Development of bio-integrated devices to enhance transplant survival for subcutaneous encapsulated cell therapies

开发生物集成设备以提高皮下封装细胞疗法的移植存活率

• 批准号: 10634688
• 负责人: Siddharth Krishnan
• 金额: $ 8.77万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10634688
• 关键词: Acceleration; Acute; Address; Adverse event; Aging; Alginates; Animals; Attention; Autoimmune Diseases; Biological Markers; Biological Sciences; Biosensor; Carbon; Carrier Proteins; Cell Death; Cell Density; Cell Line; Cell Separation; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Cellular biology; Characteristics; Chemicals; Chronic Disease; Collection; Communication; Complex; Corrosion; Dependence; Development; Device Designs; Devices; Diabetic mouse; Diffusion; Disease; Disease model; Dose; Drug Delivery Systems; Electrical Engineering; Electrochemistry; Electrodes; Electronics; Encapsulated; Engineering; Ensure; Equipment Malfunction; Exclusion; Failure; Feedback; Fellowship; Fibrosis; Film; Foreign Bodies; Foundations; Generations; Geometry; Goals; Hemophilia A; Housing; Hydrogels; Hypoxia; Immune; Immune system; Immunocompetent; Implant; Insulin-Dependent Diabetes Mellitus; Length; Location; Malignant Neoplasms; Materials Testing; Measurement; Membrane; Mentors; Metals; Microfabrication; Microfluidics; Modeling; Modification; Monitor; Mus; Neurodegenerative Disorders; Nutrient; Operative Surgical Procedures; Optics; Oxygen; Oxygen Consumption; Parkinson Disease; Patients; Performance; Permeability; Pharmaceutical Preparations; Physics; Physiological; Polymer Chemistry; Polymers; Porosity; Property; Protein Secretion; Proteins; Rattus; Regimen; Retrieval; Risk; Scheme; Site; Skin; Streptozocin; Subcategory; Surface; System; Technology; Testing; Therapeutic; Thinness; Time; Tissues; Transplantation; Treatment Efficacy; Vascularization; Wireless Charging; Work; awake; bioelectronics; capsule; cell immortalization; cell type; clinical risk; clinical translation; data acquisition; data exchange; density; design; digital; evaporation; experience; flexibility; implantable device; implantation; improved; in vitro Model; in vitro testing; in vivo; in vivo evaluation; interest; islet; materials science; microsystems; minimally invasive; monitoring device; operation; oxygen transport; physical science; prevent; protein transport; prototype; response; sensor; skills; subcutaneous; technology platform; therapeutic protein; wireless

Encapsulated cell therapies (ECT) are attractive therapeutic platforms that involve the housing of collections of transplanted cells capable of secreting therapeutic proteins within polymeric frames. These technologies represent the potential to eliminate patient dependence on complex drug-dosing regimens while maintaining circulating drug levels within healthy, nontoxic therapeutic ranges for diseases ranging from autoimmune disorders to cancer. Transplanted cells are isolated from host immune systems via encapsulation materials and semipermeable, porous polymeric membranes (immunisolation membranes) via size exclusion effects. Despite attracting significant interest, ECT devices have not found widespread clinical translation owing to transplant failure, with low oxygen tension within the transplanted cell microenvironment and fibrosis representing major causes. Size considerations related to cellular packing density represent a further translational challenge. This challenge is particularly acute in subcutaneous (SC) implants owing to the region’s low vascularization and high rates of fibrotic capsule formation. Despite these hurdles, SC implants have attracted considerable attention owing to the minimally invasive surgery requirements and potential for easy device monitoring and retrieval. In this proposal, I will use approaches in microfabrication and bioelectronic device design to improve oxygen tension within the transplanted cell microenvironment in SC-ECT devices. In Aim 1 I will develop advanced multiphysics models to predict and address oxygen need in implanted SC devices. In Aim 2, I will use surface chemical modifications to suppress fibrosis and ensure long-term transplant survival in oxygen-generating bioelectronic ECT implants. In Aim 3, I will pursue system level integration using design principles in flexible bioelectronics, biosensor development and resonant inductive wireless power transfer approaches. If successful, the resulting platform technology will support SC transplanted cell survival long term, with potential applications across cell types and disease models. The work is highly interdisciplinary, incorporating materials science, cell therapies, drug delivery and electronic/electrical engineering. If successful, the work will create a platform technology capable of addressing a wide range of unmet therapeutic needs in minimally invasive implantation sites to de-risk clinical translation. My background is primarily in the physical sciences: through this Fellowship, I will work closely with my co-mentors, Profs. Daniel Anderson and Robert Langer at MIT to develop skills that will allow me to work at the interface between engineering and the life sciences, with a focus on clinical translation.

包封细胞疗法（ECT）是有吸引力的治疗平台，其涉及外壳 能够在聚合物内分泌治疗性蛋白质的移植细胞的集合 跳转这些技术代表了消除患者对复杂药物依赖的潜力。 药物给药方案，同时将循环药物水平维持在健康、无毒 治疗范围从自身免疫性疾病到癌症。移植 细胞通过包封材料和半渗透性从宿主免疫系统中分离， 多孔聚合物膜（免疫隔离膜）。尽管 吸引了大量的兴趣，ECT设备还没有发现广泛的临床翻译， 移植失败，移植细胞微环境内的低氧张力， 纤维化是主要原因。与蜂窝堆积密度相关的尺寸考虑 这是一个进一步的翻译挑战。这种挑战在皮下注射中尤其严重。 (SC)由于该地区的低血管化和高纤维化率的胶囊植入 阵尽管存在这些障碍，但SC植入物由于以下原因引起了相当大的关注： 微创手术要求和易于器械监测的潜力， 检索在这个计划中，我将使用微制造和生物电子器件的方法 设计以改善SC-ECT中移植细胞微环境内的氧张力 装置.在目标1中，我将开发先进的多物理场模型来预测和解决氧气 需要植入SC器械。在目标2中，我将使用表面化学改性来抑制 并确保在生氧生物电子ECT中移植物长期存活 植入物.在目标3中，我将使用灵活的设计原则进行系统级集成， 生物电子学、生物传感器开发和谐振感应无线功率传输 接近。如果成功，所产生的平台技术将支持SC移植细胞 长期存活，具有跨细胞类型和疾病模型的潜在应用。这项工作是 高度跨学科，融合材料科学，细胞疗法，药物输送和 电子/电气工程如果成功，这项工作将创造一个平台技术， 能够解决微创治疗中广泛的未满足的治疗需求， 植入部位以降低临床翻译风险。我的背景主要是在物理 科学：通过这个奖学金，我将与我的共同导师，教授密切合作。丹尼尔 安德森和罗伯特兰格在麻省理工学院发展技能，使我能够在界面上工作， 在工程和生命科学之间，专注于临床翻译。