Pharmacokinetic Analysis of a Novel 3D-Printed Thermoplastic Polyurethane Continuous Sub-Tenon Drug Delivery Device in Rabbit Eyes

Pharmacokinetic Analysis of a Novel 3D-Printed Thermoplastic Polyurethane Continuous Sub-Tenon Drug Delivery Device in Rabbit Eyes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pharmacokinetic Analysis of a Novel 3D-Printed Thermoplastic Polyurethane Continuous Sub-Tenon Drug Delivery Device in Rabbit Eyes Liyan Ye, Luyun Liang, Xiaolan Liu, Yiqin Duan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7528496/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To evaluate the pharmacokinetic characteristics of a novel 3D-printed thermoplastic polyurethane continuous drug delivery device in rabbit eyes' aqueous humor and vitreous humor. Methods A continuous sub-tenon drug delivery device (CSDDD) was designed using computer-aided design and fabricated via stereolithography 3D printing. The device was implanted sub-tenon in the temporal side of the right eye in rabbits. 1 mL of triamcinolone acetonide (TA) carbomer gel (40 mg/mL) was injected into the drug reservoir for sustained release in CSDDD group. The control group was administered a single subconjunctival (SC) injection of TA at the same dose and concentration. The experimental rabbits were randomly allocated into two groups, each comprising eight temporal subgroups corresponding to 0.5 hr, 1 hr, 3 hr, 6 hr, 24 hr, 48 hr, 7 days, and 14 days post-intervention. To ensure data reliability, five biological replicates were maintained at each time point across all subgroups. Aqueous humor and vitreous humor samples were collected and High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was employed to determine TA concentration. Following the exclusion of outliers (maximum and minimum values), triplicate samples from each time point in each group were retained for subsequent statistical analysis. Descriptive statistical analysis was performed using SPSS 20.0, while pharmacokinetic parameters were calculated with DAS 2.0 software. Results In the aqueous humor, the TA concentration in the CSDDD group remained stable at approximately 0.5 ~ 0.6 μg/mL from 0.5 to 6 hr, peaked at 0.763 ± 0.275 μg/mL by 24 hr, and persisted at 0.641 ± 0.113 μg/mL at 48 hr, followed by a gradual decline thereafter. While in the SC group, the peak concentration was (1.930±0.190 μg/mL) at 1 hr, followed by a rapid decrease. In the vitreous humor, the peak TA concentration in the CSDDD group was (1.627±0.674 μg/mL) at 6 hr, with a sustained release over 14 days. In contrast, the SC group exhibited a peak concentration of (0.496±0.417 μg/mL) at 0.5 hr, remaining at low levels throughout. The CSDDD group showed significantly higher concentration and AUC0-14d in both the vitreous and the aqueous humour relative to the SC group. Conclusion The 3D-printed CSDDD demonstrated effective sustained drug release, achieving prolonged therapeutic concentrations of TA in both the aqueous and vitreous, surpassing the SC group. This device presents a promising alternative for sustained ocular drug delivery. 3D printing Ocular drug delivery device Tenon capsule Triamcinolone acetonide HPLC-MS/MS Pharmacokinetics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Contemporary techniques for ocular drug delivery encompass topical, systemic, intraocular injection and periocular routes. The periocular route is currently regarded as an effective method for drug delivery to the posterior segment [ 1 ] . The periocular roads include the retrobulbar, peribulbar, sub-tenon, and subconjunctival (SC). The sub-tenon injection specifically entails the administration of the drug into the space bordered by the sclera and Tenon’s capsule, a membrane lacking blood vessels, thereby extending the contact duration with the sclera. The sub-tenon route is regarded as a highly promising method for delivering drugs to the posterior segment [ 2 ] . Our previous study [ 3 – 4 ] examined a novel sub-tenon capsule infusion device connected to an external pump to facilitate a controlled, continuous drug delivery. However, this method had limits. The surgical process of transplanting the system may produce stress to the rabbits’ eyes, likely increasing the risk of place and intraocular injury. Next, the device's injection pump made it less user-friendly and convenient, which hindered its resilience and effectiveness. To address these challenges, we developed a novel 3D-printed device to enhance safety and convenience while maintaining the therapeutic efficacy demonstrated in prior studies. Key modifications included replacing the external pump with an integrated drug reservoir and incorporating a compact administration interface at the anterolateral aspect. Additionally, TA was formulated as a carbomer-based gel to prolong drug release and improve intraocular retention. Collectively, these innovations may enable sustained, stable ocular drug delivery, offering new insights into the feasibility of sub-tenon’s capsule continuous infusion device, with substantial experimental value and clinical translation potential. Methods and materials Continuous sub-tenon drug delivery device 3D model design Following several measurements and modifications of the drug delivery device dimensions according to the ocular specifications of normal-weight rabbits, a digital model of the continuous sub-tenon drug delivery device (CSDDD) was created in CAD (Fig. 1 ). The device is approximately 5.0 cm long, 2.0 cm wide and 1.0 cm thick. The wing-like structures on either side measure near 1.5 cm in length, 1.0 cm in maximum width, 0.2 cm in thickness, and the depth of the concave drug reservoir chamber is approximately 0.8 cm. The inner surface is an elliptical honeycomb plane of 2.0 cm in length and 1.0 cm in width, including grid apertures with a diameter of 0.05 cm. Printing procedure The virtual model was transformed into a standard tessellation language file and sent to a high-precision stereolithography (SLA) 3D printer (Lite600, Shanghai Union Technology Corporation). The printer utilized liquid photosensitive resin (C-UV9400E, Godart™, Zhongshan Dajian Technology Co., Ltd.) and ultraviolet laser curing to apply the material in 0.1 mm layers. The digital model was converted into a 3D physical object using specified parameters of 300 mW/cm² light intensity, a support speed of 1 000 mm/s, a contour speed of 2 000 mm/s, and a fill speed of 8 000 mm/s. Model replication The surrounding environment was controlled at a room temperature of 25°C with 60% to 70% humidity. The model was placed into a silicone mold and the thermoplastic polyurethane (TPU) materials (DPI8400, HEICAST™, Dongguan Zhenbang Mold Materials Co., Ltd.) were mixed in appropriate proportions and stirred until uniform, achieving a soft rubber hardness of 50A. After 45 minutes, the mold was removed, resulting in a soft, non-toxic ocular drug delivery device (Fig. 2 A, Fig. 2 B). Drug preparation: Preparation of 2% carbomer gel: 0.200 g of carbomer 934 powder(Shanghai Macklin Biochemical Co., Ltd.) was dissolved in ultrapure water to 10 mL, shaken and vortexed after 10 minutes in a 60°C water bath to form a homogeneous 2% gel, stored at room temperature. Preparation of 10% NaOH solution: 4.000 g of NaOH (Sinopharm Chemical Reagent Co., Ltd.) was dissolved in ultrapure water to 40 mL and cooled, then stored. Preparation of TA carbomer gel: Triamcinolone acetonide injection (1 mL: 40 mg) was spun at 15 000 rpm for 2 minutes at 4°C, and the supernatant was removed. Then 1 mL of 2% carbomer gel was added, followed by 0.02 mL of 10% NaOH. Finally, 1 mL of the TA carbomer gel was injected into the delivery device, with the drug exuding well through the grid holes (Fig. 3 ). Experiment animals Adult New Zealand White rabbits, each weighing between 2.5 and 3.5 kg and carrying valid health immunization certificates, were sourced from an accredited animal facility affiliated with the Second Xiangya Hospital, Central South University. This study received approval from the Animal Ethics Committee at Changsha Aier Eye Hospital. The animals were housed individually under uniform settings. Care and handling of the rabbits adhered strictly to guidelines set by the Association for Research in Vision and Ophthalmology (ARVO). All rabbits had comprehensive examinations for eye illness before being randomly assigned to various groups for subsequent pharmacokinetic analyses. Study design Rabbits were randomly assigned to either the experimental or control group. The experimental group received a CSDDD, into which 1 mL of TA (40 mg/mL) was injected for sustained release over 14 days. The control group received a single SC injection of TA at the same dose and concentration. Within each group, rabbits were further divided into eight temporal subgroups corresponding to 0.5 hr, 1 hr, 3 hr, 6 hr, 24 hr, 48 hr, 7 days, and 14 days post-intervention. To ensure data reliability, five biological replicates were maintained at each time point across all subgroups. After data collection and processing, outliers were excluded, leaving three closely matched data points at each time interval in both the experimental and control groups for subsequent analysis. Surgical procedures and Sample collection Animals were anesthetized via intramuscular injection of Xylazine Hydrochloride Injection (0.1 ~ 0.2 mL/kg, 2 mL:0.2 g, Huamu Animal Health Products Co., Jilin, China). If needed, a supplementary dose of 0.03 mL/kg could be administered either intramuscularly or intravenously during the procedure, but it was restricted to a maximum of half the initial dose. Topical anaesthesia was administered with 0.5% proparacaine hydrochloride (Alcaine; Alcon-Couvreur, Puurs, Belgium) applied three times at 2-minute intervals. In the CSDDD, an eyelid speculum was placed to reveal the bulbar conjunctiva. The bulbar conjunctiva in the superotemporal area was incised 2 mm from the corneal margin. Following the dissection of the fascia between the tenon's capsule and the sclera, the drug delivery device was positioned beneath the temporal tenon's capsule. The device's wings were situated beneath the external and inferior rectus muscles. 1 mL of TA carbomer gel (40 mg) was injected into the reservoir via the rubber tip (Fig. 4 A, Fig. 4 B), allowing the medication to gradually diffuse through the mesh holes for scleral absorption. The left eye was not treated. In the SC group, rabbits were administered 1 mL of TA solution (40 mg/mL) by injection into the superotemporal bulbar conjunctiva, positioned 3 mm from the corneal margin, following sufficient anesthesia (Fig. 4 C). At each subgroup of time point, rabbits were euthanized and the right eyes were promptly removed. The eyeballs were rinsed with physiological saline (0.9%) to remove any remaining drug residue on the surface. 100 ~ 200 µL of aqueous humor from the anterior chamber was aspirated with 1 mL syringe. Additionally, by utilising a 5 mL syringe, 0.3 ~ 0.4 mL of vitreous humor was extracted from the center of the vitreous cavity via the pars plana. All samples were maintained at a temperature of -80°C prior to analysis. Drug assay Each sample was thawed at room temperature and placed 50 µL in a 2 mL Eppendorf tube. Subsequent to the addition of 200 µL of methanol, the mixture was vortexed for 5 minutes and centrifuged at 14 000 rpm for 5 minutes. 1 mL of dichloromethane was added for liquid-liquid extraction, vortexed for another 5 minutes, and subsequently centrifuged at 14 000 rpm at 4°C for 5 minutes. A total of 900 µL of the organic layer was transferred to a 96-well plate and evaporated to dryness under nitrogen at 40°C. The residue was reconstituted with 100 µL of 0.1% formic acid in methanol and prepared for analysis. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) (AB SCIEX Triple Quad TM 4500MD, Shanghai, China) was employed to quantify the levels of TA in the rabbit samples, utilising the specified parameters. The analytical column was a Thermo Accucore C18 (2.65µm, 2.1×30 mm; Thermo Fisher Scientific, Waltham, United States), and the oven temperature was set at 50°C. The mobile phase was composed of water and methanol in a 60:40 volume ratio, flowing at a rate of 0.6 mL/min. An injection volume of 5 µL was used, with gradient elution applied. The operating conditions for electrospray ionization (ESI) were established as follows: the spray voltage was set at 5.5 kV, the nebulizer gas flow rate was maintained at 60 psi and the curtain gas flow rate was adjusted to 20 psi. Additionally, the heated gas flow rate was configured at 55 psi, drying gas temperature was set to 550 ℃ and the dwell time was 200 ms. Pharmacokinetic assessments and Statistical analysis The concentrations of TA in various tissues were individually analyzed for pharmacokinetic assessment, which are evaluated using Drug and Statistics Software (DAS) 2.0 software (Mathematical Pharmacology Professional Committee of China, Beijing, China) by one-compartment model analysis. The pharmacokinetic parameters obtained included: peak concentration (Cmax), time to peak concentration (Tmax), elimination half-life (T 1/2 ), area under the concentration-time curve between 0 and 14 days (AUC 0–14d ). The Statistical Package for the Social Sciences (SPSS) version 22.0 software (SPSS Inc., Chicago, IL, USA) was used for the statistical data analysis. Repeated measures analysis of variance(ANOVA) was used to compare the overall difference between the CSDDD and the SC group. An independent sample t-test was employed to compare the differences between two groups at each time point. The significance level α was set at 0.05. Results Concentration of TA The mean levels of TA concentrations in the aqueous humor and vitreous at different time points following CSDDD group and SC group are provided in Table 1 with results presented in Fig. 5. In the CSDDD group, the TA concentration in the aqueous humor remained stable at approximately 0.5 ~ 0.6 µg/mL from 0.5 to 6 hr, peaked at 0.763 ± 0.275 µg/mL by 24 hr, and persisted at 0.641 ± 0.113 µg/mL at 48 hr, followed by a gradual decline thereafter. In SC administration, the peak aqueous humor TA concentration (1.930 ± 0.190 µg/mL)) occurred at 1 hr after TA injection, but decreased rapidly to (0.027 ± 0.005) µg/mL at 48 hr. Repeated measures ANOVA indicated that the TA concentration in the CSDDD was significantly higher than that of the SC (F = 1.87, p = 0.001; Table 1 ). TA concentrations were analyzed using the independent t-test. Levels of TA concentration in the aqueous humor(Fig. 5a) were significantly higher at 0.5 hr, 1 hr, 3 hr and 48 hr (n = 3, p <0.05) and negligible at 6 hr, 24 hr, 7 d and 14 d (n = 3, p = 0.548 at 6 hr, p = 0.066 at 24 hr, p = 0.076 at 7 days, p = 0.825 at 14 days). In the CSDDD group, the peak concentration of TA in vitreous(1.627 ± 0.674 µg/mL) was recorded at 6 hr of continuous scleral penetration and remained at the level of (0.567 ± 0.388 µg/mL) at 7 days (Table 1 ; Fig. 5b). In the SC administration, the peak vitreous TA concentration (0.496 ± 0.417 µg/mL) occurred at 0.5 hr after TA injection, and remained at a low level throughout the study, with a concentration of (0.099 ± 0.058 µg/mL) measured on 7 days. Repeated measures ANOVA pointed out that the TA concentration in the CSDDD was significantly higher than that of SC (F = 1.783, p = 0.011; Table 1 ). By the independent t-test, levels of TA concentration in the vitreous (Fig. 5b) were significantly higher at 1 hr, 3 hr, 6 hr and 24 hr(n = 3, p <0.05) and negligible at 0.5 hr, 48 hr, 7 days and 14 days (n = 3, p = 0.635 at 0.5 hr, p = 0.102 at 48 hr, p = 0.395 at 7 days, p = 0.571 at 14 days). Table 1 TA concentrations in the aqueous humor and vitreous following CSDDD and SC group, µg/mL * . Time CSDDD group SC group p -value Aqueous humor 0.5hr 0.548 ± 0.283 1.363 ± 0.141 0.022 † 1hr 0.581 ± 0.190 1.930 ± 0.190 0.009 † 3hr 0.606 ± 0.347 1.680 ± 0.383 0.042 † 6hr 0.520 ± 0.153 0.397 ± 0.217 0.548 24hr 0.763 ± 0.275 0.223 ± 0.129 0.066 48hr 0.641 ± 0.113 0.027 ± 0.005 0.046 † 7d 0.109 ± 0.037 0.053 ± 0.009 0.076 14d 0.024 ± 0.014 0.030 ± 0.014 0.825 F = 18.567, p = 0.001 † Vitreous 0.5hr 0.773 ± 0.613 0.496 ± 0.417 0.635 1hr 1.143 ± 0.151 0.226 ± 0.223 0.009 † 3hr 1.613 ± 0.281 0.223 ± 0.211 0.005 † 6hr 1.627 ± 0.674 0.213 ± 0.148 0.044 † 24hr 1.500 ± 0.241 0.067 ± 0.024 0.001 † 48hr 0.693 ± 0.439 0.037 ± 0.031 0.102 7d 0.567 ± 0.388 0.099 ± 0.058 0.395 14d 0.024 ± 0.007 0.028 ± 0.002 0.571 F = 9.378, p = 0.011 † F-value is the testing value of repeated measures analysis of variance to compare the overall difference between two groups. † denotes the difference was statistically significant. Pharmacokinetics of TA The pharmacokinetic parameters of TA in the aqueous humor and vitreous are shown in Table 2 , the AUC curves are presented in Fig. 6 . In the CSDDD, the Cmax were 0.763 µg/mL and 1.627 µg/mL in the aqueous humor and vitreous, respectively. The Tmax was 24 hr, 6 hr, respectively. The AUC 0–14d were 87.713 µg*h/mL and 187.991 µg*h/mL, respectively. The T 1/2 were 33.56 hr and 69.32 hr respectively. Following an SC administration, the Cmax were 1.930 µg/mL and 1.496 µg/mL, respectively in the aqueous humor and vitreous, and the Tmax were 1 hr and 0.5 hr respectively. The AUC 0–14d were 28.159 µg*h/mL and 23.995 µg*h/mL, respectively. The T 1/2 were 6.71 hr, 19.51 hr, respectively. We observed that the AUC from 0.5 to 6 hours of aqueous humor was slightly higher in SC compared to the CSDDD. However, after 6 hours, the AUC in CSDDD increased exponentially, significantly surpassing that of the SC (Fig. 6 a). Similarly, the AUC of vitreous in CSDDD was comparable to SC during the first 6 hours but exhibited exponential growth thereafter, greatly exceeding the values observed in the SC group (Fig. 6 b). Table 2 The pharmacokinetic parameters of TA in the aqueous humor and vitreous following CSDDD and SC group. Parameters CSDDD group SC group Aqueous humor Vitreous Aqueous humor Vitreous AUC 0 − 14d (µg*h/mL) 87.71 187.99 28.16 24.00 T 1/2 (h) 33.56 69.32 6.71 19.51 Cmax(µg/mL) 0.763 1.627 1.930 0.496 Tmax(h) 24 6 1 0.5 Cmax: peak concentration; Tmax: time to peak concentration; AUC 0 − 14d : area under the concentration-time curve between 0 and 14 days; T 1/2 : elimination half-life. Discussion 3D printing technologies include fused deposition modeling (FDM) and stereolithography (SLA) and so on [ 5 ] . In this study, we employed SLA, one of the earliest rapid prototyping techniques to be commercialized, known for its fast processing speed, high precision and efficient material utilization [ 6 – 7 ] . The drug delivery device was constructed using thermoplastic polyurethane (TPU) after 3D printing the model. In its molecular chain, TPU, an elastomeric block copolymer with urethane groups, combines soft and hard segments made of various materials to produce exceptional elasticity and mechanical strength [ 8 – 9 ] . Through 3D printing, Abdul Samat [ 10 ] created a tracheal stent using a TPU/polylactic acid composite. Their empirical results, both in vitro and in vivo, confirmed the object's biocompatibility, exhibiting no negative consequences on cellular proliferation or movement. TPU is ideally suited for the present program because of these characteristics. In hare eyes, the device can be densely folded to fit underneath the tenon's spacecraft, where it has since regained its original shape. This method reduces the risk of muscle rejection and regional inflammatory responses and facilitates less restrictive implantation. The majority of ocular disorders are treated primarily with pharmacotherapy. The sclera constitutes about 5/6 of the whole ocular surface area and mainly comprises equally arranged, loosely structured collagen fibres, creating porous and toothbrush-like cells [ 11 ] . The amorphous collagen structure of the sclera allows drugs to enter the posterior region despite having a relatively low level of vascularization. The sclera's primary channel for drug absorption is through passive diffusion [ 12 ] . Scleral permeability depends on the molecular size, with molecules up to 70 000 Da able to permeate relatively easily [ 13 ] . Due to its large intake area and higher permeability, this is beneficial for the trans-scleral route. Trans-scleral continuous drug delivery systems significantly maintain long-lasting pharmacological effects by allowing the steady release of medicines at therapeutic concentrations. Research indicates that scleral drug absorption is driven by the constant-state flow across the sclera [ 14 ] , meaning that the medicine may remain in contact with the scleral surface long enough to create this stable condition. The large surface area of the human sclera supports diffusion and offers good tolerance to foreign objects resting on its surface, making it a viable long-term transscleral administration option in clinical practice. The tenon’s capsule, a dense fibrous sheath surrounding the eye, has loose connective tissue separating it from the sclera, creating a potential space that serves as an ideal platform for device implantation. Sub-tenon drug delivery mitigates the risks associated with intraocular injections, providing a safer and more effective method for posterior segment delivery. Therefore, we selected the sub-tenon route for implanting the drug delivery device. TA, with the molecular formula C24H31FO6 and a molecular weight of 434.5D, is a long-acting hydrophobic and lipophilic corticosteroid. Previous studies have shown that TA can inhibit the gene expression of pro-inflammatory mediators or cytokines in various cell lines at half-maximal effective concentrations ranging from 1.7 to 4.3 ng/mL [ 15 – 16 ] . Furthermore, a TA concentration of 0.01 µg/mL is sufficient to effectively suppress the expression of vascular growth factors with this inhibitory effect being dose-dependent (a level referred to as the effective therapeutic concentration [ETC]) [ 17 ] . Due to its high potency and multifaceted anti-inflammatory and anti-angiogenic effects, TA has become a well-known treatment for posterior segment ocular conditions [ 18 – 21 ] . In this study, we combined high-concentration TA with carbomer, a non-toxic, non-irritating, and very porous substance, to create an equally dispersed, short-flow TA-carbomer gel, extending the time of contact between high-concentration TA and the scleral area. Additionally, we created a drug delivery device with a porous area that corresponds to the sclera, facilitating drug-sclera touch and promoting scleral intake. The non-porous side of the device minimizes direct drug exposure to the conjunctiva, reducing clearance by blood vessels and lymphatics of conjunctival to enhance the bioavailability of TA. In this study, throughout the observation period, the TA concentrations in the CSDDD group consistently exceeded the half-maximal effective concentration, achieving and maintaining the ETC within the local ocular tissue for a prolonged period. In our experiment, deep sub-Tenon's injection was initially considered as a control but was precluded because it required a relatively large incision, which led to significant drug leakage due to wound gaping and mechanical disruption from rabbit ocular movements. These factors resulted in uncontrolled and variable drug retention, compromising experimental reproducibility. In contrast, subconjunctival (SC) injection was selected as the control because its small-gauge needle puncture (26G) created a self-sealing wound that minimized drug leakage, ensuring consistent and measurable drug delivery. In the vitreous, the CSDDD group consistently exhibited TA concentrations that were equal to or greater than those in the SC throughout the study period. In the SC, TA concentrations peaked at 0.5 hr and then steadily declined. Throughout the entire experimental period, TA levels in the SC group remained relatively low. In contrast, the CSDDD group showed a TA concentration of (0.773 ± 0.613) µg/mL at 0.5 hr, which gradually increased to a peak of (1.627 ± 0.674) µg/mL at 6 hr —3.3 times the peak concentration observed in the SC group and 163 times the ETC. Even at 14 days, the concentration remained 2.4 times above the ETC. The overall difference in drug concentrations between the two groups was statistically significant (F = 9.378, p = 0.011), with significant differences observed at 1 hr ( p = 0.009), 3 hr ( p = 0.005), 6 hr ( p = 0.044), and 24 hr ( p = 0.001). Previous studies suggested that scleral drug permeability involves a time delay [ 22 ] . Insufficient contact time between the drug and the sclera may hinder effective penetration into the vitreous cavity, which could partly explain why the TA concentration in the vitreous of the CSDDD peaked 6 hours after administration, much earlier than the peak observed at 24 hours in the aqueous humor in this study. In the CSDDD group, the device was implanted closer to the vitreous body, allowing the drug to directly penetrate the sclera and enter the vitreous. In contrast, the drug in the vitreous may need to reach the aqueous humor through the choroidal-retinal vasculature or the vitreous-posterior aqueous humor circulation. As a result, the peak time in the vitreous in the CSDDD group occurred much earlier than in the aqueous humor. In the aqueous humor, the SC group exhibited a rapid increase in TA concentration, peaking at 1 hr (1.930 ± 0.190 µg/mL), followed by a sharp decline. This behavior is likely attributed to the conjunctival injection site being closer to the aqueous humor, allowing TA to directly access the anterior segment, where it is rapidly absorbed. Due to the poor water solubility of the TA injection solution, the drug powder is more likely to accumulate in the aqueous humor following SC injection, resulting in a higher peak concentration of TA in the aqueous humor in the SC group. The peak concentration of the drug in the vitreous of the SC group was much lower (0.496 ± 0.417 µg/mL) compared to the aqueous humor (1.930 ± 0.190 µg/mL), indicating that the drug concentration reaching the vitreous through scleral penetration via subconjunctival injection was very low. Due to the presence of tears film [ 23 ] , blood-aqueous barrier and rapid nasolacrimal clearance [ 24 – 25 ] , the drug is rapidly metabolized and cleared, leading to a rapid decrease in concentration. This indicates that drug release in the SC group is concentrated in the initial phase and does not sustain a prolonged therapeutic effect. Conversely, the CSDDD group showed more stable TA concentrations, with a continuous-release mechanism resulting in lower early-phase concentrations that gradually increased, peaking at 24 hr (0.763 ± 0.275 µg/mL), approximately 76 times the ETC. Trace amounts of the drug, about 2.4 times the ETC, were still detectable at 14 days. The overall difference in drug concentrations between the two groups was statistically significant (F = 18.567, p = 0.001), with significant differences at 0.5 hr ( p = 0.022), 1 hr ( p = 0.009), 3 hr ( p = 0.042), and 48 hr ( p = 0.046). The AUC 0 − 14d for all tissues was higher in the CSDDD than in the SC. Specifically, in the vitreous, the TA exposure in the CSDDD (AUC 0 − 14d =187.991 µg×h/mL) was approximately 7.8 times that of the SC (AUC 0 − 14d = 23.995 µg×h/mL). In the aqueous humor, the TA exposure in the CSDDD (AUC 0 − 14d =87.713 µg×h/mL) was about 3.1 times higher than in the SC (AUC 0 − 14d = 28.159 µg×h/mL). These findings suggest that the continuous release mechanism of CSDDD allows for more efficient drug delivery into the eye compared to a single subconjunctival injection. In the CSDDD, TA concentrations and AUC₀₋₁₄ d were significantly higher in the vitreous than in the aqueous humor. This disparity can be attributed to the proximity of the release site and differences in metabolic rates between the vitreous and aqueous humor. The device is positioned under the tenon’s capsule, close to the vitreous, allowing the drug to more readily diffuse through the sclera into the vitreous. Additionally, the vitreous has a slower metabolic rate, lacking direct vascular supply, and its drug clearance primarily depends on slow diffusion through the vitreous matrix. This characteristic enables the maintenance of high drug concentrations and prolonged therapeutic effects within the vitreous. In contrast, the aqueous humor has a rapid turnover rate, with efficient drug clearance through the anterior circulation, significantly reducing the potential for drug accumulation in this compartment. Previous studies conducted by Zhao [ 26 ] and Huang [ 27 – 28 ] explored the development of a sub-tenon micro-perfusion system (SMS) consisting of a catheter, microneedle and micropump. By inserting a catheter into the sub-tenon area and using a micropump to support shipping, this program facilitates steady drug release of dexamethasone (molecular weight: 392.46D). As corticosteroids, dexamethasone, with a smaller molecular weight than TA, is expected to more readily penetrate the sclera and reach higher concentrations within the eye. However, during the 24-hour observation period in the SMS group, Huang's study reported lower mean drug concentrations in both the vitreous (0.022 ~ 0.071 µg/mL) and aqueous humor (0.032 ~ 0.295 µg/mL) compared to the concentrations observed in this study. Similarly, Zhao's results were consistent (vitreous: 0.109 ~ 0.882 µg/mL). From a pharmacokinetic perspective, Zhao's study showed lower AUC and T 1/2 in the vitreous (AUC 0 − 24h : 8.22 µg×h/mL; T 1/2 : 8.07 hr). Huang's study also showed lower AUC values and T 1/2 in both vitreous (AUC 0 − 24h : 1.41 µg×h/mL; T 1/2 : 14.32 hr) and aqueous humor (AUC 0 − 24h : 33.71 µg×h/mL; T 1/2 : 5.54 hr), compared to the corresponding AUC and T 1/2 in this experiment in both vitrous (AUC 0 − 14d : 187.66 µg×h/mL; T 1/2 : 6 hr) and aqueous humor (AUC 0 − 14d : 87.71 µg×h/mL; T 1/2 : 24 hr). Besides, the SMS system requires specialized micropumps and catheters, which complicate medical procedures and likely impede its adoption. Additionally, their studies were only conducted for a 24-hour pharmacokinetic observation time without examining the long-term effects on intraocular pressure or scleral integrity, which are crucial for determining the health and viability of prolonged use. These comparative results indicate that the newly developed delivery system surpasses the previously reported SMS system in maintaining therapeutic drug levels, suggesting superior drug retention and enhanced bioavailability achieved through the novel delivery approach in this study. Currently, researchers have investigated the use of reservoir-based corticosteroid formulations for intravitreal (IVT) implantation [ 29 ] . Compared to these methods, CSDDD offers the advantage of allowing medication replenishment as needed, making it suitable for clinical scenarios that require prolonged drug release. Notably, while CSDDD involves surgical insertion beneath the tenon’s capsule, it fails to mechanically disrupt the normal anatomy of the retina and choroid. Furthermore, in the event of severe complications, the device can be removed with relative ease. In contrast, IVT implants necessitate surgical infiltration through the sclera, choroid, and retina, which may allow the implant to move within the vitreous chamber and potentially cause vitreous traction. If serious complications occur, removing the implant can be difficult. Other researchers have explored transscleral drug delivery methods, including ultrasound-mediated delivery [ 30 ] and iontophoresis [ 31 ] . Although these methods avoid the complications associated with intraocular injections, they rely on emitting radiation (sound waves or electromagnetic waves) or applying magnetic fields (electric or magnetic), which generate thermal effects in biological tissues [ 32 – 33 ] . These effects can alter the structure or function of tissues and their cells [ 34 ] or increase tissue permeability through the damaging effects of electric currents on collagen structures, potentially resulting in tissue damage [ 35 ] . In contrast, CSDDD utilizes passive diffusion for drug absorption, offering a more tissue-friendly approach. In summary, the safety profile of the device material, the ideal platform, the system’s ability to release the drug over a sustained period, and the effective extension of drug contact time with the sclera ensure the feasibility of CSDDD as an effective alternative for posterior segment drug delivery. The CSDDD offers continuous and stable drug release, with superior performance in the vitreous, positioning it as an encouraging option for therapeutic intervention of vascular and inflammatory posterior segment diseases. Nonetheless, our study has certain limitations. First, at 14 days, TA concentrations in CSDDD were relatively low. This might be attributed to the tendency of the TA-carbomer gel to form unabsorbed drug residues, leading to drug accumulation in tissues or blockage of the mesh pores in the delivery device. Upcoming studies will concentrate on refining the formulation of the sustained-release drug. Over time, as the drug reservoir in the device depletes, the amount of drug released through the mesh pores diminishes compared to the initial stages, which could also contribute to the significant decline in TA concentration observed at 14 days. In subsequent experiments, we plan to supplement the sustained-release drug periodically and extend the observation period to better understand the pharmacokinetic mechanisms of CSDDD-mediated drug delivery. Moreover, our findings are based on data from rabbits, not humans. Rabbit’s eyes are characterized by their smaller size and thinner sclera, which enhance drug penetration into the choroid. They also have greater ocular blood flow and circulation rates, potentially resulting in a shorter drug half-life in rabbit eye tissues. These anatomical and physiological differences can influence the pharmacokinetics of ocular drugs. Additionally, this study was conducted on healthy rabbit eyes. Future research should extend to studying diseased eyes, particularly those with vascular or inflammatory posterior segment conditions. Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Animal Ethics Committee at Changsha Aier Eye Hospital (Date:2023.10.07/No:AEI20230019). Competing interests The authors have no relevant financial or non-financial interests to disclose. Fundings This work was supported by [Natural Science Foundation of Hunan Province] (Grant number [2020JJ4001]) and [The Science and Technology Innovation Program of Hunan Province] (Grant number [2018SK50103]). Authors' contributions All authors contributed to the study conception and design. The methodology was designed by[DuanYiqin] and [YeLiyan]. Material preparation, data collection and analysis were performed by [YeLiyan], [LiangLuyun] and [LiuXiaolan]. The first draft of the manuscript was written by [YeLiyan] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements We thank the personnel at the animal center of Changsha Aier Eye Hospital for providing physical space and technical assistance with the animal work. We thank the AIER Eye Hospital group for great support and help. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7528496","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":521659934,"identity":"c0fe40fd-8ed2-42a5-9dc5-a5ddc89ecc01","order_by":0,"name":"Liyan 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15:49:46","extension":"html","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":120678,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/4ca5b4f196a1d87ced784e69.html"},{"id":93155860,"identity":"5a775d89-41b8-4a22-86f1-ae69f5a3015d","added_by":"auto","created_at":"2025-10-09 15:33:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129668,"visible":true,"origin":"","legend":"\u003cp\u003eModel diagram of continuous sub-tenon drug delivery device for rabbit eye.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/8f54e3ac087191e38db76eef.png"},{"id":93155858,"identity":"d2ec65d9-4bd2-48f8-8e51-2e9a5076808c","added_by":"auto","created_at":"2025-10-09 15:33:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":365155,"visible":true,"origin":"","legend":"\u003cp\u003ePhotograph of continuous sub-tenon drug delivery device.\u003c/p\u003e\n\u003cp\u003eA, The inner surface of the drug delivery device, which contacts the sclera, showing the mesh pores; B, The outer surface of the drug delivery device, which contacts the conjunctiva, showing the drug reservoir.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/cc758213b266d3c40164266a.png"},{"id":93157214,"identity":"0ffc5714-5ffb-4992-be93-cbbb11505ab8","added_by":"auto","created_at":"2025-10-09 15:49:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":241296,"visible":true,"origin":"","legend":"\u003cp\u003eThe continuous sub-tenon drug delivery device following the injection of the medication (1 mL of triamcinolone acetonide carbomer gel).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/453a322f79763f2d3a21fa32.png"},{"id":93155866,"identity":"4b763baa-15ff-4699-a1c3-e27af55934a8","added_by":"auto","created_at":"2025-10-09 15:33:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":615884,"visible":true,"origin":"","legend":"\u003cp\u003eIllustration of surgical procedures and drug administration for CSDDD versus SC group.\u003c/p\u003e\n\u003cp\u003eA, CSDDD group, the wing-like structures on both sides of the drug delivery device are flexible and stretchable, fitting well after being clipped onto the extraocular muscles;\u003c/p\u003e\n\u003cp\u003eB, CSDDD group, the drug delivery device can be fully implanted under the tenon’s capsule of the rabbit eye;\u003c/p\u003e\n\u003cp\u003eC, SC group, subconjunctival injection of 1 mL TA suspension was administered, ensuring complete drug distribution in the superior bulbar subconjunctival space without leakage.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/93ddecea07b54227980e1214.png"},{"id":93155861,"identity":"e7a4cef3-f73e-481a-ae58-1737b92e4aa5","added_by":"auto","created_at":"2025-10-09 15:33:46","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":116995,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 3. TA distribution characteristics in aqueous humor (a) and vitreous (b) via CSDDD and SC.\u003c/p\u003e\n\u003cp\u003eTA: triamcinolone acetonide; CSDDD: continuous sub-tenon drug delivery device; SC: subconjunctival\u003c/p\u003e\n\u003cp\u003e* denotes the difference was statistically significant.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/bbea2ce59cf44228d9f7c0cd.png"},{"id":93156915,"identity":"1b3f525b-7250-4047-80f1-ce82a0f64350","added_by":"auto","created_at":"2025-10-09 15:41:46","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":151380,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 6. Change of AUC of TA in the aqueous humor (a) and vitreous (b).\u003c/p\u003e\n\u003cp\u003eTA: triamcinolone acetonide; CSDDD: continuous sub-tenon drug delivery device; SC: subconjunctival\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/cb2721b89dfe7ddb0173156d.png"},{"id":94469561,"identity":"283dd39f-852e-48a0-b843-f29db33f398d","added_by":"auto","created_at":"2025-10-27 15:30:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2691584,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/66352db5-793e-4508-ae47-764e53716528.pdf"},{"id":93155873,"identity":"f3201c13-fe06-4ecc-bb03-2064f7d5d630","added_by":"auto","created_at":"2025-10-09 15:33:46","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":380438,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical Abstract\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"GA.png","url":"https://assets-eu.researchsquare.com/files/rs-7528496/v1/5d95901ca4b3f1a6ad13cb98.png"}],"financialInterests":"","formattedTitle":"Pharmacokinetic Analysis of a Novel 3D-Printed Thermoplastic Polyurethane Continuous Sub-Tenon Drug Delivery Device in Rabbit Eyes","fulltext":[{"header":"Introduction","content":"\u003cp\u003eContemporary techniques for ocular drug delivery encompass topical, systemic, intraocular injection and periocular routes. The periocular route is currently regarded as an effective method for drug delivery to the posterior segment \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. The periocular roads include the retrobulbar, peribulbar, sub-tenon, and subconjunctival (SC). The sub-tenon injection specifically entails the administration of the drug into the space bordered by the sclera and Tenon\u0026rsquo;s capsule, a membrane lacking blood vessels, thereby extending the contact duration with the sclera. The sub-tenon route is regarded as a highly promising method for delivering drugs to the posterior segment \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOur previous study \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e examined a novel sub-tenon capsule infusion device connected to an external pump to facilitate a controlled, continuous drug delivery. However, this method had limits. The surgical process of transplanting the system may produce stress to the rabbits\u0026rsquo; eyes, likely increasing the risk of place and intraocular injury. Next, the device's injection pump made it less user-friendly and convenient, which hindered its resilience and effectiveness. To address these challenges, we developed a novel 3D-printed device to enhance safety and convenience while maintaining the therapeutic efficacy demonstrated in prior studies. Key modifications included replacing the external pump with an integrated drug reservoir and incorporating a compact administration interface at the anterolateral aspect. Additionally, TA was formulated as a carbomer-based gel to prolong drug release and improve intraocular retention. Collectively, these innovations may enable sustained, stable ocular drug delivery, offering new insights into the feasibility of sub-tenon\u0026rsquo;s capsule continuous infusion device, with substantial experimental value and clinical translation potential.\u003c/p\u003e"},{"header":"Methods and materials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eContinuous sub-tenon drug delivery device\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003e3D model design\u003c/strong\u003e\u003cp\u003eFollowing several measurements and modifications of the drug delivery device dimensions according to the ocular specifications of normal-weight rabbits, a digital model of the continuous sub-tenon drug delivery device (CSDDD) was created in CAD (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The device is approximately 5.0 cm long, 2.0 cm wide and 1.0 cm thick. The wing-like structures on either side measure near 1.5 cm in length, 1.0 cm in maximum width, 0.2 cm in thickness, and the depth of the concave drug reservoir chamber is approximately 0.8 cm. The inner surface is an elliptical honeycomb plane of 2.0 cm in length and 1.0 cm in width, including grid apertures with a diameter of 0.05 cm.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePrinting procedure\u003c/strong\u003e\u003cp\u003eThe virtual model was transformed into a standard tessellation language file and sent to a high-precision stereolithography (SLA) 3D printer (Lite600, Shanghai Union Technology Corporation). The printer utilized liquid photosensitive resin (C-UV9400E, Godart\u0026trade;, Zhongshan Dajian Technology Co., Ltd.) and ultraviolet laser curing to apply the material in 0.1 mm layers. The digital model was converted into a 3D physical object using specified parameters of 300 mW/cm\u0026sup2; light intensity, a support speed of 1 000 mm/s, a contour speed of 2 000 mm/s, and a fill speed of 8 000 mm/s.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eModel replication\u003c/strong\u003e\u003cp\u003eThe surrounding environment was controlled at a room temperature of 25\u0026deg;C with 60% to 70% humidity. The model was placed into a silicone mold and the thermoplastic polyurethane (TPU) materials (DPI8400, HEICAST\u0026trade;, Dongguan Zhenbang Mold Materials Co., Ltd.) were mixed in appropriate proportions and stirred until uniform, achieving a soft rubber hardness of 50A. After 45 minutes, the mold was removed, resulting in a soft, non-toxic ocular drug delivery device (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDrug preparation:\u003c/h3\u003e\n\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003ePreparation of 2% carbomer gel: 0.200 g of carbomer 934 powder(Shanghai Macklin Biochemical Co., Ltd.) was dissolved in ultrapure water to 10 mL, shaken and vortexed after 10 minutes in a 60\u0026deg;C water bath to form a homogeneous 2% gel, stored at room temperature.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePreparation of 10% NaOH solution: 4.000 g of NaOH (Sinopharm Chemical Reagent Co., Ltd.) was dissolved in ultrapure water to 40 mL and cooled, then stored.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePreparation of TA carbomer gel: Triamcinolone acetonide injection (1 mL: 40 mg) was spun at 15 000 rpm for 2 minutes at 4\u0026deg;C, and the supernatant was removed. Then 1 mL of 2% carbomer gel was added, followed by 0.02 mL of 10% NaOH. Finally, 1 mL of the TA carbomer gel was injected into the delivery device, with the drug exuding well through the grid holes (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\n\u003ch3\u003eExperiment animals\u003c/h3\u003e\n\u003cp\u003eAdult New Zealand White rabbits, each weighing between 2.5 and 3.5 kg and carrying valid health immunization certificates, were sourced from an accredited animal facility affiliated with the Second Xiangya Hospital, Central South University. This study received approval from the Animal Ethics Committee at Changsha Aier Eye Hospital. The animals were housed individually under uniform settings. Care and handling of the rabbits adhered strictly to guidelines set by the Association for Research in Vision and Ophthalmology (ARVO). All rabbits had comprehensive examinations for eye illness before being randomly assigned to various groups for subsequent pharmacokinetic analyses.\u003c/p\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eRabbits were randomly assigned to either the experimental or control group. The experimental group received a CSDDD, into which 1 mL of TA (40 mg/mL) was injected for sustained release over 14 days. The control group received a single SC injection of TA at the same dose and concentration. Within each group, rabbits were further divided into eight temporal subgroups corresponding to 0.5 hr, 1 hr, 3 hr, 6 hr, 24 hr, 48 hr, 7 days, and 14 days post-intervention. To ensure data reliability, five biological replicates were maintained at each time point across all subgroups. After data collection and processing, outliers were excluded, leaving three closely matched data points at each time interval in both the experimental and control groups for subsequent analysis.\u003c/p\u003e\n\u003ch3\u003eSurgical procedures and Sample collection\u003c/h3\u003e\n\u003cp\u003eAnimals were anesthetized via intramuscular injection of Xylazine Hydrochloride Injection (0.1\u0026thinsp;~\u0026thinsp;0.2 mL/kg, 2 mL:0.2 g, Huamu Animal Health Products Co., Jilin, China). If needed, a supplementary dose of 0.03 mL/kg could be administered either intramuscularly or intravenously during the procedure, but it was restricted to a maximum of half the initial dose. Topical anaesthesia was administered with 0.5% proparacaine hydrochloride (Alcaine; Alcon-Couvreur, Puurs, Belgium) applied three times at 2-minute intervals.\u003c/p\u003e\u003cp\u003eIn the CSDDD, an eyelid speculum was placed to reveal the bulbar conjunctiva. The bulbar conjunctiva in the superotemporal area was incised 2 mm from the corneal margin. Following the dissection of the fascia between the tenon's capsule and the sclera, the drug delivery device was positioned beneath the temporal tenon's capsule. The device's wings were situated beneath the external and inferior rectus muscles. 1 mL of TA carbomer gel (40 mg) was injected into the reservoir via the rubber tip (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eA, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eB), allowing the medication to gradually diffuse through the mesh holes for scleral absorption. The left eye was not treated.\u003c/p\u003e\u003cp\u003eIn the SC group, rabbits were administered 1 mL of TA solution (40 mg/mL) by injection into the superotemporal bulbar conjunctiva, positioned 3 mm from the corneal margin, following sufficient anesthesia (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003eAt each subgroup of time point, rabbits were euthanized and the right eyes were promptly removed. The eyeballs were rinsed with physiological saline (0.9%) to remove any remaining drug residue on the surface. 100\u0026thinsp;~\u0026thinsp;200 \u0026micro;L of aqueous humor from the anterior chamber was aspirated with 1 mL syringe. Additionally, by utilising a 5 mL syringe, 0.3\u0026thinsp;~\u0026thinsp;0.4 mL of vitreous humor was extracted from the center of the vitreous cavity via the pars plana. All samples were maintained at a temperature of -80\u0026deg;C prior to analysis.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eDrug assay\u003c/h2\u003e\u003cp\u003eEach sample was thawed at room temperature and placed 50 \u0026micro;L in a 2 mL Eppendorf tube. Subsequent to the addition of 200 \u0026micro;L of methanol, the mixture was vortexed for 5 minutes and centrifuged at 14 000 rpm for 5 minutes. 1 mL of dichloromethane was added for liquid-liquid extraction, vortexed for another 5 minutes, and subsequently centrifuged at 14 000 rpm at 4\u0026deg;C for 5 minutes. A total of 900 \u0026micro;L of the organic layer was transferred to a 96-well plate and evaporated to dryness under nitrogen at 40\u0026deg;C. The residue was reconstituted with 100 \u0026micro;L of 0.1% formic acid in methanol and prepared for analysis.\u003c/p\u003e\u003cp\u003eHigh-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) (AB SCIEX Triple Quad TM 4500MD, Shanghai, China) was employed to quantify the levels of TA in the rabbit samples, utilising the specified parameters. The analytical column was a Thermo Accucore C18 (2.65\u0026micro;m, 2.1\u0026times;30 mm; Thermo Fisher Scientific, Waltham, United States), and the oven temperature was set at 50\u0026deg;C. The mobile phase was composed of water and methanol in a 60:40 volume ratio, flowing at a rate of 0.6 mL/min. An injection volume of 5 \u0026micro;L was used, with gradient elution applied. The operating conditions for electrospray ionization (ESI) were established as follows: the spray voltage was set at 5.5 kV, the nebulizer gas flow rate was maintained at 60 psi and the curtain gas flow rate was adjusted to 20 psi. Additionally, the heated gas flow rate was configured at 55 psi, drying gas temperature was set to 550 ℃ and the dwell time was 200 ms.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePharmacokinetic assessments and Statistical analysis\u003c/h3\u003e\n\u003cp\u003eThe concentrations of TA in various tissues were individually analyzed for pharmacokinetic assessment, which are evaluated using Drug and Statistics Software (DAS) 2.0 software (Mathematical Pharmacology Professional Committee of China, Beijing, China) by one-compartment model analysis. The pharmacokinetic parameters obtained included: peak concentration (Cmax), time to peak concentration (Tmax), elimination half-life (T\u003csub\u003e1/2\u003c/sub\u003e), area under the concentration-time curve between 0 and 14 days (AUC\u003csub\u003e0\u0026ndash;14d\u003c/sub\u003e). The Statistical Package for the Social Sciences (SPSS) version 22.0 software (SPSS Inc., Chicago, IL, USA) was used for the statistical data analysis. Repeated measures analysis of variance(ANOVA) was used to compare the overall difference between the CSDDD and the SC group. An independent sample t-test was employed to compare the differences between two groups at each time point. The significance level α was set at 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eConcentration of TA\u003c/h2\u003e\u003cp\u003eThe mean levels of TA concentrations in the aqueous humor and vitreous at different time points following CSDDD group and SC group are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e with results presented in Fig.\u0026nbsp;5.\u003c/p\u003e\u003cp\u003eIn the CSDDD group, the TA concentration in the aqueous humor remained stable at approximately 0.5\u0026thinsp;~\u0026thinsp;0.6 \u0026micro;g/mL from 0.5 to 6 hr, peaked at 0.763\u0026thinsp;\u0026plusmn;\u0026thinsp;0.275 \u0026micro;g/mL by 24 hr, and persisted at 0.641\u0026thinsp;\u0026plusmn;\u0026thinsp;0.113 \u0026micro;g/mL at 48 hr, followed by a gradual decline thereafter. In SC administration, the peak aqueous humor TA concentration (1.930\u0026thinsp;\u0026plusmn;\u0026thinsp;0.190 \u0026micro;g/mL)) occurred at 1 hr after TA injection, but decreased rapidly to (0.027\u0026thinsp;\u0026plusmn;\u0026thinsp;0.005) \u0026micro;g/mL at 48 hr. Repeated measures ANOVA indicated that the TA concentration in the CSDDD was significantly higher than that of the SC (F\u0026thinsp;=\u0026thinsp;1.87, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). TA concentrations were analyzed using the independent t-test. Levels of TA concentration in the aqueous humor(Fig.\u0026nbsp;5a) were significantly higher at 0.5 hr, 1 hr, 3 hr and 48 hr (n\u0026thinsp;=\u0026thinsp;3, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05) and negligible at 6 hr, 24 hr, 7 d and 14 d (n\u0026thinsp;=\u0026thinsp;3, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.548 at 6 hr, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.066 at 24 hr, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.076 at 7 days, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.825 at 14 days).\u003c/p\u003e\u003cp\u003eIn the CSDDD group, the peak concentration of TA in vitreous(1.627\u0026thinsp;\u0026plusmn;\u0026thinsp;0.674 \u0026micro;g/mL) was recorded at 6 hr of continuous scleral penetration and remained at the level of (0.567\u0026thinsp;\u0026plusmn;\u0026thinsp;0.388 \u0026micro;g/mL) at 7 days (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Fig.\u0026nbsp;5b). In the SC administration, the peak vitreous TA concentration (0.496\u0026thinsp;\u0026plusmn;\u0026thinsp;0.417 \u0026micro;g/mL) occurred at 0.5 hr after TA injection, and remained at a low level throughout the study, with a concentration of (0.099\u0026thinsp;\u0026plusmn;\u0026thinsp;0.058 \u0026micro;g/mL) measured on 7 days. Repeated measures ANOVA pointed out that the TA concentration in the CSDDD was significantly higher than that of SC (F\u0026thinsp;=\u0026thinsp;1.783, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). By the independent t-test, levels of TA concentration in the vitreous (Fig.\u0026nbsp;5b) were significantly higher at 1 hr, 3 hr, 6 hr and 24 hr(n\u0026thinsp;=\u0026thinsp;3, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05) and negligible at 0.5 hr, 48 hr, 7 days and 14 days (n\u0026thinsp;=\u0026thinsp;3, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.635 at 0.5 hr, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.102 at 48 hr, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.395 at 7 days, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.571 at 14 days).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTA concentrations in the aqueous humor and vitreous following CSDDD and SC group, \u0026micro;g/mL\u003csup\u003e*\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCSDDD group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSC group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eAqueous humor\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0.5hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.548\u0026thinsp;\u0026plusmn;\u0026thinsp;0.283\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.363\u0026thinsp;\u0026plusmn;\u0026thinsp;0.141\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.022\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.581\u0026thinsp;\u0026plusmn;\u0026thinsp;0.190\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.930\u0026thinsp;\u0026plusmn;\u0026thinsp;0.190\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.009\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.606\u0026thinsp;\u0026plusmn;\u0026thinsp;0.347\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.680\u0026thinsp;\u0026plusmn;\u0026thinsp;0.383\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.042\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.520\u0026thinsp;\u0026plusmn;\u0026thinsp;0.153\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.397\u0026thinsp;\u0026plusmn;\u0026thinsp;0.217\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.548\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.763\u0026thinsp;\u0026plusmn;\u0026thinsp;0.275\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.223\u0026thinsp;\u0026plusmn;\u0026thinsp;0.129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.066\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e48hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.641\u0026thinsp;\u0026plusmn;\u0026thinsp;0.113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.027\u0026thinsp;\u0026plusmn;\u0026thinsp;0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.046\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.109\u0026thinsp;\u0026plusmn;\u0026thinsp;0.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.053\u0026thinsp;\u0026plusmn;\u0026thinsp;0.009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.076\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.024\u0026thinsp;\u0026plusmn;\u0026thinsp;0.014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.030\u0026thinsp;\u0026plusmn;\u0026thinsp;0.014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.825\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eF\u0026thinsp;=\u0026thinsp;18.567, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eVitreous\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0.5hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.773\u0026thinsp;\u0026plusmn;\u0026thinsp;0.613\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.496\u0026thinsp;\u0026plusmn;\u0026thinsp;0.417\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.635\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.143\u0026thinsp;\u0026plusmn;\u0026thinsp;0.151\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.226\u0026thinsp;\u0026plusmn;\u0026thinsp;0.223\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.009\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.613\u0026thinsp;\u0026plusmn;\u0026thinsp;0.281\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.223\u0026thinsp;\u0026plusmn;\u0026thinsp;0.211\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.005\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.627\u0026thinsp;\u0026plusmn;\u0026thinsp;0.674\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.213\u0026thinsp;\u0026plusmn;\u0026thinsp;0.148\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.044\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.500\u0026thinsp;\u0026plusmn;\u0026thinsp;0.241\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.067\u0026thinsp;\u0026plusmn;\u0026thinsp;0.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e48hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.693\u0026thinsp;\u0026plusmn;\u0026thinsp;0.439\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.037\u0026thinsp;\u0026plusmn;\u0026thinsp;0.031\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.102\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.567\u0026thinsp;\u0026plusmn;\u0026thinsp;0.388\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.099\u0026thinsp;\u0026plusmn;\u0026thinsp;0.058\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.395\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.024\u0026thinsp;\u0026plusmn;\u0026thinsp;0.007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.028\u0026thinsp;\u0026plusmn;\u0026thinsp;0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.571\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eF\u0026thinsp;=\u0026thinsp;9.378, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eF-value is the testing value of repeated measures analysis of variance to compare the overall difference between two groups.\u003c/p\u003e\u003cp\u003e\u0026dagger; denotes the difference was statistically significant.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003ePharmacokinetics of TA\u003c/h2\u003e\u003cp\u003eThe pharmacokinetic parameters of TA in the aqueous humor and vitreous are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the AUC curves are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eIn the CSDDD, the Cmax were 0.763 \u0026micro;g/mL and 1.627 \u0026micro;g/mL in the aqueous humor and vitreous, respectively. The Tmax was 24 hr, 6 hr, respectively. The AUC\u003csub\u003e0\u0026ndash;14d\u003c/sub\u003e were 87.713 \u0026micro;g*h/mL and 187.991 \u0026micro;g*h/mL, respectively. The T\u003csub\u003e1/2\u003c/sub\u003e were 33.56 hr and 69.32 hr respectively.\u003c/p\u003e\u003cp\u003eFollowing an SC administration, the Cmax were 1.930 \u0026micro;g/mL and 1.496 \u0026micro;g/mL, respectively in the aqueous humor and vitreous, and the Tmax were 1 hr and 0.5 hr respectively. The AUC\u003csub\u003e0\u0026ndash;14d\u003c/sub\u003e were 28.159 \u0026micro;g*h/mL and 23.995 \u0026micro;g*h/mL, respectively. The T\u003csub\u003e1/2\u003c/sub\u003e were 6.71 hr, 19.51 hr, respectively.\u003c/p\u003e\u003cp\u003eWe observed that the AUC from 0.5 to 6 hours of aqueous humor was slightly higher in SC compared to the CSDDD. However, after 6 hours, the AUC in CSDDD increased exponentially, significantly surpassing that of the SC (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003ea). Similarly, the AUC of vitreous in CSDDD was comparable to SC during the first 6 hours but exhibited exponential growth thereafter, greatly exceeding the values observed in the SC group (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003eb).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe pharmacokinetic parameters of TA in the aqueous humor and vitreous following CSDDD and SC group.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eCSDDD group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eSC group\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAqueous humor\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eVitreous\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAqueous humor\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eVitreous\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e (\u0026micro;g*h/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e187.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT\u003csub\u003e1/2\u003c/sub\u003e(h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e69.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e19.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCmax(\u0026micro;g/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.763\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.627\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.930\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.496\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTmax(h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eCmax: peak concentration; Tmax: time to peak concentration; AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e: area under the concentration-time curve between 0 and 14 days; T\u003csub\u003e1/2\u003c/sub\u003e: elimination half-life.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e3D printing technologies include fused deposition modeling (FDM) and stereolithography (SLA) and so on \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. In this study, we employed SLA, one of the earliest rapid prototyping techniques to be commercialized, known for its fast processing speed, high precision and efficient material utilization \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. The drug delivery device was constructed using thermoplastic polyurethane (TPU) after 3D printing the model. In its molecular chain, TPU, an elastomeric block copolymer with urethane groups, combines soft and hard segments made of various materials to produce exceptional elasticity and mechanical strength \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Through 3D printing, Abdul Samat \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e created a tracheal stent using a TPU/polylactic acid composite. Their empirical results, both in vitro and in vivo, confirmed the object's biocompatibility, exhibiting no negative consequences on cellular proliferation or movement. TPU is ideally suited for the present program because of these characteristics. In hare eyes, the device can be densely folded to fit underneath the tenon's spacecraft, where it has since regained its original shape. This method reduces the risk of muscle rejection and regional inflammatory responses and facilitates less restrictive implantation.\u003c/p\u003e\u003cp\u003eThe majority of ocular disorders are treated primarily with pharmacotherapy. The sclera constitutes about 5/6 of the whole ocular surface area and mainly comprises equally arranged, loosely structured collagen fibres, creating porous and toothbrush-like cells \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. The amorphous collagen structure of the sclera allows drugs to enter the posterior region despite having a relatively low level of vascularization. The sclera's primary channel for drug absorption is through passive diffusion \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Scleral permeability depends on the molecular size, with molecules up to 70 000 Da able to permeate relatively easily \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Due to its large intake area and higher permeability, this is beneficial for the trans-scleral route. Trans-scleral continuous drug delivery systems significantly maintain long-lasting pharmacological effects by allowing the steady release of medicines at therapeutic concentrations. Research indicates that scleral drug absorption is driven by the constant-state flow across the sclera \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e, meaning that the medicine may remain in contact with the scleral surface long enough to create this stable condition. The large surface area of the human sclera supports diffusion and offers good tolerance to foreign objects resting on its surface, making it a viable long-term transscleral administration option in clinical practice. The tenon\u0026rsquo;s capsule, a dense fibrous sheath surrounding the eye, has loose connective tissue separating it from the sclera, creating a potential space that serves as an ideal platform for device implantation. Sub-tenon drug delivery mitigates the risks associated with intraocular injections, providing a safer and more effective method for posterior segment delivery. Therefore, we selected the sub-tenon route for implanting the drug delivery device.\u003c/p\u003e\u003cp\u003eTA, with the molecular formula C24H31FO6 and a molecular weight of 434.5D, is a long-acting hydrophobic and lipophilic corticosteroid. Previous studies have shown that TA can inhibit the gene expression of pro-inflammatory mediators or cytokines in various cell lines at half-maximal effective concentrations ranging from 1.7 to 4.3 ng/mL \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Furthermore, a TA concentration of 0.01 \u0026micro;g/mL is sufficient to effectively suppress the expression of vascular growth factors with this inhibitory effect being dose-dependent (a level referred to as the effective therapeutic concentration [ETC]) \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Due to its high potency and multifaceted anti-inflammatory and anti-angiogenic effects, TA has become a well-known treatment for posterior segment ocular conditions \u003csup\u003e[\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn this study, we combined high-concentration TA with carbomer, a non-toxic, non-irritating, and very porous substance, to create an equally dispersed, short-flow TA-carbomer gel, extending the time of contact between high-concentration TA and the scleral area. Additionally, we created a drug delivery device with a porous area that corresponds to the sclera, facilitating drug-sclera touch and promoting scleral intake. The non-porous side of the device minimizes direct drug exposure to the conjunctiva, reducing clearance by blood vessels and lymphatics of conjunctival to enhance the bioavailability of TA. In this study, throughout the observation period, the TA concentrations in the CSDDD group consistently exceeded the half-maximal effective concentration, achieving and maintaining the ETC within the local ocular tissue for a prolonged period.\u003c/p\u003e\u003cp\u003eIn our experiment, deep sub-Tenon's injection was initially considered as a control but was precluded because it required a relatively large incision, which led to significant drug leakage due to wound gaping and mechanical disruption from rabbit ocular movements. These factors resulted in uncontrolled and variable drug retention, compromising experimental reproducibility. In contrast, subconjunctival (SC) injection was selected as the control because its small-gauge needle puncture (26G) created a self-sealing wound that minimized drug leakage, ensuring consistent and measurable drug delivery. In the vitreous, the CSDDD group consistently exhibited TA concentrations that were equal to or greater than those in the SC throughout the study period. In the SC, TA concentrations peaked at 0.5 hr and then steadily declined. Throughout the entire experimental period, TA levels in the SC group remained relatively low. In contrast, the CSDDD group showed a TA concentration of (0.773\u0026thinsp;\u0026plusmn;\u0026thinsp;0.613) \u0026micro;g/mL at 0.5 hr, which gradually increased to a peak of (1.627\u0026thinsp;\u0026plusmn;\u0026thinsp;0.674) \u0026micro;g/mL at 6 hr \u0026mdash;3.3 times the peak concentration observed in the SC group and 163 times the ETC. Even at 14 days, the concentration remained 2.4 times above the ETC. The overall difference in drug concentrations between the two groups was statistically significant (F\u0026thinsp;=\u0026thinsp;9.378, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011), with significant differences observed at 1 hr (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009), 3 hr (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), 6 hr (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044), and 24 hr (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003ePrevious studies suggested that scleral drug permeability involves a time delay \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Insufficient contact time between the drug and the sclera may hinder effective penetration into the vitreous cavity, which could partly explain why the TA concentration in the vitreous of the CSDDD peaked 6 hours after administration, much earlier than the peak observed at 24 hours in the aqueous humor in this study. In the CSDDD group, the device was implanted closer to the vitreous body, allowing the drug to directly penetrate the sclera and enter the vitreous. In contrast, the drug in the vitreous may need to reach the aqueous humor through the choroidal-retinal vasculature or the vitreous-posterior aqueous humor circulation. As a result, the peak time in the vitreous in the CSDDD group occurred much earlier than in the aqueous humor. In the aqueous humor, the SC group exhibited a rapid increase in TA concentration, peaking at 1 hr (1.930\u0026thinsp;\u0026plusmn;\u0026thinsp;0.190 \u0026micro;g/mL), followed by a sharp decline. This behavior is likely attributed to the conjunctival injection site being closer to the aqueous humor, allowing TA to directly access the anterior segment, where it is rapidly absorbed. Due to the poor water solubility of the TA injection solution, the drug powder is more likely to accumulate in the aqueous humor following SC injection, resulting in a higher peak concentration of TA in the aqueous humor in the SC group. The peak concentration of the drug in the vitreous of the SC group was much lower (0.496\u0026thinsp;\u0026plusmn;\u0026thinsp;0.417 \u0026micro;g/mL) compared to the aqueous humor (1.930\u0026thinsp;\u0026plusmn;\u0026thinsp;0.190 \u0026micro;g/mL), indicating that the drug concentration reaching the vitreous through scleral penetration via subconjunctival injection was very low.\u003c/p\u003e\u003cp\u003eDue to the presence of tears film \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, blood-aqueous barrier and rapid nasolacrimal clearance \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e, the drug is rapidly metabolized and cleared, leading to a rapid decrease in concentration. This indicates that drug release in the SC group is concentrated in the initial phase and does not sustain a prolonged therapeutic effect. Conversely, the CSDDD group showed more stable TA concentrations, with a continuous-release mechanism resulting in lower early-phase concentrations that gradually increased, peaking at 24 hr (0.763\u0026thinsp;\u0026plusmn;\u0026thinsp;0.275 \u0026micro;g/mL), approximately 76 times the ETC. Trace amounts of the drug, about 2.4 times the ETC, were still detectable at 14 days. The overall difference in drug concentrations between the two groups was statistically significant (F\u0026thinsp;=\u0026thinsp;18.567, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), with significant differences at 0.5 hr (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022), 1 hr (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009), 3 hr (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042), and 48 hr ( \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046).\u003c/p\u003e\u003cp\u003eThe AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e for all tissues was higher in the CSDDD than in the SC. Specifically, in the vitreous, the TA exposure in the CSDDD (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e=187.991 \u0026micro;g\u0026times;h/mL) was approximately 7.8 times that of the SC (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e= 23.995 \u0026micro;g\u0026times;h/mL). In the aqueous humor, the TA exposure in the CSDDD (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e=87.713 \u0026micro;g\u0026times;h/mL) was about 3.1 times higher than in the SC (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e= 28.159 \u0026micro;g\u0026times;h/mL). These findings suggest that the continuous release mechanism of CSDDD allows for more efficient drug delivery into the eye compared to a single subconjunctival injection.\u003c/p\u003e\u003cp\u003eIn the CSDDD, TA concentrations and AUC₀₋₁₄\u003csub\u003ed\u003c/sub\u003e were significantly higher in the vitreous than in the aqueous humor. This disparity can be attributed to the proximity of the release site and differences in metabolic rates between the vitreous and aqueous humor. The device is positioned under the tenon\u0026rsquo;s capsule, close to the vitreous, allowing the drug to more readily diffuse through the sclera into the vitreous. Additionally, the vitreous has a slower metabolic rate, lacking direct vascular supply, and its drug clearance primarily depends on slow diffusion through the vitreous matrix. This characteristic enables the maintenance of high drug concentrations and prolonged therapeutic effects within the vitreous. In contrast, the aqueous humor has a rapid turnover rate, with efficient drug clearance through the anterior circulation, significantly reducing the potential for drug accumulation in this compartment.\u003c/p\u003e\u003cp\u003ePrevious studies conducted by Zhao \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e and Huang \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e explored the development of a sub-tenon micro-perfusion system (SMS) consisting of a catheter, microneedle and micropump. By inserting a catheter into the sub-tenon area and using a micropump to support shipping, this program facilitates steady drug release of dexamethasone (molecular weight: 392.46D). As corticosteroids, dexamethasone, with a smaller molecular weight than TA, is expected to more readily penetrate the sclera and reach higher concentrations within the eye. However, during the 24-hour observation period in the SMS group, Huang's study reported lower mean drug concentrations in both the vitreous (0.022\u0026thinsp;~\u0026thinsp;0.071 \u0026micro;g/mL) and aqueous humor (0.032\u0026thinsp;~\u0026thinsp;0.295 \u0026micro;g/mL) compared to the concentrations observed in this study. Similarly, Zhao's results were consistent (vitreous: 0.109\u0026thinsp;~\u0026thinsp;0.882 \u0026micro;g/mL). From a pharmacokinetic perspective, Zhao's study showed lower AUC and T\u003csub\u003e1/2\u003c/sub\u003e in the vitreous (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;24h\u003c/sub\u003e: 8.22 \u0026micro;g\u0026times;h/mL; T\u003csub\u003e1/2\u003c/sub\u003e: 8.07 hr). Huang's study also showed lower AUC values and T\u003csub\u003e1/2\u003c/sub\u003e in both vitreous (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;24h\u003c/sub\u003e: 1.41 \u0026micro;g\u0026times;h/mL; T\u003csub\u003e1/2\u003c/sub\u003e: 14.32 hr) and aqueous humor (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;24h\u003c/sub\u003e: 33.71 \u0026micro;g\u0026times;h/mL; T\u003csub\u003e1/2\u003c/sub\u003e: 5.54 hr), compared to the corresponding AUC and T\u003csub\u003e1/2\u003c/sub\u003e in this experiment in both vitrous (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e: 187.66 \u0026micro;g\u0026times;h/mL; T\u003csub\u003e1/2\u003c/sub\u003e: 6 hr) and aqueous humor (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;14d\u003c/sub\u003e: 87.71 \u0026micro;g\u0026times;h/mL; T\u003csub\u003e1/2\u003c/sub\u003e: 24 hr). Besides, the SMS system requires specialized micropumps and catheters, which complicate medical procedures and likely impede its adoption. Additionally, their studies were only conducted for a 24-hour pharmacokinetic observation time without examining the long-term effects on intraocular pressure or scleral integrity, which are crucial for determining the health and viability of prolonged use. These comparative results indicate that the newly developed delivery system surpasses the previously reported SMS system in maintaining therapeutic drug levels, suggesting superior drug retention and enhanced bioavailability achieved through the novel delivery approach in this study.\u003c/p\u003e\u003cp\u003eCurrently, researchers have investigated the use of reservoir-based corticosteroid formulations for intravitreal (IVT) implantation \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Compared to these methods, CSDDD offers the advantage of allowing medication replenishment as needed, making it suitable for clinical scenarios that require prolonged drug release. Notably, while CSDDD involves surgical insertion beneath the tenon\u0026rsquo;s capsule, it fails to mechanically disrupt the normal anatomy of the retina and choroid. Furthermore, in the event of severe complications, the device can be removed with relative ease. In contrast, IVT implants necessitate surgical infiltration through the sclera, choroid, and retina, which may allow the implant to move within the vitreous chamber and potentially cause vitreous traction. If serious complications occur, removing the implant can be difficult.\u003c/p\u003e\u003cp\u003eOther researchers have explored transscleral drug delivery methods, including ultrasound-mediated delivery \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e and iontophoresis \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Although these methods avoid the complications associated with intraocular injections, they rely on emitting radiation (sound waves or electromagnetic waves) or applying magnetic fields (electric or magnetic), which generate thermal effects in biological tissues \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. These effects can alter the structure or function of tissues and their cells \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e or increase tissue permeability through the damaging effects of electric currents on collagen structures, potentially resulting in tissue damage \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. In contrast, CSDDD utilizes passive diffusion for drug absorption, offering a more tissue-friendly approach.\u003c/p\u003e\u003cp\u003eIn summary, the safety profile of the device material, the ideal platform, the system\u0026rsquo;s ability to release the drug over a sustained period, and the effective extension of drug contact time with the sclera ensure the feasibility of CSDDD as an effective alternative for posterior segment drug delivery. The CSDDD offers continuous and stable drug release, with superior performance in the vitreous, positioning it as an encouraging option for therapeutic intervention of vascular and inflammatory posterior segment diseases.\u003c/p\u003e\u003cp\u003eNonetheless, our study has certain limitations. First, at 14 days, TA concentrations in CSDDD were relatively low. This might be attributed to the tendency of the TA-carbomer gel to form unabsorbed drug residues, leading to drug accumulation in tissues or blockage of the mesh pores in the delivery device. Upcoming studies will concentrate on refining the formulation of the sustained-release drug. Over time, as the drug reservoir in the device depletes, the amount of drug released through the mesh pores diminishes compared to the initial stages, which could also contribute to the significant decline in TA concentration observed at 14 days. In subsequent experiments, we plan to supplement the sustained-release drug periodically and extend the observation period to better understand the pharmacokinetic mechanisms of CSDDD-mediated drug delivery. Moreover, our findings are based on data from rabbits, not humans. Rabbit\u0026rsquo;s eyes are characterized by their smaller size and thinner sclera, which enhance drug penetration into the choroid. They also have greater ocular blood flow and circulation rates, potentially resulting in a shorter drug half-life in rabbit eye tissues. These anatomical and physiological differences can influence the pharmacokinetics of ocular drugs. Additionally, this study was conducted on healthy rabbit eyes. Future research should extend to studying diseased eyes, particularly those with vascular or inflammatory posterior segment conditions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Animal Ethics Committee at Changsha Aier Eye Hospital (Date:2023.10.07/No:AEI20230019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFundings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by [Natural Science Foundation of Hunan Province] (Grant number [2020JJ4001]) and [The Science and Technology Innovation Program of Hunan Province] (Grant number [2018SK50103]).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. The methodology was designed by[DuanYiqin] and [YeLiyan]. Material preparation, data collection and analysis were performed by [YeLiyan], [LiangLuyun] and [LiuXiaolan]. The first draft of the manuscript was written by [YeLiyan] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the personnel at the animal center of Changsha Aier Eye Hospital for providing physical space and technical assistance with the animal work. We thank the AIER Eye Hospital group for great support and help.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and Materials Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eAll institutional and national guidelines for the care and use of laboratory animals were followed.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eConrady CD, Yeh S. A Review of Ocular Drug Delivery Platforms and Drugs for Infectious and Noninfectious Uveitis: The Past, Present, and Future. 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The role of electroosmotic flow in transdermal iontophoresis. Adv Drug Deliv Rev. 2001;46(1\u0026ndash;3):281\u0026ndash;305. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0169-409x(00)00138-1\u003c/span\u003e\u003cspan address=\"10.1016/s0169-409x(00)00138-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"3D printing, Ocular drug delivery device, Tenon capsule, Triamcinolone acetonide, HPLC-MS/MS, Pharmacokinetics","lastPublishedDoi":"10.21203/rs.3.rs-7528496/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7528496/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective \u003c/strong\u003eTo evaluate the pharmacokinetic characteristics of a novel 3D-printed thermoplastic polyurethane continuous drug delivery device in rabbit eyes' aqueous humor and vitreous humor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eA continuous sub-tenon drug delivery device (CSDDD) was designed using computer-aided design and fabricated via stereolithography 3D printing. The device was implanted sub-tenon in the temporal side of the right eye in rabbits. 1 mL of triamcinolone acetonide (TA) carbomer gel (40 mg/mL) was injected into the drug reservoir for sustained release in CSDDD group. The control group was administered a single subconjunctival (SC) injection of TA at the same dose and concentration. The experimental rabbits were randomly allocated into two groups, each comprising eight temporal subgroups corresponding to 0.5 hr, 1 hr, 3 hr, 6 hr, 24 hr, 48 hr, 7 days, and 14 days post-intervention. To ensure data reliability, five biological replicates were maintained at each time point across all subgroups. Aqueous humor and vitreous humor samples were collected and High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was employed to determine TA concentration. Following the exclusion of outliers (maximum and minimum values), triplicate samples from each time point in each group were retained for subsequent statistical analysis. Descriptive statistical analysis was performed using SPSS 20.0, while pharmacokinetic parameters were calculated with DAS 2.0 software.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eIn the aqueous humor, the TA concentration in the CSDDD group remained stable at approximately 0.5 ~ 0.6 μg/mL from 0.5 to 6 hr, peaked at 0.763 ± 0.275 μg/mL by 24 hr, and persisted at 0.641 ± 0.113 μg/mL at 48 hr, followed by a gradual decline thereafter. While in the SC group, the peak concentration was (1.930±0.190 μg/mL) at 1 hr, followed by a rapid decrease. In the vitreous humor, the peak TA concentration in the CSDDD group was (1.627±0.674 μg/mL) at 6 hr, with a sustained release over 14 days. In contrast, the SC group exhibited a peak concentration of (0.496±0.417 μg/mL) at 0.5 hr, remaining at low levels throughout. The CSDDD group showed significantly higher concentration and AUC0-14d in both the vitreous and the aqueous humour relative to the SC group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eThe 3D-printed CSDDD demonstrated effective sustained drug release, achieving prolonged therapeutic concentrations of TA in both the aqueous and vitreous, surpassing the SC group. This device presents a promising alternative for sustained ocular drug delivery. \u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Pharmacokinetic Analysis of a Novel 3D-Printed Thermoplastic Polyurethane Continuous Sub-Tenon Drug Delivery Device in Rabbit Eyes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-09 15:33:41","doi":"10.21203/rs.3.rs-7528496/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d22ef95b-2691-49e1-8fc2-53e2851f0772","owner":[],"postedDate":"October 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T13:57:54+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-09 15:33:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7528496","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7528496","identity":"rs-7528496","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}