Subretinal delivery and anchorage via angiogenesis of a polyester cell carrier for retinal pigment epithelial transplantation

通过聚酯细胞载体的血管生成进行视网膜下递送和锚定，用于视网膜色素上皮移植

• 批准号: 250537947
• 负责人: Dr. Kirsten Borchers
• 金额: --
• 依托单位: Fraunhofer-Institut für Biomedizinische Technik (IBMT)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/250537947?language=en
• 关键词: Subretinal; delivery; anchorage; via; angiogenesis

The retinal pigment epithelium (RPE) is essential for retinal homeostasis. Its dysfunction significantly contributes to the pathophysiology of age-related macular degeneration (AMD), a leading cause of blindness. AMD patients have no curative treatment option to date. If an in vitro cultured RPE transplant can be stably anchored under the retina and its metabolism ensured, then this may be a potentially curative treatment option for AMD.Currently autologous RPE/choroid patch grafts are being performed in select patients, but suffer from high complication rates. Clinical trials with suspensions of stem cell derived RPE cells in AMD patients are underway. However, RPE suspensions may fail to survive or function on aged submacular Bruchs membrane. RPE grafts on cell carriers were proposed to significantly improve long-term function and surgical manipulation. Previous work revolved around how to bring cells grown in the laboratory under the retina. To date, long-term considerations for carrier-graft bio-integration have remained unaddressed.This project proposal aims to develop foil-supported cultured RPE grafts. We propose a novel, 2nd generation approach, whereby the carrier is bio-functionalized to ensure anchorage and metabolism following implantation through therapeutic angiogenesis. To achieve this, the bottom surface will be equipped with a coating containing a growth factor reservoir and cell attachment peptides, in order to investigate the induction of vessel outgrowth from the underlying choriocapillaris in synergy with intrinsic stimuli. Migration of choroidal endothelial cells, adhesion to the transplants functionalized lower surface and maturing into capillaries will be triggered by growth factor elution and intrinsic stimuli from the transplanted RPE. To enable transport of signaling molecules, nutrients and oxygen over the foil, it must exhibit adequate porosity. To protect the graft during the surgical procedure it will be temporarily encapsulated into a thermosensitive biodegradable hydrogel based on gelatin. To stabilize the subretinal space during implantation hyaluronic acid will be evaluated as an injectable hydrogel based on its shear thinning properties.For the development of a multi-functional encapsulated implant along with its evaluation for therapeutic efficacy the University of Bonn and the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Stuttgart, plan a collaborative project. Dr. Stanzel (Bonn) will contribute with his expertise in human RPE culture and animal surgery. Dr. Borchers (Stuttgart) scientific experience encompasses development of biomaterials, surface coatings for endothelial cell attachment, encapsulation of growth factors and chemical modification of biologic origin hydrogels.Should above preclinical testing prove successful, then this concept may become applied in clinical trials in patients with AMD, with the prospect of avoiding preventable age-related blindness.

视网膜色素上皮(RPE)是视网膜动态平衡所必需的。它的功能障碍在老年性黄斑变性(AMD)的病理生理学中起重要作用，AMD是导致失明的主要原因。到目前为止，AMD患者还没有治愈的治疗选择。如果体外培养的RPE移植能够稳定地固定在视网膜下并确保其新陈代谢，那么这可能是一种潜在的治疗AMD的选择。目前，自体RPE/脉络膜补片移植正在特定的患者中进行，但存在较高的并发症发生率。干细胞来源的RPE细胞悬液用于AMD患者的临床试验正在进行中。然而，RPE悬浮液可能无法在老化的黄斑下Bruchs膜上存活或发挥作用。细胞载体上的RPE移植物被认为可以显著改善长期功能和手术操作。之前的工作围绕着如何将实验室中生长的细胞置于视网膜下。到目前为止，载体-移植物生物整合的长期考虑仍然没有得到解决。本项目提案旨在开发铝箔支撑的培养的RPE移植物。我们提出了一种新的第二代方法，通过生物功能化载体来确保植入后的锚定和代谢，通过治疗性血管生成。为了实现这一点，底部表面将配备一层包含生长因子库和细胞附着肽的涂层，以研究在内在刺激的协同下诱导脉络膜毛细血管生长的作用。移植RPE的生长因子洗脱和内源性刺激将触发脉络膜内皮细胞的迁移、黏附到功能化的下表面并成熟为毛细血管。为了使信号分子、营养物质和氧气能够在箔上传输，它必须表现出足够的孔隙度。为了在手术过程中保护移植物，它将被临时包裹在一种基于明胶的热敏性可生物降解水凝胶中。为了在植入期间稳定视网膜下空间，透明质酸将被评估为一种可注射水凝胶，基于其剪切稀释性。为了开发多功能胶囊植入物并评估其治疗效果，波恩大学和斯图加特伊比利亚的弗劳恩霍夫界面工程和生物技术研究所计划开展一个合作项目。斯坦泽尔博士(波恩)将以他在人类RPE培养和动物外科方面的专业知识做出贡献。博尔彻博士(斯图加特)的科学经验包括生物材料的开发、内皮细胞附着的表面涂层、生长因子的包裹和生物来源水凝胶的化学修饰。如果上述临床前试验被证明是成功的，那么这一概念可能会应用于AMD患者的临床试验，有望避免可预防的年龄相关性失明。