Keywords

1 Introduction

Disease-related malnutrition is an extensive problem in most healthcare settings. In cancer patients, malnutrition is a common demonstration and a major contributor to morbidity and mortality [1]. Malnutrition is characterized by changes in cellular membrane integrity and alterations in fluid balance [2]. Hence, body composition analysis is an important part of the overall nutritional evaluation in cancer patients [3, 4]. Factually, nutrition status has been assessed by several methods, including using objective parameters such as anthropometric (weight change, height change, body mass index (BMI), body circumference and skinfold thickness), subjective global assessment (SGA), and laboratory measures (measuring serum proteins such as albumin, transferrin, retinol-binding protein) [5]. However, most of them have shown limitations in terms of application. Anthropometric measures are impracticable in clinical settings because they are time-consuming and require well-trained staff. Some of the objective measurements, such as albumin serum one, are probably affected by many non-nutritional factors [5,6,7,8].

Additionally, the assessment of nutritional status changes in a short period becomes difficult because some objective parameters, such as albumin, have long half-lives. Bioelectrical Impedance Analysis (BIA), a little-used tool to evaluate nutritional status, can overcome some of these challenges. This technique is a portable method developed in recent decades that combines morphological and functional evaluation [9]. BIA is a safe, non-invasive, and consistent method for evaluating body composition in clinical practice.

BIA has been considered a method to estimate the body composition and evaluate the nutritional status of many patients with various diseases, including cancer patients [1, 10]. Nevertheless, instead of measuring body composition directly, BIA measures two bioelectrical indicators: resistance (R) and reactance (XC) [11]. When an alternating current with low amplitude and high frequency flows through tissues, R is the opposition of total body water to the flow of that current [12, 13], related to extracellular and intracellular fluid [14]. XC is the opposition proffered by the current flowing through capacitance produced by tissue interface and cell membranes [14, 15]. Namely, it reflects cell membranes’ ability to function as capacitors providing reactance when the alternating current flows through tissues [13]. XC is related to the cell membrane structure and function [16], i.e., it is related to extracellular and intracellular fluid balance, which are independent of cell membrane integrity [17]. The relationship between capacitance and resistance reflects different electrical properties of tissues affected in different ways by disease, nutritional status, and hydration status [18]. There is a low-amplitude high-frequency electric current (500–800 µA at 100 kHz) flowing through some electrodes placed on the hand and foot to evaluate body composition. Capacitance is the inducement that causes the current phase to lag behind the voltage phase, thus creates a phase shift between them. Geometrically, this shift is calculated based on the angular transformation of the capacitance to resistance ratio called the Bioelectrical Impedance Phase Angle (BIPA) [11]. BIPA is the angle created by the impedance vector and the resistance vector; it is calculated using the arctangent of the ratio XC in degrees [9]. The geometrical relationships among R impedance, reactance (XC), resistance (R), phase angle, and frequency of the current are illustrated in Fig. 1.

Fig. 1
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BIA vector and phase angle

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When an electric current is applied to the human body, a portion of the current is stored in cell membranes, creating a BIPA, which is also the phase shift between the impedance and resistance vectors [11]. Consequently, the measured BIPA is governed by many objective factors such as the number of cells with their respective cell membranes, cell membrane integrity, related permeability, the amounts of extra and intracellular fluids [19], and body cell mass (BCM). BIPA might be changed if any changes occur in BCM, either functional defects of cell membranes [2]. By assessing BIPA, it can be concluded that it reflects the relative contributions of fluids (resistance) and cellular membranes (capacitance) of the human body. Low phase angle values suggest cell death or decreased cell integrity, while higher values suggest large quantities of intact cell membranes [9]. BIPA has been considered a prognostic indicator in various clinical situations like HIV, chronic pulmonary disease, colorectal cancer because it may indicate functional changes in the cell membrane and fluid balance [15, 18, 20, 21]. The present study’s primary purpose is to design a system for automatically measuring the bioelectrical impedance phase angle with high accuracy of an individual body segment after excitation by a current source.

2 Methods and Materials

The phase angle measuring system is comprised of a sine-wave generator, a low intensity, high-frequency (100 kHz) current pump, a phase difference-to-voltage converter, and a high-resolution analog-to-digital converter (ADC). The design of the phase difference-to-voltage converter is based on a high-precision analog multiplier and a peak detector. The phase difference-to-voltage converter’s performance assessment was conducted by applying two programmable phase-difference signals generated by the pulse generator to ensure the accuracy of the phase angle difference. The converted phase angle was then read by a 16-bit ADC and displayed. The proposed research aims to develop a system for measuring electrical impedance phase angle of body segments with help from a combination of some low cost, compact, reliable, and easy design circuits. The system block diagram and circuit design are illustrated in Fig. 2 [22,23,24].

Fig. 2
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Block diagram of hardware design

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2.1 Electrode Method

Four-electrode BIA is an informative, accurate, easy to perform, and affordable method of determining joints’ impedance. The skin contact electrodes are constituted of Ag/AgCl material used mostly in bio-impedance applications [25].

2.2 Power Supply

The power unit is responsible for supplying power to the entire system. In which the current source block uses chips with a source of ±12V DC and ±15V DC. The analog signal receiving unit uses a source of ±15V DC. The digital processing unit and LCD use 5VDC power. The measurement circuit is powered by the DC-DC converter (JHM1524D12, XP Power, China) with voltage isolation of 4 kV, specifically designed for medical application, to ensure the electrical safety for measuring objects.

2.3 Current Source

In this design, the improved Howland Current Pump Topology (Fig. 3) is selected for the voltage-current converter due to its ability to provide bi-polar output current, wide frequency range, high output impedance and temperature stability. However, this topology has one drawback: it requires very precise resistors to match the ratio and an op-amp with high open loop gain and high CMRR to achieve a high output impedance current source, especially with high-frequency waveform. Because in bioimpedance measurements, the current source directly affects the quality of the recorded signal. The authors take careful consideration of PCB layout, selection of precise resistors (0.1% tolerance), and the op-amp to ensure the current source’s quality. OPA2211 is used due to prominent features such as its low noise density, low voltage, low current noise and high speed.

Fig. 3
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Schematic of the current source unit

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In this study, a sine-wave high-frequency current source with an amplitude of 4 mA and a frequency of 100 kHz is injected into the body through two electrodes; the induced voltage is picked up by using another pair of electrodes. To ensure patient safety, any residual DC offset component is blocked by a high-pass filter [26,27,28].

2.4 Instrumentation Amplifier

The body segment’s differential signals are fed to the instrumentation amplifier (INA129, Texas Instruments), which amplifies the signals from the body. A band-pass filter suppresses any unwanted noises outside of the signal band. This design’s filter type is the 2nd-order Butterworth active filter, which ensures the maximal flatness and phase linearity, according to Sallen-Key topology, with a passband of 80–120 kHz. The schematic of the amplifier unit is shown in Fig. 4.

Fig. 4
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Schematic of the amplifier unit

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2.5 Bioelectrical Impedance Phase Angle Measurement Unit

The current is injected simultaneously into the body segment and a well-known reference resistor (470 Ω) in series. The voltage across the reference resistor and the instrumentation amplifier’s signal is then fed to the multiplier IC (Analog Devices). The output voltage of AD633 is calculated as the following formula.

$$ V = \frac{A.B}{{2 \times SF}}\cos\varphi $$
(1)

A is the amplitude of the reference signal, B is the amplitude of the signal attained from the body, SF is an adjusted scale factor of IC AD633, φ is the phase difference between the reference signal and the signal attained from the body. B is determined by a high-precision, high-speed peak detector unit. The schematic of the peak detector unit is illustrated in Fig. 5.

Fig. 5
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Schematic of the peak detector unit

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The phase difference-to-voltage converter includes an analog multiplier using a high-precision voltage reference generator and an active low-pass filter. The detailed schematic of the phase difference-to-voltage converter is illustrated in Fig. 6.

Fig. 6
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Schematic of the multiplier unit

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3 Results and Discussion

3.1 Assessment of the Sine-Wave Generator Using AD9833

The designed generator using AD9833 can simultaneously generate two sine-wave signals with the precise programmable frequency range of 50–200 kHz and phase difference range of 0° to 180°. Figure 7 shows examples of the two generated sinewave signals at phase differences of 90° and 45°, respectively. The data used in the figures was sampled and extracted from a digital oscilloscope (MSOX2024A, KEYSIGHT).

Fig. 7
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The two generated sine-wave signals at a phase difference of 90° and 45°

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Figure 7 demonstrates that setting up two signals with a custom phase difference using AD9833 gives the desired result. The accuracy of the two signals helps reduce the error of the results obtained from the phase shift measurement unit; thus, they are more accurate.

3.2 Assessment of the Current Source

The ability to supply a constant current independent of load resistance is the most important technical specification of the current source. To assess the current source, the current amplitude was fixed at the value of 1 mA; then the load resistors were changed within resistor values of 100 Ω, 220 Ω, 560 Ω, 680 Ω, 1 kΩ, 1.2 kΩ, 2 kΩ, 5.1 kΩ, and 10 kΩ. The voltage dropping in the load resistors was then measured to plot a dependency graph (Fig. 8) of the load resistance and the voltage to check the linearity in a certain range of resistors that the current source is designed to meet. From the figure, we can conclude that the curve is linear, with the load’s resistance smaller than 4 kΩ. This means the maximum load which the current source can supply without distortion. It is approximately 4 kΩ.

Fig. 8
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Voltage–load dependency graph

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While the body’s internal impedance is less than 1181 Ω [29], the resistance of the load used in this assessment ranges from 0 to 4 kΩ in which the supplied constant current is independent of the load resistance. This means the current source will work effectively when the proposed system is used for body measurements without harming the patients.

3.3 Assessment of the Phase Angle Measuring Unit

This sub-section evaluates the accuracy of the phase angle measurement circuit. The evaluation is based on comparing the phase difference between the setup values and the measuring results. The two identical-frequency sine-wave signals were programmatically generated with phase angle difference step of 10° and ranged from 10° to 90° for phase difference-to-voltage converter inputs. A 12-bit ADC then sampled the signal with the sampling rate of 100 samples/s. The measuring phase angle values are shown in Table 1. The measuring results show the error of 0.5° ± 0.2° (mean ± standard deviation).

Table 1 The table of setup and measuring phase angle results
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Figure 9 illustrates the correlation between measuring phase values and setup phase values. The proposed system’s measuring results have a high correlation with the setup values (coefficient of determination R2 = 0.997).

Fig. 9
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The correlation between measuring phase values and setup phase values

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The results obtained from the measuring circuit give an acceptable error of 0.5° ± 0.2°over the range of 10° to 90°. Adjusting methods and the deviation of component values are the main factors causing the error above. These results show that the proposed system built on the given method is feasible and performs the desired function. When performing bioelectric impedance phase angle measurements, the results obtained in colorectal cancer patients range from 2° to 8° [18]; the thresholds used for classification at advanced cancer patients or liver cirrhosis ones are also below 10° [1, 9]. Hence the authors want to continue to improve the system, narrow the measuring range to 0 to 10° and increase the accuracy of the measurement results. Then, the direct measurement of the BIPA index on the body applied to monitor patients’ nutritional status will bring great value.

4 Conclusion

Based on the results and analysis described earlier, the proposed measuring system works effectively in the measuring range and performs the desired function. This system offers an ability to automatically measure the bioelectrical impedance phase angle with low error. The initial results of this study are promising. They can be potentially developed to become instrumentation devices capable of detecting the bioelectrical impedance phase angle to support the clinical diagnosis and research purposes. The overall evaluation of the system could be temporarily performed on a well-known R-C model. In further studies, the authors would assess the system on individual body segments after meeting the safeguards and being approved by the ethics committee for clinical and research applications. The results would be published in further studies.