Mechanobiology-on-a-chip for Bone Biomechanics Study

背景：器官芯片是一个正在发展的领域，在过去的几年里受到了相当大的关注。在器官芯片平台上进行的实验结果被认为更具生理学相关性。然而，许多这些已建立的器官芯片系统缺乏所有生命系统所具有的一个关键特征-细胞群体特异性动态机械微环境。机械环境对细胞的功能和代谢起着至关重要的作用。缺乏这一关键成分极大地限制了在这些器官芯片平台上进行的研究的生理学相关性。因此，迫切需要将细胞群体特异性机械输入整合到当前的器官芯片系统设计中。高频低量级（HFLM）振动已被证明是骨重塑的有效调节剂，在癌症骨转移中起着关键作用。目前尚不清楚是哪些主要的骨驻留细胞直接响应HFLM振动并参与调控乳腺癌骨转移，振动调控骨转移的有效性和机制也不清楚。不幸的是，目前的体外和体内模型缺乏识别HFLM振动响应的骨驻留细胞群和解剖响应HFLM振动和乳腺癌转移调节的骨驻留细胞之间的实时双向串扰的能力。这个新的发现项目旨在开发骨芯片上的机械生物学。具体来说，在拨款期间（5年）的重点将集中在三个同时发生的目标上：目标1：我们将开发一种多路微尺度流体剪切集成骨芯片系统，以允许同时对细胞进行生理相关的机械刺激，并在不同细胞群体之间进行细胞信号分子的实时反馈通信。目的2：我们将开发一种微型振动集成的癌症骨转移芯片系统，以了解癌细胞迁移和外渗的振动调节。目标3：我们将开发并集成基于纳米线的传感器到我们的微流体机械生物学芯片系统中，以便在机械刺激下实时表征细胞通信信号。新颖性和预期意义：本研究的目标是开发骨的机械生物学芯片平台。所提出的装置将使我们首次研究机械载荷如何在生理相关环境和疾病环境（如癌症骨转移）中调节骨细胞功能。在这个研究计划中，学生将获得微加工设计、纳米材料、洁净室微加工、实验设计、成像、细胞力学以及有效沟通和协作技能方面的专业知识。所有这些技能将帮助学生打造成功的工业或学术生涯。

Background: Organ-on-a-chip is a growing field and has received considerable attention in the last few years. Results from experiments conducted on organ-on-a-chip platforms are considered more physiologically relevant. However, many of these established organ-on-a-chip systems lack one key feature that presents in all living system - the cell population-specific dynamic mechanical microenvironment. It has been well established that mechanical environment is critical for cell function and metabolism. Lacking this critical component greatly limits the physiological relevance of studies carried on these organ-on-a-chip platforms. Therefore, there is an urgent need to integrate cell population-specific mechanical inputs into the current organ-on-a-chip system design. High frequency low magnitude (HFLM) vibration has been shown to be a potent regulator of bone remodeling, which plays a critical role in cancer bone metastasis. It is unclear which major bone-residing cells respond to HFLM vibration and contribute to the regulation of breast cancer bone metastasis directly, and the effectiveness and mechanism underlying vibration regulation of bone metastasis is unclear. Unfortunately, current in vitro and in vivo models lack the ability to identify HFLM vibration responsive bone residing cell population(s) and dissect real-time bi-directional cross-talk among bone-residing cells in response to HFLM vibration and in regulation of breast cancer metastasis. This new Discovery Project sets out to develop Mechanobiology-on-a-chip for Bone. Specifically, the focus during the grant period (5-years) will be on three, concurrent aims: Aim 1: We will develop a multiplex microscale fluid shear integrated-Bone-on-a-Chip system to allow simultaneous physiologically relevant mechanical stimulation of cells and real-time feedback communications of cell signaling molecules among different cell populations. Aim 2: We will develop a microscale vibration integrated-Cancer Bone Metastasis-on-a-Chip system for understanding vibration regulation of cancer cell migration and extravasation. Aim 3: We will develop and integrate nanowire-based sensors into our microfluidic mechanobiology-on-a-chip systems to allow real-time characterization of cell communication signaling under mechanical stimulation. Novelty and expected significance: The goals of this research are to develop Mechanobiology-on-a-Chip platform for bone. The proposed devices will allow us, for the first time, investigate how mechanical loading regulate bone cell function in a physiologically-relevant environment and disease environment such as cancer bone metastasis. In this proposed research program, students will gain expertise in microfabrication design, nano materials, cleanroom microfabrication, experimental design, imaging, cell mechanics, as well as in effective communication and collaboration skills. All of these skills will help the students forge successful industrial or academic careers.