Piezoelectric ceramic sensor and sensor array for detection of molecular makers

Abstract

A sensor is provided for the detection of a marker in a sample in which the sensor includes a high frequency 500 kHz-1 GHz piezoelectric ceramic resonator, with the system measuring resonant frequency change. In one embodiment, the piezoelectric sensor operates in the thickness extensional (TE) mode, with the high frequency and TE mode permitting fabrication of an exceptionally small size sensor capable of being arrayed in a handheld unit.

Description

RELATED APPLICATIONS[0001]This Application claims rights under 35 USC §119(e) from U.S. Application Ser. No. 61 / 103,268 filed Nov. 20, 2007, the contents of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention relates to a high-frequency ceramic piezoelectric sensor and sensor array for detection and analysis of molecular markers in various samples by detecting the change in frequency before and after sample introduction using either a dry condition or a wet condition process.BACKGROUND OF THE INVENTIONSensor Technology[0003]Sensors are analytical devices composed of a recognition element coupled to a physical transducer measuring mass or optical, electrochemical or thermal properties for qualitative and quantitative detection of analytes.[0004]Sensors have wide applications in: medical, food, industrial, environmental and biodefense areas.[0005]The increasing trend in healthcare strives for early detection for disease screening and prevention. The in...

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Benefits of technology

[0033]In one embodiment, the system described herein uses a thickness extensional (TE) mode piezoelectric ceramic resonator as a sensing material. The capturing molecule which is specific for the analytes is immobilized on the sensor surface for capturing the analyte and detection of mass change is done directly through resonance frequency change. For high sensitivity sample detection, a high frequency probing of the piezoelectric material is required. This is possible as high frequency piezoelectric ceramic resonators can be easily manufactured for sample detection, whereas quartz crystals cannot. Thus, the high frequency of the subject provides a sensor that system is sensitive enough to detect a low analyte level that provides valuable information for clinical applications. Besides, TE mode ceramic resonators (poled in the thickness direction) are more effective for very flexible structures when compared to thickness-shear mode ceramic resonators (poled in the longitudinal direction) that are more effective for stiffer structures. IE mode ceramic resonators are also uniquely suitable for array type sensor development due to their compact size and low cost. In addition, the TE mode provides uniform displacement along the thickness direction thus providing uniform measurements. As a result, the subject sensing material or sensing mechanism is different from that described in other publications in which quartz, cantilever or acoustic wave detection mechanisms are described.

[0038]The present invention has several important applications including disease diagnosis and in particular, cancer detection in humans. In one embodiment, the subject technique offers simultaneous detection of multiple cancer markers with simple, fast and high throughput operation, and at a reduced cost. The biosensor platform established is used for development of a series of products for other applications including, but not limited to cardiovascular disease diagnostics, autoimmune disease diagnostics, coagulation disorder diagnostics, and food analysis.

[0040]For example, the presence or the tendency of cancer development is determined with high sensitivity and selectivity by detecting and quantifying the tumor markers. The preferred use of the subject invention is via a bench top sensor that is connected to a computation system, thereby facilitating a simple and convenient test of samples by technical staff in a hospital or by doctors at clinics. The sensor and sensor array described herein is well suited to the simultaneous detection of multiple cancer markers and development of sensors for other disease diagnostics such as cardiovascular diseases, autoimmune diseases, coagulation disorder, food safety analysis. Thus, with the use of the subject system, the opportunities for early medical intervention are increased.

[0059]The frequency range of the ceramic resonators is the same. However, to prevent interference between the resonators when they are arranged in an array format, the frequency for the adjacent resonators have a frequency difference of 1 MHz (e.g. adjacent resonators would have frequencies: Resonator 1 with frequency of 40 MHz and Resonator 2 with frequency of 41 MHz or 39 MHz respectively).

[0069]Ceramics are available at lower cost than quartz, which is a very important consideration for medical diagnostic applications. Versatility is another key feature of the materials, as compositions are selected and modified to achieve a desirable combination of properties. Besides, miniaturization of the ceramic material is possible, which makes it suitable to manufacture protein microarrays. Thus, piezoelectric ceramic resonators are used for sensor platform development in the different applications indicated above.

Problems solved by technology

While the demand for sensors in each of the above five areas increases at a high annual rate, the applications in the medical area overshadows the other seemingly important application areas.

Nevertheless, as the sensitivity of piezoelectric sensors depends on the oscillating frequency and the area and thickness of the material, there are technical difficulties in producing thinner, smaller quartz devices with higher frequency.

These physical barriers limit the application of quartz crystal sensors due to their low sensitivity and high cost.

However, quartz microbalances have the sensitivity problems noted above, and as compared with the subject ceramic-based product, the differences are as follows:

However, due to the sensitivity problems noted above, it uses complicated steps for analyzing the presence of a target in the sample through indirect measurement of mass changes.

This setup is used due to the low sensitivity of the setup for direct mass detection that would require amplification using a signal generating product deposit on the sensor surface.

Besides, the complicated procedures described by WO 91 / 05261 may not be directly applicable in clinical diagnostics, as simplicity, speed, high through put and low cost are desirable.

However, the application of ceramics to biological sample detection is limited.

Binding of the analyte induces stress in the microsensor which results in deflection of the microsensor.

The ceramic disc has a relatively low frequency range of 100-200 kHz, and it has been found that the viability of such a low-frequency system for use as a biosensor is questionable.

The PZT rod used is much larger in size than the subject sensor and detection is in the low frequency range, not comparable to the ceramic resonators described herein and not suitable for development into an array of sensors for multiple sample measurement.

However the relatively low frequencies used present problems.

Unhealthy lifestyles are another cause for increased cancer incidence, such as smoking, poor or imbalanced diet, inactive lifestyles, and increased exposure to ultraviolet light and polluted environments.

In addition, these methods usually require a radioisotope, an enzyme, fluorescence or a colloidal gold-labeled antibody or antigen, and may suffer from drawbacks of requiring skilled personnel, time-consuming procedures and expensive chemicals.

Existing methods for cancer marker detection are based on immunoassays, which detect one protein marker at a time and are unsuitable for clinical applications that require the ability to determine multiple markers in a timely and cost-effective manner.

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