Choroidal neovascular membrane inhibition in a laser treated rat model with intraocular sustained release triamcinolone acetonide microimplants

Abstract

Aim: To determine if intravitreal microimplants containing triamcinolone acetonide (TAAC) inhibit experimental fibrovascular proliferation (FVP) induced by laser trauma in a rat as a model of choroidal neovascular membranes (CNVMs).

Methods: 20 anaesthetised male Brown Norway rats received a series of eight krypton red laser lesions per eye (647 nm, 0.05 s, 50 micro m, 150 mW). Three types of sterilised TAAC microimplant designs were evaluated: implant A consisting of 8.62% TAAC/20% polyvinyl alcohol (PVA) matrix (by dry weight); implant B consisting of 3.62% TAAC/20% PVA matrix; and implant C consisting of a dual 8.62% TAAC/20% PVA matrix design combined with a central core (0.5 mm) of compressed TAAC to extend the implant release time. For each animal studied, one eye received one of the three aforementioned TAAC implant designs, while the fellow eye received a control implant consisting of PVA but without TAAC. The animals were sacrificed at day 35 and ocular tissues were processed for histological analysis. Serial histological specimens were methodically assessed in a masked fashion to analyse each laser lesion for the presence or absence of FVP; maximum FVP thickness for each lesion was measured from the choriocapillaris.

Results: All three types of TAAC implants inhibited FVP relative to controls in a statistically significant fashion. In the eyes that received implant A (n = 8), the mean thickness of the recovered lesions (n = 36) measured 32 (SD 22) micro m, compared to 52 (30) micro m (p <0.005) for the recovered lesions (n = 40) from the fellow control eyes. In the eyes that received implant B (n = 6), the mean thickness of the recovered lesions (n = 31) measured 28 (15) micro m, compared to 50 (29) micro m (p <0.001) for the lesions (n = 19) recovered from the fellow control eyes. In the eyes that received implant C (n = 6), the mean thickness of the recovered lesions (n = 21) measured 39 (24) micro m, compared to 65 (30) micro m (p <0.001) for the lesions (n = 39) recovered from the fellow control eyes.

Conclusions: All three of the tested TAAC microimplant designs produced potent inhibition of FVP in a rat model of CNVMs. There were no differences in inhibition of FVP between the three different types of implants evaluated. This study provides evidence that: (1) corroborates previous investigations that propose TAAC as a potential treatment for CNVMs in humans, and (2) demonstrates TAAC can be effectively delivered via long acting sustained release intraocular microimplants. It should be noted, however, that the FVP observed in this rat laser trauma may not reflect the CNVM observed in human with exudative age related macular degeneration (AMD).

Figure 1

Microimplant designs. The control implant (20% PVA only, far left), implant A (8.62% TAAC matrix, left centre), implant B (3.62% TAAC matrix, right centre), and implant C (dual 8.62% TAAC matrix with a 200 μg TAAC central reservoir, far right). The matrix for each design consists of 20% polyvinyl alcohol (PVA).

Figure 2

Cumulative mean release of TAAC (μg (1 SD)) versus the square root of time from implants A and B.

Figure 3

Cumulative mean release of TAAC (μg (1 SD)) versus time from implant C.

Figure 4

Representative histology (radial view) of four untreated control and four TAAC treated lesion sites at 35 days following lesion induction and placement of control versus TAAC microimplants, or of control versus TAAC intravitreal injections. Tissues were stained with haematoxylin and eosin. The scale bar in each photograph represents 30 μm. (A) PVA only microimplant control (fellow eye to implant A). Note the FVP (fibrovascular proliferation) arising through the disrupted retinal pigment epithelium (RPE) and Bruch’s membrane and infiltrating the retina. Well stained erythrocytes can be observed within lumenal structures. (B) Implant A, 8.62% (w/v) TAAC treated. Note the prominent defects in the RPE and Bruch’s membrane with a striking inhibition of FVP. The retina is drawn into the defect. (C) PVA only microimplant control (fellow eye to implant B). Note the FVP arising through the disrupted RPE and Bruch’s membrane and infiltrating the retina. (D) Implant B, 3.62% (w/v) TAAC treated. Note the prominent defects in the RPE and Bruch’s membrane with a striking inhibition of FVP. The retina is drawn into the defect, similar to the lesions from the eyes treated with the implant A design. (E) PVA only microimplant control (fellow eye to implant C). Note the FVP arising through the disrupted RPE and Bruch’s membrane with infiltration into the proximal retina, similar to the control lesions from the other control eyes. (F) Implant C, 8.62% (w/v) TAAC matrix with central TAAC reservoir treated. Note the inhibition of FVP on the left side of defect, with partial FVP development on the right side. (G) Intravitreal injection control (20 μl physiological saline). Similar to the other control eyes, note the FVP arising from the laser induced defect in the choroid and RPE with extensive retinal infiltration. (H) TAAC intravitreal injection treated (0.8 mg). Note the marked inhibition of FVP, similar to the effect produced in eyes receiving TAAC microimplants.