A vascularized 3D biomimetic for islet function and physiology

用于胰岛功能和生理学的血管化 3D 仿生模型

• 批准号: 9169717
• 负责人: CHRISTOPHER S CHEN
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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/9169717
• 关键词: Adoption; Affect; American; Animal Model; Biomedical Engineering; Biomimetics; Cell Survival; Cell physiology; Cells; Cellular Structures; Cellular biology; Communities; Development; Developmental Cell Biology; Devices; Diabetes Mellitus; Direct Costs; Disease; Disease model; Endocrine; Event; Exposure to; Facilities and Administrative Costs; Failure; Functional disorder; Glucose; Goals; Health; Human; Immune; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Intestines; Islets of Langerhans; Lead; Liquid substance; Maintenance; Methods; Modeling; Molds; Molecular; Mus; Organoids; Patients; Performance; Phenotype; Physiology; Population; Positioning Attribute; Production; Protocols documentation; Rodent; Source; Staging; Stem cells; System; Tissues; design; diabetes mellitus therapy; experience; in vivo; induced pluripotent stem cell; innovation; islet; novel; portability; progenitor; programs; reconstitution; scaffold; success; tool; Adoption; Affect; American; Animal Model; Biomedical Engineering; Biomimetics; Cell Survival; Cell physiology; Cells; Cellular Structures; Cellular biology; Communities; Development; Developmental Cell Biology; Devices; Diabetes Mellitus; Direct Costs; Disease; Disease model; Endocrine; Event; Exposure to; Facilities and Administrative Costs; Failure; Functional disorder; Glucose; Goals; Health; Human; Immune; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Intestines; Islets of Langerhans; Lead; Liquid substance; Maintenance; Methods; Modeling; Molds; Molecular; Mus; Organoids; Patients; Performance; Phenotype; Physiology; Population; Positioning Attribute; Production; Protocols documentation; Rodent; Source; Staging; Stem cells; System; Tissues; design; diabetes mellitus therapy; experience; in vivo; induced pluripotent stem cell; innovation; islet; novel; portability; progenitor; programs; reconstitution; scaffold; success; tool

 DESCRIPTION: The goals of our proposal are to bring together an expert team of bioengineers and stem cell/developmental biologists to create a Human Islet Biomimetic that will facilitate (i) long term culture and manipulation of human islets and (ii) maturation of stem-cell derived or reprogrammed islets. Specifically, we will combine our expertise in cell and developmental biology with our experience molding three dimensional vascularized scaffolds in which cellular inputs, matrix composition, and microscale organization (including flow) can be varied with precision. Although much is known about islet function under homeostatic conditions in vivo, current methods for studying islet physiology and pathophysiology are severely limited. Studies that rely on model organisms - particularly mice - are hampered by cellular and molecular discrepancies between human and rodent islets. The use of human islets for studies of islet physiology is also problematic, as limited availability and exposure to non-physiological conditions during isolation impede the use of this cellular source. Most importantly, there is no system currently available which supports the full function of islets or b-cells for more than a fe days in culture. Thus, our understanding of islet function and dysfunction - particularly as it relates to type 1 diabetes (T1D) - has been constrained by the lack of tools for maintaining and studying human islets in vitro. Into this gap, we will take cadaveric human islets, pancreatic progenitors from human ES and iPS cells, and endocrine cells that are trans-differentiated from intestinal stem cells as starting material, and incorporate them into innovative scaffold devices that provide control over local structure, cellular content, and fluid dynamics to stabilize b-cell function. Overall, we plan to reconstitute human islet biomimetics that recapitulate the diverse cellular types and their organization within the natural human islet. In addition, we will use the system to explore the reasons why islets are prone to lose function when placed ex vivo and to model human islet diseases. This system will be critical for the success of other HIRN consortia, as well for the b-cell biology community at large by providing an accessory system for studying b-cell survival, immune interactions, and alternate sources of b-cells. Our Aims are as follows: Aim 1: To establish a human islet biomimetic for sustained islet viability and function in vitro. Aim 2: To optimize human islet biomimetic function with respect to glucose sensing, insulin release, and stable maintenance of islet phenotypes. Our study is designed to provide a deeper understanding of the molecular and cellular events that lead to islet dysfunction in T1D and related islet disorders and to help develop strategies to restore normal islet function in these disorders.

 描述：我们提案的目标是将一个由生物工程师和干细胞/发育生物学家组成的专家团队，以创建人类胰岛仿生剂，以促进（i）长期培养和对人类胰岛的操纵以及（ii）（ii）干细胞派生或重编程的胰岛的成熟。具体而言，我们将在细胞和发育生物学方面的专家与我们的经验相结合的三维血管化脚手架的经验，其中细胞输入，矩阵组成和微观组织（包括流）可以用精度来改变。尽管对体内稳态条件下的胰岛功能知之甚少，但目前研究胰岛生理学和病理生理学的方法受到严重限制。依靠模型生物（尤其是小鼠）的研究受到人与啮齿动物胰岛之间的细胞和分子差异的阻碍。人类胰岛用于研究胰岛生理学的研究也有问题，因为在隔离期间的有限和对非生理条件的暴露阻碍了这种细胞来源的使用。最重要的是，目前尚无系统可支持胰岛或B细胞的全部功能，以超过Fe Day的文化。这是，我们对胰岛功能和功能障碍的理解 - 尤其是与1型糖尿病有关（T1D）的理解，这受到缺乏在体外维持和研究人类胰岛的工具的限制。进入这个差距，我们将采用尸体人类胰岛，人类ES和IPS细胞的胰祖细胞以及与肠干细胞的反差异的内分泌细胞作为起始材料，并将其结合到创新的支架设备中，并将其纳入对局部结构，流体含量和流体动力学的控制型支架，并稳定B细胞动力学，并稳定 功能。总体而言，我们计划重新建立人类胰岛生物元素，以概括自然人类胰岛内的多元化细胞类型及其组织。此外，我们将使用该系统来探讨胰岛在放置离体并建模人类胰岛疾病时容易失去功能的原因。该系统对于其他HIRN联盟的成功至关重要，对于B-Cell生物学社区的成功，通过提供用于研究B细胞生存，免疫相互作用和B细胞替代来源的附件系统。我们的目的如下：目标1：建立人类胰岛仿生剂以在体外持续的胰岛生存能力和功能。目标2：相对于葡萄糖感应，胰岛素释放和胰岛表型的稳定维护，优化人类胰岛仿生功能。我们的研究旨在更深入地了解分子和细胞事件，这些事件导致T1D和相关胰岛疾病中胰岛功能障碍，并帮助制定策略以恢复这些疾病中正常的胰岛功能。