Arunn Narasimhan

Arunn Narasimhan

Drug Delivery in Human Eye

Created Last modified 6 min read

About this note

A plain-language summary of the 3 publications listed under this topic on Academic Publications (Topic-wise). Full citations are under References.

Why this matters

Many causes of blindness, such as uveitis, age-related macular degeneration (AMD), retinopathy and retinal detachment, sit in the posterior segment, the back of the eye made up of the retina, choroid and sclera. Getting a drug there in useful amounts is hard. The eye defends itself with static barriers (the layered cornea, sclera and retina) and dynamic ones (blood flow in the choroid and conjunctiva, lymphatic drainage and tear dilution). Eye drops are drained away by tears and held back by the cornea; drugs carried by the bloodstream are largely kept out by the barrier between blood and the inner eye and risk side effects elsewhere in the body. As a result, eye drugs are often given repeatedly over months or years (Narasimhan and Sundarraj, 2015; Shrinivas and Narasimhan, 2023).

Two routes get around these problems. In transscleral delivery, the drug is placed just outside the white of the eye (the sclera) and diffuses inwards. In intravitreal delivery, it is injected straight into the vitreous chamber, the large fluid-filled space in front of the retina. Our work examined one of each: what stops a transscleral drug from arriving, and how an intravitreal drug can be made to arrive faster.

What we did

Transscleral delivery through porous tissue

With Ramanathan Vishnampet, we modelled the delivery of anecortave acetate, a drug used for AMD, from a depot placed against the back of the sclera (Narasimhan and Ramanathan, 2012). The sclera and the choroid behind it were treated as porous media, solid tissue threaded with fluid-filled pores. Their porosity (about 0.39) was measured by image analysis of published electron microscope pictures of the sclera, and the drug’s effective diffusivity was obtained from an experimental correlation between scleral permeability and molecular weight. Blood flowing through the choroid was included explicitly. We followed the drug for 23 days after a single dose and compared the predicted drug levels in the choroid with published measurements.

Intravitreal delivery helped by convection

This idea is the sequel to our study of vitreous circulation during laser therapy, told in Bio-Fluid Dynamics of Human Eye. That study began with my father’s retinal tear. Repairing a tear removes the vitreous gel, seals the retina with a laser, and leaves the space to fill with watery body fluid, so eyes with a liquid vitreous are common among older patients. Once we had found that gentle laser heating sets such fluid circulating, the natural next question was whether the circulation could carry a drug to the retina. This time the student, C. Sundarraj, needed no persuading.

When a drug is injected into the vitreous it normally spreads by diffusion alone, which is slow; reaching effective levels at the retina can take hours to days. In an eye whose vitreous gel has been surgically removed and replaced by a watery fluid (a vitrectomised eye), the fluid can move. With C. Sundarraj, we proposed using gentle laser heating of the retina to set up natural convection, a buoyancy-driven circulation, so that the flow carries the drug to the retina. A two-dimensional eye model with a 300 mW laser over a 4 mm spot (a power level used therapeutically and not known to damage tissue) was used to compare diffusion alone with convection-assisted diffusion for drug injected at the centre of the vitreous, near the lens, near the retina and at the bottom of the chamber (Narasimhan and Sundarraj, 2015).

With Shrinivas Vibhute, we then tested the idea in the laboratory (Shrinivas and Narasimhan, 2023). A glass eye of realistic size was filled with water or silicone oil, a small heater on the retinal surface mimicked the laser, and 15 microlitres of a dye mimicked the drug. Dye concentrations at a central spot on the retinal pigmented epithelium and at an upper retinal spot were measured from video using a colour-intensity calibration.

What we found

For transscleral delivery, the choroidal blood flow is the villain. Blood sweeps the drug away before it can reach the retina, and over the normal range of choroidal blood speeds this circulation loss is the dominant route of loss inside the eye. The peak drug concentration in the choroid fell by about 70% between the low and high ends of the normal blood-speed range. Reducing blood flow helps only up to a point: below about 0.4 cm/s, losses into the vitreous take over. The model predicted the peak concentration within the experimental range for 3, 15 and 30 mg doses and showed drug persisting in the choroid for about three weeks (Narasimhan and Ramanathan, 2012).

For intravitreal delivery, convection made a large difference. In the simulations, after 60 minutes the average drug level in the retinal target region was 5.7 times higher than with diffusion alone for a central injection. Injecting at the bottom of the chamber did about ten times better than injecting at the centre, because the circulation is strongest near the walls and weakest in the middle. Convection also helped large, slowly diffusing molecules such as therapeutic antibodies, and a patient lying horizontally received about 10% more drug at the retina than one sitting upright (Narasimhan and Sundarraj, 2015).

The glass-eye experiments confirmed the idea. Dye injected near the lens reached 12.95 micrograms per millilitre at the central retinal spot in 12 minutes with heating, compared with 12 hours without. Convection-assisted transport reached steady state in about 1.5 hours instead of 9, and the steady-state concentration at the retinal target was 56.25 times higher. Across injection sites and target spots, the time to reach a given concentration fell by 97% to 99% (Shrinivas and Narasimhan, 2023). The heating needed is mild, below that used in routine retinal laser surgery, so the method could make injected drugs act faster and reduce the need for repeated injections.

References

  1. Shrinivas, V. and Narasimhan, A., (2023) “Convection-assisted intra-vitreous drug delivery in human eye: An experimental investigation,” Heat Transfer May 2023, 1-13. [ DOI: 10.1002/htj.22899 | Abstract | IITM Tech Talk News | BioVoice News ]
  2. Narasimhan, A. and Sundarraj, C., (2015) “Convection-Enhanced Intravitreous Drug Delivery in Human Eye”   ASME J. of Heat Transfer 137(12), 121003 (Aug 11, 2015) (7 pages) [DOI: 10.1115/1.4030916 | Abstract ]
  3. Narasimhan, A. and Ramanathan, V. G., (2012), “Effect of choroidal blood flow on transscleral retinal drug delivery using a porous medium model,”  Int. J. Heat and Mass Transfer, 55 (21), 5665–5672.[DOI: 10.1016/j.ijheatmasstransfer.2012.05.060].

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