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Tumor Microenvironment Drug Response

Exosomal RNA Markers of KRAS Inhibitor Resistance in Lung Cancer Vascularized Microenvironment [In progress]

Drug resistance is one of the main contributors of lung cancer poor prognosis with 30% survival rate. Tumor microenvironment communicate key pathways of drug resistance via exosomal RNA (exoRNA). Therefore, there is an urgent need to intercept and decode exosomal RNA messages from tumor microenvironment to predict drug response for a better medical intervention strategy. To develop a drug screening model for exoRNA resistance markers, we first have to address the heterogeneous cancer-derived exosomal RNA profile (i.e., different RNA languages) that changes with variations in tumor microenvironment. To address this, we aim to develop an in-vitro 3D vasculature lung tumor model to more accurately recapitulate lung tumor microenvironment drug response in-vivo. This physiological-relevant model provides a scalable approach for drug screening and capable of extracting exoRNA resistance markers. The driving hypothesis of this proposal is that exoRNA extracted from 3D vascularized lung tumor will reflect key markers for drug response. Our preliminary data revealed a different exoRNA composition from 2D and 3D KRASG12C lung cancer cell models in response to small molecule KRASG12C inhibitor (KRASi) treatment. In addition, we demonstrate promising results of differentially expressed genes that are related to poor survival outcome from TCGA data. In this proposal, I will expand our analysis to study the influence of other components of tumor microenvironment (i.e. vascularized endothelial cells and fibroblasts) on drug response exoRNA markers. In-vitro vasculature technology is well positioned to speed preclinical studies of drug screening. In addition, a critical but yet poorly understood exoRNA holds a promise to reveal the underlying mechanisms of drug resistance. Findings from this study will lay the groundwork for the development of RNA-based liquid biopsy assays to predict drug response.

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Tumor cells migrate to the bloodstream in a very low quantity with different sizes (e.g. circulating tumor cells (CTCs)) and structures (e.g. circulating tumor microemboli (CTM)). The size polydispersity makes it even more challenging to detect these rare cells in the blood for diagnostic purposes. In this paper, we report the discovery of a new dynamic size-selective separation and capture method for rare cells that can be tuned by modulating the flow rate in an expansion-contraction channel. This is significant because it allows for tunable capture using a single fabrication process to achieve the flexibility to isolate cells of all sizes or cell clusters in the same device.

Flow in channels and ducts with adjoining cavities are common in natural and engineered systems. Here we report numerical and experimental results of 3D confined cavity flow, identifying critical conditions in the recirculating flow formation and mass transport over a range of channel flow properties (0.1 ≤ Re ≤ 300) and cavity aspect ratio (0.1 ≤ H/Xs ≤ 1). In contrast to 2D systems, a mass flux boundary is not formed in 3D confined cavity-channel flow. Streamlines directly enter a recirculating vortex in the cavity and exit to the main channel leading to an exponential increase in the cavity mass flux when the recirculating vortex fills the cavity volume. These findings extend our understanding of flow entry and exit in cavities and suggest conditions where convective mass transport into and out of cavities would be amplified and vortex particle capture reduced.

Programming magnetic fields with microscale control enable interfacing automation at the scale of cell biology. Magnetic cell sorting methods based on hard/soft magnetic materials lack programmability at the single-cell level, unlike smart magnetoelastic materials that enable magnetic and strain-mediated multiferroic control at the microscale. We demonstrate the largest single-domain microstructures (20 μm) of Terfenol-D, which has the highest magnetostrictive coefficient of any known magneto-elastic material. These Terfenol-D microstructures enabled controlled localization of magnetic particles with sub-micron precision. Magnetically labeled cells were captured by the field gradients generated from the single domain microstructures, without an external biasing magnetic field. We demonstrate a magnetic state switch to release individual cells via voltage-induced strain on PMN-PT substrates. These electronically addressable micromagnets pave the way to high-throughput multiferroics-based single-cell sorting, a highly pursued upgrade in automated cell engineering technologies.

Multiferroic Micromotors Manipulation Technology

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Designing and implementing means of locally trapping magnetic beads and understanding the factors underlying the bead capture force are important steps toward advancing the capture-release process of magnetic particles for biological applications. In particular, capturing magnetically labeled cells using magnetic microstructures with perpendicular magnetic anisotropy (PMA) will enable an approach to cell manipulation for emerging lab-on-a-chip devices. Here, a Co (0.2 nm)/Ni (0.4 nm) multilayered structure was designed to exhibit strong PMA and large saturation magnetization (Ms). Finite element simulations were performed to assess the dependence of the capture force on the value of Ms. The magnetic beads were captured and localized to the edge of the disks as predicted by the simulations. This approach has been demonstrated to enable uniform assembly of magnetic beads without external fields and may provide a pathway toward precise cell manipulation methods.

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In this work, we investigate polycrystalline Ni and FeGa magnetostrictive microstructures on pre- poled (011)-cut single crystal with a linear strain profile versus the applied electric field. Magnetostrictive microstructure arrays with various geometries are patterned on PMN-PT. Functionalized magnetic beads are trapped by localized stray fields originating from the microstructures. With an applied electric field, the magnetic domains are actuated, inducing the motion of the coupled particles with sub-micrometer precision. This work shows promise of using energy-efficient electric-field-controlled magnetostrictive micro- and nanostructures for manipulating magnetic beads via a linear strain response. The work also demonstrates the viability of cells suspended in solution on these structures when subject to applied electric fields, proving the cytocompatibility of the platform for live cell sorting applications.

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Precise control and manipulation of nano-beads have various applications, e.g. cell sorter, 3D printing and nano-motors. In this paper we present an approach in which we use voltage on a piezolecetric substrate in order to reorient the magnetization of a nano-disk. In turn this magnetization drives the dynamic of the nano-beads. This is an energy efficient method to control the nano-beads motion since only voltage is applied to the substrate. The mechanism consists of a Ni disk and three pairs of surface electrodes placed on a PZT substrate. By controlling the voltage applied on the different pairs of electrodes, the magnetization of the Ni disk will rotate with constant angular velocity. The rotating magnetization will then generate magnetic force on the soft-magnetic nano-beads driving the motion. For the beads, full 3D dynamics consider both translation and rotation and the forces considered are magnetic, drag, friction and adhesion. With this model we are able to have a realistic description for the particle behavior.

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