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

1150733 DemirciTIssue工程技术有望实现糖尿病、肾脏、肝脏和心力衰竭等疾病的替代疗法。组织工程中的一种常见方法是在可生物降解的支架中种植细胞(自上而下)，这种方法将细胞聚集在一起，模仿天然组织。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。目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)控制细胞的接近和微尺度分辨率，(Iii)通过支架孔洞和嵌入的微通道增强转运，模拟体内的血管网络。纳米和微米级粒子的定向组装引起了人们的极大兴趣，并在包括电子学、纳米材料在内的许多领域得到了应用，在组织工程方面具有巨大的潜力。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，以形成具有空间控制的、模仿天然组织的微结构的有组织的3D组织结构。这一提议的智力价值在于开发了一种平台技术，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种广泛适用的、基于纳米颗粒的“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，用于在体外创建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、教育和医学产生相当大的影响。这项建议的更广泛的教育目标包括：a)通过布里格姆和妇女医院学生成功就业计划，吸引、培训和指导波士顿当地最低收入社区的高中生；b)通过麻省理工学院本科生研究机会计划；以及c)研究生利用本项目中确定的关于微型结构磁性组装的复杂的多学科性质的知识，将基于书籍的知识转化为实践。拟议研究的更广泛影响涉及地方、国家和国际教育层面，对公众对生物学和微流体技术的接口的认识产生了广泛的影响。在地方一级，其目的是向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，首席调查员(PI)将从哈佛大学代表不足的少数族裔研究项目中招收学生。每年夏天，这个项目都会把其他大学中代表不足的少数族裔和女性带到哈佛大学，让他们从事拟议中的研究项目。PI还将开发研究生课程，并安排与当地高中的实地考察，教育学生有关微流体研究的知识。在国家一级，国际和平研究所将对学生和其他机构的公众进行技术和科学挑战的教育。此外，国际和平协会将致力于国际教育工作，并担任国家科学基金会资助的国际暑期学校等活动的讲师。

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.