral spur at the ciliary body and posteriorly to the optic nerve. Its thickness is estimated to be approximately 35 μm. Normally a thin space due to intraocular pressure, it can expand with fluid injection. Injected drugs move posteriorly via the uveoscleral outflow pathway. The compartmentalization of this space allows concentrated delivery to target tissues while minimizing contact with the anterior segment 1).
Suprachoroidal injection is a minimally invasive procedure that can be performed on an outpatient basis 1). Unlike subretinal injection, which requires vitrectomy, it is a simple procedure using a microneedle. A characteristic feature is the wide biodistribution of the injected agent; whereas subretinal injection is limited to the area around the bleb (localized retinal detachment), suprachoroidal injection allows the drug to reach a broad area of the eye 1).
Intravitreal injection administers the drug into the vitreous body, where the internal limiting membrane and vitreous structure act as barriers to drug delivery. Suprachoroidal injection can deliver the drug closer to the target tissue, and animal studies have shown up to 12 times greater delivery efficiency compared to intravitreal injection. Both procedures can be performed on an outpatient basis.
Suprachoroidal injection is a therapeutic procedure, not a disease itself. The only indication currently approved by the FDA is macular edema associated with non-infectious uveitis.
The main subjective symptoms of macular edema are as follows:
The PEACHTREE trial was a randomized, double-masked, sham-controlled study. The group that received suprachoroidal injection of triamcinolone acetonide (CLS-TA) at day 0 and week 12 showed significant improvement in macular edema and visual acuity compared to the sham group. At week 24, the proportion of patients with a gain of 15 or more letters in BCVA (best-corrected visual acuity) was 47% in the CLS-TA group.
The MAGNOLIA trial is a long-term extension of the PEACHTREE trial. The median time from the last dose to rescue medication use was 257.0 days in the CLS-TA group versus 55.5 days in the sham group, confirming a significantly longer duration of effect.
In non-infectious uveitis, chronic intraocular inflammation disrupts the blood-retinal barrier, leading to macular edema. Macular edema is a major cause of vision loss in patients with uveitis.
Treatment of uveitis in Japan is performed in multiple stages depending on the degree of inflammation. When inflammatory changes in the posterior pole of the fundus are severe, sub-Tenon injection of triamcinolone acetonide (Kenacort-A) has been used to reduce inflammation. Suprachoroidal injection is positioned as a new option in addition to these existing routes of administration.
Accurate evaluation using the following examinations is necessary to determine the indication for suprachoroidal injection.
In Japanese clinical practice, treatment for non-infectious uveitis is performed in a stepwise manner.
Suprachoroidal injection is not currently established as a standard covered treatment in Japan, but it is attracting attention as a new therapeutic option for macular edema associated with non-infectious uveitis.
Triamcinolone acetonide (Xipere 40 mg/mL; Bausch & Lomb) is the only FDA-approved drug for suprachoroidal injection. Repeat administration should be at least 12 weeks apart from the previous injection.
The only FDA-approved device for suprachoroidal administration is the Xipere microneedle, available in 900 μm or 1,100 μm lengths. The 900 μm needle is commonly used for the initial injection. If resistance is high and access to the suprachoroidal space is insufficient, the needle is changed to 1,100 μm.
Other access techniques include the following:
| Technique | Features | Considerations |
|---|---|---|
| Microcatheter | LED-guided precise targeting possible | Invasive, operator skill-dependent |
| Standard hypodermic needle | Easily available, minimally invasive | Cannot be visualized, requires advanced skill |
| Hollow microneedle | Can be performed in outpatient setting, simple | FDA-approved device available |
Injection site: Approximately 4–4.5 mm from the corneal limbus in the superotemporal quadrant.
Preparation and anesthesia:
Procedure steps:
Bilateral injection on the same day is possible, but each eye should be treated as a separate procedure, using different vials and injectors.
After injection, subconjunctival hemorrhage and mild eye pain may occur. Sudden changes in vision, severe redness, photophobia, or worsening pain may be signs of serious complications and require prompt ophthalmologic evaluation.
The suprachoroidal space is a potential space located between the sclera and the choroid. Injection into the suprachoroidal space expands this space, and the injected drugs or particles distribute within it. A wide range of particle sizes from 20 nm to 10 μm can be injected and retained, persisting for several months 1).
Drugs move posteriorly from the injection site via fluid flow through the uveoscleral outflow pathway. The compartmentalized structure of the space suppresses unwanted drug diffusion to the anterior segment, enabling targeted delivery to the retina and choroid.
Intravitreal Injection
Advantages: Can be performed on an outpatient basis. A widely established procedure.
Disadvantages: The internal limiting membrane hinders gene vector access to the retina1). Hyaluronic acid promotes nanoparticle aggregation1). May induce an immunogenic humoral immune response1).
Subretinal Injection
Advantages: Direct administration to an immune-privileged site. Enables efficient delivery to the retinal pigment epithelium and photoreceptors.
Disadvantages: It is an invasive procedure requiring vitrectomy1). Drug distribution is limited to the area around the injection site1). There is a risk of postoperative complications (cataract, retinal detachment, hemorrhage)1).
Suprachoroidal injection
Advantages: Can be performed as a minimally invasive outpatient procedure1). Shows wide biodistribution1). Lower humoral immune response compared to intravitreal injection1).
Disadvantages: Located outside the blood-retinal barrier and is not a fully immune-privileged site1).
Suprachoroidal injection of triamcinolone acetonide controls posterior segment inflammation in uveitis from a site close to the target. Compared with conventional posterior subtenon injection, it may deliver the drug more directly to the choroid and retina.
Intravitreal triamcinolone injection (IVTA) is used to treat inflammation in both the anterior and posterior segments, but it causes elevated intraocular pressure in over 50% of cases 2). In the PEACHTREE trial, suprachoroidal injection had a relatively low rate of intraocular pressure elevation of 12–14%.
Suprachoroidal gene therapy using an AAV8 vector is being evaluated in clinical trials for wet age-related macular degeneration (wet AMD) and diabetic retinopathy1).
The AAVIATE trial (Phase 2) investigated suprachoroidal injection of ABBV-RGX-314 (an AAV8 vector expressing anti-VEGF protein) in patients with wet age-related macular degeneration. Among 56 patients who received the highest dose of 1.0×10¹² GC/eye, 50% did not require additional anti-VEGF injections. The BCVA change in those not requiring additional injections was +1.0 letters, confirming good visual acuity maintenance1).
The ALTITUDE trial (Phase 2) targeted patients with diabetic retinopathy. In the dose level 2 (5.0×10¹¹ GC/eye) group, vision-threatening events (VTE) were reduced by 89% compared to the control group1).
Regarding inflammation, in the group receiving 1.0×10¹² GC/eye without steroid prophylaxis, intraocular inflammation was observed in 20% and episcleritis in 37.1%1). Both resolved promptly with topical steroids, and the incidence decreased with prophylactic steroid administration1). There are also reports that episcleritis after AAV suprachoroidal administration occurs in about 14% at 5.0×10¹¹ vg/eye and about 37% at 1.0×10¹² vg/eye3).
Suprachoroidal injection can be performed on an outpatient basis, and the injected vector distributes widely across the eye1). Unlike subretinal injection, it does not require vitrectomy, and the humoral immune response is lower than with intravitreal injection1). Another advantage is that a single injection can be expected to provide sustained anti-VEGF protein expression.
Poly(beta-amino ester) (PBAE) nanoparticles are attracting attention as biodegradable non-viral gene delivery vectors 1).
Suprachoroidal injection of PBAE nanoparticles has been shown to sustain GFP expression for over 6 months. Additionally, suprachoroidal injection is superior to intravitreal and subretinal injections in both the amount and distribution of gene expression 1).
In large animal (minipig) studies, a single suprachoroidal injection of PBAE nanoparticles (19 μg/50 μL) resulted in widespread transfection around the entire circumference of the eye. Hematoxylin and eosin staining showed no toxicity or inflammatory cells, and expression persisted or increased up to 12 weeks 1).
PBAE nanoparticles have the following advantages compared to viral vectors:
Current treatment for wet age-related macular degeneration and diabetic macular edema requires frequent intravitreal anti-VEGF injections, but gene therapy is expected to provide long-term therapeutic effects with a single administration. In the AAVIATE trial, the annual injection rate was reduced by 80%, and 50% of patients did not require additional injections 1). However, not all patients benefit, and further research is needed.
