(3fc) Brillouin Microscopy for Cell and Tissue Biomechanics

Research Interests : My research interest integrates the optical technology, physical science, and biomedical principles in order to understand the biomechanical aspect of physiological processes and diseases. The overarching goal of my career is to establish a research group at the interface between optical technology development and biomedical research. The motivation behind my current and future research stems from the fact that biological research and clinical medicine can both greatly benefit from the development of novel technologies and quantitative tools deriving from optical physics and engineering.

My training and research paths fit this type of interdisciplinary research and are in line with my career goal. During my Ph.D. and the first brief postdoc in optical physics and engineering, I have successfully developed several novel optical instruments for applications in applied physics. These accomplishments demonstrate that I have a strong and solid expertise in all aspects of optical technologies and instrumentation. In my comprehensive training as a postdoc at the University of Maryland, I have innovated an emerging optical technique (Brillouin microscopy) and tailored it to a known need in biomedical research. Now, as an Assistant Research Professor, I am exploring my technology innovation in several areas of biomedicine. The interdisciplinary character of my scientific profile is further strengthened by a five-year NIH K25 career development award which is providing me with formal training in biological science. Complementing my technology background with such biomedical expertise is a powerful combination for the multidisciplinary research I envision.

My recent and current research exemplify this vision: the continuous development of Brillouin microscopy, a novel imaging modality for biomechanics and mechanobiology research, has opened and continuous to open research lines in diverse areas of biomedical research.

Technology Development: The mechanical cues have been recognized as a central player in regulating many cellular functions (e.g. proliferation, migration, and gene expression) as well as system-level behaviors (e.g. embryo development, tissue morphogenesis, and cancer metastasis). To characterize the mechanical interplay within biological samples, we need tools to quantify the mechanical properties of the biological material. However, existing techniques for mechanical tests in biomedicine are limited: contact-based, invasive, sample-labelled, or low resolution. A decade ago, an innovative technique called Brillouin microscopy was first demonstrated its promising application in biomedicine. Brillouin microscopy is an all-optical technique that can directly quantify mechanical property in a non-contact, non-invasive, label-free manner and with 3D subcellular resolution. Six years ago, I started the continuous development of this technique aiming for broad applications in biological fields. I have developed a line-scan Brillouin microscopy that was 300 times faster than the standard configuration thus allowed mechanical mapping of large sample (Zhang et al. Sci. Rep. 2016). I have also developed a Brillouin flow cytometry that greatly improved the measurement throughput and allows mechanical analysis of cell population (Zhang et al. Lab Chip, 2017). In addition, I have worked with colleagues to improve the spectral unambiguous range as well as the noise-rejection ability of Brillouin technique (Berghaus, Zhang et al. Opt. Lett. 2015; Fiore, Zhang et al. Appl. Phys. Lett. 2016), which enabled the measurement of non-transparent samples such as embryonic tissue (Raghunathan, Zhang, et al. J. Biomed. Opt. 2017).

Biomechanics in embryo development: I am exploring the application of Brillouin technique in developmental biology by targeting a crucial public health problem, the neural tube defects (NTDs), which affects >10 in every 10,000 new births worldwide. Evidences have indicated that NTDs are related to the dysregulation of biomechanical cues in the closure of neural tube during development, but the underlying mechanism has not been elucidated, mainly due to the lack of technique that can quantify 3D biomechanics of intact embryonic tissue. To address this issue, I have validated Brillouin technique is a proper tool in such application (Zhang et al. Birth Defects Res. 2019). In the next years, I will investigate how the neural tube closure is regulated by the mechanical properties of neural tissue with mouse model (funded by NIH K25, PI: Zhang). If successful, this project will provide sufficient preliminary data for a R01 application on the understanding of mechanical regulation of neural tube defect.

Biomechanical regulation of neural crest cell (NCC) behavior and development: Vertebrate NCCs are a transient embryonic cell population and have the capacity to differentiate into a wide variety of cell types after cessation of migration. Consequently, aberrant NCC development can lead to congenital and hereditary malformations and disease. Interaction between NCCs and their surrounding environment are crucial during NCC development. While the regulations of molecular signals and gene expression changes have been extensively studies, the impact of mechanical cues from surrounding tissue on NCC migration and the formation of derivatives are still obscure. To address this scientific gap, I am currently collaborating with an established developmental biologist (Taneyhill, UMD) to elucidate the role of tissue mechanics in regulating NCC epithelial-to-mesenchymal transition, early migration, and formation of trigeminal ganglion in chick model (NIH R21 proposal submitted, PI: Taneyhill & Zhang). If successful, the obtained data from this R21 could lead to a R01 application to investigate the later stage of trigeminal ganglion formation and examine how tissue mechanics impact the expression and function of adhesion and signaling molecules.

Nuclear biomechanics: As the largest organelle of most eukaryotic cells, nucleus serves as both a container of genetic material and a mechanosensory that can respond to external mechanical cues. As such, nuclear mechanics regulates many important functions through mechanotransduction, such as cell migration, gene transcription and stem cell differentiation. However, there is a lack of direct measurements about the mechanical behavior of the intact nucleus since it is enclosed by the cytoplasm and not accessible with conventional tools. Using Brillouin techniques, I have overcome this obstacle and obtained the direct quantification of nuclear mechanics in physiological conditions (Zhang et al. Small 2020). The methodology established in this work provides me with a ‘all-purpose platform’ to study the role of cellular nuclear mechanics in physiological and pathological conditions. This is especially powerful in the research of cell migration through confined region and cancer metastatic cascade. The latest collaboration demonstrated the success of such application (Wisniewski, ..., Zhang et al. Sci. Adv. 2020).

Potential new directions: Although Brillouin technique is rapidly recognized, it is still in the early stage of application and has technical limitations. Hence, I will continue to develop the technique to improve its performance, emphasizing on the acquisition speed and penetration depth. In addition, I will explore the integration of Brillouin technique with a force-measurement tool, which can assess both the force distribution and mechanical response of the material in biological samples thus enables the comprehensive understanding of the regulation of mechanical cues in biomedicine. Once again, these technology advances will open up new lines in the fields of biomedical research.

Teaching Interest: My interdisciplinary background and my experience as teaching assistant as well as mentor have set a solid foundation, which will allow me to train next-generation engineers and researchers and help them pave their way to a successful career in the biomedical engineering field. Furthermore, as an immigrant to the United States, I have experienced and understand the challenges of adapting to a new environment and thus fully embrace the diversity of the backgrounds, cultures, and perspectives.

My goal as an instructor and advisor is to create an active atmosphere which can foster interactions between students, inspire new ideas, and promote diversity. With such goal in mind, I plan to provide a distinctive perspective by combining my education background and research experiences. I have strong background in all aspect of optical science and technology and has been trained in bioengineering. This allows me to teach a variety of subjects, including biomedical optics and imaging, microscopy and spectroscopy, device and instrument design, biostatistics. I am comfortable teaching both undergraduate and graduate-level courses. I am also interested in supervising senior design projects and theses.