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Peer-reviewed articles

2025

Garg,P., Shokrollahi,P., Darge,H., Phan,C-M., Jones,L. Controlled PVA Release from Chemical-Physical Interpenetrating Networks to Treat Dry Eyes ACS Omega 2025;10(1):1249-1260

Garg,P., Shokrollahi,P., Darge,H., Phan,C-M., Jones,L. 3D-Printed Contact Lenses to Release Polyvinyl Alcohol as a Therapeutic Agent for the Treatment of Dry Eyes Pharmaceutics 2025;17(2):219 [ Show Abstract ]

Purpose: Dry eye disease is highly prevalent, and the most common treatment, lubricating eye drops, only remains effective for a very short period of time. This project aims to 3D print a proof-of-concept, custom-fit, polyvinyl alcohol (PVA)-eluting contact lens (CL) for the treatment of dry eye disease. PVA is a commonly used viscosity enhancer in eye drops, with the capability of reducing symptoms of dry eye by stabilizing the tear film and reducing tear evaporation. The protective effects of PVA could be attributed to its water-retaining ability, which provides moisturization and prevents the loss of water.

Method: In this work, a low-cost stereolithography-based 3D printer was retrofitted with a humidity and temperature control kit to 3D print a PVA-loaded custom-fit CL. To evaluate the print quality of the 3D-printed CL, circularity was used to evaluate the shape fidelity in 3D printing. The PVA release from these lenses was assessed, along with its role in acting as a viscosity enhancer. The effect of PVA was further analyzed by a dry eye disease (desiccation stress) cell model.

Results: The shape fidelity evaluation of the 3D-printed CL displayed excellent circularity. The diameter, sagittal depth, and base curve of the 3D-printed lenses were measured to be 14.27 ± 0.06 mm, 3.77 ± 0.16 mm, and 6.4 ± 0.24 mm, respectively. The PVA release curves showed that approximately 1300 µg of PVA was released over the study duration of 24 h.

Conclusions: Overall, this work demonstrates that a 3D-printed PVA-eluting CL is a promising candidate for the treatment of dry eye.

Garg,P., Shokrollahi,P., Phan,C.-M., Jones,L. Biodegradable 3D-Printed Conjunctival Inserts for the Treatment of Dry Eyes
Polymers 2025;17(5): [ Show Abstract ]

Purpose: To fabricate 3D-printed, biodegradable conjunctival gelatin methacrylate (GelMA) inserts that can release polyvinyl alcohol (PVA) when exposed to an ocular surface enzyme.

Method: In this work, biodegradable conjunctival inserts were 3D-printed using a stereolithography-based technique. The release of PVA from these insert formulations (containing 10% GelMA and 5% PVA (P-Gel-5%)) was assessed along with different mathematical models of drug release. The biodegradation rates of these inserts were studied in the presence of a tear-film enzyme (matrix metalloproteinase-9; MMP9). The morphology of the inserts before and after enzymatic degradation was monitored using scanning electron microscopy.

Results: The 3D-printed P-Gel-5% inserts formed a semi-interpenetrating network, which was mechanically stronger than GelMA inserts. The PVA release graphs demonstrate that at the end of 24 h, 222.7 ± 20.3 µg, 265.5 ± 27.1 µg, and 242.7 ± 30.4 µg of PVA were released when exposed to 25, 50, and 100 µg/mL of MMP9, respectively. The release profiles of the P-Gel-5% containing hydrogels in the presence of different concentrations of MMP9 showed the highest linearity with the Korsmeyer–Peppas model. The results suggest that the degradation rate over 24 h is a function of MMP9 enzyme concentration. Over 80% of P-Gel-5% inserts were degraded at the end of 8 h, 12 h, and 24 h in the presence of 100, 50, and 25 µg/mL MMP9 enzyme solutions, respectively.

Conclusions: These results demonstrate the potential for 3D printing of GelMA for use as conjunctival inserts. These inserts could be used to deliver PVA, which is a well-known therapeutic agent for dry eye disease. PVA release is influenced by multiple mechanisms, including diffusion and enzymatic degradation, which is supported by morphological studies and biodegradation results.

Shokrollahi,P., Garg,P., Wulff,D., Hui,Al., Phan,C-M., Jones,L. Vat Photopolymerization 3D Printing Optimization: Analysis of Print Conditions and Print Quality for Complex Geometries and Ocular Applications International Journal of Pharmaceutics 2025;668(January):124999 [ Show Abstract ]

Abstract: 3D printing, also known as additive manufacturing, continues to reshape manufacturing paradigms in healthcare by providing customized on-demand object fabrication. However, stereolithography-based 3D printers encounter a conflict between optimizing printing parameters, requiring more time, and print efficiency, requiring less time. Moreover, commonly used metrics to assess shape fidelity of 3D printed hydrogel materials like ‘circularity’ and ‘printability’ are limited by the soft nature of hydrogels, that can cause irregularities in their boundary. To unlock the full potential of 3D printing of biomaterials, it is also necessary to understand correlation between printing parameters and ink properties. In this work, a method based on curing depth, overcuring (cumulative cure), and print thickness was developed, which enables a time-efficient and reliable determination of printing conditions for complex geometries using gelatin methacrylate hydrogel biomaterial ink. We also examined the impact of printing direction on the print quality in terms of object/print thickness and aspect ratio. Moreover, the effects of dye concentration, exposure time, and layer thickness on print quality were evaluated, with discussions focused on the correlation between print dimension to layer thickness. Further evaluation was achieved by successfully printing bioinspired corneal stroma-like scaffold and delicate structures like a contact lens and a model eyeball, substantially expanding the scope of this method in producing high-quality prints with intricate details. We also demonstrate the effectiveness of ‘Feret ratio,’ another measure of object shape, in assessing the shape fidelity of different prints. Overall, the results highlight the practical potential of this method in enhancing the speed and reliability of the 3D printing processes involving complex geometries using a low-cost 3D printers.

2023

Pereira-da-Mota,A. F., Vivero-Lopez, M., Garg,P., Phan,C-M., Concheiro,A., Jones,L., Alvarez-Lorenzo,C. In vitro–in vivo correlation of drug release profiles from medicated contact lenses using an in vitro eye blink model Drug Delivery and Translational Research 2023;13(4):1116-1127 [ Show Abstract ]

There is still a paucity of information on how in vitro release profiles from drug-loaded contact lenses (CLs) recorded in 3D printed eye models correlate with in vivo profiles. This work aims to evaluate the release profiles of two drug-loaded CLs in a 3D in vitro eye blink model and compare the obtained results with the release in a vial and the drug levels in tear fluid previously obtained from an animal in vivo study. In vitro release in the eye model was tested at two different flow rates (5 and 10 µL/min) and a blink speed of 1 blink/10 s. Model CLs were loaded with two different drugs, hydrophilic pravastatin and hydrophobic resveratrol. The release of both drugs was more sustained and lower in the 3D eye model compared to the in vitro release in vials. Interestingly, both drugs presented similar release patterns in the eye model and in vivo, although the total amount of drugs released in the eye model was significantly lower, especially for resveratrol. Strong correlations between percentages of pravastatin released in the eye model and in vivo were found. These findings suggest that the current 3D printed eye blink model could be a useful tool to measure the release of ophthalmic drugs from medicated CLs. Nevertheless, physiological parameters such as the composition of the tear fluid and eyeball surface, tear flow rates, and temperature should be optimized in further studies.

Scientific Presentations

2024

Garg P, Shokrollahi P, Phan CM, Jones L. 3D printing of PVA loaded ocular inserts for ocular drug delivery The Association for Research in Vision and Ophthalmology, Seattle, WA, May 9, 2024 [ Show Abstract ][ PDF ]

Purpose: To develop ocular inserts comprised of polyvinyl alcohol (PVA) and gelatin methacrylate (GelMA), using 3D printing technology.

Methods: Inserts were synthesized using a bioink formulation consisting of 10% (w/v) GelMA, 5% (w/v) and 7.5% (w/v) PVA, 0.6% (w/v) lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), and 5% (v/v) yellow dye as a light absorbing agent to improve print resolution. They had a 4mm diameter, 1mm thickness and were fabricated using a commercial masked-stereolithography (mSLA) 3D printer at 95% humidity and 37°C temperature. Morphology of the inserts was investigated by freeze-drying samples and imaging them using a scanning electron microscope (SEM). Release of PVA over 5 hours was studied by incubating at 35°C in PBS in an incubator shaker at 50rpm. The hydrogel samples were freeze dried and their equilibrium swelling was studied in PBS using gravimetric method.

Results: The PVA-loaded ocular inserts were 3D printed within 30 minutes. SEM images showed that 7.5% PVA loaded inserts had more uniform pore size distribution compared to the gels with no PVA. Approximately 37% of PVA was released within the first 2 hrs from the inserts containing PVA, and the release continued up to approximately 4 hrs before reaching a plateau. The release kinetics can be attributed primarily due to passive diffusion. The swelling curves of these hydrogels suggest that they reach equilibrium swelling within 24hr. From the slope of the swelling curve in the first hour, it can be inferred that swelling happens at a slower rate for GelMA/PVA compared to GelMA alone. This slower swelling rate helps to control the release and supports a sustained release of PVA from the combination.

Conclusions: This study showed that a GelMA-PVA based bioink can be used to 3D print ocular inserts that can release PVA for up to 4 hours. Future work will focus on designing 3D scaffolds to increase the release duration of PVA from these gels.

Ho B, Phan CM, Garg P, Shokrollahi P, Jones L. A screening platform for simultaneous evaluation of biodegradation and therapeutic release from an ocular hydrogel and its effect on human corneal epithelial cells The Association for Research in Vision and Ophthalmology, Seattle, WA, May 7, 2024 [ Show Abstract ][ PDF ]

Purpose: To integrate human corneal epithelial cells (HCECs) into a millifluidic screening platform that quantifies biodegradation and release of an entrapped therapeutic from an ocular hydrogel.

Introduction: Biodegradable hydrogels are novel drug delivery methods designed to release entrapped drugs or therapeutics as the gel degrades in situ. The primary challenge in developing biodegradable hydrogels for drug delivery lies in accurately measuring their degradation over time, while simultaneously being able to evaluate the drug release kinetics, which is typically a cumbersome procedure. To properly evaluate the biodegradation of a hydrogel, it is also essential to simulate key factors of the target tissue environment. In the context of the eye, this includes ocular temperature, tear flow, and low tear volume. Recent advances in organ-on-a-chip technologies have made it possible to emulate the human corneal environment. This will allow more accurate measurements of hydrogel degradation rates, subsequent drug or therapeutic release, and ultimately the overall effect on human corneal epithelial cells.

Methods: Gelatin Methacrylate (GelMA) ocular inserts with polyvinyl alcohol (PVA) (10% GelMA 7.5% PVA) were placed inside a custom-designed millifluidic device. Ocular inserts were degraded with up to 200 μg/mL of matrix metallipeptidase 9 (MMP9) for 24 hours at 37oC in PBS. Biodegradation of the ocular insert was quantified using a computational image analysis pipeline. The eluates containing the degradation products were collected to measure PVA released using a spectrophotometric assay, and its toxicity on human corneal epithelial cells (HCECs) was determined by alamarBlueTM assays.

Results: There was significant biodegradation of the GelMA-PVA inserts with increasing concentration of MMP9 in the millifluidic device, which was accurately quantified using a custom computational analysis. Degradation products in the eluate were collected, and there was a ~2-fold increase of PVA released in samples treated with MMP9 compared to the control. The same eluates were non-toxic to HCECs, and interestingly protected HCECs from hyperosmotic conditions mimicking dry eye disease.

2023

Garg P, Wulff D, Phan CM, Jones L. Evaluation of a biodegradable bioink for the fabrication of ophthalmic devices using 3D printing The Association for Research in Vision and Ophthalmology, New Orleans, LA, USA, April, 2023 [ Show Abstract ][ PDF ]

Purpose: To develop a degradable bioink for fabricating ophthalmic devices using 3D printing.

Methods: The bioink formulation consisted of 10% gelatin methacrylate (GelMA), 0.6% lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), and 5% yellow dye as a light absorbing agent to improve print resolution. The bioink was used to 3D print square sheets (7x7x1 mm) using a commercial masked-stereolithography (mSLA) 3D printer at 95% humidity and 37°C temperature. The degradation of printed sheets was evaluated with different concentrations (0,25,50,100 μg/ml) of matrix metalloproteinase (MMP9) enzyme 37°C. MMP9s are naturally found in the tear film and elevated in various diseased states such as in corneal wounds and dry eye disease. The weights of the sheets were measured at t = 0,4,6,8,12,16,24 hrs. Another set of cubes (1x1x1 cm) was autoclaved and kept sealed in storage at different temperatures (4°C, 25°C, and 37°C) in phosphate buffered saline (PBS) and their weight was measured on day 10. An attempt was made to fabricate a contact lens using this bioink.

Results: Samples that were exposed to MMP9 enzymes showed a time-dependent degradation with increasing enzyme concentration. The samples incubated with 100 and 50 μg/ml of MMP9 were completely degraded by the end of 12 and 16 hrs, respectively. At the end of 24 hrs, the samples incubated at 25 μg/ml enzyme showed 72.8% degradation whereas the control samples did not show any signs of degradation. Interestingly, samples that were autoclaved and kept in storage also did not show any signs of degradation at all temperatures. A 3D-printed CL with overall diameter 14mm and thickness 1mm was printed without any support structures within 1 hour.

Conclusion: This study showed GelMA-based bioink can be used to fabricate biodegradable devices such as contact lenses. The biomaterials degrade in the presence of MMP-9 and future work will work on tuning the degradation kinetics of these materials, as well as incorporating ocular drugs.

Garg P, Wulff D, Phan CM, Jones L. Fabrication of a degradable ocular drug delivery system using 3D printing CBB 2023 Conference: Waterloo for Health, Technology and Society, March, 2023 [ PDF ]

2022

Phan C-M, Wulff D, Garg P, Jones L.. Developing a novel in vitro eye model using 3D bioprinting for drug delivery studies The Association for Research in Vision and Ophthalmology, Denver, CO, USA, May 1, 2022 [ Show Abstract ]

Purpose: To develop an in vitro eye model using a novel 3D bioprinting method for testing the release of ophthalmic formulations to the posterior ocular region.

Methods: The eye model was designed using CAD software and includes both an anterior aqueous chamber and a posterior vitreous chamber. The vitreous chamber is surrounded by a blood chamber to mimic vessels that can be used to transport a blood-like substance. Three inlet ports control the flow of fluid into the chambers and the blood channels, and the three outlet ports allow fluids to exit these compartments. The eye model was 3D printed on a commercial mSLA printer (Photon Mono X, AnyCubic), which was retrofitted with a humidity and temperature control module to create a printing environment at 37°C and >80% humidity. The bioink formulation consisted of 10% gelatin methacrylate (GelMa). After printing, the models were incubated at 37°C to remove any uncured GelMa within any hollow compartments. For this study, phosphate-buffered saline was used as an aqueous and vitreous humour mimic. To evaluate the diffusion of a small hydrophilic molecule on the eye model, a contact lens (Air Optix) was soaked with a water-soluble red food dye for 1 hour and then placed on the eye model. The amount of dye in the anterior chamber, posterior chamber, and blood channels was measured using UV spectrophotometry after 24 hours.

Results: The entire model can be printed without any support structures within approximately 3 hours. The 3D printed eye model can also be autoclaved for testing that requires sterility. Because there were no diffusion barriers present in the current model, the red dye was detected in all three chambers after 24 hours. The highest concentration of dye was found in the anterior chamber, followed by the blood chamber and then the posterior chamber.

Conclusions: The prototype developed in this study can be used as a starting point to develop enhanced 3D printed eye models to test drug release kinetics of various devices and formulations. Future work will focus on adding the appropriate diffusion barriers to better simulate drug diffusion through ocular tissues.

Layman Abstract: The aim of the study was to create an advanced eye model using commercial 3D printing methods. Current 3D bioprinters are extremely expensive and regular commercial 3D printers do not have the capabilities to print biological materials. We are developing a method to 3D print sophisticated eye models using inexpensive 3D printers. The models from this research can further be refined for studying drug absorption in the eye. This research will also enable researchers to create their own biological models using 3D printing methods.

Professional Publications

2023

Garg P. Fast Forward to the Future: Biodegradable CLs Contact Lens Spectrum 2023;38, February: