Microbiome-Bone Chip

最近人们认识到微生物群在人类健康中的核心作用，这导致了医学范式的转变，人们越来越多地意识到这些宿主特有的微生物群落如何影响患者的健康。在过去的十年里，肠道微生物群已经成为全身疾病过程的贡献者，但直到最近才被证明影响骨科生物力学。早期的发现表明，微生物组可能有助于回答目前干预措施没有很好解决的骨科生物力学问题，并突显了新兴领域“肌肉骨骼微生物学”的前景。到目前为止，肠道微生物组串扰的分析几乎完全依赖于对从人类或动物采集的样本的基因组或元基因组分析。这是因为在体外还没有建立稳定的肠道共生微生物群落的方法，这些微生物直接接触肠上皮及其覆盖的粘液层。虽然动物模型已经被用来分析宿主-微生物组的相互作用及其对病理生理学的贡献，但还没有可用的体外系统来验证与复杂的人类微生物组培养的人类细胞中的这些相互作用。因此，对能够维持复杂的人类需氧和厌氧微生物群与活体人体组织接触的实验模型的巨大需求尚未得到满足，以分析动态和生理上相关的人类宿主-微生物组相互作用。该项目将结合Verbroggen博士应用的芯片器官技术来开发一个骨芯片模型，利用这一肌肉骨骼微生物学这一新领域的创始人Hernandez教授开发的动物模型中的微生物组培养和代谢数据。在领先的器官芯片技术制造商Emulate的工业支持下，以及联合调查员Krishna Kumar博士在微生物组3D模型方面的现场专业知识的支持下，该项目将建立一个概念验证的多器官芯片系统，将肠道微生物组与骨芯片模型连接起来。这种芯片模型将提供一个精确的模型来分析重要的生物机制，并提供一种新技术来加快药物测试，同时使用更少的动物，从而实现药物发现的飞跃。

The recent recognition of the central role played by the microbiome in human health has lead to a paradigm shift in medicine, with ever-increasing awareness of how these host-specific communities of microorganisms can affect patient health. In the past decade, the gut microbiome has emerged as a contributor to disease processes throughout the body, but only recently has been shown to influence orthopaedic biomechanics. Early findings suggest that the microbiome may help answer questions in orthopaedic biomechanics that are not well addressed by current interventions and highlight the promise of the emerging field of "Musculoskeletal Microbiology".To date, analysis of gut-microbiome crosstalk has almost exclusively relied on the genomic or metagenomic analysis of samples collected from humans or animals. This is because no method exists to establish stable complex communities of gut commensal microorganisms in direct contact with intestinal epithelium and its overlying mucus layer in vitro. Although animal models have been used to analyse host-microbiome interactions and their contributions to pathophysiology, there are no in vitro systems available to verify these interactions in human cells cultured with a complex human microbiome. Thus, there is a great unmet need for experimental models that can sustain complex populations of human aerobic and anaerobic microbiota in contact with living human tissues to analyse dynamic and physiologically relevant human host-microbiome interactions.This project will bring together the Organ-on-a-Chip technology applied by Dr Verbruggen to develop a bone-chip model, with microbiome cultures and metabolomic data from an animal model developed by a founder of this new field of Musculoskeletal Microbiology, Prof Hernandez. With industrial support from the leading manufacturer of organ-chip technology, Emulate, and on-site expertise in 3D models of the microbiome, from Co-Investigator Dr Krishna Kumar, this project will build a proof-of-concept multi-organ chip system that links the gut microbiome with a bone-chip model. This chip model will provide a leap forward in drug discovery by providing a precision model to pick apart the important biological mechanisms, as well as providing a new technology to speed up drug testing while using less animals.