Peer-reviewed Articles

Please use the year list below to look at past peer-reviewed articles.

2024

Aziz,A., Kuppusamy,R., Mazumder,K., Hui,A., Maulvi,F., Stapleton,F., Willcox,M. Absorption and attachment of atropine to etafilcon A contact lenses Contact Lens Anterior Eye 2024;Online ahead of print [ Show Abstract ]

Purpose: Myopia (short-sightedness) is a growing vision problem worldwide. Currently atropine eye drops are used to control the progression of myopia but these suffer from potential lack of bioavailability and low ocular residence time. Commercially available myopia control contact lenses are also used to limit myopia progression, but neither atropine nor contact lenses individually completely stop progression. Development of myopia control contact lenses which could deliver therapeutic doses of atropine is thus desirable and may provide increased efficacy. This study was designed to explore the feasibility of attaching atropine to etafilcon A contact lenses through an esterification reaction.

Methods: Carboxylic acid groups on etafilcon A contact lenses were quantified using Toluidine Blue O. The carboxylic acid groups in etafilcon A contact lenses were activated using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC-HCl) and N-hydroxysuccinimide (NHS) crosslinkers after which atropine was added to undergo potential binding via esterification. Atropine was released from lenses by alkaline hydrolysis. Reverse phase high performance liquid chromatography (HPLC) was used to detect and quantify the released atropine and its degradation products in solution. Contact lenses that had not been activated by EDC-NHS (controls) were also examined to determine the amount of atropine that could be absorbed rather than chemically bound to lenses.

Results: Each etafilcon A contact lens contained 741.1 ± 5.5 µg carboxylic acid groups which may be available for esterification. HPLC had a limit of detection for atropine of 0.38 µg/mL and for tropic acid, an atropine degradation product, of 0.80 µg/mL. The limits of quantification were 1.16 µg/mL for atropine and 2.41 µg/mL for tropic acid in NH4HCO3. The etafilcon A lenses adsorbed up to 7.69 μg atropine when incubated in a 5 mg/mL atropine solution for 24 h. However, there was no evidence that atropine could be chemically linked to the lenses, as washing in a high concentration of NaCl removed all the atropine from the contact lenses with no atropine being subsequently released from the lenses after incubating in 0.01 N NH4HCO3.

Conclusions: Etafilcon A contact lenses contain free carboxylic acids which may be an appropriate option for attaching drugs such as atropine. Etafilcon A lenses adsorbed up to 7.69 μg atropine, which would be more than enough to deliver atropine to eyes to control myopia. However, atropine could not be chemically bound to the carboxylic acids of the etafilcon A lenses using this methodology.

Bose,S., Phan,C.-M., Rizwan,M., Tse,J. W., Yim,E., Jones,L. Fabrication and Characterization of an Enzyme-Triggered, Therapeutic-Releasing Hydrogel Bandage Contact Lens Material Pharmaceutics 2024;16(1):Article 26 [ Show Abstract ]

Purpose: The purpose of this study was to develop an enzyme-triggered, therapeutic-releasing bandage contact lens material using a unique gelatin methacrylate formulation (GelMA+).

Methods: Two GelMA+ formulations, 20% w/v, and 30% w/v concentrations, were prepared through UV polymerization. The physical properties of the material, including porosity, tensile strain, and swelling ratio, were characterized. The enzymatic degradation of the material was assessed in the presence of matrix metalloproteinase-9 (MMP-9) at concentrations ranging from 0 to 300 µg/mL. Cell viability, cell growth, and cytotoxicity on the GelMA+ gels were evaluated using the AlamarBlueTM assay and the LIVE/DEADTM Viability/Cytotoxicity kit staining with immortalized human corneal epithelial cells over 5 days. For drug release analysis, the 30% w/v gels were loaded with 3 µg of bovine lactoferrin (BLF) as a model drug, and its release was examined over 5 days under various MMP-9 concentrations.

Results: The 30% w/v GelMA+ demonstrated higher crosslinking density, increased tensile strength, smaller pore size, and lower swelling ratio (p < 0.05). In contrast, the 20% w/v GelMA+ degraded at a significantly faster rate (p < 0.001), reaching almost complete degradation within 48 h in the presence of 300 µg/mL of MMP-9. No signs of cytotoxic effects were observed in the live/dead staining assay for either concentration after 5 days. However, the 30% w/v GelMA+ exhibited significantly higher cell viability (p < 0.05). The 30% w/v GelMA+ demonstrated sustained release of the BLF over 5 days. The release rate of BLF increased significantly with higher concentrations of MMP-9 (p < 0.001), corresponding to the degradation rate of the gels.

Discussion: The release of BLF from GelMA+ gels was driven by a combination of diffusion and degradation of the material by MMP-9 enzymes. This work demonstrated that a GelMA+-based material that releases a therapeutic agent can be triggered by enzymes found in the tear fluid.

Chow,A. H. Y., Mungalsingh,M., Thai,D., Selimos,Z., Yan,S. K., Xu,H., Jones,D. A. Suitability of multifunction devices Myah and Myopia Master for monitoring myopia progression in children and adults Ophthalmic and Physiological Optics 2024;44(5):1017-1030 [ Show Abstract ]

Purpose: To assess the feasibility of using multifunction instruments to measure axial length for monitoring myopia progression in children and adults.

Methods: Axial length was measured in 60 children (aged 6–18 years) and 60 adults (aged 19–50 years) with multifunction instruments (Myah and Myopia Master) and stand-alone biometers (Lenstar LS900 and IOLMaster 700). Repeatability (measurements by the same examiner) and reproducibility (measurements by different examiners) were computed as the within-subject standard deviation (Sw) and 95% limits of agreement (LoA). Inter-instrument agreement was computed as intraclass correlation coefficients. The threshold for detecting myopic progression was taken as 0.1 mm. Measures were repeated only in children following the administration of 1% tropicamide to determine the impact of cycloplegia on axial length.

Results: Overall, the IOLMaster 700 had the best repeatability in children (0.014 mm) and adults (0.009 mm). Repeatability Sw values for all devices ranged from 0.005 to 0.021 mm (children) and 0.003 to 0.016 mm (adults). In children, reproducibility fell within 0.1 mm 95% of the time for the Myah, Myopia Master and IOLMaster 700. Agreement among all devices was classified as excellent (ICC 0.999; 95% CI 0.998–0.999), but the 95% LoA among the Myah, Myopia Master and Lenstar LS900 was ≥0.1 mm. Cycloplegia had no statistically significant effect on axial length (all p > 0.13).
Conclusions: The Myah and Myopia Master multifunction instruments demonstrated good repeatability and reproducibility, and their accuracy was comparable to stand-alone biometers. Axial length measurements using different instruments can be considered interchangeable but should be compared with some caution. Accurate axial length measurements can be obtained without cycloplegia. The multifunction instruments Myah and Myopia Master are as well suited for monitoring myopia progression in children as the stand-alone biometers IOLMaster 700 and Lenstar LS900.

Dang,R., Ehrmann,K., Jalbert,I., Hui,A., Kang,P. Refractive power profiles of commercially available soft multifocal contact lenses for myopia control Ophthalmic and Physiological Optics 2024;Online ahead of print [ Show Abstract ]

Purpose: Lens power profiles can provide valuable insights on the imposed optical defocus and visual experience of contact lens wearers, especially in the context of myopia control. This study measured the refractive power profiles of multifocal soft contact lenses (MFCLs) currently used or that have the potential for use in myopia control using high spatial resolution aberrometry. The instrument's repeatability for determining MFCLs power profiles was also assessed.

Method: The power profiles of 10 MFCLs of various designs (centre-distance, centre-near and extended depth of focus) were measured using the Lambda-X NIMOEVO, a phase shifting Schlieren-based device. Power profiles were graphically expressed as measured power at each chord position and the maximum add power was calculated. The repeatability of the NIMOEVO was expressed as the within-subject standard deviation at each chord position for a subset of five MFCLs.

Results: The measured distance powers differed from nominal powers for more than half of the MFCLs with a definable distance zone. There were variations in the chord position of the distance and near correction zones, rate of power transitions and calculated maximum add between the MFCLs which did not depend on lens design. For half of the MFCLs, the power profile shape was inconsistent between different nominal back vertex powers of the same design. The repeatability of the NIMOEVO was dependent on the lens design, with designs featuring faster rates of power change exhibiting worse repeatability.

Conclusions: Significant differences in MFCL power profiles were found which were not adequately represented in labelling. This is likely due to the small number of parameters used to define lens power characteristics. Eye health care practitioners should be aware of potential differences in power profiles between different MFCLs, which will impact the retinal defocus introduced during lens wear and the wearer's visual experience.

Fadel,D., Macedo-de-Araújo,R. J., Barnett,M. The Patient-Physician Relationship and Role of Empathic Communication in Contact Lens Practice Journal of Contact Lens Research and Science 2024;8(1):20-36

Jabeen,A., Luensmann,D., Woods,J., Hill,J. S., Jones,L. Evaluation of Lag of Accommodation with Full-Field Diffusion Optics Technology™ (DOT) Contrast Management Spectacle Lenses in Emmetropic Children Clinical Ophthalmology 2024;2024(18):1181-1190 [ Show Abstract ]

Purpose: To evaluate the impact on the lag of accommodation (LOA) in emmetropic children after short-term wear of full-field Diffusion Optics TechnologyTM (DOT) spectacle lenses, designed to modulate retinal contrast to control myopia progression.

Patients and Methods: This was a single-visit, prospective, randomized, subject-masked study of emmetropes (ametropes ±1.00D or less in each meridian) with no history of myopia control treatment. Unaided logMAR visual acuity was measured, and ocular dominance was determined using the sighting method. In a randomized order, participants wore plano full-field contrast management (DOT) spectacles (no clear central aperture) or control spectacles (standard single vision spectacle lenses). Each participant was given 5 minutes for adaptation to the respective lenses before open field autorefraction measurements were taken at 6 meters and 40 cm. Ten measurements were taken for each eye. Data were evaluated from the right eye and the dominant eye separately.

Results: A total of 30 participants (20 females and 10 males) with a mean age of 10.4 ± 2.8 (7 to 17) years completed the study. There was no significant difference in right eye mean LOA with contrast management spectacles 0.57 ± 0.39D versus control spectacles 0.62 ± 0.34D; Wilcoxon test, p = 0.37. For dominant eyes, LOA values were 0.60 ± 0.40D and 0.68 ± 0.33D with contrast management spectacles and control spectacles, respectively (p = 0.14). Additionally, no significant difference was observed in mean LOA between males and females or between age groups (7–11 years vs 12–17 years) for either right or dominant eyes with contrast management or control spectacles (all p > 0.05).

Conclusion: Full-field contrast management spectacle lenses had no significant effect on LOA compared to standard single vision spectacle lenses, indicating no differential impact on accommodative response over the short period of lens wear tested.

Jabeen,A., Luensmann,D., Woods,J., Hill,J., Jones,L. Evaluation of Lag of Accommodation with Full-Field Diffusion Optics Technology™ (DOT) Contrast Management Spectacle Lenses in Emmetropic Children Clinical Ophthalmology 2024;18(May):1181-1190 [ Show Abstract ]

Purpose: To evaluate the impact on the lag of accommodation (LOA) in emmetropic children after short-term wear of full-field Diffusion Optics TechnologyTM (DOT) spectacle lenses, designed to modulate retinal contrast to control myopia progression.

Patients and methods: This was a single-visit, prospective, randomized, subject-masked study of emmetropes (ametropes ±1.00D or less in each meridian) with no history of myopia control treatment. Unaided logMAR visual acuity was measured, and ocular dominance was determined using the sighting method. In a randomized order, participants wore plano full-field contrast management (DOT) spectacles (no clear central aperture) or control spectacles (standard single vision spectacle lenses). Each participant was given 5 minutes for adaptation to the respective lenses before open field autorefraction measurements were taken at 6 meters and 40 cm. Ten measurements were taken for each eye. Data were evaluated from the right eye and the dominant eye separately.

Results: A total of 30 participants (20 females and 10 males) with a mean age of 10.4 ± 2.8 (7 to 17) years completed the study. There was no significant difference in right eye mean LOA with contrast management spectacles 0.57 ± 0.39D versus control spectacles 0.62 ± 0.34D; Wilcoxon test, p = 0.37. For dominant eyes, LOA values were 0.60 ± 0.40D and 0.68 ± 0.33D with contrast management spectacles and control spectacles, respectively (p = 0.14). Additionally, no significant difference was observed in mean LOA between males and females or between age groups (7-11 years vs 12-17 years) for either right or dominant eyes with contrast management or control spectacles (all p > 0.05).

Conclusion: Full-field contrast management spectacle lenses had no significant effect on LOA compared to standard single vision spectacle lenses, indicating no differential impact on accommodative response over the short period of lens wear tested.

Jin,Y., Minten,C., Jenkins,M., Jones,L., Gorbet,M. Investigation of the rhythmic recruitment of tear neutrophils to the ocular surface and their phenotypes Scientific Reports 2024;147061 [ Show Abstract ]

Hundreds of thousands of polymorphonuclear neutrophils (PMNs) are collected from the ocular surface upon waking, while few are harvested during daytime. This study aimed to investigate potential factors contributing to the circadian infiltration of tear PMNs, including changes in IL-8 and C5a in tears, and their phenotypes across different time points in a 24-h cycle. Tear PMNs were collected using a gentle eyewash after 2-h and 7-h of sleep (eye closure, EC) at night, after 2-h EC during the day, and towards the end of the afternoon. Significantly fewer cells were collected after 2-h EC during the day compared to 2-h EC at night. A positive correlation between IL-8 and PMN numbers existed, but not with C5a. Tear PMNs collected after 2-h EC at night were less degranulated and possessed a larger activation potential compared to 7-h EC. Tear PMNs from 7-h EC at night exhibited hyper-segmented nuclei and more NETosis compared to 2 h EC night, indicating an aged and activated phenotype. The diurnal-nocturnal recruitment pattern of tear PMNs may be driven by increased IL-8 in nighttime tears. Higher degranulation and NETs point to the significant activation of tear PMNs on the ocular surface during prolonged eye closure at night.

Mishra,S. K., Baidya,S., Bhattarai,A., Shrestha,S., Homagan,S., Rayamajhee,B., Hui,A., Willcox,M. Bacteriology of Endotracheal Tube Biofilms and Antibiotic Resistance: A Systematic Review Journal of Hospital Infection 2024;Online ahead of print [ Show Abstract ]

Background
Bacteria commonly adhere to surfaces and produce polymeric material to encase the attached cells to form communities called biofilms. Within these biofilms, bacteria can appear many times more resistant to antibiotics or disinfectants. This systematic review explores the prevalence and microbial profile associated with biofilm production of bacteria isolated from endotracheal tubes and its associations with antimicrobial resistance.

Methods
A comprehensive search was performed on databases PubMed, Embase, and Google Scholar for relevant articles published between January 1, 2000 and December 31, 2022. The relevant articles were exported to Mendeley Desktop 1.19.8 and screened by title and abstract, followed by full text screening based on the eligibility criteria of the study. Quality assessment of the studies was performed using the Newcastle-Ottawa Scale (NOS) customized for cross-sectional studies. Furthermore, the prevalence of antimicrobial resistance in biofilm-producers isolated from endotracheal tube specimens was investigated.

Results
Twenty studies encompassing 981 endotracheal tubes met the eligibility criteria. Pseudomonas spp. and Acinetobacter spp. were predominant isolates among the biofilm producers. These biofilms provided strong resistance against commonly used antibiotics. The highest resistance rate observed in Pseudomonas spp. was against fluoroquinolones whereas the least resistance was seen against piperacillin-tazobactam. A similar trend of susceptibility was observed in Acinetobacter spp. with a very high resistance rate against fluoroquinolones, third-generation cephalosporins and carbapenems.

Conclusion
Endotracheal tubes were associated with colonisation by biofilm forming bacteria with varying levels of antimicrobial resistance. Biofilms may promote the occurrence of recalcitrant infections in endotracheal tubes which need to be managed with appropriate protocols and antimicrobial stewardship. Research focus should shift towards meticulous exploration of biofilm-associated infections to improve detection and management.

Mohseni,M., Shokrollahi,P., Barzin, J. Gelatin/O-carboxymethyl chitosan injectable self-healing hydrogels for ibuprofen and naproxen dual release International Journal of Biological Macromolecules 2024;263, Part 1(April):Art No 130266

Phan,C. M., Chan,V. W. Y., Drolle,E., Hui,A., Ngo,W., Bose,S., Shows,A., Liang,S., Sharma,B., Subbaraman,L., Zheng,Y., Shi,X., Wu,J., Jones,L. At this time no specific clinical outcome instrument can be recommended on the basis of an evidence-based review of the literature, but the CLDEQ-8 best approaches the most validated measure Contact Lens Anterior Eye 2024;47(2):102129 [ Show Abstract ]

Purpose
To evaluate the in vitro wettability and coefficient of friction of a novel amphiphilic polymeric surfactant (APS), poly(oxyethylene)–co-poly(oxybutylene) (PEO-PBO) releasing silicone hydrogel (SiHy) contact lens material (serafilcon A), compared to other reusable SiHy lens materials.

Methods
The release of fluorescently-labelled nitrobenzoxadiazole (NBD)-PEO-PBO was evaluated from serafilcon A over 7 days in a vial. The wettability and coefficient of friction of serafilcon A and three contemporary SiHy contact lens materials (senofilcon A; samfilcon A; comfilcon A) were evaluated using an in vitro blink model over their recommended wearing period; t = 0, 1, 7, 14 days for all lens types and t = 30 days for samfilcon A and comfilcon A (n = 4). Sessile drop contact angles were determined and in vitro non-invasive keratographic break-up time (NIKBUT) measurements were assessed on a blink model via the OCULUS Keratograph 5 M. The coefficient of friction was measured using a nano tribometer.

Results
The relative fluorescence of NBD-PEO-PBO decreased in serafilcon A by approximately 18 % after 7 days. The amount of NBD-PEO-PBO released on day 7 was 50 % less than the amount released on day 1 (6.5±1.0 vs 3.4±0.5 µg/lens). The reduction in PEO-PBO in the lens also coincided with an increase in contact angles for serafilcon A after 7 days (p 0.05). The other contact lens materials had stable contact angles and NIKBUT over their recommended wearing period (p > 0.05), with the exception of samfilcon A, which had an increase in contact angle after 14 days as compared to t = 0 (p < 0.05). Senofilcon A and samfilcon A also showed an increase in coefficient of friction at 14 and 30 days, respectively, compared to their blister pack values (p < 0.05).

Conclusion
The results indicate that serafilcon A gradually depletes its reserve of PEO-PBO over 1 week, but this decrease did not significantly change the lens performance in vitro during this time frame.

Sara,M. Hui,A., Yasir,M., Hari Kumar,P., Kalaiselvan,P., Willcox,M. Intrastromal Corneal Ring Implants Associated Bacterial Infections Current Eye Research 2024;Online ahead of print [ Show Abstract ]

Purpose: This study examines the incidence of infection and resistance associated with Intracorneal Ring Segment (ICRS) implantation, a common outpatient surgical treatment for correcting refractive errors and corneal ectatic diseases. Although ICRS procedures are typically safe and reversible, there is a low but notable risk of microbial infections, which require prompt and sometimes invasive treatment.

Methods: Three electronic databases, PubMed, Web of Science (WoS), and Scopus, were utilised to search for literature according to PRISMA guidelines to identify infections related to the implantation of ICRS in the cornea between January 2000 and December 2022.

Results: Gram-positive organisms were involved in 86% of cases: 35.7% S. aureus, 25% coagulase-negative staphylococci species, 17.8% streptococci and 7.1% Nocardia species. Less commonly recorded were Gram-negative bacteria (14%), with Pseudomonas aeruginosa (circa 10%) and Klebsiella pneumonia (4%) being the most common Gram-negative bacteria. In rare cases, fungi have also been reported. ICRS-related bacterial infections can be categorised into early or late onset. Early onset infection typically manifests within the first few weeks after implantation and is often associated with contamination during surgery, unhygienic practices, or inadequate sterilisation techniques. On the other hand, late-onset infection may develop months or even years after the initial procedures and may be associated with persistent bacterial colonisation, secondary infections, or prolonged use of prophylactic antibiotics. S aureus is encountered in both early and late-onset infections, while Nocardia species and K. pneumoniae have generally been reported to occur in late-onset infections. In addition, vision recovery from S. aureus infections tends to be poor compared to other bacterial infections.

Conclusion: S. aureus is a predominant pathogen that often requires surgical intervention with poor outcomes. Early infections result from incision gaps and ring segment rubbing, while late infections are linked to prolonged antibiotic use. Further research is needed on novel antimicrobial ICRS to procure the vision.

Wolffsohn,J. S., Berkow,D., Chan,K. Y., Chaurasiya,S. K., Fadel,D., Haddad,M., Imane, T., Jones,L., Sheppard,A. L., Vianya-Estopa,M., Walsh,K., Woods,J., Zeri,F., Morgan,P. B. BCLA CLEAR Presbyopia: Evaluation and diagnosis Contact Lens Anterior Eye 2024;Online ahead of print [ Show Abstract ]

It is important to be able to measure the range of clear focus in clinical practice to advise on presbyopia correction techniques and to optimise the correction power. Both subjective and objective techniques are necessary: subjective techniques (such as patient reported outcome questionnaires and defocus curves) assess the impact of presbyopia on a patient and how the combination of residual objective accommodation and their natural DoF work for them; objective techniques (such as autorefraction, corneal topography and lens imaging) allow the clinician to understand how well a technique is working optically and whether it is the right choice or how adjustments can be made to optimise performance. Techniques to assess visual performance and adverse effects must be carefully conducted to gain a reliable end-point, considering the target size, contrast and illumination. Objective techniques are generally more reliable, can help to explain unexpected subjective results and imaging can be a powerful communication tool with patients. A clear diagnosis, excluding factors such as binocular vision issues or digital eye strain that can also cause similar symptoms, is critical for the patient to understand and adapt to presbyopia. Some corrective options are more permanent, such as implanted inlays / intraocular lenses or laser refractive surgery, so the optics can be trialled with contact lenses in advance (including differences between the eyes) to better communicate with the patient how the optics will work for them so they can make an informed choice.

Wu,T.-Y., Huang,C.-C., Tsai,H.C., Lon,T.-K., Chen,P.-Y., Darge,H. F., Hong,Z.-X., Ham,H.-J., Lin,S.-Z., Lai,J.-Y., Chen,Y.-S. Mucin-mediated mucosal retention via end-terminal modified Pluronic F127-based hydrogel to increase drug accumulation in the lungs Biomaterials Advances 2024;Jan(156):213722 [ Show Abstract ]

Noninvasive lung drug delivery is critical for treating respiratory diseases. Pluronic-based copolymers have been used as multifunctional materials for medical and biological applications. However, the Pluronic F127-based hydrogel is rapidly degraded, adversely affecting the mechanical stability for prolonged drug release. Therefore, this study designed two thermosensitive copolymers by modifying the Pluronic F127 terminal groups with carboxyl (ADF127) or amine groups (EDF127) to improve the viscosity and storage modulus of drug formulations. β-alanine and ethylenediamine were conjugated at the terminal of Pluronic F127 using a two-step acetylation process, and the final copolymers were characterized using 1H nuclear magnetic resonance (1H NMR) and Fourier-transform infrared spectra. According to the 1H NMR spectra, Pluronic F127 was functionalized to form ADF127 and EDF127 with 85 % and 71 % functionalization degrees, respectively. Rheological studies revealed that the ADF127 (15 wt%) and EDF127 (15 wt%) viscosities increased from 1480 Pa.s (Pluronic F127) to 1700 Pa.s and 1800 Pa.s, respectively. Furthermore, the elastic modulus of ADF127 and EDF127 increased, compared with that of native Pluronic F127 with the addition of 5 % mucin, particularly for ADF127, thereby signifying the stronger adhesive nature of ADF127 and EDF127 with mucin. Additionally, ADF127 and EDF127 exhibited a decreased gelation temperature, decreasing from 33 °C (Pluronic F127 at 15 wt%) to 24 °C. Notably, the in vitro ADF127 and EDF127 drug release was prolonged (95 %; 48 h) by the hydrogel encapsulation of the liposome-Bdph combined with mucin, and the intermolecular hydrogen bonding between the mucin and the hydrogel increased the retention time and stiffness of the hydrogels. Furthermore, ADF127 and EDF127 incubated with NIH-3T3 cells exhibited biocompatibility within 2 mg/mL, compared with Pluronic F127. The nasal administration method was used to examine the biodistribution of the modified hydrogel carrying liposomes or exosomes with fluorescence using the IVIS system. Drug accumulation in the lungs decreased in the following order: ADF127 > EDF127 > liposomes or exosomes alone. These results indicated that the carboxyl group-modified Pluronic F127 enabled well-distributed drug accumulation in the lungs, which is beneficial for intranasal administration routes in treating diseases such as lung fibrosis.