具有高级脉络膜毛细血管的 3D 外血-视网膜屏障的生成及其在微生理系统中糖尿病视网膜病变中的应用,ACS Biomaterials Science & Engineering

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具有高级脉络膜毛细血管的 3D 外血-视网膜屏障的生成及其在微生理系统中糖尿病视网膜病变中的应用
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2023-07-26 , DOI: 10.1021/acsbiomaterials.3c00326
Ungsig Nam ₁ , Seokhun Lee ₁ , Jessie S Jeon _{1,

2}

Affiliation

外层血视网膜屏障（oBRB）通过调节视网膜下腔和脉络膜毛细血管之间的分子交换为感光器的功能提供最佳环境，其功能障碍可能会损害感光器的功能和视力。现有的体外模型在重现 oBRB 和脉络膜毛细血管的屏障功能或生理特征方面存在局限性。在这里，我们设计了一个基于微生理系统的 oBRB-脉络膜毛细血管模型，该模型同时包含所需的生理特征并且易于制造。首先，我们生成了模拟脉络膜毛细血管的微血管网络，并研究了成纤维细胞在血管生成中的作用。通过将视网膜色素上皮细胞添加到由内皮细胞和成纤维细胞形成的血管的一侧并优化其培养基条件，我们建立了oBRB-脉络膜毛细血管模型。为了验证我们的oBRB-脉络膜毛细血管模型的生理相似性，我们鉴定了视网膜色素上皮、布鲁赫膜和脉络膜毛细血管窗孔隔膜的紧密连接的极化和表达。最后，我们试图在我们的模型中用高血糖和糖尿病相关细胞因子来概括糖尿病环境。这导致紧密连接完整性降低、屏障功能丧失和血管收缩，类似于在 oBRB 和脉络膜毛细血管中观察到的体内病理变化。使用微生理系统开发的 oBRB-脉络膜毛细血管模型有望为临床前应用中的视网膜和脉络膜血管疾病提供有价值的体外平台。

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Generation of a 3D Outer Blood–Retinal Barrier with Advanced Choriocapillaris and Its Application in Diabetic Retinopathy in a Microphysiological System

The outer blood–retinal barrier (oBRB) provides an optimal environment for the function of the photoreceptor by regulating the exchange of molecules between subretinal space and the choriocapillaris, and its dysfunction could impair the photoreceptor’s function and vision. The existing in vitro models have limitations in reproducing the barrier function or physiological characteristics of oBRB and choriocapillaris. Here, we engineered a microphysiological system-based oBRB-choriocapillaris model that simultaneously incorporates the desired physiological characteristics and is simple to fabricate. First, we generated microvascular networks to mimic choriocapillaris and investigated the role of fibroblasts in vasculogenesis. By adding retinal pigment epithelial cells to one side of blood vessels formed with endothelial cells and fibroblasts and optimizing their culture medium conditions, we established an oBRB-choriocapillaris model. To verify the physiological similarity of our oBRB-choriocapillaris model, we identified the polarization and expression of the tight junction of the retinal pigment epithelium, Bruch’s membrane, and the fenestral diaphragm of choriocapillaris. Finally, we tried to recapitulate the diabetes mellitus environment in our model with hyperglycemia and diabetes-related cytokines. This induced a decrease in tight junction integrity, loss of barrier function, and shrinkage of blood vessels, similar to the in vivo pathological changes observed in the oBRB and choriocapillaris. The oBRB-choriocapillaris model developed using a microphysiological system is expected to offer a valuable in vitro platform for retinal and choroidal vascular diseases in preclinical applications.

更新日期：2023-07-26

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