Mechanobiology-on-a-chip for Bone Biomechanics Study

背景：芯片上的器官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。在芯片上器官平台上进行的实验结果被认为更具生理学相关性。然而，许多已建立的芯片上器官系统缺乏一个在所有生命系统中都存在的关键特征--特定细胞群体的动态机械微环境。机械环境对细胞的功能和新陈代谢起着至关重要的作用。缺乏这一关键组成部分极大地限制了在这些芯片上器官平台上进行的研究的生理学相关性。因此，迫切需要将特定于细胞种群的机械输入集成到当前的芯片上器官系统设计中。高频低幅度(HFLM)振动被证明是骨重建的有效调节因素，而骨重建在癌症骨转移中起着关键作用。目前尚不清楚哪些主要的骨驻留细胞对HFLM的振动作出反应并直接参与乳腺癌骨转移的调控，也不清楚振动调控骨转移的有效性和机制。不幸的是，目前的体外和体内模型缺乏识别HFLM振动响应的骨居住细胞群(S)和剖析实时双向串扰在骨居住细胞之间的实时双向串扰，以响应HFLM振动和在调节乳腺癌转移。这个新的发现项目致力于开发用于骨骼的单芯片机械生物学。具体地说，在授权期(5年)内，重点将集中在三个同时存在的目标上：目标1：我们将开发一种多路微尺度流体剪切集成芯片上的骨系统，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：我们将开发一种微尺度的振动集成-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：我们将开发基于纳米线的传感器，并将其集成到我们的微流控单芯片机械生物学系统中，以允许实时表征机械刺激下的细胞通信信号。新颖性和预期意义：本研究的目标是开发用于骨骼的机械生物学芯片平台。提出的设备将使我们第一次能够研究机械负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。在这个拟议的研究项目中，学生将获得微制造设计、纳米材料、无尘室微制造、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。所有这些技能都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.