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.

封装细胞疗法（ECT）是有吸引力的治疗平台，涉及外壳能够在聚合物内分泌治疗蛋白的移植细胞的集合这些技术代表了消除患者对复杂框架的依赖的潜力。药物剂量方案，同时将循环药物水平维持在健康、无毒的范围内治疗范围从自身免疫性疾病到移植癌症。细胞通过封装材料和半透性与宿主免疫系统分离，尽管存在尺寸排阻效应，但多孔聚合物膜（免疫隔离膜）。 ECT 设备引起了极大的兴趣，但尚未得到广泛的临床转化移植失败，移植细胞微环境中氧张力低，纤维化代表与细胞堆积密度相关的尺寸考虑因素。这一挑战在皮下尤其严重 (SC) 植入物归因于该区域的低血管化和高纤维化囊发生率尽管存在这些障碍，SC 植入物还是引起了相当大的关注。微创手术的要求和轻松设备监控的潜力在本提案中，我将使用微加工和生物电子设备中的方法。旨在改善 SC-ECT 移植细胞微环境内氧张力的设计在目标 1 中，我将开发先进的多物理场模型来预测和解决氧气问题。在目标 2 中，我将使用表面化学修饰来抑制植入 SC 设备中的需要。纤维化并确保产氧生物电子 ECT 中的长期移植存活在目标 3 中，我将利用灵活的设计原则追求系统级集成。生物电子学、生物传感器开发和谐振感应无线电力传输如果成功，由此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。高度跨学科，融合了材料科学、细胞疗法、药物输送和如果成功，这项工作将创建一个平台技术。能够解决微创领域广泛的未满足的治疗需求降低临床翻译风险的植入部位我的背景主要是物理方面的。科学：通过这个奖学金，我将与我的共同导师 Daniel 教授密切合作。麻省理工学院的安德森和罗伯特·兰格培养我在界面上工作的技能工程和生命科学之间的领域，重点是临床转化。