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BY-NC-ND 4.0 license Open Access Published by De Gruyter September 30, 2016

Application of microwave sensor technology in cardiovascular disease for plaque detection

  • David Wagner EMAIL logo , Sebastian Vogt , Farabi Ibne Jamal , Subhajit Guha , Christian Wenger , Jan Wessel , Dietmar Kissinger , Kai Pitschmann , Ulrich Schumann , Bertram Schmidt and Markus Detert

Abstract

Arteriosclerosis and associated cardiovascular disease remains the leading cause of mortality. Improved methods for vascular plaque detection allow early diagnose and better therapeutic options. Present diagnostic tools require intense technical expenditure and diminish value of modern screening methods. Our group developed an microwave sensor for on-site detection of plaque formation in arterial vessels. The sensor is an oscillator working around 27 GHz which is coupled to a microstrip stub line. The final flexible polyimid interposer has a length of 38 cm, a width of 1.2 mm and a thickness of 200 μm. Because of its minimal size the interposer completed a catheter with a diameter of 8F ready for further clinical use in cardiology and heart surgery.

1 Introduction

Atherosclerosis is the leading cause of death worldwide [1]. Our paper presents a new method which allows differentiation between lipid and calcified plaque. Lipid-rich plaque formation represents an increased vulnerability and danger for rupture. Subsequent occlusion of arteries results in myocardial infarction and stroke. The search for improved evaluation procedures can improve medical diagnosis and treatment in future. Since, the goal of recent research is focussed on an development miniaturized medical tools, enable a safe differentation between “hard” and “soft” plaques composed of predominant Calcium Phosphate or Lipids, respectively. A plaque represents a hexagonal hydroxyapatite structure according to our electron backscattern pattern analysis (EBSP). Because of the mineralogical behavior it is Whitelockite [2]. The rationale for a new plaque detection principle is based on the need for reduction of x-ray exposure and the technical benefit of on-site screening for lipid and calcified plaques during catheter’s intubation into the coronary main stems in coronary angiography or during aortic cannulation when extracorporeal circulation in cardiovascular surgery is needed.

Figure 1 shows heterogeneous formation of plaque architecture in different magnifications of electron microscopy (400 μm down to 5 μm). Calcium minerals are surrounded by fibrocytic frames but full of rents. From this point, interventional techniques remains risky and dangerous, although indicated to safe patient’s life. The novel microwave sensor appears promising to improve intervention’s safety. The miniature size of the detector opens a way to establish new diagnostic cardiologic catheters where the sensor is attached inside or surgical tools of pen size that artery’s indwell lipid plaques can be found easely and plaque rupture is prevented. In conclusion of our cooperative study the new sensor technology is available but remains to be transferred into clinical applications.

Figure 1: Electron microscopy: A) Calcium Phosphate minerals are surrounded by fibrocyts, B) crack between tissue and Calcium Phosphate mineral, C) vascular inner wall.
Figure 1:

Electron microscopy: A) Calcium Phosphate minerals are surrounded by fibrocyts, B) crack between tissue and Calcium Phosphate mineral, C) vascular inner wall.

2 Sensor development

The basic sensor structure is an oscillator working around 27 GHz which is coupled to a microstrip stub line [3]. The input admittance of this line strongly depends on the dielectric properties of the surrounding material. A sample in close proximity to those lines is affecting the input characteristics and with that the oscillation frequency of the attached oscillator. The oscillation frequency becomes an indicator for the samples dielectric constant.

To evaluate the frequency of oscillation, the next stage converts the high frequency signal into corresponding DC voltages by using a frequency discriminator. This discriminator consists of a delay line, a mixer and a low-pass filter as indicated in Figure 2. The dielectric information of the material under test (MUT) is translated to DC voltages from varying oscillation frequencies. The design of the complete sensor combines both: sensing and read-out circuitry. They are described in detail in the following.

Figure 2: Architecture of the sensor.
Figure 2:

Architecture of the sensor.

Sensing oscillator: The sensing oscillator is a common collector differential circuit based on a Colpitts topology as depicted in Figure 3. In a conventional voltage controlled oscillator (VCO), the tunable capacitance of a varactor changes the oscillation frequency. In the demonstrated design, a planar microstrip open-stub structure has been chosen as the sensing element in the place of a varactor [3], [4]. The open-stub’s capacitance changes depending on the material under test and with it the frequency of oscillation. The sensing open-stub line is implemented in the top metal layer so it is close to the material under test. The effect of changes in the output power at different oscillation frequencies has been alleviated by using a common-base buffer amplifier. It follows the oscillator core and delivers a constant saturated power to the next stage.

Figure 3: The sensing oscillator core with common-base buffer.
Figure 3:

The sensing oscillator core with common-base buffer.

To match the oscillator core output to the buffer input, a line (TLm) is used. The buffer output is also matched with the next stage using microstrip line matching along with metal-insulator-metal (MIM) capacitors. The free running oscillation frequency is 27.14 GHz, i.e. for an unloaded sensor. According to simulations, the corresponding output power is 2.87 dBm.

Frequency discriminator: The frequency discriminator circuit converts the frequency information into a corresponding DC voltage. The oscillator generates two output signals denoted with OUTd and OUTi in Figure 2. One of the signals is passing a delay line causing a phase shift φd depending on the oscillation frequency. The following stage is a mixer performing a multiplication of the delayed signal and the signal retrieved from the second output OUTi. The resulting output signal of the mixer output can be derived as follows:

(1)Sout=SiSd=Amcos(2ωt+φi+φd)+Amcos(φd).

Here, ω0 is the angular frequency of oscillation, φi the signal phase at the output of the oscillator and Am the signal amplitudes, respectively. Equation 1 indicates that the mixer generates one signal component at twice the input frequency.

This is eliminated by the following low-pass filter, leaving the information about the phase delay φd evoked by the delay line. This is a measure for the frequency of oscillation according to:

(2)ω0=φdvphL,

where vph is the phase velocity and L the length of the line. Figure 4 shows the schematic of the frequency discriminator. The differential signals from the oscillator are passed on to the depicted stage. One of them is delayed by the delay line (TLd) and fed to the base of mixing transistor (Tm). The other signal is directly fed to the emitter. An inductor (Le) at the emitter is used to provide a ground path for well-defined bias conditions. The low-pass filter is implemented as an RC network (RC and CC) at the collector output. The sensor circuit was fabricated in a 0.13 μm SiGe BiCMOS process. It features hetero-junction bipolar transistors with fT/fmax = 250 GHz/330 GHz. The technology also offers five thin and two thick aluminum layers for interconnection and inductor realization. The fabricated sensor Chip is displayed in Figure 5. To make it suitable for integration into catheters, it has a very small width of 0.5 mm leading to an overall chip area of 2.1 mm2.

Figure 4: The frequency discriminator: the delay line, single transistor mixer and low-pass filter.
Figure 4:

The frequency discriminator: the delay line, single transistor mixer and low-pass filter.

Figure 5: Chip-photo.
Figure 5:

Chip-photo.

3 Assembly of the demonstrator

After designing and pretesting the chip, an interposer was needed to fix and electrically connect the chip.

Preperation: As a first step in according to the specifications the geometries of an unpackaged chip were used for the design of a circuit diagram which was developed as a flexible interposer (Figure 6).

Figure 6: Interposer Layout: A) chip, B) bonding area, C) 01005 components.
Figure 6:

Interposer Layout: A) chip, B) bonding area, C) 01005 components.

At the layout the final components in package size 01005, the bonding areas and the position of the chip are shown.

Assembly steps: For electrical and mechanical fixation of the chip there has to be handle with different process steps in compliance with medical requirements [5]. The components in structure size 01005 were built up complete in surface mount technique. The components are resistors with different values for realizing a voltage divider and some capacitors for signal enhancement. The mounting of the sensor chip was carried out with a special SMT assembly adhesive on the back side of the chip. The electrical contacting of the chip has some technological difficulties when using an aluminium wire for bonding the chip contacting pads with the landing areas at the interposer. The main problem was the fixing of the wire on the flexible substrate and the chip. To solve this problem, a special gold wire for flexible substrates was used. After this technological adjustment the secure and reliable contacting of the chip was solved. Figure 7 shows the individual assembly steps in detail.

Figure 7: Assembly steps: A) apply solder paste, B) set components, C) soldering with a hot plate, D) chip application with special SMT assembly adhesive, E) wire bonding, F) glob top.
Figure 7:

Assembly steps: A) apply solder paste, B) set components, C) soldering with a hot plate, D) chip application with special SMT assembly adhesive, E) wire bonding, F) glob top.

Function test: After the electronic packaging of the chip a first test setup was built up to validate the functionality of the chip. Therefore the chip was connected to an input voltage of 3.3 V with a maximum current consumption of 32 mA. The output signal was a voltage which has a value of 0.56 V in unloaded condition (air). Then the chip are loaded with three different solutions. The result values were for ethanol 0.48 V, for isopropanol 0.45 V and for deionized water 1.20 V. So a first function test was succesful and a measurement on human tissue could built up.

The evaluation of the human tissue with a first version of a demonstrator was successfully carried out. In a Figure 8 lower sliding extension between healthy and pathological tissue is shown. Figure 8A shows the measurement of healthy tissue with an output voltage value of the microwave sensor of 0.5 V. If the microwave sensor was placed on a calcified plaque, the voltage value was changing to 1.74 V (Figure 8B). Hence, the ability to distinguish healthy and calcified human tissue could be demonstrated.

Figure 8: Measurement of healthy human tissue (A) and pathological human tissue (B) with the microwave sensor and corresponding histology results (coloring: HE - Hemalum/Eosin; EvG - Elastica van Giesson).
Figure 8:

Measurement of healthy human tissue (A) and pathological human tissue (B) with the microwave sensor and corresponding histology results (coloring: HE - Hemalum/Eosin; EvG - Elastica van Giesson).

4 Conclusion

According to our preliminary data and experiences the demonstrator sufficiently detected “hard” plaque formations in the arterial wall. The system is robust and adjusted to the medical routine. In detail we have to point out:

  • Near field detection of plaques can be shown with human tissues

  • Detector enables a precise differentiation between “hard” and “soft” plaques

  • Reduction of detector size enables plaque detection inside the femoral artery, the aorta or the coronary main stem, respectively

  • Absorptions coefficients and permittivity of blood remains a significant problem (Influences of blood turbulences unknown)

  • Increased detection frequencies result in additional power release and tissue heating.

  • Present detector can be used for “hard” plaque detection in case of femoral artery puncture (cardiology, cath lab) or aorta cannulation (heart surgery).

Acknowledgement

Authors are indebt to thank Dr. Rabia Ramzan, Mrs. Petra Weber and Mrs. Annika Rhiel, Dr. W. Nimphius and Dr. A. Ramaswamy from the Marburg group for their support. The group of microsystem technology from University of Magdeburg would like to thank Mr. Friesecke, Mrs. Wittig and Mr. Jeutner.

Author’s Statement

Research funding: We would like to thank the Ministry of Education and Science (BMBF) for the support of the funded project “PlaqueCharM - Charakterisierung mittels mm-Wellen auf einem Katheter”, project number 16M3198B. Conflict of interest: Authors state no conflict of interest. Material and Methods: Informed consent: Informed consent has been obtained from all individuals included in this study. Ethical approval: The research related to human use complies with all the relevant national regulations, institutional policies and was performed in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.

References

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Published Online: 2016-9-30
Published in Print: 2016-9-1

©2016 David Wagner et al., licensee De Gruyter.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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