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

基本信息

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
项目类别：
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

项目摘要

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.

封装的细胞疗法（ECT）是涉及外壳的有吸引力的治疗平台能够在聚合物中分泌治疗蛋白的移植细胞的集合帧。这些技术代表了消除患者依赖复合物的潜力药物剂量方案，同时保持健康，无毒的循环药物水平从自身免疫性疾病到癌症的疾病的治疗范围。移植细胞通过封装材料和可半透明，从宿主免疫系统中分离出来，多孔聚合膜（免疫溶解膜）通过尺寸排除效应。尽管引起极大的兴趣，ECT设备尚未发现宽度的临床翻译。移植衰竭，在移植细胞微环境中具有低氧张力和代表主要原因的纤维化。与细胞堆积密度有关的尺寸注意事项代表了另一个翻译挑战。该挑战在皮下特别急剧（SC）由于该地区的低血管化和纤维化胶囊速率高而使形成。尽管有这些障碍，但SC的侵犯还是引起了很大的关注微创手术的要求以及轻松监控的潜力和潜力检索。在此提案中，我将在微加工和生物电子设备中使用方法设计以改善SC-ECT移植细胞微环境内的氧气张力设备。在AIM 1中，我将开发高级多物理模型来预测和解决氧气需要植入的SC设备。在AIM 2中，我将使用表面化学修饰来抑制纤维化并确保生成氧生物电子的长期移植生存植入物。在AIM 3中，我将使用灵活的设计原理购买系统级集成生物电子学，BIOSENOR开发和共振电感无线电源传递方法。如果成功，最终的平台技术将支持SC移植的单元格长期生存，跨细胞类型和疾病模型的潜在应用。工作是高度跨学科，融合了材料科学，细胞疗法，药物输送和电子/选择工程。如果成功，这项工作将创建平台技术能够在微创中满足多种未满足的治疗需求植入地点向去风险的临床翻译。我的背景主要在物理中科学：通过这一奖学金，我将与我的联合官员密切合作。丹尼尔麻省理工学院的安德森（Anderson）和罗伯特·兰格（Robert Langer）开发技能，使我能够在界面上工作在工程学和生命科学之间，重点是临床翻译。