Punctum and canalicular anatomy for hydrogel-based intracanalicular insert technology
Abstract
Aim: Despite advances in cataract surgery, postoperative ocular inflammation and pain occurs. To address compliance issues with topical corticosteroid administration, a hydrogel-based dexamethasone insert was developed for intracanalicular administration. The objective is to understand the anatomy to best administer the insert and learn how the anatomy and hydrogel properties help retain the insert in the canaliculus over time. Materials & methods: Human cadavers (n = 5) were dissected to assess dimensions of punctum and canaliculus as part of drug discovery and development. Results & conclusions: Mean measures for punctal diameter was 0.5 ± 0 mm and vertical canaliculi length was 2.4 ± 0.5 mm and width was 1.6 ± 0.5 mm. Vertical canalicular width was larger than the punctal opening, a critical understanding for placing and retaining intracanalicular inserts.
Cataracts are a common result of advancing age, affecting more than 24.4 million people in the USA ≥40 years old. By age 75, approximately half of all Americans will have developed visually significant cataracts [1]. Globally, cataracts are a significant cause of visual impairment and blindness [2]. Small-incision cataract surgery using phacoemulsification has become the standard of care for treating patients with cataracts [3]. New developments in surgical techniques and instrumentation have contributed to excellent clinical outcomes following cataract surgery [4]; however, postoperative ocular inflammation observed in >95% of patients (placebo-treated) during the first 24 h [5,6] and pain reported in at least 50% of patients during the first 24 h [7] remains a common occurrence following cataract surgery [8].
Topical steroids including dexamethasone have been used in ophthalmology for over half a century [9] and are widely prescribed for treating postoperative inflammation and pain of the anterior segment after cataract surgery [10,11]. A typical weekly tapered administration of dexamethasone, starting at four-times daily in the first week and tapering to one-time daily over 4 weeks following cataract surgery, has been shown to significantly reduce anterior chamber inflammation, conjunctival hyperemia, corneal and lid edema, ocular infection, ocular pain, photophobia and tearing [12].
Although the mainstay of drug delivery to the eye has traditionally consisted of patient administration of topical eye drops, problems associated with this route include difficulty with proper administration [8,13,14] and noncompliance [15,16], dry eye symptoms due to adverse reactions to preservatives [7,17–19] and bioavailability limited to less than 5% [20–22], placing a significant burden on the patients and physicians [23]. Eyedrops require a time investment by healthcare professionals to train patients on proper self-administration techniques, and follow-up to ensure compliance and to address complications that may arise from imperfect technique or noncompliance, the sum of which can be burdensome to the practice [23]. Patients may not always be able to get the prescribed steroid drop at that pharmacy. Patient and pharmacy questions regarding use of substitutions of postcataract surgery eyedrop prescriptions are major drivers of calls to physician offices [16]. One calculation estimates that approximately 3000 staff hours are consumed each year by responding to calls regarding the prescribed postcataract surgery eyedrops [16]. The requirement of patients to taper the dosing of topical steroid eyedrops on their own contributes significantly to the complexity of the dosing regimen and may compromise their ability to apply the medication as prescribed [6]. Changing the frequency of drop application increases patient difficulty in remembering the specifics of the regimen [23].
To address these problems, a resorbable dexamethasone ocular insert has been developed and US FDA-approved for intracanalicular administration of dexamethasone (DEXTENZA® [dexamethasone ophthalmic insert] 0.4 mg, for intracanalicular use; Ocular Therapeutix, Inc., MA, USA). It is the first and only FDA-approved drug-eluting intracanalicular hydrogel-based insert. The insert is comprised of a dehydrated, covalently crosslinked synthetic hydrophilic polyethylene glycol-based hydrogel designed to continuously deliver a self-tapering dose of dexamethasone to the surface of the eye [24]. The dexamethasone hydrogel insert is fluorescein-conjugated to aid with visualization. Polyethylene hydrogels are inert, biocompatible materials and have been used extensively in various biomedical applications, including in vivo drug delivery [25,26].
Hydrogels are excellent vehicles for drug delivery and are well-suited for controlled drug delivery. They were one of the earliest biomaterials designed for use in the human body [27] and have since been further developed for many biomedical applications. Hydrogels are a network of polymeric chains that are hydrophilic in nature, capable of absorbing large amounts of water from biological fluids while maintaining a distinct 3D structure. Following hydration, they consist of 90% water, which contributes to their biocompatibility, allowing them to be used in any part of the body including the eye with low potential for inflammation or rejection. They can be manipulated to incorporate small molecules or large proteins within its 3D structure, which can be programmed to enable a uniform, controlled release or tapered delivery over a few days to months through enzymatic, hydrolytic or environmental stimuli [28]. Hydrogels biodegrade over time to water without the need for removal [29]. These attributes provide the flexibility for engineering the hydrogel structure to various sizes or shapes with the potential for addressing ocular conditions in the front and back of the eye.
The dexamethasone insert was FDA-approved and indicated for the treatment of ocular inflammation (20 June 2019) and pain (30 November 2018) following ophthalmic surgery in the USA [30]. Following insertion into the intracanalicular space, the dehydrated hydrogel absorbs physiologic water and swells in cross-sectional width to comfortably fit the canaliculus [24] where it occludes the punctum and reduces tear flow through the canaliculus of the eye (Figure 1). Dry insert dimensions are approximately 0.5 mm in diameter and 3 mm in length and, upon hydration, the insert becomes wider and shorter, conforming to the shape of the canaliculus. A 0.4-mg dose of preservative-free dexamethasone is delivered to the eye in a tapered manner for up to 30 days [31]. A small amount of fluorescein (<0.1% of the overall drug weight) is crosslinked within the hydrogel, which affords postoperative monitoring. Covalent binding of the dye prevents free fluorescein from leaching from the insert. To visualize the insert, a blue light is passed over the exterior of the canalicular area which excites the fluorescein. The application of a yellow filter further enhances visualization as the fluorescein emits a yellow-green glow readily visible through the eyelid tissue. Once the drug is depleted, the insert softens, liquefies and is cleared through the nasolacrimal duct without the need for removal. If removal is necessary, saline irrigation or manual expression can be performed to remove the insert [30]. The safety and efficacy of dexamethasone ocular inserts was established in three Phase III clinical trials involving over 900 subjects [6,32].
As the dexamethasone ophthalmic insert is intended for insertion into the intracanalicular space, understanding the lacrimal system anatomy and dimensions is very valuable to optimize dosing and administration (Figure 2). The primary aim of the paper is to understand the anatomy of the punctum and canaliculus from a perspective of how a hydrogel-based intracanalicular insert can be administered into the canaliculus and how the anatomy and the properties of the hydrogel helps retain the insert in the canalicular space over time. The lacrimal system begins at the punctum. Immediately below the punctum is the lacrimal canaliculus that has a short vertical section (vertical canaliculus) followed by a long horizontal section (horizontal canaliculus) closing into the common canaliculus that adjoins the inferior and superior canaliculi, which ends at the nasolacrimal duct. Numerous other studies have measured these dimensions of the human lacrimal system; however, there has been much variability in the reported results. Variability can be attributed to the methodology used in capturing the dimensions through cadaver studies [33] or structural imaging using an optical coherence tomography [34–37], different terminology used to describe the anatomical structures in the human lacrimal system [38,39] or wide variation in subject anatomy [40]. Gaining a better understanding of the underlying anatomy can help with the nuances during insert administration. The objective of this study was to further characterize the punctum and canalicular dimensions of the human lacrimal system.
The vertical canaliculus was found to be somewhat oval (as shown in cross-section). The width data reported are for the minor axis of the oval. Scissors were used to cut transverse sections of the horizontal canaliculus at 0, 25, 50 and 75% of the distance from the vertical/horizontal canaliculus junction to the common canaliculus.
Methods
Human cadavers of elderly but otherwise healthy male and female individuals (n = 5), 67–75 years old, were made available by a neurological disease treatment and research facility (Barrows Neurological Institute, AZ, USA). Much of the tissue around the superior and inferior punctum and canaliculi was removed prior to creating any sections. The skin and subcutaneous tissues were dissected from the structures prior to sectioning for measurements.
Transverse sectional method using scissors was deemed the best way to obtain measurements. Following punctum measurement, the vertical canaliculus was sectioned by placing one point of the scissors at the punctum and cutting through one wall. The opposite side of the vertical canaliculus (described commonly as the ampulla) was then cut open the same way. Using scissors, transverse sections of the vertical canaliculus were made in one axis only. The width and length of the vertical canaliculus were measured under a microscope using a millimeter ruler. As the vertical canaliculus was found to be somewhat oval, with a major axis (longest diameter of an ellipse) and a minor axis (shortest diameter of an ellipse) (Figure 2), the vertical canaliculus width was reported for the minor axis. Scissors were also used to cut transverse sections of the horizontal canaliculus at 0, 25, 50 and 75% of the distance from the vertical/horizontal canaliculi junction to the common canaliculus (Figure 2). Measurements of the canaliculi were made under the microscope by inserting a punctal gauge (Coroneo™ Punctal Gauge, Eagle Vision) into the canaliculus at a point where it was opened, but not distended. Structure length was measured in some samples using a ruler to measure the distances.
Results
The lacrimal systems of human male and female cadavers (n = 5) were dissected and measured. There was no significant difference in measurements obtained from superior and inferior lids or from female and male cadavers. The mean punctal diameter was 0.5 ± 0 mm (mean ± standard deviation [SD]) and ranged from 0.4 to 0.5 mm. All measurement data are listed in Table 1.
| Puncta diameter (mm) | Vertical canaliculus measurement (mm) | Diameters measurement at % distances from vertical/horizontal canaliculus junction and the common canaliculus (mm) | Horizontal canaliculus (mm) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Gender | Age (years) | Eye | Lid | Diameter | Width | Length | 0% | 25% | 50% | 75% | Length |
| 1 | N/A | N/A | Right | Superior | – | – | – | 0.7 | 0.9 | 0.85 | 0.6 | – |
| 2 | Male | 75 | Left | Superior | 0.5 | 2 | 3.2 | – | – | – | – | – |
| 2 | Male | 75 | Left | Inferior | 0.5 | – | – | – | – | – | – | – |
| 2 | Male | 75 | Right | Inferior | 0.5 | 2 | 2.5 | 0.8 | 0.8 | 0.65 | 0.65 | – |
| 2 | Male | 75 | Right | Superior | – | 1.5 | 2 | 0.85 | 0.78 | 0.8 | 0.8 | – |
| 3 | Male | 79 | Left | Superior | 0.5 | 1 | 3 | 0.8 | 0.65 | 0.8 | 0.4 | – |
| 3 | Male | 79 | Left | Inferior | 0.5 | 1.2 | 2 | 0.8 | 0.65 | 0.75 | 0.6 | – |
| 4 | Female | 69 | Left | Superior | 0.5 | 1.5 | 3 | 0.8 | 0.65 | 0.6 | 0.5 | – |
| 4 | Female | 69 | Left | Inferior | 0.5 | 0.8 | 2.1 | 0.5 | 0.55 | 0.55 | 0.5 | 13 |
| 4 | Female | 69 | Right | Superior | 0.45 | 1.7 | 2 | 0.8 | 0.7 | 0.8 | 0.5 | 9 |
| 4 | Female | 69 | Right | Inferior | 0.5 | 1.9 | 2.1 | 0.8 | 0.6 | 0.75 | 0.6 | 9 |
| 5 | Female | 67 | Left | Superior | 0.45 | 2.4 | 2.1 | 0.9 | 0.8 | 0.85 | 0.8 | 8 |
| 5 | Female | 67 | Left | Inferior | 0.4 | 1.7 | 2.5 | 0.8 | 0.65 | 0.7 | 0.65 | 7 |
| Mean (SD) | 0.5 (0.0) | 1.6 (0.5) | 2.4 (0.5) | 0.8 (0.1) | 0.7 (0.1) | 0.7 (0.1) | 0.6 (0.1) | 9.2 (2.3) | ||||
| Min, max | 0.4, 0.5 | 0.8, 2.4 | 2.0, 3. 2 | 0.5, 0.9 | 0.6, 0.9 | 0.6, 0.9 | 0.4, 0.8 | 7.0, 13.0 | ||||
Vertical canaliculus observations
The lumen size of all vertical canaliculi increased considerably once past the punctum, with a mean ± SD vertical canaliculus length of 2.4 ± 0.5 mm. The body of the vertical canaliculus was oval shaped, with a mean minor axis of 1.6 ± 0.5 mm. The major axis, which is parallel to the skin surface of the eyelid, was difficult to measure with the sectioning method used. Finally, the small cul-de-sac (ampulla) in the vertical canaliculus base opposite the punctum was frequently observed, but not measured.
Horizontal canaliculus observations
Most canaliculi sections were oval or completely collapsed and many sections contained particulate matter. The diameter of the horizontal canaliculi was 0.6–0.8 mm for 75% along length from the vertical/horizontal canaliculus junction to the common canaliculus (Figure 2). While the diameter along most of the lumen remained fairly constant, there appeared to be a consistent narrowing as the common canaliculus was approached. The length of the horizontal canaliculus was only measured in a few eyes averaging to 9.2 ± 2.3 mm.
Pertinent clinical trial data experience
Methods from the dexamethasone ophthalmic insert clinical trials have been previously published [6,32]. Investigators were instructed to visualize the punctum and surrounding area under slit lamp and document the punctal appearance, lid apposition and tear meniscus. Further, investigators assessed the presence of the test article at each study visit through the final visits, using a slit lamp with a blue light and yellow filter. Ease of visualization was graded and recorded. If removal of the insert was required, investigators recorded details pertaining to when removed, cause for removal, method employed and ease of removal.
The dexamethasone insert was retained in over 99% of patients (n = 537) through day 14 in three clinical trials as measured by fluorescein visualization; by day 30 of the postoperative period, the retention rate was found to be 90.4% as measured by fluorescein visualization. (Figure 3). A majority of investigators assessed the ease of visualization as ‘easy’ across all time points through day 30 (Table 2). Two inserts (0.4%, n = 538) required removal due to patient complaints; both inserts were removed via manual pressure and were graded ‘easy or moderately easy’ to remove [41].
| Ease of visualization | Day 2 n = 537 n (%) | Day 4 n = 533 n (%) | Day 8 n = 533 n (%) | Day 14 n = 533 n (%) | Day 30 n = 479 n (%) |
|---|---|---|---|---|---|
| Easy | 505 (94.0) | 497 (93.2) | 492 (92.3) | 479 (89.9) | 399 (83.3) |
| Moderate | 23 (4.3) | 29 (5.4) | 30 (5.6) | 40 (7.5) | 61 (12.7) |
| Difficult | 9 (1.7) | 7 (1.3) | 11 (2.1) | 14 (2.6) | 19 (4.0) |
Discussion
The results of the current study demonstrated the mean punctal diameter of 0.5 mm, ranging from 0.4 to 0.5 mm. Mean vertical canaliculus length was 2.4 mm. The results are in close agreement to a previous study examining the lower lacrimal canaliculus of human cadavers histologically that revealed a mean ± SD width of the vertical segment opening (punctal diameter) to be 0.44 ± 0.07 mm and the mean length of the vertical segment (vertical canaliculus length) to be 2.58 ± 0.24 mm [39]. The results of several other studies using optical coherence tomography (OCT) in healthy volunteers showed varying dimensions for punctal diameter ranging from 0.41 ± 0.16 to 0.65 ± 0.15 mm [34–36,42]. Possible reasons for this difference may be the use of cadavers versus living subjects or the technique used to obtain measurements. Although several of the OCT imaging studies also captured vertical canaliculus length, they truly represent punctal length rather than the true vertical canaliculus height, as the OCT imaging system has limited lid tissue penetration and is unable to capture the total height [34].
The lumens of most vertical canaliculus sections were oval. It was found that the width of the vertical canaliculus (mean width: 1.6 mm) was much larger (∼4×) than the punctal opening (0.5 mm). Clinically, this is important regarding treatment considerations with the intracanalicular dexamethasone (0.4 mg) inserts in patients with small punctal openings, pointing to the need for punctal dilation in these patients during administration.
The vertical canaliculus length and width findings with cadavers shown here as well as the dimension data shown in previous healthy volunteer studies with anterior segment OCT [34–36,42] provide important context regarding the diameter and length dimensions of commercially available punctal/canalicular plugs as well as the intracanalicular dexamethasone insert. Vertical canaliculus permanent plugs range from 0.3 to 0.4 mm in diameter and much shorter (<2 mm long). Complete punctual occluders or more short duration plugs are much smaller on average than the intracanalicular dexamethasone insert and offer a range of sizes, usually 0.2–0.4 mm [43]. The intracanalicular dexamethasone insert dry dimensions (∼0.5 mm in diameter and 3 mm in length) are different, physically and physiologically, compared with the commercially available permanent punctual/canalicular plugs. However, as the canaliculus is much wider than the punctum, once the insert is placed successfully within the intracanalicular space and hydrated, the hydrogel may afford additional benefits of softening (reduced chances of foreign body sensation) and conforming to the surrounding space taking the shape of the canalicular lumen (reduced chances of insert extrusion).
Based on findings from this study and literature, the best method for administering the insert is to open up the canaliculus by gently pulling the lid temporally to align the vertical and horizontal canaliculi while dilating the punctum with an ophthalmic dilator angled in toward the nose (Figure 4). This ensures the system is elongated for diameter as well as length. Dry the punctal opening with an ophthalmic sponge just before insert placement as the insert hydrates upon contact with moisture in about 5–10 s. After drying the punctal area, a blunt (nontoothed) forceps should be used to grasp the insert and place it into the lacrimal canaliculus angling the insert nasally [30]. To aid insert insertion it may be helpful to continue to pull the lid margin temporally so as to align the vertical and horizontal canaliculi and allow placement of the 3 mm long insert. It should be placed just below the punctal opening aiming for 100% insertion with the first push. If <100% of the insertion is achieved with the first attempt, then forceps should be used to grasp, tap or push the exposed remainder of the insert in.
This ensures the system is elongated for length while being careful not to perforate the canaliculus.
A small amount of fluorescein (<0.1% of the overall intracanalicular insert weight) is crosslinked within a hydrogel constituent before hydrogel formation, which prevents free fluorescein from leaching from the insert. This enables visualization of the insert when illuminated by a blue light source (e.g., slit lamp or hand-held blue light) with yellow filter in most patients (Figure 5). The hydrogel liquifies via bulk hydrolysis and drains through the lacrimal drainage system. Although there is no need to remove the insert, it may be removed if necessary. Saline irrigation or manual expression can be performed to remove the insert [30]. With traditional punctal plugs, the rate of extrusion ranged from 25 to 50% across trials after 1 month to 2 years [43]; however, the retention rate of the dexamethasone hydrogel insert was over 99% of patients (n = 537) through day 14 in three clinical trials; by day 30 of the postoperative period, the retention rate was found to be 90.4%. Retention was assessed by proxy through fluorescein visualization which can be difficult with certain skin tones. Therefore, these values may actually underestimate the true retention rate. Most queried subjects (96%) described the insert as very or extremely satisfied, comfortable, convenient and would very or extremely likely to request the insert again [44].
Figure shows the insert in place in the lower canaliculus. Insert seen with slit lamp using blue light (left) and when applying a yellow filter (right) which enhances visibility.
There are several limitations to our study. The study was performed on cadavers that may have slightly different anatomical measurements that live humans and measurements were manual. The specimens used were all from elderly individuals mirroring the cataract population and therefore it is possible that anatomical findings in younger individuals might be different. In addition, the study was performed on a small number of specimens because of the low availability of cadavers.
Administration of eye drops following eye surgery can be challenging for many patients. The dexamethasone ophthalmic insert currently indicated for the treatment of ocular inflammation and pain following ophthalmic surgery, can be an alternative method of dosing. To successfully place the insert, it is essential to understand the underlying lacrimal system anatomy so that positioning of the lid and insert is optimal. These findings offer further insight into clinical decision-making context regarding vertical canaliculus measures and insertion with an intracanalicular dexamethasone (0.4 mg) insert.
Future perspective
The dexamethasone ophthalmic insert is currently indicated for the treatment of ocular pain and inflammation following ophthalmic surgery. Although this technology has been primarily studied for use following cataract surgery, it has also been studied for treating problems with the ocular surface including: chronic allergic conjunctivitis and dry eye disease. Clinical trials are ongoing. The sustained-release hydrogel platform used to continuously deliver dexamethasone to the eye following ocular surgery may be expanded to include a range of medications used to treat other ocular diseases and conditions.
Administration of eye drops can be challenging, especially among elderly patients even with family support. Problems associated with eye drops include missing the eye, instilling an incorrect amount of drops and contaminating the bottle tip. Treatment compliance is diminished when eye drops must be administered multiple times daily.
DEXTENZA®, a dexamethasone (0.4 mg) ophthalmic insert, is a single-application intracanalicular hydrogel insert currently indicated for the treatment of ocular inflammation and pain following ophthalmic surgery. Using a proprietary sustained-release hydrogel platform, it continuously releases a tapered dose of dexamethasone over 30 days.
The length of the dexamethasone insert is 3.0 mm.
The length of the vertical canaliculus is 2.4 mm.
As the canaliliculus lumen (1.6 mm) is much wider than punctum (0.5 mm), dilating the punctum with an ophthalmic dilator should aid in the administration process.
To successfully place the insert, it is essential to open up the canaliculus by pulling the lid to align the vertical and horizontal canaliculi and then administering the insert using a forceps after drying the area around the punctal opening.
During Phase III clinical trials, the retention rate of the insert was >99%. Investigators reported they were easy to insert and subjects found them to be very comfortable, convenient and satisfied.
Financial & competing interest disclosure
SL Tyson received grant funding from Ocular Therapeutix, Inc. P Campbell, J Biggins, A Driscoll, A Gibson, S Vantipalli, JL Metzinger and MH Goldstein are employees of Ocular Therapeutix, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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