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A Urinary Bcl-2 Surface Acoustic Wave Biosensor for Early Ovarian Cancer Detection

In this study, the design, fabrication, surface functionalization and experimental characterization of an ultrasonic MEMS biosensor for urinary anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) detection with sub ng/mL sensitivity is presented. It was previously shown that urinary Bcl-2 levels are reliably elevated during early and late stages of ovarian cancer. Our biosensor uses shear horizontal (SH) surface acoustic waves (SAWs) on surface functionalized ST-cut Quartz to quantify the mass loading change by protein adhesion to the delay path. SH-SAWs were generated and received by a pair of micro-fabricated interdigital transducers (IDTs) separated by a judiciously designed delay path. The delay path was surface-functionalized with monoclonal antibodies, ODMS, Protein A/G and Pluronic F127 for optimal Bcl-2 capture with minimal non-specific adsorption. Bcl-2 concentrations were quantified by the resulting resonance frequency shift detected by a custom designed resonator circuit. The target sensitivity for diagnosis and identifying the stage of ovarian cancer was successfully achieved with demonstrated Bcl-2 detection capability of 500 pg/mL. It was also shown that resonance frequency shift increases linearly with increasing Bcl-2 concentration.

Surface Modification on Acoustic Wave Biosensors for Enhanced Specificity

Changes in mass loading on the surface of acoustic biosensors result in output frequency shifts which provide precise measurements of analytes. Therefore, to detect a particular biomarker, the sensor delay path must be judiciously designed to maximize sensitivity and specificity. B-cell lymphoma 2 protein (Bcl-2) found in urine is under investigation as a biomarker for non-invasive early detection of ovarian cancer. In this study, surface chemistry and biofunctionalization approaches were evaluated for their effectiveness in presenting antibodies for Bcl-2 capture while minimizing non-specific protein adsorption. The optimal combination of sequentially adsorbing protein A/G, anti-Bcl-2 IgG and Pluronic F127 onto a hydrophobic surface provided the greatest signal-to-noise ratio and enabled the reliable detection of Bcl-2 concentrations below that previously identified for early stage ovarian cancer as characterized by a modified ELISA method. Finally, the optimal surface modification was applied to a prototype acoustic device and the frequency shift for a range of Bcl-2 concentration was quantified to demonstrate the effectiveness in surface acoustic wave (SAW)-based detection applications. The surface functionalization approaches demonstrated here to specifically and sensitively detect Bcl-2 in a working ultrasonic MEMS biosensor prototype can easily be modified to detect additional biomarkers and enhance other acoustic biosensors.

A Synthetic Phased Array Surface Acoustic Wave Sensor for Quantifying Bolt Tension.

In this paper, we report our findings on implementing a synthetic phased array surface acoustic wave sensor to quantify bolt tension. Maintaining proper bolt tension is important in many fields such as for ensuring safe operation of civil infrastructures. Significant advantages of this relatively simple methodology is its capability to assess bolt tension without any contact with the bolt, thus enabling measurement at inaccessible locations, multiple bolt measurement capability at a time, not requiring data collection during the installation and no calibration requirements. We performed detailed experiments on a custom-built flexible bench-top experimental setup consisting of 1018 steel plate of 12.7 mm (½ in) thickness, a 6.4 mm (¼ in) grade 8 bolt and a stainless steel washer with 19 mm (¾ in) of external diameter. Our results indicate that this method is not only capable of clearly distinguishing properly bolted joints from loosened joints but also capable of quantifying how loose the bolt actually is. We also conducted detailed signal-to-noise (SNR) analysis and showed that the SNR value for the entire bolt tension range was sufficient for image reconstruction.

A structural health monitoring system with ultrasonic MEMS transducers

In this paper, we will summarize our efforts on exploring guided acoustic waves generated by MEMS ultrasonic transducers enabling a non-destructive, ultra-low powered, wireless SHM system. State-of-the-art SHM systems employ bulk piezoelectric transducers. However, they are not environmentally benign (contain lead), not cost feasible for monitoring every bridge in the U.S., require significant power for operation, lack integration capability for wireless interrogation, need precise matching layers, and have only 25-50 percent fractional bandwidth, limiting the detection resolution. To alleviate most of these shortcomings, a low impedance MEMS transducer, called a capacitive micromachined ultrasonic transducer (CMUT), is explored.

A MEMS ultrasonic sensor design for early detection of ovarian cancer

In this study, we investigate a simple, disposable, low-cost, ultrasensitive, and fully-integrated biosensor chip for early ovarian cancer detection. The proposed sensor quantifies urinary anti-apoptotic protein Bcl-2 level that is elevated at various stages of ovarian cancer. Our approach utilizes MEMS ultrasonic transducers that have been demonstrated to be advantageous when compared to piezoelectric transducers. Piezoelectric transducers are expensive, bioincompatible (contain lead), and cannot be integrated in a fully-packaged chip. More importantly, these transducers lack the sensitivity required for early ovarian cancer detection, expensive, not biocompatible (contains Lead) and cannot be integrated for a fully-packaged chip. Our experimentally verified simulations indicate 0.15 pg/ml mass sensitivity with our sensor.

Design of Urinary Biomarker Sensor for Early Ovarian Cancer Detection

In this paper, our efforts on the design, surface functionalization and characterization of ultrasonic MEMS sensor for early ovarian cancer is presented. The sensor detects urinary anti-apoptotic protein Bcl-2 level that has been presented as being elevated for different stages of ovarian cancer. Our novel biosensor approach employs a pair of MEMS ultrasound transducers for generating and sensing surface acoustic waves and a delay path in-between with oriented Bcl-2 antibodies (C8C) attached. Piezoelectric surface acoustic wave devices are employed for sensor for their high coupling efficiency and ease of fabrication. The sensor quantifies the cancer progression by detecting mass loading change generated by adhesion of Bcl-2 molecules to antibodies on the sensor surface. The device is fabricated using common MEMS fabrication techniques and a multi-step surface functionalization is utilized for effective protein adhesion. As a result, our biosensor platform has various unique advantages such as: ultra-sensitive (sub pg/ml), low cost, and simple operation (reminiscent of a pregnancy test) not necessitating trained personnel.Copyright

An Urinary Biosensor for Early Stage Ovarian Cancer Detection: Experimental Characterization

In this study, an experimental characterization of a piezoelectric ultrasonic MEMS biosensor for detection of anti-apoptotic protein Bcl-2 in sub ng/ml scale is presented. Bcl-2 is demonstrated to be elevated at different stages of ovarian cancer in urine ranging from 0.5 to 12 ng/ml. Here, shear horizontal (SH) polarized surface acoustic waves (SAWs) were utilized by interdigital transducers (IDTs), which were micro fabricated on piezoelectric ST cut Quartz wafers. SH SAWs were generated and sensed by a pair of IDTs, separated by judiciously designed a delay path in-between with for most effective Bcl-2 capture. The Bcl-2 concentration is characterized with respect to the change in resonance frequency. The target sensitivity for diagnosis and quantifying the stage of ovarian cancer is achieved with successful detection of Bcl-2 levels as low as 0.5 ng/ml. The results are promising for the sensor system to be used in a lab-on-a-chip platform for point of care urinary ovarian cancer monitoring diagnosis.© 2012 ASME

MEMS ultrasonic transducers for biomedical applications

Abstract: Microelectromechanical systems (MEMS) ultrasonic transducers, commonly referred to as capacitive micromachined ultrasonic transducers (CMUTs), have emerged as viable alternatives to traditional bulk piezoelectric transducers. In this chapter, we will discuss the design, fabrication, and integration of this transducer technology with accompanying front-end electronics. Then, we will review the wide variety of biomedical applications enabled by MEMS ultrasonic transducers including biological and chemical sensors, high-intensity focused ultrasound (HIFU) for medical therapeutics, blood flow rate measurement, and ultrasound imaging.

Surface Functionalization of an Ovarian Cancer Diagnostic Biosensor

Ovarian cancer is the fifth leading cause of death among women in United States and the disease has 1.4% (1 in 71) lifetime risk. Patients with ovarian cancer have a short median survival time after diagnosis with their 5-year survival rate being less than 40%. Early stage ovarian cancer represents an important target for screening since it is lethal in most late stage cases (1). Currently the primary screening procedure for ovarian cancer are blood levels of cancer antigen (CA) 125, however CA 125 levels can also be elevated due to other disorders and do not provide conclusive results (2). Utilizing the research done at the Cell and Molecular Biology department at the University of South Florida which conclusively revealed that urinary levels of bcl-2 are elevated in ovarian cancer patients (3), this research it the first of its kind looking to assess the capture of an analyte protein on a series of potential bioconjugated surfaces for use in a novel acoustic biosensor. Therefore, this research addresses the need for a reliable and economic testing platform to detect ovarian cancer.Copyright

Detailed Investigation of Capacitive Micromachined Ultrasound Transducer Design Space for Optimal Operation

This paper presents our detailed design studies on capacitive micromachined ultrasound transducers (CMUTs) via finite element models developed in ANSYS 12. In this study, we will discuss our experimentally verified coupled field finite element simulations for operation frequency and bandwidth. The effects of device geometry, type of coupling media, material selection and properties are investigated for the frequency response, and bandwidth using an analytical approach. A commercial design of experiment software, Minitab is utilized for sample runs for obtaining response curves. The design principles for CMUTs are given in detail for effective and quick design. The design guidelines illustrate that, the frequency response is a strong function of transducer geometry, material selection and coupling media.© 2011 ASME