Engineering a Human Physiomimetic Islet Microsystem

设计人体拟态胰岛微系统

• 批准号: 8813808
• 负责人: Ashutosh Agarwal
• 金额: $ 487.46万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813808
• 关键词: 3-Dimensional; Address; Autoimmune Diseases; Autoimmune Process; Beta Cell; Biochemical; Biomedical Engineering; Biomimetics; Cells; Childhood; Chronic; Clinical Trials; Collection; Coupling; Cues; Devices; Diabetes Mellitus; Diagnosis; Diet; Digestive System Disorders; Disease; Disease model; Docking; Endocrine; Engineering; Environment; Evaluation; Extracellular Matrix; Functional disorder; Gases; Generations; Goals; Health; Human; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Diseases; Knowledge; Lead; Left; Liquid substance; Maintenance; Microfluidic Microchips; Microfluidics; Mission; Modeling; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Oxygen; Pancreas; Pathology; Pharmacologic Substance; Phase; Physiological; Play; Public Health; Regulation; Replacement Therapy; Sampling; Source; Stem cells; Structure; Structure of beta Cell of islet; Symptoms; System; Technology; Testing; Therapeutic; Time; Tissue Engineering; Transplantation; body system; cellular development; cost; culture plates; design; diabetes management; diabetic; improved; in vivo; innovation; insight; interest; islet; microsystems; multidisciplinary; nanofabrication; non-invasive monitor; prevent; progenitor; public health relevance; research study; response; stem cell biology

 DESCRIPTION: Engineering a Human Physiomimetic Islet Microsystem Type 1 diabetes mellitus, an autoimmune disease resulting in destruction of the insulin- producing pancreatic beta cells, is one of the most common and costly chronic pediatric diseases. A significant impediment to understanding disease pathology and the development of cellular replacement therapies for Type 1 diabetes is the inability to sustain mature human beta cells in culture. In this proposal, we seek to engineer physiomimetic 3D niches within microfluidics devices for maturation, maintenance, and monitoring of human beta cells via the convergence of technologies from stem cell biology, matrix engineering, micro/nano fabrication, and microsensors. The microfluidic devices will connect to universal docks and provide intimate control over the cellular microenvironment by independent and simultaneous modulation of liquid and gas phases, multiparameteric monitoring, and assessment of cellular readouts and samplers for off-line biochemical analyses. With this degree of control, the effect of various niche parameters on human islet maintenance and generation of mature islets from human pancreatic precursors can be clearly delineated. Of particular interest in this application are the contributions of the physiological and extracellular matrix environment on islet health and maturation. Physiological oxygen, a critical parameter in steering pancreatic progenitor differentiation towards endocrine lineage, can be intimately modulated on the microscale via the control afforded by the microfabricated platform. Further, systematic evaluation of the contributions of matrix components on promoting islet health and directing islet differentiation within controlled 3D niches is feasible via tailored presentation of native extracellular matrix components. The ultimate goals of this proposal are twofold: 1) engineer a microfabricated "device and dock" system capable of providing microscale control of soluble and physiological conditions and agile assessment of multiple functional readouts in an enclosed, long-term culture system; and 2) utilize this innovative platform to systematically delineate critical factor capable of supporting both human islet maintenance and maturation of islet-like structures from human pancreatic progenitor cells. The project builds on recent breakthroughs by our team in creating microphysiological systems for other organ systems, engineering perifusion systems, matrix engineering, recreating oxygen controlled microenvironments, and progenitor differentiation. As such, the multidisciplinary consortium assembled herein is well poised to address these grand challenges.

 产品说明：1型糖尿病是一种导致产生胰岛素的胰腺β细胞破坏的自身免疫性疾病，是最常见和最昂贵的慢性儿科疾病之一.理解1型糖尿病的疾病病理学和开发细胞替代疗法的一个重要障碍是不能在培养物中维持成熟的人β细胞。在这项提案中，我们试图通过干细胞生物学，基质工程，微/纳米制造和微传感器技术的融合，在微流体设备中设计仿生3D壁龛，用于人类β细胞的成熟，维护和监测。微流体装置将连接到通用码头，并通过独立和同时调制液相和气相，多参数监测以及评估细胞读数和采样器来提供对细胞微环境的密切控制，以进行离线生化分析。通过这种程度的控制，可以清楚地描绘各种生态位参数对人胰岛维持和从人胰腺前体产生成熟胰岛的影响。在本申请中特别感兴趣的是 生理和细胞外基质环境对胰岛健康和成熟的贡献。生理氧，在转向胰腺祖细胞向内分泌谱系分化的关键参数，可以密切调制的微观尺度上通过控制提供的微加工平台。此外，系统评价基质组分对促进胰岛健康和指导受控3D小生境内的胰岛分化的贡献是可行的，通过定制呈现天然细胞外基质组分。该提议的最终目标是双重的：1）设计一种微制造的“装置和对接”系统，该系统能够在封闭的长期培养系统中提供对可溶性和生理条件的微尺度控制以及对多个功能读数的敏捷评估;和2）利用该创新平台系统地描述能够支持人胰岛维持和胰岛成熟的关键因子，类似于人类胰腺祖细胞的结构。该项目建立在我们团队最近在为其他器官系统创建微生理系统、工程灌注系统、基质工程、重建氧控微环境和祖细胞分化方面的突破基础上。因此，在此聚集的多学科联合体已做好充分准备应对这些重大挑战。

项目成果

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets.

• DOI: 10.1021/acs.jproteome.7b00160
• 发表时间: 2017-06-02
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Garcia-Contreras M;Tamayo-Garcia A;Pappan KL;Michelotti GA;Stabler CL;Ricordi C;Buchwald P
• 通讯作者: Buchwald P

Microelectrode Array based Functional Testing of Pancreatic Islet Cells.

基于微电极阵列的胰岛细胞功能测试。

• DOI: 10.3390/mi11050507
• 发表时间: 2020
• 期刊: Micromachines
• 影响因子: 3.4
• 作者: Alassaf,Ahmad;Ishahak,Matthew;Bowles,Annie;Agarwal,Ashutosh
• 通讯作者: Agarwal,Ashutosh

Engineering biomimetic materials for islet transplantation.

用于胰岛移植的工程仿生材料。

• DOI: 10.2174/1573399811666150317130440
• 发表时间: 2015
• 期刊: Current diabetes reviews
• 影响因子: 3.3
• 作者: Yang,EthanY;Kronenfeld,JoshuaP;Stabler,CherieL
• 通讯作者: Stabler,CherieL