Building biophysical and biochemical complexity in 3D cell and tissue constructs

摘要 在健康的成人组织、发育中的有机体和疾病环境中，细胞存在于环境中， 在那里，它们根据表型状态接收和整合外部信号， 细胞活动和行为或对表型状态的修饰。对细胞的基本理解 功能和疾病进展部分取决于我们系统地建立和干扰模型的能力 体外细胞系统，转化医学中紧迫的生物医学挑战可能会得到解决 通过技术，使突破组织工程，包括在满足关键的 等待器官移植的病人的需求。在过去的几十年里，一系列生物制造技术 已经用于在二维和三维结构内精确排列细胞和材料。这些 技术拓宽了我们对生物学的理解，增加了组织构建的复杂性， 可以用于治疗。虽然在这段时间内开发的生物制造方法已经大大 有利于我们探索和理解生物学问题的能力-特别是关于细胞及其 环境和工程细胞材料的结构，概括了天然组织的特点， 在构建多尺度仿生组织构建物方面仍然存在挑战。我们实验室的研究重点是 通过开发和应用新的生物制造技术应对这些挑战， 基于水凝胶生物材料的设计和使用的创新。在未来五年内，该实验室的目标是 开发和应用独特的基于水凝胶的生物打印技术，以满足 创建血管化组织构建体的能力，其中细胞和材料复杂性可以在 血管外区域，并且可以支持密集的细胞群。该实验室还将开发新的生物织物 这些技术将允许对细胞和材料结构进行高分辨率控制的独特能力 在宏观结构中，目标是能够同时控制广泛的 微环境特征-包括细胞-细胞相互作用，生化线索和生物力学线索- 一个特定的细胞经历。我们的目标是发展技术能力，并最终将这些能力应用于 构建复杂的组织结构，可用作研究组织和血管反应的平台， 物理和生物刺激的扰动，并解决组织工程中的关键挑战， 开发治疗性组织构建体。因此，本建议中的工作旨在提高各领域的能力 生物制造和组织工程，在应用和转化研究中具有广泛的潜在影响。

Abstract Within healthy adult tissues, a developing organism, and disease environments alike, cells exist in environments where they receive and integrate external signals according to a phenotypic state, yielding responses in cellular activities and behaviors or modifications to phenotypic state. Fundamental understanding of cellular functioning and disease progression depends in part on our ability to systematically build and perturb model cellular systems in vitro, and pressing biomedical challenges in translational medicine might be addressed through the technology that enables breakthroughs in tissue engineering, including in meeting the critical needs of patients awaiting organ transplants. Over the past decades, a range of biofabrication technologies have been used to precisely arrange cells and materials within two- and three-dimensional structures. These technologies have broadened our understanding biology and increased the complexity of tissue constructs that might be used therapeutically. While biofabrication approaches developed over this time have greatly benefitted our abilities to probe and understand biological questions—especially with respect to cells and their environments—and to engineer cell-material constructs that recapitulate features of native tissues, significant challenges persist in building multiscale biomimetic tissue constructs. Our lab’s research is focused on addressing these challenges through the development and application of new biofabrication technologies that are based on innovation in the design and use of hydrogel biomaterials. Within the next five years, the lab aims to develop and apply unique hydrogel-based technology to bioprinting to address the critical need for capabilities to create vascularized tissue constructs in which cell and material complexity can be specified in extravascular regions and that can support dense cell populations. The lab will also develop new biofabrication technologies that will allow unique capabilities for high resolution control over cellular and material structures within macroscale constructs, with the goal of being able to simultaneously control a broad range of microenvironmental features—including cell-cell interactions, biochemical cues, and biomechanical cues—that a given cell experiences. We aim to develop technological capabilities and ultimately apply these capabilities to building complex tissue constructs that might be used as platforms for studying tissue and vascular responses to perturbations by physical and biological stimuli and to address key challenges in tissue engineering to develop therapeutic tissue constructs. The work in this proposal thus aims to advance capabilities in the fields of biofabrication and tissue engineering, with broad potential impacts in applied and translational research.