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。

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.