Establishing Liposome-Immobilized Dexamethasone-Releasing PDMS Membrane for the Cultivation of Retinal Pigment Epithelial Cells and Suppression of Neovascularization.

Tzu-Wei Lin,Ke-Hung Chien,Yi-Ying Lin,Aliaksandr A Yarmishyn,Yi-Ping Yang,Shih-Jen Chen,Mong-Lien Wang,Chih-Chien Hsu,Chi-Hsien Peng,Yueh Chien,De-Kuang Hwang

doi:10.3390/ijms20020241

Abstract

Age-related macular degeneration (AMD) is the eye disease with the highest epidemic incidence, and has great impact on the aged population. Wet-type AMD commonly has the feature of neovascularization, which destroys the normal retinal structure and visual function. So far, effective therapy options for rescuing visual function in advanced AMD patients are highly limited, especially in wet-type AMD, in which the retinal pigmented epithelium and Bruch’s membrane structure (RPE-BM) are destroyed by abnormal angiogenesis. Anti-VEGF treatment is an effective remedy for the latter type of AMD; however, it is not a curative therapy. Therefore, reconstruction of the complex structure of RPE-BM and controlled release of angiogenesis inhibitors are strongly required for sustained therapy. The major purpose of this study was to develop a dual function biomimetic material, which could mimic the RPE-BM structure and ensure slow release of angiogenesis inhibitor as a novel therapeutic strategy for wet AMD. We herein utilized plasma-modified polydimethylsiloxane (PDMS) sheet to create a biomimetic scaffold mimicking subretinal BM. This dual-surface biomimetic scaffold was coated with laminin and dexamethasone-loaded liposomes. The top surface of PDMS was covalently grafted with laminin and used for cultivation of the retinal pigment epithelial cells differentiated from human induced pluripotent stem cells (hiPSC-RPE). To reach the objective of inhibiting angiogenesis required for treatment of wet AMD, the bottom surface of modified PDMS membrane was further loaded with dexamethasone-containing liposomes via biotin-streptavidin linkage. We demonstrated that hiPSC-RPE cells could proliferate, express normal RPE-specific genes and maintain their phenotype on laminin-coated PDMS membrane, including phagocytosis ability, and secretion of anti-angiogenesis factor PEDF. By using in vitro HUVEC angiogenesis assay, we showed that application of our membrane could suppress oxidative stress-induced angiogenesis, which was manifested in decreased secretion of VEGF by RPE cells and suppression of vascularization. In conclusion, we propose modified biomimetic material for dual delivery of RPE cells and liposome-enveloped dexamethasone, which can be potentially applied for AMD therapy.

Highlights

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness among people older than 55 years old and is classified into two categories, atrophic and exudative AMD [1]
Vascular endothelial growth factor (VEGF) is the key regulator of angiogenesis [4], which plays a critical role in the pathogenesis of wet AMD [5]
Our results indicated that PDMS-PmL enhanced retinal pigment epithelium (RPE) cell attachment, proliferation, polarization, maturation and specific behavior, such as pigment epithelium-derived factor (PEDF) secretion, melanosome pigment deposits, and phagocytotic ability

Summary

Introduction

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness among people older than 55 years old and is classified into two categories, atrophic (dry) and exudative (wet) AMD [1]. No effective drugs or therapeutic strategies exist for treatment of dry AMD, especially for the advanced stage with large area of RPE loss [2]. The current treatment of wet AMD depends on angiogenesis inhibitors [6], including anti-VEGF agents targeting vessel formation and maturation [7,8,9]. The currently used anti-VEGF-based therapy requires monthly intravitreal injections, which increases the risk of infection, retinal detachment and lens damage. This life-long treatment is a big burden due to the medical expenses, and is not a fully curative treatment of wet AMD. More recent treatment approaches have included early intervention that precedes RPE cell loss and, in later stages, implantation of stem cell-derived RPE or photoreceptor cells

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