Ultrasound-Mediated Ocular Drug Delivery: From Physics and Instrumentation to Future Directions

Abstract

Drug delivery to the anterior and posterior segments of the eye is impeded by anatomical and physiological barriers. Increasingly, the bioeffects produced by ultrasound are being proven effective for mitigating the impact of these barriers on ocular drug delivery, though there does not appear to be a consensus on the most appropriate system configuration and operating parameters for this application. In this review, the fundamental aspects of ultrasound physics most pertinent to drug delivery are presented; the primary phenomena responsible for increased drug delivery efficacy under ultrasound sonication are discussed; an overview of common ocular drug administration routes and the associated ocular barriers is also given before reviewing the current state of the art of ultrasound-mediated ocular drug delivery and its potential future directions.

Keywords: acoustic cavitation; acoustic streaming; ocular barriers; ocular drug delivery; targeted drug delivery; ultrasound.

Figure 1

Schematic of transducer cross-section [86].

Figure 2

(a) Bubble action under varying acoustic pressure. (b) Non-inertial cavitation-generated microstreaming and shear stress on cell membrane. (c) Microjetting towards cell membrane under inertial cavitation [102].

Figure 3

(a) Ultrasound and passive cavitation detector setup for mouse BBB disruption. (b) Fluorescent images showing dextran distribution in the hippocampus after (A) short pulse (pulse length = 5 cycles, PRF = 1.25 kHz) ultrasound treatment and after (B) long pulse (pulse length = 10,000 cycles, PRF = 0.5 Hz) ultrasound treatment [110].

Figure 4

Routes of administration for ocular drug delivery and associated ocular barriers [114].

Figure 5

Structure of (a) drug-loaded (green) micelle [141], (b) liposome, and (c) dendrimer [142].

Figure 6

(a) Vitreal and retinal distribution of cationic polyethyleneimine nanoparticles 6 (A), 24 (B), and 72 (C) hours post injection. (b) Vitreal and retinal distribution of anionic hyaluronic acid nanoparticles 6 (A), 24 (B), and 72 (C) hours post injection [153].

Figure 7

Diffusion cell setup used by Zderic et al. [70] to measure rabbit cornea permeability.

Figure 8

Ratio of permeability of treated cornea to control cornea to various drugs for various treatment durations in the presence of atenolol (A), carteolol (C), timolol (T), and betaxolol (B) [70].

Figure 9

Microscope images of the cornea following a 60 min ultrasound treatment. The images show (a) partial detachment of the epithelium from the stroma and (b) the appearance of “bubble-like” structures in the epithelium (black arrow) and in the stroma (white arrow) [70].

Figure 10

(a) (A) Structure of the vasculature supplying the retina, composing the inner BRB and the choroid adjacent to the retinal pigment epithelium (RPE) forming the outer BRB. (B) Illustration of the disruption of the BRB by gas bubble volume oscillation during ultrasonic cavitation. (b) The passage of substances through the resultant openings in blood vessels and cell membranes [169,170].

Figure 11

Acoustic pressure distribution in a rat eye using focused ultrasound for BRB disruption [168].

Figure 12

Photomicrographs showing points of accumulation (arrow heads) of Evans Blue dye (left), immunoglobulin G (centre), and immunoglobulin M (right) macromolecules in retinal parenchyma following ultrasound treatment [169].

Figure 13

Diagram of (A) the experimental setup and (B) probe placement for ultrasound treatment with microbubble perfusion in an ex vivo porcine eye to investigate drug delivery to the retina [172].

Figure 14

Percentage of cells lining examined blood vessel exhibiting accumulation of dye and dextrans [172]. ** = p < 0.005; ns = not significant.