New model of proliferative vitreoretinopathy in rabbit for drug delivery and pharmacodynamic studies

Blinding retinal diseases become more epidemic as the population ages. These diseases, such as diabetic retinopathy and macular edema, are of chronic nature and require protracted drug presence at the disease site. A sustained intravitreal porous silicon delivery system with dexamethasone (pSiO₂-COO-DEX) was evaluated in a new rabbit model of proliferative vitreoretinopathy (PVR) in a real treatment design. In contrast to the pretreatment design model, pSiO₂-COO-DEX was intravitreally injected into the eyes with active inflammation. Subretinal injection of vascular endothelial growth factor (VEGF) and Matrigel induced a late-onset vitreoretinal inflammation that gradually developed into PVR. This method mimics the human disease better than PVR induced by either intravitreal cell injection or trauma. The pSiO₂-COO-DEX intervened eyes had minimal PVR, while balanced saline solution or free dexamethasone intervened eyes had significantly more PVR formation. In addition, adding VEGF to the Matrigel for subretinal injection induced greater inflammation and retinal neovascularization in comparison to only Matrigel injected under the medullary ray. Clinical and pathological examinations, including fundus fluorescein angiography and optical coherence tomography, confirmed these changes. In the current study, neither subretinal injection of Matrigel or subretinal injection of VEGF and Matrigel induced choroidal neovascularization. However, the current PVR model demonstrates a chronic course with moderate severity, which may be useful for drug screening studies.

随着人口老龄化，致盲性视网膜疾病的发病率日益攀升。此类疾病包括糖尿病视网膜病变（diabetic retinopathy）与黄斑水肿（macular edema），均为慢性病程，需要药物在病灶部位持续发挥药效。本研究针对一种搭载地塞米松的多孔硅玻璃体内递送系统（pSiO₂-COO-DEX），在新型增殖性玻璃体视网膜病变（proliferative vitreoretinopathy, PVR）兔模型中，采用贴合临床真实治疗的给药方案开展药效评价。与预处理造模模型不同，本研究将pSiO₂-COO-DEX直接注射至已出现活动性炎症的眼内。通过视网膜下注射血管内皮生长因子（vascular endothelial growth factor, VEGF）与基质胶（Matrigel），可诱导迟发性玻璃体视网膜炎症，该炎症可逐渐进展为PVR。相较于玻璃体内细胞注射或创伤诱导的PVR模型，该造模方法更贴近人类疾病的自然进程。接受pSiO₂-COO-DEX干预的眼球，其PVR病变程度极轻微；而接受平衡盐溶液或游离地塞米松干预的对照组眼球，则出现了显著更严重的PVR病变。此外，相较于仅在视网膜髓射线区域下注射基质胶的组别，视网膜下联合注射VEGF与基质胶可诱导更强烈的炎症反应与视网膜新生血管生成。临床与病理学检查手段——包括眼底荧光素血管造影与光学相干断层扫描——验证了上述实验结果。本研究中，无论是单独视网膜下注射基质胶，还是联合注射VEGF与基质胶，均未诱导脉络膜新生血管生成。不过，本次构建的PVR模型呈现出中等严重程度的慢性病程，可用于药物筛选相关研究。