SMART BIOELECTRONIC IMPLANTS FOR CONTROLLED DELIVERY OF THERAPEUTIC PROTEINS IN VIVO AND ITS APPLICATION IN LONG-TERM TREATMENT OF HEMOPHILIA A

基于细胞的治疗，其中自然或人工工程细胞分泌治疗性 蛋白质被嫁接到身体上充当生物制药厂，是一种诱人的 血友病、糖尿病和肝脏等慢性疾病的长期治疗方法 精神错乱。然而，“现成”的治疗细胞对宿主是免疫原性的，而且必须是 不受宿主免疫系统的影响。细胞封装已经成为一种有吸引力的 在没有慢性免疫抑制的情况下移植这些细胞的策略。在这里，单元格被放置 在免疫隔离设备中，该设备物理地将细胞与 免疫系统，同时提供氧气和营养物质。可检索的宏比例尺单元- 封装设备(宏设备)在这种情况下很有吸引力，因为它们提供了更安全的 临床翻译之路。不幸的是，一个独立的宏设备在 由于两个核心挑战，人类在很长时间(&gt；6个月)内仍未实现：1) 异物对植入装置的反应引起炎症和纤维化；2) 对被包裹的细胞的氧气和营养供应不足。在此，我们建议 建立在生物材料设计、微制造、 来自我们的生物电子学和细胞工程学团队开发了一种先进的“智能” 具有集成电子元件的宏设备平台，克服了主要 当前设备设计的局限性。首先，我们将开发一种工程细胞系，它是 易于长期封装，适合临床翻译。机舱内的起落架 这些细胞将确保稳定的转基因表达，从而允许广泛控制治疗 蛋白质分泌(目标1)。另外，我们将开发一种生物电子宏器件作为 为这些细胞在体内长期移植的平台。我们的设备将结合小说 具有均匀/可控的孔径和增强的氧气传输性能的膜。在……里面 同时，我们将开发新的表面涂层技术，以最大限度地减少纤维化并确保长期- 移植物长期存活率。我们将把质子交换膜和光电子学结合起来 允许a)原位氧气产生的组件，以及b)光学基因激活以允许 被包裹的细胞对蛋白质生产的可触发控制(目标2)。最后，我们将测试 该装置在B6小鼠身上使用模型蛋白(SEAP)来测试细胞的长期存活和 蛋白质传递的外部控制。我们将开发该设备作为交付的平台 用于治疗血友病A的第八因子(目标3)作为模型疾病。如果成功，则 Platform将代表着细胞治疗领域的质的技术进步。

Cell-based therapies, where naturally or artificially engineered cells secreting therapeutic proteins are grafted onto the body to act as biological drug factories, are an attractive approach for long-term treatment of chronic diseases such as hemophilia, diabetes and liver disorders. However, ‘off the shelf’ therapeutic cells are immunogenic to the host and must be protected from the host immune system. Cell-encapsulation has emerged as an attractive strategy to transplant these cells without chronic immunosuppression. Here, cells are placed in an immune-isolating device which physically separates the cells from the components of the immune system while providing access to oxygen and nutrients. Retrievable macroscale cell- encapsulation devices (macrodevice), are attractive in this context as they provide a safer path to clinical translation. Unfortunately, a standalone macrodevice that remains functional in humans over long-periods (>6 months) is yet to be realized due to two core challenges: 1) a foreign-body reaction to the implanted device causing inflammation and fibrosis, and 2) inadequate supply of oxygen and nutrients to the encapsulated cells. Here, we propose to build on several promising recent advances in biomaterials design, microfabrication, bioelectronics and cell engineering from our team to develop an advanced “smart” macrodevice platform with integrated electronic components which overcomes the major limitations of current device designs. First, we will develop an engineered cell line which is amenable to long term encapsulation and suitable for clinical translation. Landing pads within these cells will ensure stable transgene expression, allowing for broad control of therapeutic protein secretion (Aim 1). Separately, we will develop a bioelectronic macrodevice as a platform for long- term transplant of these cells in vivo. Our device will incorporate novel membranes with uniform/controlled pore-sizes and enhanced oxygen transport properties. In parallel, we will develop new surface coating techniques to minimize fibrosis and ensure long- term graft survival. We will integrate proton exchange membranes and optoelectronic components to allow a) in-situ oxygen generation, and b) optical gene activation to allow for triggerable control of protein production by the encapsulated cells (Aim 2). Finally, we will test the device in B6 mice using a model protein (SEAP) to test for long term survival of cells and external control of protein delivery. We will develop the device as a platform to delivery of Factor VIII for the treatment of Hemophilia A (Aim 3) as a model disease. If successful, the platform will represent a qualitative technological advancement in the field of cell therapy.