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1. Compliant 3D frameworks instrumented with strain sensors for characterization of millimeter-scale engineered muscle tissues

   https://doi.org/10.1073/pnas.2100077118  

   Zhao, Hangbo; Kim, Yongdeok; Wang, Heling; Ning, Xin; Xu, Chenkai; Suh, Judy; Han, Mengdi; Pagan-Diaz, Gelson J.; Lu, Wei; Li, Haibo; et al (May 2021, Proceedings of the National Academy of Sciences)

   null (Ed.)

   Tissue-on-chip systems represent promising platforms for monitoring and controlling tissue functions in vitro for various purposes in biomedical research. The two-dimensional (2D) layouts of these constructs constrain the types of interactions that can be studied and limit their relevance to three-dimensional (3D) tissues. The development of 3D electronic scaffolds and microphysiological devices with geometries and functions tailored to realistic 3D tissues has the potential to create important possibilities in advanced sensing and control. This study presents classes of compliant 3D frameworks that incorporate microscale strain sensors for high-sensitivity measurements of contractile forces of engineered optogenetic muscle tissue rings, supported by quantitative simulations. Compared with traditional approaches based on optical microscopy, these 3D mechanical frameworks and sensing systems can measure not only motions but also contractile forces with high accuracy and high temporal resolution. Results of active tension force measurements of engineered muscle rings under different stimulation conditions in long-term monitoring settings for over 5 wk and in response to various chemical and drug doses demonstrate the utility of such platforms in sensing and modulation of muscle and other tissues. Possibilities for applications range from drug screening and disease modeling to biohybrid robotic engineering. 

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2. Assessment of the Behaviors of an In Vitro Brain Model On-Chip under Shockwave Impacts

   https://doi.org/10.1021/acsami.4c08026  

   Rubby, Md Fazlay; Fonder, Catherine; Uchayash, Sajid; Liang, Xiaogan; Sakaguchi, Donald S; Que, Long (July 2024, ACS Applied Materials & Interfaces)

   Herein we report the assessment of the effects of shockwave (SW) impacts on adult rat hippocampal progenitor cell (AHPC) neurospheres (NSs), which are used as in vitro brain models, for enhancing our understanding of the mechanisms of traumatic brain injury (TBI). The assessment has been achieved by using culture dishes and a new microchip. The microchip allows the chemicals released from the brain models cultured inside the cell culture chamber under SW impacts to diffuse to the nano sensors in adjacent sensor chambers through built-in diffusion barriers, which are used to prevent the cells from entering the sensor chambers, thereby mitigating the biofouling issues of the sensor surface. Experiments showed the negative impact of the SW on the viability, proliferation, and differentiation of the cells within the NSs. A qPCR gene expression analysis was performed and appeared to confirm some of the immunocytochemistry (ICC) results. Finally, we demonstrated that the microchip can be used to monitor lactate dehydrogenase (LDH) released from the AHPC-NSs subjected to SW impacts. As expected, LDH levels changed when AHPC-NSs were injured by SW impacts, verifying this chip can be used for assessing the degrees of injuries of AHPC-NSs by monitoring LDH levels. Taken together, these results suggest the feasibility of using the chip to better understand the interactions between SW impacts and in vitro brain models, paving a way for potentially establishing in vitro TBI models on a chip. 

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3. MAxSIM: multi-angle-crossing structured illumination microscopy with height-controlled mirror for 3D topological mapping of live cells

   https://doi.org/10.1038/s42003-023-05380-2  

   Gardeazabal Rodriguez, Pedro Felipe; Lilach, Yigal; Ambegaonkar, Abhijit; Vitali, Teresa; Jafri, Haani; Sohn, Hae Won; Dalva, Matthew; Pierce, Susan; Chung, Inhee (December 2023, Communications Biology)

   Abstract Mapping 3D plasma membrane topology in live cells can bring unprecedented insights into cell biology. Widefield-based super-resolution methods such as 3D-structured illumination microscopy (3D-SIM) can achieve twice the axial ( ~ 300 nm) and lateral ( ~ 100 nm) resolution of widefield microscopy in real time in live cells. However, twice-resolution enhancement cannot sufficiently visualize nanoscale fine structures of the plasma membrane. Axial interferometry methods including fluorescence light interference contrast microscopy and its derivatives (e.g., scanning angle interference microscopy) can determine nanoscale axial locations of proteins on and near the plasma membrane. Thus, by combining super-resolution lateral imaging of 2D-SIM with axial interferometry, we developed multi-angle-crossing structured illumination microscopy (MAxSIM) to generate multiple incident angles by fast, optoelectronic creation of diffraction patterns. Axial localization accuracy can be enhanced by placing cells on a bottom glass substrate, locating a custom height-controlled mirror (HCM) at a fixed axial position above the glass substrate, and optimizing the height reconstruction algorithm for noisy experimental data. The HCM also enables imaging of both the apical and basal surfaces of a cell. MAxSIM with HCM offers high-fidelity nanoscale 3D topological mapping of cell plasma membranes with near-real-time ( ~ 0.5 Hz) imaging of live cells and 3D single-molecule tracking. 

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4. Measurement of oxygen consumption rates of human renal proximal tubule cells in an array of organ-on-chip devices to monitor drug-induced metabolic shifts

   https://doi.org/10.1038/s41378-022-00442-7  

   Kann, Samuel H.; Shaughnessey, Erin M.; Coppeta, Jonathan R.; Azizgolshani, Hesham; Isenberg, Brett C.; Vedula, Else M.; Zhang, Xin; Charest, Joseph L. (December 2022, Microsystems & Nanoengineering)

   Abstract Measurement of cell metabolism in moderate-throughput to high-throughput organ-on-chip (OOC) systems would expand the range of data collected for studying drug effects or disease in physiologically relevant tissue models. However, current measurement approaches rely on fluorescent imaging or colorimetric assays that are focused on endpoints, require labels or added substrates, and lack real-time data. Here, we integrated optical-based oxygen sensors in a high-throughput OOC platform and developed an approach for monitoring cell metabolic activity in an array of membrane bilayer devices. Each membrane bilayer device supported a culture of human renal proximal tubule epithelial cells on a porous membrane suspended between two microchannels and exposed to controlled, unidirectional perfusion and physiologically relevant shear stress for several days. For the first time, we measured changes in oxygen in a membrane bilayer format and used a finite element analysis model to estimate cell oxygen consumption rates (OCRs), allowing comparison with OCRs from other cell culture systems. Finally, we demonstrated label-free detection of metabolic shifts in human renal proximal tubule cells following exposure to FCCP, a drug known for increasing cell oxygen consumption, as well as oligomycin and antimycin A, drugs known for decreasing cell oxygen consumption. The capability to measure cell OCRs and detect metabolic shifts in an array of membrane bilayer devices contained within an industry standard microtiter plate format will be valuable for analyzing flow-responsive and physiologically complex tissues during drug development and disease research. 

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5. Wide-field, high-resolution lensless on-chip microscopy via near-field blind ptychographic modulation

   https://doi.org/10.1039/C9LC01027K  

   Jiang, Shaowei; Zhu, Jiakai; Song, Pengming; Guo, Chengfei; Bian, Zichao; Wang, Ruihai; Huang, Yikun; Wang, Shiyao; Zhang, He; Zheng, Guoan (March 2020, Lab on a Chip)

   We report a novel lensless on-chip microscopy platform based on near-field blind ptychographic modulation. In this platform, we place a thin diffuser in between the object and the image sensor for light wave modulation. By blindly scanning the unknown diffuser to different x – y positions, we acquire a sequence of modulated intensity images for quantitative object recovery. Different from previous ptychographic implementations, we employ a unit magnification configuration with a Fresnel number of ∼50 000, which is orders of magnitude higher than those of previous ptychographic setups. The unit magnification configuration allows us to have the entire sensor area, 6.4 mm by 4.6 mm, as the imaging field of view. The ultra-high Fresnel number enables us to directly recover the positional shift of the diffuser in the phase retrieval process, addressing the positioning accuracy issue plaguing regular ptychographic experiments. In our implementation, we use a low-cost, DIY scanning stage to perform blind diffuser modulation. Precise mechanical scanning that is critical in conventional ptychography experiments is no longer needed in our setup. We further employ an up-sampling phase retrieval scheme to bypass the resolution limit set by the imager pixel size and demonstrate a half-pitch resolution of 0.78 μm. We validate the imaging performance via in vitro cell cultures, transparent and stained tissue sections, and a thick biological sample. We show that the recovered quantitative phase map can be used to perform effective cell segmentation of a dense yeast culture. We also demonstrate 3D digital refocusing of the thick biological sample based on the recovered wavefront. The reported platform provides a cost-effective and turnkey solution for large field-of-view, high-resolution, and quantitative on-chip microscopy. It is adaptable for a wide range of point-of-care-, global-health-, and telemedicine-related applications. 

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