3D Microvascular Networks in Hydrogels Fabricated with Sacrificial Structures

描述（由申请人提供）：候选人我从高中开始就一直在学术实验室从事研究工作，并且很早就知道我想成为一名教授。我在天文学、环境科学和应用物理学等领域都有研究经验，现在我正专注于利用我在研究生毕业时开发的一种制造技术来解决组织工程领域的一个重大问题。我的兴趣在于智能材料和生物材料的发展，我认为自然组织本身就是智能材料的一种终极形式，能够以非常复杂的方式与环境相互作用。我不仅对学术界的研究方面感兴趣，也非常关心教学和指导青年学生；我曾指导过几名本科生和一名硕士生，帮助指导本科生在课堂上的研究，并自愿参加了各种各样的推广项目。在兰格实验室的博士后期间，我将学习成为一名独立研究者所需的技能（如提案写作、指导、与学术官僚机构打交道等），并计划在几年内申请教师职位。我还计划学习更多关于生物医学工程领域的知识，以及与之相关的独特问题。在本提案的指导阶段讨论的工作将在MIT的Langer实验室进行。兰格实验室是广泛领域的领先研究小组之一，包括药物输送、组织工程、智能材料和生物医学设备工程。兰格实验室位于麻省理工学院，这是美国领先的研究机构之一，与当地几家医院有着密切的联系。该提案的独立阶段将在具有强大生物医学工程和材料科学研究计划的大学进行。研究（请注意突出显示的部分包含专有信息）本提案中讨论的工作重点是在水凝胶内开发3D微流体网络，作为工程组织中的人工血管系统。这种血管网络对于任何具有显著厚度（临床上有用的）的工程组织都是必需的，因为扩散限制了营养物质和气体进出嵌入支架深处的细胞的能力。制造技术是基于使用牺牲熔融纺微纤维网络，由具有ph依赖性溶解度的材料制成。在许多方面产生的结构模仿自然毛细血管网络，并以快速，简单，廉价和可扩展的过程产生。本提案的目的是讨论产生所需结构的技术，以及在通道壁（作为内皮衬里）和水凝胶材料（作为3D矩阵中的功能细胞）上播种细胞的技术。在所有情况下，细胞将通过通过三维通道系统的介质流来维持。在这项工作的指导阶段，支架制造技术将被开发，细胞在通道壁上的播种将被演示。这一阶段还将包含优化牺牲技术所需的初始工作，以便将细胞放置在水凝胶中，尽管这一目标可能会持续到独立阶段。独立阶段将展示在一个充满细胞的水凝胶中制造3D网络（首先没有细胞，然后有细胞排列在通道壁上）。然后，独立阶段将在这些血管化的水凝胶中开发共培养系统，并且还可能研究使用3D通道网络来传递影响嵌入水凝胶中的干细胞的因子。

DESCRIPTION (provided by applicant): Candidate I have been performing research in academic labs since high school, and have for a long time known that I want to pursue a carer in academia as a profesor. I have research experience in fields ranging from astronomy to environmental science to applied physics, and am now focusing on exploiting a fabrication technology I developed at the end of graduate school to solve a major problem in the field of tisue engineering. My interests lie in the development of smart materials and biomaterials, and I consider natural tissue in itself to be an ultimate form of smart material, able to interact with its environment in extraordinarily complex ways. I am not only interested in the research aspects of academia, but also care a great deal about teaching and mentoring young students; I have mentored several undergraduates and a masters student, helped direct student research in a class as an undergraduate, and have volunteered for a wide variety of outreach programs. During my postdoctoral experience in the Langer Lab, I will learn the skills necessary to become an independent investigator (such as proposal writing, mentoring, dealing with academic bureaucracies, etc.), and plan to apply for a faculty position within a few years. I also plan to learn more about the field of biomedical engineering, and the unique issues that are associated with it Environment The work discussed in the mentored phase of this proposal will be performed in the Langer Lab at MIT. The Langer lab is widely known as one of the leading research groups in a wide range of fields, including drug delivery, tissue engineering, smart materials, and biomedical device engineering. The Langer Lab is located at MIT, one of the leading research institutes in the country, with strong connections to several local hospitals. The independent phase of this proposal will be performed at a university with a strong biomedical engineering and materials science research program. Research (Please note highlighted sections contain proprietary information) The work discussed in this proposal focuses on developing 3D microfluidic networks inside hydrogels to act as artificial vascular systems in engineered tissue. Such vascular networks will be required for any engineered tissue of significant (and clinically useful) thickness, as diffusion limits the ability of nutrients and gasses to pass to and from cells embedded deep within a scaffold. The fabrication technique is based on the use of sacrificial melt-spun microfiber networks made from materials with pH-dependant solubility. The structures produced in many ways mimic natural capillary networks, and are produced with a rapid, simple, inexpensive, and scalable process. The aims in this proposal discuss techniques to produce the desired structures, as well as techniques for seeding cells on the channel walls (as an endothelial lining) as well as in the hydrogel material (as functional cells in a 3D matrix). In all cases, the cells will be maintained by media flow through the 3D channel system. In the mentored phase of this work, the scaffold fabrication technique will be developed, and seeding of cells on the channel walls will be demonstrated. This phase will also contain the initial work necessary to optimize the sacrificing technique to allow cells to be placed in the hydrogel, though it is possible this aim may continue through to the independent phase. The independent phase will demonstrate fabrication of 3D networks in a cell-laden hydrogel (first without, and then with, cells lining the channel walls as well). The independent phase will then develop co- culture systems in these vascularized hydrogels, and may also investigate the use of the 3D channel network to deliver factors to affect stem cells embedded within the hydrogel.