High Aspect-ratio Biomimetic Hair-like Microstructure Arrays for MEMS Multi-Transducer Platform

Many emerging applications of sensing microsystems in health care, environment, security and transportation systems require improved sensitivity and selectivity, redundancy, robustness, increased dynamic range, as well as small size, low power and low cost. Providing all of these features in a system consisting of one sensor is not practical or possible. Micro electro mechanical microsystems (MEMS) that combine a large sensor array with signal processing circuits could provide these features. To build such multi-transducer microsystems we get inspiration from “hair”, a structure frequently used in nature. Hair is a simple yet elegant structure that offers many attractive features such as large length to cross-sectional area ratio, large exposed surface area, ability to include different sensing materials, and ability to interact with surrounding media in sophisticated ways. In this thesis, we have developed a microfabrication technology to build 3D biomimetic hair structures for MEMS multi-transducer platform. Direct integration with CMOS will enable signal processing of dense arrays of 100s or 1000s of MEMS transducers within a small chip area. We have developed a new device structure that mimics biological hair. It includes a vertical spring, a proof-mass atop the spring, and high aspect-ratio narrow electrostatic gaps to adjacent electrodes for sensing and actuation. Based on this structure, we have developed three generations of 3D high aspect-ratio, small-footprint, low-noise accelerometers. Arrays of both high-sensitivity capacitive and threshold accelerometers are designed and tested, and they demonstrate extended full-scale detection range and frequency bandwidth. The first-generation capacitive hair accelerometer arrays are based on Silicon-on-Glass (SOG) process utilizing 500 µm thick silicon, achieving a highest sensor density of ~100 sensors/mm2 connected in parallel. Minimum capacitive gap is 5 μm with device height of 400 μm and spring length of 300 μm. A custom-designed Bosch deep-reactive-etching (DRIE) process is developed to etch ultra-deep (> 500 µm) ultra-high aspect-ratio (UHAR) features (AR > 40) with straight sidewalls and reduced undercut across a wide range of feature sizes. A two-gap dry-release process is developed for the second-generation capacitive hair accelerometers. Due to the large device height at full wafer thickness of 1 mm and UHAR capacitive transduction gaps at 2 µm that extend > 200 µm, the accelerometer achieves sub-µg resolution (< 1µg/√Hz) and high sensitivity (1pF/g/mm2), having an area smaller than any previous precision accelerometers with similar performance. Each sensor chip consists of devices with various design parameter to cover a wide range. Bonding with metal interlayers at < 400 °C allows direct integration of these devices on top of CMOS circuits. The third-generation digital threshold hair accelerometer takes advantage of large aspect-ratio of the hair structure and UHAR DRIE structures to provide low noise (< 600 ng/√Hz per mm2 footprint proof-mass due to small contact area) and low power threshold acceleration detection. 16-element (4-bit) and 32-element (5-bit) arrays of threshold devices (total chip area being < 1 cm2) with evenly-spaced threshold gap dimensions from 1 µm to 4 µm as well as with hair spring cross-sectional area from 102 µm to 302 µm are designed to suit specific g-ranges from < 100 mg to 50 g. This hair sensor and sensor array technology is suited for forming MEMS transducer arrays with circuits, including high performance IMUs as well as miniaturized detectors and actuators that require high temporal and spatial resolution, analogous to high-density CMOS imagers.PHDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143975/1/yemin_1.pd

Chimeric Antigen Receptor-Modified T Cells Redirected to EphA2 for the Immunotherapy of Non-Small Cell Lung Cancer

Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) is overexpressed in more than 90% of non-small cell lung cancer (NSCLC) but not significantly in normal lung tissue. It is therefore an important tumor antigen target for chimeric antigen receptors (CAR)-T-based therapy in NSCLC. Here, we developed a specific CAR targeted to EphA2, and the anti-tumor effects of this CAR were investigated. A second generation CAR with co-stimulatory receptor 4-1BB targeted to EphA2 was developed. The functionality of EphA2-specific T cells in vitro was tested with flow cytometry and real-time cell electronic sensing system assays. The effect in vivo was evaluated in xenograft SCID Beige mouse model of EphA2 positive NSCLC. These EphA2-specifc T cells can cause tumor cell lysis by producing the cytokines IFN-γ when cocultured with EphA2-positive targets, and the cytotoxicity effects was specific in vitro. In vivo, the tumor signals of mice treated with EphA2-specifc T cells presented the tendency of decrease, and was much lower than the mice treated with non-transduced T cells. The anti-tumor effects of this CAR-T technology in vivo and vitro had been confirmed. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive NSCLC

Effect of radiation on chemical reactions.

http://deepblue.lib.umich.edu/bitstream/2027.42/6471/5/bac8631.0001.001.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/6471/4/bac8631.0001.001.tx

Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition

Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT.Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT.Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%.Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932-43. ©2018 AACR