1. Injection Forces

Suprachoroidal (SC) injections using a microinjector require only manual force applied by a physician's hand. In in vivo porcine eyes, an average glide force of 2.07 N was recorded for delivering suprachoroidal triamcinolone acetonide (SCTA) [70,71]^[1][2]. A prototype SCTA formulation called X-TA was developed to minimize friction, foaming, and microbubble formation during SC injections [70]^[1]. When compared to Triesence TA (TRI) formulated for IV injections, X-TA exhibited a smaller and more consistent glide force (0.73 N) similar to air (0.19 N) and water (0.23 N), while TRI required a higher and less consistent glide force (1.31 N) likely due to its larger particle size [70]^[1]. Customizing formulations for SC injections has the potential to reduce glide force requirements and enhance procedure stability, leading to improved success rates in treating ocular diseases [72]^[3].

2. Volume and Injections into Multiple Quadrants

Achieving optimal SCS coverage is crucial for the effective treatment of posterior segment pathologies, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusions (RVOs) [1]^[4]. The volume of injectate plays a significant role in drug distribution and therapeutic coverage [2]^[5]. Gu et al. demonstrated that injecting 20 μL of saline and triamcinolone acetonide (TA) expanded the SCS by 130% to 200% more than a 10 μL injection, highlighting the influence of injectate volume [3]^[6]. Larger volumes primarily increased circumferential coverage rather than thickness [4]^[7]. Quantitatively, injecting ≥75 μL of fluorescein covered at least 50% of the choroidal surface, while 100 μL covered approximately 75% of the posterior globe [5,6]^[8][9]. The presence of lamellae structures between the choroid and sclera restricts SCS expansion, directing fluid flow posteriorly with larger volumes [6]^[9]. To enhance coverage, collagenase can be used to degrade fibrils, resulting in a 20% to 45% increase in SCS coverage [7]^[10]. Non-uniform fluid distribution in the SCS is influenced by anatomical barriers, such as the scleral spur, optic nerve, and short ciliary arteries [8]^[11]. Multiple injections in opposing quadrants increase coverage, with 50 μL of sodium fluorescein being sufficient to cover the entire choroid [9]^[12]. This comprehensive coverage is particularly important in treating generalized choroidal-retinal dystrophies like retinitis pigmentosa [9]^[12]. Therefore, employing multiple injections in opposing quadrants can maximize SCS coverage and treatment efficacy [9]^[12].

3. Viscosity and Polymeric Solution Formulations

The viscosity of formulations can be adjusted to optimize treatment for specific posterior segment conditions. Fluids with different viscosities, such as HBSS, DisCoVisc, and 5% CMC, have been studied [75,78]^[13][14]. Higher viscosity agents lead to greater expansion and slower SCS collapse rates due to their low aqueous solubility and slow dissolution rate [68]^[15]. Fluids with shear-thinning (S-T) behavior, characterized by lower viscosity at higher shear rates, were investigated by Kim et al. [79]^[16]. HBSS showed rapid spread compared to moderate and high S-T fluids. Circumferential spread increased more for moderate S-T fluids over time, while high S-T fluids remained relatively unchanged [79]^[16]. In situ-forming hydrogels of Bevacizumab and HA cross-linked with poly(ethylene glycol) diacrylate demonstrated prolonged clearance times compared to liquid Bevacizumab alone [80]^[17]. These findings highlight the importance of viscosity in fluid behavior and the manipulation of polymeric solutions for optimizing SC injections. Polymers with elevated molecular weight and moderate non-Newtonian behavior, like HA, promote particle dispersion, while polymers with pronounced non-Newtonian characteristics, such as MC and CMC, tend to remain stationary at the injection site. This approach enhances treatment efficiency by maintaining a higher and sustained drug concentration at the target site, reducing systemic absorption [80]^[17]. Manipulating viscosity and utilizing polymeric solutions offer opportunities for improved drug delivery in the SCS.

4. Particle Suspensions

Particle suspensions with gradual dissolution properties offer advantages for achieving prolonged therapeutic effects in ocular tissues [81]^[18]. The clearance kinetics of these suspensions are influenced by both the molecular weight (MW) and size of the particles [81,82]^[18][19]. Chiang et al. demonstrated that while fluorescein was detectable for only 1 day, fluorescent polymeric particles in HBSS suspension remained detectable for up to 21 days post-injection [81]^[18]. Similarly, a comparison between fluorescein (detectable for 12 hours) and fluorescent dextran (higher MW and hydrodynamic radius than fluorescein, detectable up to 4 days) revealed that MW influenced the duration of detection [82,83]^[19][20].

In terms of particle size, clearance routes involve diffusion into the sclera and choroid, transscleral leakage, and choroidal blood flow [79]^[16]. The fenestrations of the choriocapillaris allow particles within the size range of 6 to 12 nm to be cleared through choriocapillaris circulation, while larger particles (20 nm to 10 μm) can remain in the SCS for several months [79]^[16]. Hackett et al. conducted an experiment using 7 μm-sized polymeric microparticles loaded with acriflavine (ACF) in Brown Norway rats, where the particles persisted in the SCS throughout the 16-week study period [84]^[21].

Larger particles face challenges in SCS delivery due to potential blockage by collagen fibers in the sclera, especially with short microneedles [85]^[22]. Glide force becomes crucial for successful delivery of formulations with larger particles [85]^[22]. Patel et al. found that shorter needles showed significant distribution differences between small particles (20-100 nm) and large particles (500-1000 nm), while longer microneedles (1000 μm) achieved similar behavior for all particles, indicating successful SCS reach [3]^[6].

Kim et al. and Chiang et al. reported that particles ranging from 20 nm to 10 μm remained in the SCS for up to 3 months, with consistent fluorescence levels, indicating that particle size does not substantially affect SCS distribution, but clearance kinetics depend on the choriocapillaris and scleral extracellular matrix pore size [19,79]^[23][16]. Overall, particle suspensions can be tailored to suit therapeutic needs.

5. Osmotic Characteristics and Ionic Charges of Formulation

Osmotic power and ionic charge impact drug distribution in the SCS. Jung et al. demonstrated osmotic power by injecting a highly concentrated HA solution after a less concentrated HA solution with fluorescent particles, resulting in greater SCS expansion and displacement of particles towards the posterior pole [86]^[24].

In terms of ionic charge, when negatively charged nanoparticles were injected into the SCS and exposed to a positively charged cathodal current, their concentration significantly increased in the posterior pole [87]^[25]. Touchard et al. obtained similar results with negatively charged DNA particles exposed to electric current in a rat model [88]^[26].

Therefore, osmotic power and ionic charge are fluid properties that can be utilized to optimize drug distribution in SC injections.

6. Compartmentalization and Duration of Injectates in the SCS

C injection offers advantages in terms of injectate compartmentalization and prolonged drug effect, minimizing side effects by avoiding exposure to distal ocular tissues. Patel et al. conducted microscopic analysis of SC injections in porcine eyes using red fluorescent sulforhodamine injectate [3]^[6]. Quantification of choroid and retina targeting was performed in vivo on rabbit models, revealing that SC injection of fluorescein resulted in 10 to 100 times higher content detection in the choroid and retina compared to IV injections, which showed more uniformly distributed signals throughout the visual axis [12]^[27]. Tyagi et al. demonstrated that SC injections of NaF achieved peak concentrations in the choroid and retina that were 36 times higher than subconjunctival injections and 25 times higher than IV injections, resulting in 6-fold and 2-fold higher NaF exposure in the choroid and retina compared to the posterior subconjunctival and IV routes, respectively [23]^[28].

Similar compartmentalization patterns were observed in studies involving TA injections in rabbit models, where negligible amounts of TA were detected in the anterior segment of the eye after 91 days, while the sclera, choroid, and RPE showed the highest concentrations [89]^[29]. SCTA led to 12 times higher scleral, choroidal, and retinal concentrations compared to IV injections, with concentrations in the lens, iris-ciliary body, and vitreous humor being 460, 32, and 22 times lower, respectively. Aqueous humor levels were negligible, and plasma levels were undetectable [90]^[30]. Similar findings were observed with other molecules such as Axitinib and A01017, reaching maximal concentrations in the SCR at 67 days and 90 days, respectively [91,92]^[31][32]. Compartmentalization was further demonstrated in a study on SCTA, where plasma levels remained below 1 ng/L for up to 24 weeks [93]^[33].