CAREER: Non-invasive fields for directed 3D microgel assembly for tissue engineering

[150733]组织工程在糖尿病、肾脏、肝脏和心力衰竭等疾病的替代疗法方面有着巨大的前景。组织工程中常见的一种方法是将细胞植入可生物降解的支架中（自上而下），将细胞聚集在一起模拟原生组织。随着时间的推移，这些支架有望降解并被细胞生长和细胞外基质沉积所取代。当前组织工程方法面临的挑战是：(i)实现复杂的三维（3D）细胞结构和组织，（ii）控制细胞接近度和微尺度分辨率，（iii）通过支架孔隙和嵌入微通道增强运输，模拟体内血管网络。纳米和微尺度粒子的定向组装引起了人们的极大兴趣，并在许多领域得到了应用，包括电子、纳米材料，并在组织工程中具有巨大的潜力。组织是由重复的功能单位组成的。自下而上的组织工程旨在组装微尺度水凝胶（微凝胶）作为构建块，形成有组织的三维组织结构，并通过空间控制微结构模拟天然组织。该提案的智力优势在于开发了一种平台技术，该技术利用纳米颗粒和微凝胶作为构建块，通过外部磁场创建3D复杂的多层结构。该项目的最终成果将提供一个广泛适用的、基于纳米粒子的“磁致微凝胶组装”平台。该平台将成为一种广泛可用的生物技术工具和方法，可以在体外创建3D组织模型，可用于组织/器官替代，再生医学，高通量筛选以及药物发现。该项目的成果将为物理和生物研究开辟新的途径，并对基础科学和应用科学、教育和医学产生重大影响。本建议的更广泛影响包括教育目标，包括参与、培训和指导：a)通过布莱根妇女医院学生成功工作计划，来自最低收入社区的波士顿当地高中学生；b)通过麻省理工学院本科生研究机会计划的本科生；c)研究生通过利用该项目中确定的原理，将基于书本的知识转化为实践，该项目涉及微观结构的磁性组装的复杂多学科性质。拟议研究的更广泛影响涵盖地方，国家和国际教育层面，并对公众对生物学和微流体技术界面的认识产生广泛影响。在地方一级，目标是为学生提供跨学科科学的经验，使他们能够进行研究并学习科学方法。此外，首席研究员（PI）将从哈佛大学代表性不足的少数民族研究项目中招募学生。这个项目每年夏天都会把其他大学中未被充分代表的少数族裔和女性带到哈佛，让她们参与拟议的研究项目。PI还将开发研究生课程，并与当地高中一起安排实地考察，以教育学生有关微流体研究的知识。在国家层面，PI将对其他机构的学生和公众进行有关技术和科学挑战的教育。此外，PI将继续开展国际教育工作，并在NSF支持的国际暑期学校等活动中发挥讲师的作用。

1150733DemirciTissue engineering holds great promise to enable alternative therapies for diseases such as diabetes, kidney, liver, and heart failure. A common approach in tissue engineering is seeding cells in biodegradable scaffolds (top-down), which brings cells together to mimic native tissues. These scaffolds are expected to degrade and be replaced by cellular growth and extracellular matrix deposition over time. Challenges in current tissue engineering approaches are: (i) achieving complex three-dimensional (3D) cellular architecture and organization, (ii) control over cellular proximity and microscale resolution, (iii) enhancing transport through scaffold porosity and embedded microchannels, mimicking vascular network in vivo. Directed assembly of nano- and micro-scale particles is of great interest and has found applications in many fields including electronics, nanomaterials, and holds great potential for tissue engineering. Tissues are made up of repeating functional units. Bottom-up tissue engineering aims to assemble microscale hydrogels (microgels) as building blocks to form organized 3D tissue constructs with spatial control over microarchitecture mimicking native tissues. The intellectual merit of this proposal lies in developing a platform technology that utilizes nanoparticles and microgels as building blocks to create 3D complex multi-layer constructs via external magnetic fields. The final outcome of the project will offer a broadly applicable, nanoparticle-based, "magnetic-induced microgel assembly" platform. This platform would become a broadly available biotechnological tool and method to create 3D tissue models in vitro that could be used for tissue/organ replacement, regenerative medicine, high throughput screening, as well as pharmaceutical drug discovery. The outcomes of this project will open new avenues for physical and biologic research and have a considerable impact on fundamental and applied science, education, and medicine. The broader impacts of this proposal include educational aims to involve, train and mentor: a) local Boston high school students from the lowest income communities through Brigham and Women's Hospital Student Success Jobs Program, b) undergraduate students through Massachusetts Institute of Technology Undergraduate Research Opportunities Program, and c) graduate students to translate book-based knowhow to practice by utilizing the principles identified in this project on the complex multidisciplinary nature of magnetic assembly of microscale structures. The broader impacts of the proposed research cover levels at the local, national and international education with an extended influence on public awareness about the interface of biology and microfluidic technologies. At the local level, the aim is to provide students with experience with interdisciplinary science, allowing them to perform research and learn scientific methods. Further, the principal investigator (PI) will recruit students from Harvard University's underrepresented minority research program. This program brings underrepresented minorities and women to Harvard from other universities every summer allowing them to work on the proposed research project. The PI will also develop graduate courses and arrange field trips with local high schools in educating students about microfluidics research. At the national level, the PI will educate the students and the public at other institutions on technological and scientific challenges. Additionally, the PI will pursue international educational efforts as well as play a role as a lecturer for activities such as NSF supported international summer schools.