A porcine commotio retinae model for preclinical evaluation of posttraumatic photoreceptor degeneration
Juan Amaral, Irina Bunea, Arvydas Maminishkis, Maria M. Campos, Francesca Barone, Rohan Gupta, Mitra Farnoodian, Jonathan Newport, M. Joseph Phillips, Ruchi Sharma, David M. Gamm, Kapil Bharti, Richard J. Blanch
Juan Amaral, Irina Bunea, Arvydas Maminishkis, Maria M. Campos, Francesca Barone, Rohan Gupta, Mitra Farnoodian, Jonathan Newport, M. Joseph Phillips, Ruchi Sharma, David M. Gamm, Kapil Bharti, Richard J. Blanch
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Research Article Neuroscience Ophthalmology

A porcine commotio retinae model for preclinical evaluation of posttraumatic photoreceptor degeneration

Abstract

Commotio retinae (CR) resulting from retinal trauma can lead to focal photoreceptor degeneration and permanent vision loss. Currently no therapies exist for CR-induced retinal degeneration, in part because of the lack of a large-animal model that replicates human injury pathology and allows testing of therapeutics. Severe CR is clinically characterized by subretinal fluid and focal photoreceptor outer nuclear layer thinning. To develop a porcine CR model, we developed a laser-guided projectile apparatus and optimized projectile delivery procedure using porcine cadaveric eyes embedded in a 3D-printed porcine skull. Scleral and corneal impacts resulted in retinal damage consistent with patient injury, but corneal impacts also led to cornea damage and opacification, which precluded follow-up imaging. In live porcine eyes, scleral impacts of 39.5 m/s induced transient blood-retinal barrier breakdown evidenced by subretinal fluid on optical coherence tomography (OCT), leakage observed on fluorescein and indocyanine green angiography, and transient photoreceptor outer segment disruption seen by OCT and multifocal electroretinography. Impacts above 39.5 m/s induced longer-lasting photoreceptor degeneration but only transient blood-retinal barrier breakdown. This porcine model, combined with clinically relevant imaging and diagnostic modalities, will be valuable for testing the safety and efficacy of therapies to restore vision after focal photoreceptor degeneration.

Authors

Juan Amaral, Irina Bunea, Arvydas Maminishkis, Maria M. Campos, Francesca Barone, Rohan Gupta, Mitra Farnoodian, Jonathan Newport, M. Joseph Phillips, Ruchi Sharma, David M. Gamm, Kapil Bharti, Richard J. Blanch

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Figure 3

Short-term evaluation of pig eyes with CR injury.

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Short-term evaluation of pig eyes with CR injury. (A) High magnification...
(A) High magnification of color fundus photograph of CR-injured eye showing: 1, preretinal hemorrhage at the impact site; 2, the whitening zone; 3, the adjacent visual streak. (B–E) FA images (left panels) show fluorescein dye leakage in early phase (1 minute) on day 0 (B) and late phase (10 minutes) on day 0 after injury (C), but not on day 8 after injury (D, early phase; E, late phase). ICGA images (right panels) show no dye leakage on day 0 after injury (B, early phase; C, late phase) and day 8 (D, early phase; E, late phase). Scale bars: 2 mm. (F) Schematic depicting the 3 distinct zones seen on color fundus and OCT images: impact zone showing hematoma (zone 1); whitening zone with extensive outer blood retina barrier (oBRB) damage and subretinal fluid (SRF) accumulation (zone 2); and zone with ellipsoid zone (EZ) disruption (zone 3). (G and H) OCT (G) and H&E staining (H) depicting the 3 zones described in F. Scale bars: 500 μm. (I–L) Higher-magnification OCT images: at baseline (BL) showing the ellipsoid zone (arrowhead, I); SRF accumulation on day 0 after CR injury (J); and fluid resorption by day 11 but missing ellipsoid zone (arrowhead, K), which persists on day 14 (L). Scale bars: 500 μm. (M and N) H&E section depicting healthy retina at baseline (BL) (M), and disruptions of ONL and photoreceptor outer segments (arrowhead) 11 days after CR injury (N). Scale bars: 20 μm. (O and P) mfERG signal heatmap at baseline (BL) (O) and day 11 (P) after injury showing the visual streak (vs) (dotted circle) and surrounding areas retina light response. Nine eyes were used for short-term evaluation of CR injury. NFL, nerve fiber layer; IPL, inner plexiform layer; INL, inner nuclear layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium.