A swarm of slippery micropropellers penetrates the vitreous body of the eye

Abstract

The intravitreal delivery of therapeutic agents promises major benefits in the field of ocular medicine. Traditional delivery methods rely on the random, passive diffusion of molecules, which do not allow for the rapid delivery of a concentrated cargo to a defined region at the posterior pole of the eye. The use of particles promises targeted delivery but faces the challenge that most tissues including the vitreous have a tight macromolecular matrix that acts as a barrier and prevents its penetration. Here, we demonstrate novel intravitreal delivery microvehicles-slippery micropropellers-that can be actively propelled through the vitreous humor to reach the retina. The propulsion is achieved by helical magnetic micropropellers that have a liquid layer coating to minimize adhesion to the surrounding biopolymeric network. The submicrometer diameter of the propellers enables the penetration of the biopolymeric network and the propulsion through the porcine vitreous body of the eye over centimeter distances. Clinical optical coherence tomography is used to monitor the movement of the propellers and confirm their arrival on the retina near the optic disc. Overcoming the adhesion forces and actively navigating a swarm of micropropellers in the dense vitreous humor promise practical applications in ophthalmology.

Fig. 1. Schematic of the three-step targeted delivery procedure used for the slippery micropropellers.

(1) Injection of the micropropellers into the vitreous humor of the eye. (2) Magnetically driven long-range propulsion of the micropropellers in the vitreous toward the retina. (3) Observation of the micropropellers at the target region near the surface of the retina by OCT.

Fig. 2. Fabrication and characterization of the perfluorocarbon-coated “slippery” micropropellers.

(A) Schematic of the fabrication process. (B) SEM (top) and ESB-SEM (bottom) images of the micropropellers. The yellow arrows indicate the length (l) of the propeller and the diameter (d) of the head of the propeller. The white area is the nickel part of the propeller. Scale bars, 500 nm. (C) FTIR spectroscopy of the micropropellers without coating and with the perfluorocarbon coating, and the perfluorocarbon liquid. The enlarged spectra are displayed at the bottom right, proving the presence of the perfluorocarbon. The contact angles of the wafer with an array of coated helices (top) and uncoated helices (bottom) are shown, respectively.

Fig. 3. Controllable movement of the perfluorocarbon-coated micropropellers in the vitreous humor.

(A) Schematic and time-lapse microscopy images showing the incomplete rotation of an uncoated micropropeller for one period (p) in the vitreous. (B) Schematic and time-lapse images showing the magnetically powered propulsion of the coated slippery propeller in the vitreous for 1.5 s (nine periods). In both schematic images, the green and the red dashed lines indicate the original position of the particles and the position of the particles during the application of the rotating magnetic field, respectively. The red arrows in both figures indicate the propulsion direction of the propeller. Scale bars, 1 μm. (C) Rotation angle of the uncoated propeller and the slippery propeller in the vitreous under the application of a rotating magnetic field. (D) Measured passive diffusion coefficients of uncoated silica particles and the slippery layer–functionalized particles in the vitreous. (E) Controllable magnetic field–driven propulsion of the coated micropropellers in the vitreous. The lines indicate the trajectories of the propellers (movie S4). Scale bar, 20 μm. (F) Dependence of the propulsion velocity of the slippery micropropellers on the driving frequency of the magnetic field in the vitreous, 25% glycerol solution, and water, respectively. Error bars represent SDs.

Fig. 4. Characterization of the movement the slippery micropropellers in the vitreous.

(A) Two typical trajectories of the micropropellers and their corresponding dynamic velocities (inset). (B) Histograms of the dynamic velocities of the microhelices in the vitreous and 25% glycerol. (C) Flexural trajectories of the slippery micropropellers in the vitreous over a horizontal distance of 100 μm. (D) Directionalities between the start and end points over a horizontal distance of 100 μm. The distribution of the TA of the micropropellers in the vitreous is statistically analyzed (n > 60).

Fig. 5. Movement of the slippery micropropellers in the complete eyeball.

(A) Schematic illustrating the movement of the slippery micropropellers in the vitreous (V) toward the retina (R). Passive fluorescent particles are injected with the micropropellers to mark the injection position. (B) Fluorescent microscopy image of the incised retina at the target region after the magnetic propulsion. Micropropellers [loaded with fluorescent nanodiamonds (red)] are observed on the retina [cell nuclei stained by DAPI (blue)]. Scale bar, 20 μm. (C) Fluorescence image shows that the passive fluorescent particles are located near the center of the vitreous. Scale bar, 1 mm. (D) Autofluorescence image of the retina near the optic disc. “D” stands for optic disc. Scale bar, 1 mm. (E) Colormap calculated by the three-dimensional (3D) reconstruction of the OCT scans, showing the distribution of the micropropellers in the corresponding dashed-line box in (D). (F and G) OCT images of X and Y scans, respectively, near the propellers’ landing zone. The dashed-line circles label the region of the micropropellers near the retina. The scan planes are indicated as green arrows in (D). (H) OCT image of the Y scan away from the optic disc, indicated as the yellow arrow in (D). Scale bars, 500 μm in (F to H).