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. Author manuscript; available in PMC: 2022 Sep 5.
Published in final edited form as: Int J Pharm. 2021 Jul 14;606:120887. doi: 10.1016/j.ijpharm.2021.120887

Non-invasive monitoring of suprachoroidal, subretinal, and intravitreal implants using confocal scanning laser ophthalmoscope (cSLO) and optical coherence tomography (OCT)

Madhoosudan A Patil 1, Uday B Kompella 1,2,3,4,#
PMCID: PMC8429194  NIHMSID: NIHMS1724362  PMID: 34271155

Abstract

To address the need for noninvasive monitoring of injectable preformed drug delivery implants in the eye, we developed noninvasive methods to monitor such implants from different locations within the eye. Cylindrical polymeric poly(lactide-co-glycolide) or metal implants were injected into isolated bovine eyes at suprachoroidal, subretinal, and intravitreal locations and imaged noninvasively using the cSLO and OCT modes of a Heidelberg Spectralis HRA+OCT instrument after adjusting for the corneal curvature. Length and diameter of implants were obtained using cSLO images for all three locations, and the volume was calculated. Additionally, implant volume for suprachoroidal and subretinal location was estimated by integrating the cross-sectional bleb area over the implant length in multiple OCT images or using the maximum thickness of the implant based on thickness map along with length in cSLO image.

Simultaneous cSLO and OCT imaging identified implants in different regions of the eye. Image-based measurements of implant dimensions mostly correlated well with the values prior to injection using blade micrometer. The accuracy (82–112%) and precision (1–19%) for noninvasive measurement of length was better than the diameter (accuracy 69–130%; precision 3–38%) using cSLO image for both types of implants. The accuracy for the measurement of volume of both types of implants from all three intraocular locations was better with cSLO imaging (42–152%) compared to those obtained using OCT cross-sectional bleb area integration (117–556%) or cSLO and thickness map (32–279%) methods.

Suprachoroidal, subretinal, and intravitreal implants can be monitored for length, diameter, and volume using cSLO and OCT imaging. Such measurements may be useful in noninvasively monitoring implant degradation and drug release in the eye.

Keywords: Implant, noninvasive monitoring, suprachoroidal, subretinal, intravitreal

Graphical abstract:

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1. Introduction

Intraocular implant drug delivery systems are useful in sustaining drug delivery to the back of the eye tissues for a few months or years. Vitrasert® (ganciclovir Bausch & Lomb Pharmaceuticals, Inc.), Retisert® (fluocinolone acetonide, Bausch and Lomb Inc.), Iluvien® (fluocinolone acetonide, Alimera Sciences Inc.), Yutiq® (fluocinolone acetonide, EyePoint Pharmaceuticals, Inc.) and Ozurdex® (dexamethasone, Allergan Pharmaceuticals) are FDA approved intravitreal implant drug delivery systems for the treatment of serious back of the eye diseases including acquired immune deficiency syndrome-associated cytomegalovirus retinitis (Jabs, 2011; Muccioli and Belfort, 2000), chronic uveitis (Freitas-Neto et al., 2015; Hunter and Lobo, 2011; Leinonen et al., 2018), macular edema secondary to retinal vein occlusion (Coelho et al., 2019; Jain et al., 2012), and diabetic macular edema (Boyer et al., 2014; Chhablani, 2016). While Vitrasert and Retisert, two non-degradable implants, were approved for surgical placement in the vitreous humor, Iluvien and Yutiq (non-degradable) and Ozurdex (degradable) were approved for injection into the vitreous humor.

The use of Ozurdex, a biodegradable implant based on poly(lactide-co-glycolide) (PLGA), is a relatively a new approach to achieve sustained drug delivery to the various back of the eye tissues in patients (Haller et al., 2010). Durysta® (bimatoprost, Allergan Pharmaceuticals, Inc.), another biodegradable implant, was approved by the FDA in 2020 to sustain drug delivery to treat glaucoma as an alternative to daily topical eye drop therapies (Saati et al., 2010; Shen et al., 2020; Thanos et al., 2004). We anticipate that implant delivery systems will be developed in the future for placement in the suprachoroidal and subretinal spaces to facilitate targeted drug delivery primarily to the choroid and retina, respectively (Hartman and Kompella, 2018; Kelley et al., 2020; Kompella et al., 2021). Such intraocular sustained release delivery systems will require low drug quantities relative to conventional eye drop therapy and minimize systemic drug exposure, thereby improving the patient risk-benefit ratio.

To better understand the disposition of a degradable implant delivery system in the eye, it is crucial to monitor its location as well as changes in dimensions over time. Ideally, a noninvasive method should be instituted for monitoring an implant during the treatment period. At present, there are no established methods for monitoring intraocular implants or drug delivery noninvasively. Therefore, as a first step, the objective of this study was to address this unmet need by developing techniques for noninvasive monitoring of intraocular implants.

We hypothesized that optical coherence tomography (OCT) and confocal scanning laser ophthalmoscopy (cSLO) imaging technologies could be used to monitor the length, diameter, and volume of intraocular implants injected in the suprachoroidal, subretinal, and intravitreal locations in the eye. OCT is an interferometry-based non-invasive imaging technique that is commonly used in ophthalmology clinics (Murthy et al., 2016). During OCT imaging the reflected light from various tissue layers is determined to be in- or out of- phase with a reference beam, resulting in an interference pattern across the depth of the tissue (Aumann et al., 2019; Popescu et al., 2011; S et al., 2019). This interference pattern for each small subsection of the retina collectively forms a 3-dimensional view of the retina and choroid. With this, OCT non-invasively generates high-resolution, cross-sectional, histology like images from backscattered light, allowing clinicians to monitor the health of various eye tissues (Drexler and Fujimoto, 2015; Fujimoto et al., 2000; Murthy et al., 2016).

The transparency and heterogeneous nature of the tissue are the basic properties required to obtain transverse images using OCT (Gora et al., 2017; Moiseev et al., 2013). While the completely transparent nature of the cornea, aqueous humor, lens, and vitreous humor provides direct visualization of the back of the eye, the semitransparent nature of the retina and choroid helps to delineate those layers in transverse images using OCT. This technique was invented by Fujimoto’s group at MIT in 1991 and within a very short period of time it became an important imaging tool in the biomedical field beyond ophthalmology including dermatology (Olsen et al., 2018; Sattler et al., 2013), neuroscience (Lamirel et al., 2009; Saidha et al., 2015), cardiology (Roleder et al., 2015; Terashima et al., 2012), urology (Kharchenko et al., 2013; Wang and Chen, 2014), dentistry (Hsieh et al., 2013; Machoy et al., 2017), and embryology (Raghunathan et al., 2016; Syed et al., 2011).

Another noninvasive technique routinely used in clinical diagnostics and research is cSLO (Alexandrescu et al., 2010; Diniz et al., 2013; Helb et al., 2010). cSLO provides two-dimensional high-resolution en face images based on fluorescence or other signals using a raster scan of the retina with a laser beam of light (LaRocca et al., 2013; Merino and Loza-Alvarez, 2016; Ooto et al., 2011). Many groups have demonstrated the visualization of a wide array of ocular pathologies and/or anatomical features using cSLO. Such features include abnormal ocular phenotypes (Bell et al., 2016), age-related or light-induced changes (Hartmann et al., 2011; Morgan et al., 2008), and retinal/choroidal angiography (Querques et al., 2010; Staurenghi et al., 2005). cSLO minimizes the effect of light scattering and the depth imaged depends on the tissue transparency.

Because of the light transparent nature of the retina and anterior eye tissues, we can accurately obtain retinal en face and transverse images using cSLO and OCT respectively. Placement of foreign material in subretinal (Gekeler et al., 2007; Hsu et al., 2018) or suprachoroidal (Lampen et al., 2018) spaces create elevation/deformity in surrounding tissue layers. In this study, we exploited this feature in conjunction with the use of cSLO and OCT to monitor the location, length, diameter, and volume of suprachoroidal, subretinal, and intravitreal PLGA implants after injection into ex-vivo bovine eyes. The techniques were validated using metal implants as controls with more defined and non-deformable dimensions.

2. Materials and Methods

2.1. Implants

Blank cylindrical polymeric implants prepared using hot melt extrusion (HME) and poly(DL-lactide-co-glycolide) 50:50 polymers were used in this study (Kelley et al., 2020). Specifically, a mixture of B6013–1 (acid terminated end group; 80%) and B6017–1 (ester terminated end group; 20%) polymers were used. The polymers were purchased from Durect Corporation (Cupertino, CA). Implant strands of diameter about 0.4 mm were cut to the length of about 2, 4, and 6 mm using a scalpel blade. Precisely cut metal cylindrical implants (0.65 × 6.35 mm, 0.57 × 6.35 mm, 0.23 × 9.51 mm, and 1.27 × 6.45 mm) were purchased from Component Supply (Sparta, TN). The length and diameter of the polymeric and metal implants were measured before use, with a blade micrometer (LCD Blade micrometer, No. 156–101-10 stand, Mitutoyo, Inc., Kawasaki, Japan) as shown in Figure 1.

Figure 1. Measurement of implant length and diameter using blade micrometer.

Figure 1.

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(A) Picture depicting length and diameter measurements of implants using a blade micrometer. (B) Pictures of representative (x) precision cut metal implant (L = 6.35 mm; D = 0.65 mm), and (y) biodegradable polymeric implant (L = 6.09 mm; D = 0.41 mm). Injection assembly for the injection of implants into the intraocular space. (C, D) Cartoon showing the implant measurement procedure, e.g., length and diameter.

2.2. Bovine eyes

Eyes were obtained on the day of the experiment from local slaughterhouses (Elizabeth Meat Locker, Elizabeth, CO; or Arapahoe Meat Company, Lafayette, CO). The eyes were transported to the lab in cold PBS (pH 7.4). The tissues surrounding the eye globe was removed on a cool wet (with PBS) ceramic tile and eyes were stored in ice-cold PBS prior to use.

2.3. Injection of a preformed implant at suprachoroidal, subretinal, and intravitreal locations:

Implants of different sizes were individually loaded into the beveled tips of needles with a plunger for injection into the ex vivo bovine eyes. One implant was injected into each eye using a 19G needle for implants of diameter 0.4, 0.57, and 0.65 mm, 22G needle for implants of diameter 0.23 mm, or polyethylene (PE) tubing (following a scleral incision with a blade) with an inner diameter of around 1.5 mm for implants of diameter 1.27 mm. The implant inside the needle or the PE tubing was gently pushed into the desired intraocular location using a metal plunger.

The needle or PE tubing was inserted approximately at 10 mm posterior to the limbus with the bevel facing upwards, at an angle of 10 and 45o to the sclera for suprachoroidal and subretinal/intravitreal injections, respectively. When inserting a needle into the eye, initially some resistance is felt because of the outer hard scleral tissue. For suprachoroidal injections, as soon as this resistance for needle movement subsided, further needle insertion was stopped and the implant was pushed inside by advancing the plunger. For subretinal injections, the needle was inserted slightly beyond the fall in scleral resistance to reach the subretinal space and the needle was gently rotated by 180o to bring the bevel face to the retina before advancing the plunger to release the implant in subretinal space. For the intravitreal injections, the needle was inserted further inside the eye for about 1 cm from the scleral surface before the implant was released. Following the implant injection, the needle and plunger assembly was gently removed from the eye. Fresh polymeric implants were used for each injection while metal implants were recovered from the eye following imaging and reused.

2.4. Imaging and image analysis:

A Spectralis HRA+OCT instrument (Heidelberg Engineering) with spectral domain OCT capability, which was previously employed to monitor a subretinal bleb (Bartuma et al., 2015), retinal degeneration (Muraoka et al., 2012), retinal photocoagulation lesions (Koinzer et al., 2013), and retinal thickness and retinal nerve fiber layer thickness (Alkin et al., 2013), was used in this study. cSLO images, spectral domain OCT images, and thickness map were obtained for each intraocular implant using with a 30o objective lens at a focus value (D value) of zero and an optimized corneal curvature or “C-Curve” value described subsequently. While cSLO imaging provides an en face view of the retina, OCT provides a volume scan with a transverse view of the retina along a straight line across the cSLO image. The thickness map provides merged information from the cSLO and OCT images. Table 1 shows various methods used to obtain the length, diameter, and volume of the implants before and after injection. Three independent approaches were used to determine the volumes of suprachoroidal and subretinal implants: cSLO length and diameter-based calculation, integrated bleb area along the implant length in OCT image, and cSLO image and thickness map-based volume estimation. For intravitreal implant volumes, because it was not possible to use integrated bleb area and thickness map methods, only the cSLO approach was used.

Table 1:

Measurement or calculation of length, diameter, and volume of suprachoroidal, subretinal, and intravitreal implants using cSLO and OCT imaging.

Length (L) Diameter (D=2r) Cross-sectional area (A) Volume (V)
Pre-injection Micrometer Micrometer Micrometer (Л*r2) Micrometer (L*A)
Intravitreal cSLO image cSLO image cSLO image (Л*r2) cSLO image (L*A)
Subretinal cSLO image cSLO image cSLO image (Л*r2) cSLO image (L*A)
72 µm slices along the entire implant length Integrated bleb area at multiple slices OCT image – integration of cross-sectional bleb area over implant length
cSLO image cSLO image and thickness map-central max thickness corrected for background cSLO image and thickness map (Л*r2) cSLO image and thickness map (L*A)
Suprachoroidal cSLO image cSLO image OCT image (Л*r2) cSLO image (L*A)
72 µm slices along the entire implant length Integrated bleb area at multiple slices OCT image – integration of cross-sectional bleb area over implant length
cSLO image cSLO image and thickness map-central max thickness corrected for background cSLO image and thickness map (Л*r2) cSLO image and thickness map (L*A)
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Optimization of the “C-Curve” value

The size of an object in any ocular image depends upon the magnifying power of the ophthalmoscope and the eye and the distance of the object from the cornea. The D focus value setting, or the instrument magnification was fixed for all measurements. The corneal curvature or “C-Curve” is a key factor that affects the magnification power of the eye (Nawa, 2008). It is expressed as an average radius of the anterior and posterior corneal surfaces. Typically, it is measured using keratotomy (Loring, 1880) or corneal topography (Tomlinson, 1976).

When using the HRA+OCT instrument, a “C-Curve” value is set by the user to correct for corneal curvature. To determine the optimal C-Curve value for bovine eyes, a polymeric implant of known size was injected intravitreally into an ex vivo eye close to the retina, and cSLO images were obtained using different “C-Curve” values (8.7, 9, 10, and 13). The length of the implant was then measured from resulting cSLO images and compared with known values measured previously using a blade micrometer. The “C-Curve” value that provided the most accurate measurement of length was used for further experiments.

Estimation of length, diameter, and volume of implant from cSLO image

Wherever feasible, during cSLO imaging, the implant was oriented vertically so that the maximum number of horizontal cross-sections along the implant could be obtained. All the cSLO images were obtained using infrared reflectance (“IR”) and “High Resolution” imaging modes of the Spectralis instrument from suprachoroidal, subretinal and intravitreal locations of the implant.

Two dimensions of the implant (length along the middle of the implant and average of diameter at 3 locations, which were at each end and the middle) were measured from cSLO images using the “Measure Distance” tool in Heidelberg Eye Explorer (HEYEX) software (Figure 2). The dark area surrounding the implant was omitted from these measurements. The volume of the implant was calculated from the measured length and diameter using the equation πr2h. The dimensions (length, diameter, and volume) of intraocular implants from the cSLO image were compared to the values obtained using the blade micrometer prior to injection.

Figure 2. Measurement of length and diameter of intraocular implants using cSLO image.

Figure 2.

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cSLO images of suprachoroidal, subretinal, and intravitreal polymeric (~5 × ~ 0.4 mm) and metal (0.57 × 6.35 mm) implants. Length and diameter (at three locations: each end and center) of the implants measured from cSLO images by using the HEYEX software are displayed. Key: SC- Suprachoroidal, SR- Subretinal, and IVT- Intravitreal.

Estimation of volume of an implant from Integrated bleb area in OCT image

An OCT volume scan of size 30o x 25o view was obtained simultaneously with the cSLO image using “IR+OCT” mode with an enhanced depth imaging (EDI) modality. A total of 121 OCT images with a step of 72 µm between each was obtained from each subretinal and suprachoroidal implant. An OCT image is expected to display a tissue bleb (elevation of tissue from its original position) in the retina alone for a subretinal implant and in both choroid and retina for a suprachoroidal implant upon successful injection.

The HEYEX software automatically defines the retinal upper boundary at the inner limiting membrane (ILM) and the lower boundary at the Bruch’s Membrane (BM) (Figure 3). However, in some cases, the software fails to appropriately define a segmentation line for the BM. For these implants, the desired boundaries were manually defined using the

Figure 3. Measurement of bleb area due to suprachoroidal implant from OCT image.

Figure 3.

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Simultaneously collected retinal cSLO and OCT images of a suprachoroidal implant in an ex vivo bovine eye. The cSLO image displays en face view of suprachoroidal implant and total scan area represented by green rectangle along with horizontal scan positions represented by green line(s). The OCT image displays the transverse view(s) of the retina corresponding to horizontal green arrow on cSLO image. Automatic segmentation of retinal boundaries is denoted by red lines, while the area of the tissue bleb due to a suprachoroidal implant is bordered with green lines in the OCT image. The corresponding area measurement is also displayed. (A) Cartoon depicting components of OCT image along with angle of elevation. (B) Series of horizontal green arrows indicating the location of OCT images shown on the right. Each subsequent transverse view in OCT image is separated by 72 µm distance along the implant length. Key: ILM - Inner limiting membrane, BM - Bruch’s membrane.

“Segmentation tool”. The area for the bleb due to implant was manually marked using the “Draw Region” tool in the HEYEX software. Here the lower boundary of the area was overlaid onto the lower straight segmentation line whereas the upper boundary of the bleb was marked based on the visibility of retina/choroid elevation. Tissue elevation of about >20o was included by marking, whereas lower elevation was omitted. The readings obtained automatically for the marked bleb area in each OCT image, along with the known distance between consecutive OCT images (72 µm) was used to calculate the bleb volume using the formula ∑area x distance. The sum of bleb volumes obtained from OCT images along a given implant length was considered as the volume of that implant based on bleb area integration.

Estimation of volume of an implant using cSLO image and thickness map

After the completion of cSLO and OCT scan acquisitions, the software automatically generated a pseudo-color thickness map by assigning tissue thickness values to each pixel on the cSLO image based on the volume scan. A thickness map was obtained for each subretinal and suprachoroidal implant.

Determination of the volume of a tissue bleb from the thickness map was obtained using an Early Treatment Diabetic Retinopathy Study (ETDRS) type grid (Figure 4). The grid is a set of 3 concentric circles with a fixed radius portioned into four quadrants, and when overlaid on the top of a thickness map, it provides the maximum, minimum, and average thickness corresponding to each region of the grid. It was originally designed to determine the average diameter of the retina around and at the macula at five different regions namely foveal, nasal, temporal, superior, and inferior (Kafieh et al., 2015). The central circle of the grid, which was used in this study is 1 mm in diameter.

Figure 4. Thickness maps corresponding to implant in various locations.

Figure 4.

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Retinal cSLO images on the left show the pseudo-color thickness map of the retina obtained by simultaneous cSLO + OCT imaging. ETDRS type grid overlaid on the retinal cSLO image at the location of implant shows thickness and volumes of corresponding regions of the grid towards the right. Key: SC- Suprachoroidal, SR- Subretinal, and IVT- Intravitreal.

The central circle (1 mm diameter) of the ETDRS grid was overlaid on top of the implant region in a pseudo-color thickness map at three different locations along the implant to obtain the maximum thickness within that circle (Figure 4). Similar thickness measurement was obtained away from the implant to determine the thickness of the tissue without implant. The volume of implant was obtained using the diameter measured as background subtracted maximum tissue thickness at the implant location and the cSLO-based length of implant. This volume of implant was correlated to that obtained using blade micrometer.

2.5. Statistical analysis

The length, diameter, and volume of suprachoroidal, subretinal, and intravitreal implants obtained by various methods were correlated to those obtained using blade micrometer using Microsoft Excel. For each comparison, the coefficient of determination (r2) is reported. Using the same software, a two-tailed paired t-test was conducted to compare the implant dimensions for each dimension before and after the injection. The p value less than or equal to 0.05 indicated significant difference between the measurements. Percentage accuracy was calculated by using the formula: Percentage accuracy = (Value from imaging technique x 100)/(Value based on blade micrometer). Precision was calculated by using the formula: Precision (% RSD) = (Standard deviation x 100)/Average.

3. Results

3.1. Corneal curvature “C-Curve”

At a “C-Curve” value of 10 the intravitreal implant length had the lowest error (1.34%) compared to that measured using blade micrometer prior to injection. “C-Curve” values of 8.7, 9, and 13 showed a higher measurement error of 5.04%, 3.32%, and 18.96%, respectively. Therefore, a “C-Curve” value of 10 was used during the rest of the study.

3.2. Injection of a preformed implant at suprachoroidal, subretinal, and intravitreal locations

The presence of an intact implant within suprachoroidal, subretinal, or intravitreal space was verified using cSLO and OCT images. We were able to determine the integrity of the implant after the injection in all three locations.

As shown in Figure 5, the cSLO image showed the presence of an intravitreal implant above the retina. It was not possible to confirm the implant location either in the subretinal or suprachoroidal locations by cSLO imaging alone. However, the corresponding OCT images with a bleb area beneath the retina or choroid revealed the subretinal or suprachoroidal implant locations, respectively. No such tissue bleb was seen for intravitreal implants in the OCT image. However, thin, bright lines in the retina/choroid layers just beneath the intravitreal polymeric implant, on either border of the implant, were observed. For intravitreal metal implants, the breaks in retina/choroid layers beneath the implant were continuous, with the corresponding region of the image appearing as a white, blank region. Similar breaks were evident in the choroid layer beneath subretinal implants.

Figure 5. Suprachoroidal, subretinal and intravitreal locations of polymeric and metal implants as seen in cSLO and OCT images.

Figure 5.

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cSLO images of suprachoroidal (top), subretinal (middle), and intravitreal (bottom) polymeric and metal implants (red arrow) obtained by Spectralis HRA+OCT (Heidelberg Engineering). Corresponding OCT images are shown on the right, with tissue layers labeled in the first of OCT images. Retinal blebs due to suprachoroidal (*) and subretinal (#) implant are clearly visible. Key: SC- Suprachoroidal, SR- Subretinal, and IVT- Intravitreal.

3.3. Estimation of length, diameter, and volume of an implant from cSLO image:

The diameter and length of all implants were determined using a blade micrometer before injecting them into the eye (Figure 1). After injection, cSLO images of the implant were collected and measurements of the length and diameter were obtained from a directly visible intravitreal implant or en face view of the tissue bleb developed due to subretinal or suprachoroidal implants. The metal implants from all three intraocular locations showed a better coefficient of determination (r2 >0.816), and a positive slope (0.647–1.048) for the length and diameter values obtained from cSLO imaging relative to those obtained by using a blade micrometer (Figure 6 & 7; Tables 2–4). The intravitreal implants were directly visible in the cSLO image, providing closer estimations of the implant dimensions. The polymeric implants from all three intraocular locations showed a very good coefficient of determination (r2 >0.942) with a positive slope with near 1:1 relationship (0.948–1.048) for length measured by cSLO image compared to blade micrometer. The correlation of the diameter measurement of these implants was not obtained because only a single diameter of polymeric implants was used in this study. Length and diameter measurements using cSLO imaging for all the implants showed an average accuracy of 82–112% and 69–130%, and a precision of 1–19% and 3–38% respectively, compared to those measured by a blade micrometer (Table 2).

Figure 6. Correlation of length, diameter and volume of intraocular metal implants measured using different imaging methods with those obtained using a blade micrometer.

Figure 6.

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The correlation between length, diameter, and volume of metal implants at all three intraocular (suprachoroidal, subretinal, and intravitreal) locations based on cSLO images, OCT image, and cSLO image and thickness map methods after the injection with those measured using the blade micrometer before the injection. The zone around regression line represents the 95% confidence interval (dark zone) and 95% prediction interval (light zone). Each dot represents one implant and one eye. In all 13–16 implants were used for each correlation. Key: SC- Suprachoroidal, SR- Subretinal, and IVT- Intravitreal.

Figure 7. Correlation of length, diameter and volume of intraocular polymeric implants measured using different imaging methods with those obtained using a blade micrometer.

Figure 7.

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The correlation between length, diameter, and volume of polymeric implants at all three intraocular (suprachoroidal, subretinal, and intravitreal) locations based on cSLO images, OCT image, and cSLO image and thickness map methods after the injection with those measured using the blade micrometer before the injection. The zone around regression line represents the 95% confidence interval (dark zone) and 95% prediction interval (light zone). Correlations for diameter are not plotted due to the use of a single polymeric implant diameter. Each dot represents one implant and one eye. In all 13–16 implants were used for each correlation. Key: SC- Suprachoroidal, SR- Subretinal, and IVT- Intravitreal.

Table 2:

Percent accuracy, precision (relative standard deviation) and paired two tailed t-test (P-value) for noninvasive length and diameter measurements of suprachoroidal, subretinal, and intravitreal implants using cSLO imaging approach. P > 0.05 indicates no significant differences between the two types of measurements. Data are presented as mean SD for n=4–5 eyes. Key: SC- Suprachoroidal, SR- Subretinal, and IVT- Intravitreal. NE-Not estimated.

Accuracy (%), precision (%) and p-value for length and diameter estimation compared to blade micrometer values
Accuracy (%) Precision (%) p-value
SC SR IVT SC SR IVT SC SR IVT
Metal implant-Length
0.65×6.35 mm 98±2 96±1 97±1 2 1 1 0.169 0.002 0.017
0.57×6.35 mm 97±4 98±5 110±5 4 5 5 0.278 0.496 0.029
0.23×9.51 mm 87±8 98±2 104±7 9 2 7 0.053 0.217 0.303
1.27×6.45 mm 100±4 100±4 112±5 4 4 4 0.885 0.944 0.018
Polymeric implant-Length
~0.4×2 mm 82±18 87±19 97±12 19 17 14 0.139 0.233 0.637
~0.4×4 mm 98±17 99±3 102±3 15 1 4 0.771 0.603 0.262
~0.4×6 mm 98±4 92±10 99±3 3 10 3 0.366 0.205 0.589
Metal implant-Diameter
0.65×6.35 mm 95±13 69±8 79±5 14 11 6 0.498 0.004 0.003
0.57×6.35 mm 97±12 84±9 76±8 12 11 10 0.670 0.043 0.008
0.23×9.51 mm 130±22 109±3 99±25 17 3 26 0.071 0.010 0.933
1.27×6.45 mm 79±20 79±3 95±7 25 4 7 0.122 0.001 0.279
Polymeric implant-Diameter
~0.4×2 mm 69±22 103±11 99±10 38 14 10 0.065 0.572 0.857
~0.4×4 mm 72±20 102±8 89±3 26 8 4 0.075 0.659 0.010
~0.4×6 mm 102±21 96±5 82±3 14 10 3 0.975 0.146 0.001
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Table 4:

Coefficient of determination (r2) and slope of a regression line of intraocular implant measurements obtained using different imaging approaches compared to those obtained using blade micrometer before the injection. Coefficient of determination and slope was not estimated for intravitreal metal and polymeric implants due to the absence of volume in thickness map and bleb in OCT image. Coefficient of determination and slope was not estimated for polymeric implant diameter due to the use of implants with a single diameter. Key: SC- Suprachoroidal, SR- Subretinal, and IVT- Intravitreal. NE- Not estimated.

Coefficient of determination (r2) when compared to blade micrometer values Slope of a regression line when compared to blade micrometer values
SC SR IVT SC SR IVT
Metal Implants
cSLO image-Length 0.837 0.974 0.880 0.647 0.997 1.005
cSLO image-Diameter 0.816 0.960 0.960 0.674 0.730 0.975
cSLO image-Volume 0.730 0.966 0.964 0.593 0.611 1.066
OCT image-Integrated bleb area over length-Volume 0.746 0.953 NE 1.076 2.507 NE
cSLO image and thickness map- Volume 0.670 0.974 NE 0.587 0.991 NE
Polymeric implants
cSLO image-Length 0.950 0.942 0.988 1.048 0.948 1.008
cSLO image-Diameter NE NE NE NE NE NE
cSLO image-Volume 0.551 0.852 0.862 1.079 0.818 0.541
OCT image-Integrated bleb area over length-Volume 0.733 0.903 NE 1.915 1.895 NE
cSLO image and thickness map- Volume 0.893 0.830 NE 0.641 0.642 NE
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Implant volumes for all three intraocular locations were calculated using the lengths and diameters obtained from cSLO image and compared with blade micrometer-based calculations. The volumes of metal and polymeric implants from all three intraocular locations are shown in Figures 6 & 7. The volume measurements from cSLO images exhibited better coefficient of determination for the metal implants (r2 >0.730; slope= 0.593–1.066) relative to the polymeric implants (r2 >0.551; slope= 0.541–1.079) (Table 4). Implant volume measurements for almost all implants showed relatively better accuracy with cSLO method (42–152%) compared to the other methods used (32–556%) (Table 3).

Table 3:

Percent accuracy, precision (relative standard deviation) and paired two tailed t-test (p-value) for noninvasive volume measures for suprachoroidal, subretinal, and intravitreal implants. P > 0.05 indicates no significant differences between the two types of measurements. Data are presented as mean SD for n=4–5 eyes. Key: SC- Suprachoroidal, SR- Subretinal, and IVT- Intravitreal, NE-Not estimated.

Accuracy (%), precision (%) and p-value for volume estimation compared to blade micrometer values
Accuracy (%) Precision (%) p-value
SC SR IVT SC SR IVT SC SR IVT
Metal implant
0.65×6.35 mm cSLO image 90±26 46±10 61±7 29 22 12 0.490 0.002 0.002
OCT image-Integrated bleb area over length 157±2 186±20 NE 2 11 NE 0.000 0.003
cSLO image and thickness map 79±7 105±23 NE 9 22 NE 0.009 0.680
0.57×6.35 mm cSLO image 93±25 70±18 65±11 26 25 17 0.624 0.043 0.008
OCT image-Integrated bleb area over length 154±69 200±44 NE 45 22 NE 0.217 0.020
cSLO image and thickness map 63±30 101±28 NE 47 27 NE 0.089 0.937
0.23×9.51 mm cSLO image 152±57 116±8 105±48 38 7 46 0.165 0.027 0.847
OCT image-Integrated bleb area over length 552±313 556±127 NE 57 23 NE 0.065 0.005
cSLO image and thickness map 111±56 279±53 NE 51 19 NE 0.731 0.007
1.27×6.45 mm cSLO image 65±29 62±6 102±14 45 10 14 0.097 0.001 0.800
OCT image-Integrated bleb area over length 124±48 252±37 NE 57 23 NE 0.394 0.004
cSLO image and thickness map 61±34 104±8 NE 51 19 NE 0.108 0.381
Polymeric implant
~0.4×2 mm cSLO image 42±31 95±33 94±14 89 41 18 0.045 0.790 0.509
OCT image-Integrated bleb area over length 117±54 165±79 NE 55 46 NE 0.660 0.125
cSLO image and thickness map 32±17 66±26 NE 61 38 NE 0.014 0.042
~0.4×4 mm cSLO image 55±32 104±17 81±7 55 16 11 0.080 0.789 0.003
OCT image-Integrated bleb area over length 135±11 175±33 NE 10 38 NE 0.007 0.044
cSLO image and thickness map 45±10 91±26 NE 27 45 NE 0.001 0.676
~0.4×6 mm cSLO image 104±42 85±15 67±6 28 30 8 0.977 0.111 0.002
OCT image-Integrated bleb area over length 183±58 181±30 NE 23 27 NE 0.044 0.014
cSLO image and thickness map 53±8 89±19 NE 21 35 NE 0.003 0.280
Open in a new tab

3.4. Estimation of volume of an implant from integrated bleb area in OCT image:

The volume of suprachoroidal and subretinal implants was estimated by integrating the bleb area from the OCT image (Figure 3). These measurements could not be obtained for intravitreal implants due to the absence of a tissue bleb. For the subretinal and suprachoroidal implants, there was either an over- or under-estimation of the volumes in some cases (Figure 6 & 7). It was observed that the coefficient of determination for the volume measurement using integrated bleb area was better for subretinal implants (r2 > 0.903, slope= 1.895–2.507) than suprachoroidal (r2 >0.733; slope= 1.076–1.915) (Table 4). The accuracy for the volume measurement using bleb area integration method was in the range of 117–252% for both metal and polymeric implants except the thinnest (diameter 0.23mm) metal implant used.

3.5. Estimation of volume of an implant using cSLO image and thickness map

The volumes of suprachoroidal and subretinal implants were estimated using implant length from cSLO image and diameter of the implant from thickness map (Figure 4). The coefficient of determination of volume for implants using a thickness map compared to that of a blade micrometer was better for subretinal (r2 >0.830; slope=0.642–0.991) compared to suprachoroidal (r2 >0.670; slope=0.587–0.641) implants. We were not able to determine the volume of intravitreal implants using this method, since there were no changes in retinal thickness expected. This method showed an average accuracy of 32–279% for all the implants (Table 3; Figure 6 & 7).

4. Discussion

4.1. Injection of a preformed implant at suprachoroidal, subretinal, and intravitreal locations

Though the injection of preformed implants into intravitreal (Esen et al., 2017; Garweg and Zandi, 2016; Lee et al., 2017; Sanford, 2013) or intracameral (Kim et al., 2016; Lee et al., 2018; Lee et al., 2019; Lewis et al., 2017) locations are routinely performed during experimental or clinical studies, we are not aware of any similar studies for subretinal and suprachoroidal implants relevant for drug delivery, with the exception of one recent study which assessed the delivery of tauroursodeoxycholic acid (TUDCA) using a surgically placed suprachoroidal implant (Olsen et al., 2020). Although several studies have shown successful subretinal or suprachoroidal injections (Gilger et al., 2013; Patel et al., 2012; Patel et al., 2011), they have only injected drug solutions (Chiang et al., 2017), drug suspensions (Prieto et al., 2018; Willoughby et al., 2018; Yeh et al., 2019), in-situ gel (Tyagi et al., 2013), or gaseous compounds (Uji, 2012). In this study, in addition to intravitreal injections, we successfully injected preformed cylindrical implants to the subretinal and suprachoroidal locations in bovine eyes. These locations were verified using cSLO and OCT images (Figure 5). In treating back of the eye diseases, it may be beneficial to administer and verify the drug product near the affected area, which might be achieved precisely using nonivasive imaging.

4.2. Estimation of length, diameter, and the volume of an implant from cSLO image:

In this study, diameter measurements of the intraocular implants from cSLO images showed more variation compared to their length measurements (Figure 6 & 7; Table 2). This may be because the longer dimension of length minimizes any error due to the placement of crosshairs at the boundaries of the implant, with the error magnified for diameter measurements. Additionally, another source of error is the reduced accuracy of boundary determination with implants located in deeper layers. While boundaries of intravitreal implants are clearly visible in cSLO images, suprachoroidal and subretinal implants were not directly visible in these images; therefore, we had to rely on en face image of the tissue elevations for such measurements which obscured the implant boundaries. Further, because the estimation of volume from the cSLO images was a mathematical calculation, propagation of error from the measurement of length or diameter was observed.

Metal implants showed a hyperreflective surfaces for subretinal and intravitreal implants in cSLO images due to their highly reflective surface for infrared radiations (Figure 5). No such hyperreflectivity was seen for polymeric implants since most of the light passes through the implant.

4.3. Estimation of volume of an implant from integrated bleb area in OCT image

The tissue bleb area method overestimated the volume measurements of suprachoroidal as well as subretinal implants (Figure 6 & 7). This could be due to the consideration of the volume of the whole bleb as opposed to only the implant within the bleb. This volume included the empty area adjacent to the implant. A similar approach has been used by other researchers to obtain the volume of choroidal neovascularization (CNV) in animals or humans where they measured the thickness and spread area of the CNV lesion to obtain their volume (Nie et al., 2015; Sulaiman et al., 2015). Although our current method is found to overestimate the volume of intraocular implants, it might be useful to measure the change in volume of the tissue bleb area over time as a measurement of implant degradation and ultimately drug release.

4.4. Estimation of volume of an implant using cSLO image and thickness map

The volume of suprachoroidal and subretinal implants of both types obtained using the cSLO image and thickness map method when compared to those obtained using the blade micrometer showed a good coefficient of determination (r2 > 0.67), with the value being generally better for subretinal implants (r2 = 0.830–0.974) compared to suprachoroidal implants (r2 = 0.670–0.893). This might be due to the non-reflective surface of polymeric implants, defining boundaries in a thickness map was more challenging than for metal implants. Further, the boundaries were more obscured for suprachoroidal implants than subretinal implants.

4.5. Hyperreflective shadows adjacent to or beneath the implants

Previous observations indicated that in the absence of adaptive optics, the conventional OCT displays hyporeflective shadows of blood vessels, which obscure the view of the underlying tissue (Leitgeb et al., 2014). This is mainly caused by excessive light-scattering and the absorptive nature of blood (Mauer et al., 2017). In the present study, a hyperreflective shadow pattern appeared where there was an absence of tissue image either partially (polymeric implants) or completely (metal implants) underneath the implant (Figure 5). This was evident in the case of subretinal and intravitreal implants, as they lie above or beneath the retina, which is transparent. While the hyperreflective shadow was evident along the edges of the polymeric implant, the shadow was present underneath the entire cross-section of the metal implant. While the hyperreflective bands interrupted segments of choroid on either side of implant, the interruption was continuous under the metal implant. The dislocation of the tissues visible behind subretinal and intravitreal polymeric implants in the OCT image was possibly due to the phase changes of the light beam, while passing through and back from the implant material.

In the case of suprachoroidal metal implants the penetration of light across the choroid is negligible making it impossible to obtain the images of the tissues below (Figure 5). However, more light is reflected by the metal implants, characterized by the intense reflection in the cSLO image.

4.6. Potential applications

The present study has several potential applications. PLGA or other preformed polymeric implants can be injected at suprachoroidal, subretinal, and intravitreal locations within the eye and can be monitored non-invasively for their length, diameter, and volume using a combination of cSLO and OCT imaging. Although cSLO imaging proved to be more accurate, all three methods generally provided good coefficient of determination relative to the blade micrometer-based measures. Thus, there is a potential for the application of a correction factor to better estimate implant metrics by the various methods. The imaging-based measurements, even when they correlate well with a slope close to 1 and or a high coefficient of determination, they can statistically differ from the blade micrometer measurements, especially when each method is very precise (Tables 2–4). The techniques evaluated in this study can potentially be used to track the changes in implant dimensions including volume over time, to better understand implant performance in vivo. The techniques may also be useful to determine the integrity of the implant at the end of the injection procedure. If microspheres (Conti et al., 1997), or other formulations injected in the eye form a depot, the depot size may also be monitored with the techniques used in this study. Even if the implant may not degrade uniformly, based on the combination of cSLO and OCT approaches, we might be able to monitor implant breakdown, degeneration, or a decrease in the bleb volume. Additionally, the intensity of reflected light observed in cSLO image might shed light on changes in material properties. This study is a critical step in accurate and reproducible noninvasive assessment of implant dimensions in multiple locations using cSLO and OCT.

Of the three modes of injections, intravitreal injection is most established, performed routinely, and does not require an ophthalmoscope, although it might be beneficial. The suprachoroidal injection has yet to be approved. Subretinal injection is performed in the clinic via anterior transvitreal approach, while visualizing the inside of the eye (Hartman and Kompella, 2018). We did not use an ophthalmoscope during the injections in this study. Due to the large size of the eye, intravitreal injections are relatively easy to perform. The other two were based on perception of needle resistance and depth. The imaging techniques used in this study helped us visualize the implant after administration. This study used a transscleral approach for all three modes of implant injection, which may be further developed in future.

5. Conclusions

To the best of our knowledge this is the first extensive study to inject and noninvasively monitor intraocular implants in three different locations within the eye. Clearly our study demonstrates that preformed implants can be injected into suprachoroidal and subretinal spaces in addition to the intravitreal space in the eye and that implant length, diameter, and volume can be monitored using noninvasive cSLO and OCT imaging (Figure 5). The specific findings include: 1) The location of an implant in the suprachoroidal, subretinal, and intravitreal spaces can be verified using the OCT and/or cSLO imaging methods. The appearance of a choroidal and retinal or retinal bleb in an OCT image along with the appearance of an implant in the cSLO image confirms the suprachoroidal and subretinal locations, respectively. The appearance of an implant in a cSLO image and the absence of a choroidal or retinal bleb in the OCT image confirms the intravitreal location of an implant (Figure 5). 2) With cSLO imaging, length and diameter can be measured reliably, with accuracy and precision being superior for the measurement of length than the diameter (Table 2). 3) When both implant types and all three implant locations are considered together, measurement of volume using cSLO image generally showed better accuracy compared to the other two methods (Tables 3 and 4).

Acknowledgements

This study was supported by the NIH grant EY029887. The authors are thankful to Dr. Kelsey Barcomb and Rachel Hartman for their critical review of the manuscript and editorial assistance. The authors are thankful to Dr. Alireza Ghaffari for the implant preparation and the injector assembly. The authors also appreciate the helpful discussions with Dr. David Bourne during this project. This work was presented in part as a poster at the 2019 meeting of the Association for Ocular Pharmacology and Therapeutics (AOPT).

Footnotes

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Disclosure: The authors declare no conflicts of interest.

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