Received December 9, 2021, accepted December 23, 2021, date of publication December 28, 2021, date of current version January 20, 2022. Digital Object Identifier 10.1109/ACCESS.2021.3139223 Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy: A Comparison of the 3- and 4-Electrode Methods GEORGINA COMPANY-SE 1 , LEXA NESCOLARDE 1 , VIRGINIA PAJARES2 , ALFONS TORREGO2 , PERE J. RIU 1 , (Senior Member, IEEE), JAVIER ROSELL 1 , (Senior Member, IEEE), AND RAMON BRAGÓS 1 1 Department of Electronic Engineering, Universitat Politècnica de Catalunya, 08034 Barcelona, Spain 2 Department of Respiratory Medicine, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain Corresponding author: Lexa Nescolarde (lexa.nescolarde@upc.edu) This work was supported in part by the Spanish Ministry of Science and Innovation under Grant RTI2018-098116-B-C21/C22, and in part by the Secretariat of Universities and Research of the Generalitat de Catalunya and the European Social Fund. This work involved human subjects or animals in its research. Approval of all ethical and experimental procedures and protocols was granted by the Ethics Committee on Clinical Investigation of the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, under Application No. CEIC-73/2010. ABSTRACT Multiple imaging techniques are used for the diagnosis of lung diseases. The choice of a technique depends on the suspected diagnosis. Computed tomography (CT) of the thorax and positron emission tomography (PET) are imaging techniques used for the detection, characterization, staging and follow-up of lung cancer, and these techniques use ionizing radiation and are radiologist-dependent. Electrical impedance spectroscopy (EIS) performed through a bronchoscopic process could serve as a minimally invasive non-ionizing method complementary to CT and PET to characterize lung tissue. The aim of this study was to analyse the feasibility and ability of minimally invasive EIS bioimpedance measures to differentiate among healthy lung, bronchial and neoplastic lung tissues through bronchoscopy using the 3- and 4-electrode methods. Tissue differentiation was performed in 13 patients using the 4-electrode method (13 healthy lung, 12 bronchial and 3 neoplastic lung tissues) and the 3-electrode method (9 healthy lung, 10 bronchial and 2 neoplastic lung tissues). One-way analysis of variance (ANOVA) showed a statistically significant difference (P < 0.001) between bronchial and healthy lung tissues for both the 3- and 4-electrode methods. The 3-electrode method seemed to differentiate cancer types through changes in the cellular structures of the tissues by both the reactance (Xc) and the resistance (R). Minimally invasive measurements obtained using the 3-electrode method seem to be most suitable for differentiating between healthy and bronchial lung tissues. In the future, EIS using the 3-electrode method could be a method complementary to PET/CT and biopsy in lung pathology diagnosis. INDEX TERMS Bronchi, bronchoscopy, electrical impedance spectroscopy (EIS), electrode methods, lung. I. INTRODUCTION second-leading cause in women [2]. However, diagnosis in Respiratory diseases are among the most prevalent illnesses early-stage disease is associated with substantially improved worldwide, along with heart complications. Moreover, each overall survival. year, an estimated 3 million people die due to respira- There are different ways to proceed to diagnoses of lung tory disease complications, making respiratory diseases the diseases. Computed tomography (CT) allows the detailed third leading cause of death worldwide [1]. Lung cancer is representation of interstitial, pleural, mediastinal and vas- the leading cause of cancer-related death in men and the cular structures [4]. Positron emission tomography (PET) provides information about cellular metabolism. Integrated The associate editor coordinating the review of this manuscript and CT with PET (PET/CT) [5] combines the anatomical infor- approving it for publication was Zhen Ren . mation from CT with the metabolic information from This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. For more information, see https://creativecommons.org/licenses/by-nc-nd/4.0/ 7354 VOLUME 10, 2022 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy PET, which makes it possible to obtain a more accurate Bioimpedance measures can be obtained using single or diagnosis. multiple frequencies. When the measures are obtained using Flexible bronchoscopy, the least invasive bronchoscopic a single frequency, the most common frequency is 50 kHz procedure, is of limited value for obtaining tissue from lesions due to its high signal-to-noise ratio [10]. Regarding non- in the peripheral segments of the lung. invasive single frequency (50 kHz), Toso et al. [11] observed The selection of the biopsy site is relatively simple a decrease in the Xc parameter and, as a consequence, when the patient has endobronchial involvement. However, a decrease in the PA, preserving the R component in patients in peripheral tumours without endobronchial involvement, with lung neoplasms. additional techniques are necessary to help to confirm that Different studies can be found regarding the applica- the location of the biopsy is correct. The increasing need to bility of EIS for tissue differentiation and characteriza- efficiently and safely sample lung lesions has led to the devel- tion [12]–[21]. Dean et al. [12] and Héroux and Bordages [13] opment of virtual bronchoscopy (VB), radial endobronchial studied the properties of the electrical impedance of bio- ultrasound (r-EBUS), electromagnetic navigation (EMN) and logical tissue. They observed changes in impedance as a ultrathin bronchoscopes. The diagnostic yield using these function of frequency, arriving at the conclusion that the bronchoscopic techniques remains suboptimal [6], [7], and data obtained and the changes in impedance were consis- their high economic cost makes them unavailable in most cen- tent according to the basic principles of the bioimpedance tres. To complement the current methods of diagnosing lung already introduced. Other studies, such as da Silva et al. [14] diseases, we aim to use electrical impedance spectroscopy and Yoon et al. [15], investigated the possible use of the (EIS). EIS could allow the differentiation of healthy tissue technique for the distinction of different types of tissue. The from tumour tissue and help in the choice of the specific first study was focused on breast tissue and the differen- sampling location. tiation between cancerous and healthy tissue. The second Impedance analysis techniques (such as EIS) consist of study focused on the evaluation of the frequency response the application of electrical current to biological tissues to of bioimpedance measures in rabbits’ tendons through two observe changes in their passive electrical properties [8]. different types of measures, one longitudinal and other trans- Impedance is the general term used to define the opposition of verse in relation to the tendon fibbers to detect pathological a conductor to a current flow [9]. When a current is injected changes in tendons to find the exact location of a tendini- into biological tissue, the opposition that biological tissues tis lesion. Skourou et al. [16] and Desai et al. [17] evaluated produce to the current is called bioimpedance. Bioimpedance the ability of impedance spectroscopy to detect tumours in is composed of two components, resistance (R) and reactance their initial stages. The first concluded that the technique (Xc). On the one hand, the opposition that the physiolog- allowed the detection of tumours that were not possible to ical fluid, both intracellular and extracellular, presents to a detect with other conventional techniques, such as CT, due to given current flow produces the resistive component. On the their reduced size. Hillary et al. [18] analysed the spectrum other hand, reactance is given by the polarization of the of the impedance values obtained for different soft tissues cellular membranes and the tissue interfaces, producing a located in the neck, including adipose, parathyroid, thyroid, delay between the current flow and the voltage. This delay and muscle tissues. The purpose of the study was to cor- defines the parameter called the phase angle (PA) [10], [11]. rectly identify the parathyroid tissue to preserve it to facilitate Both components of bioimpedance (R and Xc) are positively surgery on the parathyroid glands and reduce the occur- correlated. The current flow applied to the tissues can be rence of post-surgery hypoparathyroidism. A bioimpedance either direct current or alternating current. When direct cur- method to detect cancer, using a custom-designed catheter rent is applied, the reactive effect disappears, making the with 4-electrodes placed on the front face of a catheter, bioimpedance completely resistive. This means that when was tested for Barret’s Esophagus [19] and for cervical direct current is applied, the current flow circulates only neoplasia [20]. through the physiological fluid. However, when alternating Regarding the use of EIS to measure lung bioimpedance, current is applied to tissues, the current is able to flow Gabriel et al. [21] proposed a model to predict dielectric data for both physiological fluid and capacitive elements. This based on the data present in the literature for different tissues, phenomenon makes bioimpedance a frequency-dependent among which they analysed the inflated lung. Desai et al. [17] measure [10]. At low frequencies, the current is not able to studied the ability of the technique to differentiate between penetrate the cellular membranes, so there is no conduction carcinogenic and healthy cells by extracting different cancer within the cells, which is due to the high impedance of cell types and through pattern recognition techniques evaluat- the cellular membranes and the tissue interfaces. Therefore, ing the ability to differentiate between the two types of cells. we define the bioimpedance (Z) as a vector as a function They studied multiple cancer types, including lung cancer. of R and Xc [9] and the PA as the arctangent of the ratio Sanchez et al. [22], in a previous report, validated the between Xc and R. use of minimally invasive EIS with the 4-electrode method The impedance modulus (|Z|) is highly correlated with the for lung bioimpedance measures through a bronchoscopic resistive component, with |Z| being slightly higher than R process. Later, Riu et al. [23] published a preliminary report because of the reactive component [10]. using a single frequency response with a 4-electrode method VOLUME 10, 2022 7355 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy to differentiate among healthy lung tissue, bronchi and mul- a rugged PC platform based on a PXI system from National tiple parenchymal pathologies. They found a statistically Instruments; and an analog–optical interface front end to significant difference with respect to the PA at 33 kHz connect the PXI with the insulated front end. The system between healthy lung tissue and bronchial tissue and between includes an arbitrary waveform generator that generates a bronchial tissue and multiple parenchymal pathologies. multisine excitation signal, which is a broadband signal com- Later more references will be added in the discussion posed of 26 frequencies between 1 kHz and 1 MHz. The front- section, to highlight their relationship with our findings. The end includes an AC-coupled current source which ensures a use of 4 electrodes in the tip of the catheter produces a local current lower than the maximum allowable patient auxiliary estimation of the tissues in contact with the electrodes and current stablished in the IEC 60601-1:2005 (<1 mA rms mea- reduces the contribution of electrode-tissue impedances to sured with the circuit proposed in the IEC 60601-1:2005). the measurements; however, we hypothesize that the use of The voltage (V(t)) and current (I(t)) are simultaneously 4 electrodes is more prone to artefacts due to the difficulties acquired. The excitation is converted into an optical sig- in obtaining good contact between all four electrodes and the nal with the optical–analog interface connected to the PXI. surrounding tissue. Using the 3-electrode method (typical in This optical signal is then reconverted into an electrical sig- electrochemical EIS but not so typical in biomedical mea- nal inside the front end. The voltage and current signals, surements), only one contact must be established between which are optically transmitted from the front end to the the catheter and the surrounding tissues. Additionally, the optical–electrical interface, are filtered (cut-off frequency catheter could be simpler, reducing its cost and size. However, 10 MHz) and acquired with the digitizer card. A schematic there are no previous studies regarding the use of EIS for representation of the bioimpedance acquisition system is minimally invasive lung measures for tissue differentiation shown in Fig. 1. using the 3- and 4-electrode methods. Bioimpedance measures were obtained using the The aim of this study was to analyse the capability of 4-electrode method and the 3-electrode method through bron- minimally invasive EIS, using 3 and 4-electrode methods, choscopy. With the 4-electrodes method, the 4 electrodes to differentiate healthy lung tissue and bronchial and neo- located in the distal part of the catheter were placed in plasm lung tissue the desired area. The external electrodes injected electrical current (high current (HC) and low current (LC)), while the II. MATERIALS AND METHODS internal electrodes measured the voltage differences gener- ated (high potential (HP) and low potential (LP)). When A. PARTICIPANTS measuring with three electrodes, the electrode placed at the Minimally invasive EIS was performed in 13 patients tip of the catheter was used to inject the current (HC) and to (69 ± 12 yr; 70.1 ± 15.1 kg; 25.7 ± 4.7 kgm−2 ) for whom detect the potential (HP), and the LC and LP electrodes were bronchoscopy was indicated during July 2020 at the ‘‘Hospi- the two skin electrodes placed on the right side of the patient tal de la Santa Creu i Sant Pau’’. The bioimpedance measures at rib level. A schematic representation of both methods is were obtained via the 4-electrode method (13 healthy lung, shown in Fig. 2. 12 bronchial and 3 neoplastic lung tissues) and 3-electrode method (9 healthy lung, 10 bronchial and 2 neoplastic lung C. MEASUREMENT PROTOCOL tissues). To obtain the bioimpedance measures, bronchoscopy, a med- Ethics approval was obtained from the Hospital de la Santa ical procedure used to inspect the airways, was performed. Creu i Sant Pau (CEIC-73/2010) according to principles Prior to bronchoscopy, a radiological imaging technique (CT of the Declaration of Helsinki for experiments with human or PET/CT) was performed as part of the diagnostic process. beings. All patients provided signed informed consent. In addition, the catheter was inserted through a port of the bronchoscope. B. MEASUREMENT SYSTEM During the process, patients were placed in a supine posi- To acquire the bioimpedance measures, a tetrapolar catheter, tion. The upper airway was anaesthetized with topical 2% 115 cm long with a diameter of 1.65 mm (5 F), was used lidocaine; intravenous sedation was provided throughout the (Medtronic 5F RF Marinr steerable catheter with electrode procedure with midazolam, fentanyl and propofol. All sam- separation 2/5/2 mm) (Fig. 2). To convert the 4-electrode ples were harvested through a flexible bronchoscope during measurement system of the catheter to the 3-electrode system, procedures that included endoscopic exploration and other a switch was introduced so that the same catheter could be diagnostic tests as required. used for the measures obtained with both three and four elec- Once at the region of interest, measures were taken first trode methods (Fig. 1). Moreover, for the measures obtained with 4 electrodes and then with 3 electrodes after clos- with 3 electrodes, two skin electrodes placed on the right side ing the switch (Fig. 1). The process was always the same. of the patients at the level of the ribs were used (Fig. 2). First, bronchial measures were taken, followed by healthy The measurement system consists of 3 devices (Fig. 1): an lung tissue measures and then pathological lung tissue insulated front end, which is an optically insulated battery- (if any) measures. Once the bronchoscope arrived at the powered patient interface, including the impedance front end; region of interest, we had to ensure that the patient was 7356 VOLUME 10, 2022 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy FIGURE 1. Schematic representation of the bioimpedance acquisition system. For better understanding of the electrodes’ connection in each case, please also see Figure 2. FIGURE 2. Schematic representation of the 4- (left image) and 3- (right image) electrode methods. Blue lines represent the current lines, and orange lines represent the voltage lines. In 4-electrode method, the four electrode are inside the lung, while 3-electrode method, LC and LP are on the skin using skin surface electrode. In the central figure, the dimensions of the electrodes are represented. not moving during the 15 seconds of recording for each was substituted by a measurement over a known resistor location. (100 Ohms) connected to the catheter tip and to the external electrode connectors. D. EIS MEASUREMENTS Bioimpedance measurements were obtained at the same E. DATA ANALYSIS location with both 4 and 3 electrodes, with approximately In this study, the averaged spectra of the bioimpedance 15 seconds of difference between the measurements. EIS measurements, obtained using the 3 and 4-electrode meth- consisted on the application of a multisine current signal ods, throughout the acquisition time were used for the tis- (26 frequencies from 1 kHz to 1 MHz) and the acquisition sue differentiation analysis among healthy lung, bronchial of the voltage and current signals. The fast Fourier trans- and neoplastic lung tissues. The frequency range chosen to form (FFT) was calculated for both the acquired voltage and visualize the data was 5 kHz – 209 kHz. The values from current signals. The bioimpedance was calculated by obtain- the frequencies higher and lower than this range were dis- ing the ratio between the voltage and current coefficients of carded due to electrode and capacitive errors. The interval of the FFT corresponding to each injected frequency. 50 spectra 11 kHz – 95 kHz showed a better discriminatory response for per second were acquired along 15 s for each measurement tissue differentiation. and were averaged to reduce the effect of the modulation For mono-frequency analysis, a central frequency of induced by ventilation and perfusion. 33 kHz was chosen (as done in Riu et al. [23]) to develop The 4 electrode configuration measurements were cali- the statistical analysis of |Z|, PA, R and Xc for tissue differ- brated with 3 saline solutions which covered the measurement entiation between healthy lung tissue and bronchial tissue. impedance range and following the method described in [24]. The normality of the distribution of the variables was In the configuration with 3 electrodes, and being two of determined by the Shapiro-Wilk test. Normally distributed them in the body surface, this set-up could not be used and variables are shown as the mean ± standard error of the VOLUME 10, 2022 7357 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy FIGURE 3. The mean (continuous line) and SD (dashed line) values from the bioimpedance signal along the different frequencies analysed obtained with 4-electrode method. The (a) modulus, (b) phase angle, (c) resistance and (d) capacitive reactance. Green: healthy lung tissues; blue: bronchial tissues; red: neoplastic lung tissues. mean (SEM) and 95% confidence interval for the mean frequency range (5 kHz - 209 kHz) used for the measures (lower limit and upper limit). One-way analysis of vari- obtained with 4 and 3-electrode method, respectively. The ance (ANOVA) was used to determine statistically significant green line represents healthy lung tissue, the blue line repre- differences in the |Z|, PA, R and Xc values between healthy sents bronchial tissue, and the red line represent tissues from lung tissue and bronchial tissue for both the 3- and 4-electrode three different types of lung neoplasms. The vertical dashed methods. black lines represent the frequency (33 kHz) at which the data In the case of the measurements in neoplasic lung tissue, were analysed for tissue differentiation. due to the small sample size, the descriptive analysis (for Table 1 and Table 2 show the values of |Z|, PA, R and both the 3- and 4-electrode methods) was performed using Xc at a frequency of 33 kHz according to measurement loca- the mean impedance spectra. tion (healthy lung tissue and bronchial tissue) obtained with The statistical software IBM R SPSS R version 26.0 (IBM 4 and 3 electrodes, respectively, in the sample of patients. Corp, Armonk, NY, United States) was used for data analysis. The level of statistical significance was set at P < 0.05. B. TISSUE DIFFERENTIATION Table 3 lists the descriptive parameters, specified as the mean ± SEM, 95% confidence interval for the mean (lower limit III. RESULTS and upper limit), of |Z|, PA, R and Xc and the results of A. MULTI-FREQUENCY RESPONSE FOR MINIMALLY the one-way ANOVA including the Fisher coefficient (F) for INVASIVE LUNG EIS MEASURES the 4-electrode method (healthy tissues: n = 13; bronchial Fig. 3 and Fig. 4 show the mean (continuous line) and SD tissues: n = 12) and the 3-electrode method (healthy tissues: (dashed line) values of |Z|, PA, R and Xc plotted along the n = 9; bronchial tissues: n = 10). 7358 VOLUME 10, 2022 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy FIGURE 4. The mean (continuous line) and SD (dashed line) values from the bioimpedance signal along the different frequencies analysed obtained with 3-electrode method. The (a) modulus, (b) phase angle, (c) resistance and (d) capacitive reactance. Green: healthy lung tissues; blue: bronchial tissues; red: neoplastic lung tissues. With the use of four electrodes, a statistically significant represent the frequency (33 kHz) at which the data were difference (P < 0.001) between healthy tissue and bronchial analysed. Each of the colours of the graphs represents a tissue was observed, with higher Fisher coefficient in different neoplasm sample. Histologically, lung squamous Xc (F = 52.103; P < 0.001), |Z| (F = 50.719; P < 0.001) carcinoma (infiltrating: black and non-infiltrating: red) and and R (F = 48.648; P < 0.001) and lower Fisher coefficient lung adenocarcinoma (cyan) were identified. In Fig. 6, the in PA (F = 30.471; P < 0.001). With the use of 3 electrodes, values obtained from the lung adenocarcinoma (cyan) were a statistically significant difference (P < 0.001) between discarded due to poor electrode contact because patient healthy tissue and bronchial tissue was also observed, with coughed. higher F in |Z| (F = 46.417; P < 0.001), R (F = 46.002; Table 4 shows the values of |Z|, PA, R and Xc obtained P < 0.001) and PA (F = 43.796; P < 0.001) and lower in at a frequency of 33 kHz from lung neoplasms with both the Xc (F = 36.784; P < 0.001). 4- and 3-electrode methods. In addition, the type of cancer is specified in Table 4. C. LUNG NEOPLASM MEASURES The different cancer types could also be distinguished Fig. 5 and Fig. 6 show the mean impedance spectra of using only bioimpedance measures, as the measures obtained the values of |Z|, PA, R and Xc plotted along the fre- from different neoplasm types were different from each other, quency range (5 kHz - 209 kHz) for the measures obtained as shown in Fig. 5 and Fig. 6. from lung neoplasms with 4 and 3 electrodes, respectively; Fig. 7 shows the PET/CT images and CT images of each these values could be used to differentiate the different of the lung neoplasm types according to the histological neoplasm types evaluated. The vertical dashed black lines diagnosis. VOLUME 10, 2022 7359 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy TABLE 1. Individual values of |Z|, PA, R and Xc at 33 kHz extracted from the bioimpedance measurements obtained with 4 electrodes. TABLE 2. Individual values of |Z|. PA. R and Xc at 33 kHz extracted from the bioimpedance measurements obtained with 3 electrodes. IV. DISCUSSION characteristics. Therefore, differences in bioimpedance mea- This project, developed by the Universitat Politècnica de surement can be expected based on the type of tissue and its Catalunya (UPC) Biomedical Engineering Instrumentation state. Group and the Interventional Pulmonology Unit of the Res- This work reports the use of minimally invasive EIS piratory Medicine Department of the Hospital de la Santa in lungs through a bronchoscopic process using the Creu i Sant Pau, evaluates the ability of EIS to differentiate 4- and 3-electrode methods to differentiate among healthy lung tissue according to disease state and anatomical location lung tissue, bronchi and lung neoplasms. A previous study using 3 and 4 electrodes to obtain the measures. The lungs regarding the validation of minimally invasive EIS for are the organs of the respiratory system, whose most basic lung bioimpedance measures through a bronchoscopic pro- function is to facilitate gas exchange [25]. Other structures cess [22] obtained the measures using the 4-electrode config- of the respiratory system are trachea, bronchi, bronchioles. uration, while the 3-electrode strategy has been used in heart Each of these structures has anatomical and histological applications [26]. 7360 VOLUME 10, 2022 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy TABLE 3. Descriptive parameters of |Z|, PA, R and Xc extracted from the bioimpedance measurements obtained with 4 and 3 electrodes and one-way ANOVA test results. TABLE 4. Individual values of lung neoplasm measurements of |Z|, PA, R and Xc extracted from the bioimpedance measurements obtained with 4 and 3 electrodes and the corresponding lung neoplasm type. The measured bioimpedance used in this work is propor- sensitive to the region in contact with the electrodes. In the tional to the intrinsic properties of the tissues (conductivity 3-electrode method, only one electrode is used in the dis- and permittivity) multiplied by a factor, the so called ‘‘cell tal tip of the catheter, while the other two electrodes are constant’’ that depends on geometric factors of electrode placed on the skin surface of the thorax [26]. There is an arrangement and tissue distribution. In order to know the effect on the measured impedance related to the effective feasibility to differentiate different tissues we used the mea- area of contact of the electrodes in the catheter against the sured impedance because the application of a cell con- lung tissue to be investigated. Reducing the contact area stant will not modify the comparative results, and also will increase the measured impedance due to the increase because the cell constant will be unknown for in vivo of current density in the tissue. In the tubular structure of measurements. the bronchi and bronchioles the measured impedance will Measures obtained with 4 electrodes reduce the effect of increase if the diameter of the catheter and the diameter of the the impedance of the electrode-tissue interfaces. The elec- tubular structure are similar but will decrease as the diameter trodes are all placed in the distal part of a catheter and are of the bronchi is bigger and the electrode is losing contact VOLUME 10, 2022 7361 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy FIGURE 5. Results of the parameters extracted from the bioimpedance signal along the different frequencies analysed obtained with 4 electrodes from lung neoplasms. The a) modulus, b) phase angle, c) resistance and d) reactance of the bioimpedance of all the different measures obtained. Black: lung squamous carcinoma (infiltrating); red: lung squamous carcinoma (non-infiltrating); and cyan: lung adenocarcinoma. with the tissue surface. Another factor that will modify the diameter) for many in-vivo applications. Reference [27] measured impedance is the mucosa content (or other liquids acknowledged these limitations and developed a probe which for example in the case of carcinoma) in the bronchi or bron- is 2 mm in diameter. One of the main problems with all chiole. This effect will be higher for healthy tissue because these probes is the very small electrode area (0.5 mm2 , the impedance of the liquid is lower than the impedance of 0.8 mm2 and 0.2 mm2 respectively) which increases electrode healthy tissue. impedance at low frequencies, up to a point where it is The simplest method, the two-electrode method using not possible to make measurements due to instrumentation the tip of the catheter and an external skin electrode, limitations. These limitations are clearly shown in in-vivo was discarded because the impedance of the skin elec- measurements [28], where usable data is only at frequencies trode is also measured and it has high interpatient vari- over 500 kHz, much above the frequency range where we ability (that is not related to the characteristics of the found significant differences in lung tissues. In addition, lung tissue) and depends on skin hydration and sweat these probes need to make a perpendicular contact with the regulation. tissue, which is not granted in lung tissue at the level of Other authors [19] [20] have proposed electrode arrange- bronchioles. ments based on 4 electrodes on the front face of a catheter, In contrast, our catheter has only a diameter of 1.67 mm either intended to be introduced through an endoscope [19] (5F) while keeping electrode areas of about 10 mm2 . Contact or to be used as a pencil-like probe [20]. However, these can be difficult in the bronchi, but it is granted at the alveolar implementations are very thick (3.2 mm and 5.5 mm in level. At that level, it would be impossible to make contact 7362 VOLUME 10, 2022 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy FIGURE 6. Results of the parameters extracted from the bioimpedance signal along the different frequencies analysed obtained with 3 electrodes from lung neoplasms. The a) modulus, b) phase angle, c) resistance and d) reactance of the bioimpedance of all the different measures obtained. Black: lung squamous carcinoma (infiltrating) and red: lung squamous carcinoma (non-infiltrating). FIGURE 7. PET/TC and CT images of the lung neoplasms. The histological diagnoses were a) lung squamous carcinoma (infiltrating), b) lung squamous carcinoma (non-infiltrating) and c) lung adenocarcinoma. with a frontal electrode arrangement without risking breaking probe, and to our knowledge, it can also risk damaging the the walls of the alveoli. tissue. Other authors, like [29], have proposed more sophisticated Following this description, and due to the trabecular arrangements to make measurements in lung tissue in-vivo. structure of the lung, the placement of the electrodes with However, there are no experimental results with this proposed the 3-electrode method is easier to perform than with the VOLUME 10, 2022 7363 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy 4-electrode method (Fig. 1 and Fig. 2) since the 4 elec- the 4-electrode method, following the preliminary report of trodes are internal and need to be in contact with the lung Riu et al. [23]. According to the results obtained (Fig. 3 and tissue. During the bronchoscopy process (used to obtain Fig. 4), the optimal frequency could be different from the one the bioimpedance measurements of the lungs), patients may analyzed in this work (33 kHz). In the bioimpedance equation cough, despite sedation, and contact between the electrode (Z = R + jX c ), the variable R describes the behaviour and the tissue of interest may be lost, resulting in a loss of of the medium through which the injected current flows, 1 data. while X c = − wC describes the capacitive component of the In this preliminary study the same patient was measured cellular membranes [9], [10]. The values of modulus Z and first with 4 electrodes and then with 3 electrodes, increasing q   R2 + Xc2 and 8 = tan−1 Xc  the measurements time. Despite sedation, some of them did PA (|Z| = R , respectively) not tolerate long time without coughing. For this reason, some are dependent on the values of R and Xc. Regarding tissue measurements made with the 3-electrode method had to be differentiation at 33 kHz, in both the 4- and the 3-electrode removed. methods, one-way ANOVA reported significant results Another aspect taken into account was the possible loss of (P < 0.001) for all variables (|Z|, PA, R and Xc). contact in the two skin surface electrodes in the case of the The Fisher coefficient represents the relationship between 3-electrode method (Fig. 2). However, this problem did not the inter-group variance and the intra-group variance. occur. Therefore, a higher F coefficient indicates a greater In addition, ensuring the contact of the four electrodes inter-group variance than intra-group variance [33]. For in a 4-electrode lateral configuration is not easy and the the 4-electrode method, the Fisher coefficient (F) is loss of contact of one of the electrodes may be diffi- higher for Xc, while for the 3-electrode method, F is cult to detect. Using the described 3-electrode configura- higher for R. tion, the loss of contact of one of the electrodes is clearly The small number of cancer sample allows only an obser- detected. vational analysis of the medical images obtained by PET/CT, The multi-frequency range from 11 kHz to 95 kHz shows for which the strongest point of CT is the detailed represen- a better discriminatory response for tissue differentiation. tation of interstitial structures [6]; the confirmation of biopsy Healthy lung tissue is clearly differentiable from bronchial sample findings; and the mean impedance spectra of Z|, PA, and neoplastic lung tissues in both the 4- and 3-electrode R and Xc. methods, while bronchial and neoplastic lung tissues show The types of cancer analysed (lung squamous carcinoma a similar frequency response. and lung adenocarcinoma) are included among the non- |Z| and R were higher in healthy lung tissue than in bronchi, small-cell lung cancers [34]. while PA and Xc were lower in these locations. Additionally, The sample sizes of the different cancer types analysed |Z| and R values obtained with 3 electrodes were higher than did not allow us to perform a comparative analysis of the those obtained with 4 electrodes. A decrease in the mean PA cancer histological observations; and the bioimpedance val- and Xc values obtained using the 3-electrode method com- ues (|Z|, PA, R and Xc) obtained. Moreover, the small pared with the 4-electrode method was observed. This could sample size did not allow us to perform a statistical be explained because with the 4-electrode method, the voltage analysis of the measurements obtained with a single fre- drop is sensed at the probe where the current is injected, quency at 33 kHz. However, all results seem to indicate meaning there are no surrounding tissues that could influ- that the 3-electrode method seems to differentiate the can- ence the measure. In contrast, with the 3-electrode method, cer types in terms of changes in the cellular structures the voltage drop includes the tissue-electrode impedance of the tissue (by Xc) as well as in terms of changes in of the HC electrode (the distal electrode of the catheter) the extracellular fluid-related parameters (R), whereas with and the tissues between the catheter and the skin electrodes the 4-electrode method, only R is able to differentiate placed on the right side of the patient (LP) at the level of between the cancer types. To be able to differentiate using the ribs, producing an increase in the values of |Z| and R. both parameters (R and Xc) with the 4-electrode method, The main contribution to this increment of impedance is we should increase the frequency at which the bioimpedance due to the tissue-electrode interface because the 3-electrode samples are analysed; this frequency should be between method shows more sensitivity at the catheter tip due to the 70 kHz and 80 kHz. decay of sensitivity with the distance to the current injection The mean impedance spectra of the bioimpedance data of point [30]. the measures obtained with the 4-electrode method and the As expected, the |Z| and R values obtained are similar, 3-electrode method show a higher differentiation between showing a higher influence of R than Xc on |Z|. cancer samples (black: lung infiltrating squamous carci- Emphasizing the importance of the analysis of R and Xc noma and red: lung non-infiltrating squamous carcinoma) according to the theory of Lukaski et al. [9], [10], [31], [32], in the 3-electrode method (|Z| ∼ 114.16 , PA ∼ −3.91◦ , we selected the frequency (33 kHz) that allowed us to differ- R ∼ 112.83  and Xc ∼ −20.48 ) than in the 4-electrode entiate among tissues with the 3-electrode method as well as method (|Z| ∼ 20.38 , PA ∼ 1.01◦ , R ∼ 20.37  7364 VOLUME 10, 2022 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy and Xc ∼ −1.17 ), which also seems to indicate that the Marta Navarro Colom, and Laura Romero Roca from 3-electrode method is a suitable method to differentiate the Interventional Pulmonology Unit, Respiratory Medicine among cancer types. Although the number of samples in Department, Hospital de la Santa Creu i Sant Pau for invalu- this study is very small, these preliminary observations in able support. neoplastic lung tissue are encouraging for the design of future studies to evaluate the ability of EIS to aid in the selection of REFERENCES biopsy location and thereby the histological characterization [1] The Global Impact of Respiratory Disease, Forum of International Respi- of lung diseases. ratory Societies, Lausanne, Switzerland, 2017. [2] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, ‘‘Global cancer statistics 2018: GLOBOCAN estimates of inci- V. CONCLUSION dence and mortality worldwide for 36 cancers in 185 countries,’’ CA, In conclusion, the 3- and 4-electrode methods showed a Cancer J. Clinicians, vol. 68, no. 6, pp. 394–424, Nov. 2018, doi: 10.3322/ caac.21492. statistically significant difference (P < 0.001) to differen- [3] C. H. Park, K. Han, J. Hur, S. M. Lee, J. W. 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Nanobiosci., vol. 18, no. 3, pp. 369–372, Jul. 2019, doi: tion, the authors would like to thank Laia García Bellmunt, 10.1109/TNB.2019.2920743. VOLUME 10, 2022 7365 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy [18] S. L. Hillary, B. H. Brown, N. J. Brown, and S. P. Balasubramanian, GEORGINA COMPANY-SE received the B.S. ‘‘Use of electrical impedance spectroscopy for intraoperative tis- degree in biomedical engineering from the Univer- sue differentiation during thyroid and parathyroid surgery,’’ World sitat Politècnica de Catalunya (UPC), Barcelona, J. Surg., vol. 44, no. 2, pp. 479–485, Feb. 2020, doi: 10.1007/ Spain, in 2018, and the M.S. degree in compu- s00268-019-05169-7. tational biomedical engineering from Universitat [19] C. A. Gonzalez-Correa, B. H. Brown, R. H. Smallwood, N. Kalia, Pompeu Fabra (UPF), Barcelona, in 2019. She is C. J. Stoddard, T. J. Stephenson, S. J. Haggie, D. N. Slatter, and currently pursuing the Ph.D. degree in biomedi- K. D. Bardhan, ‘‘Virtual biopsies in Barrett’s esophagus using an cal engineering with UPC. Her research interests impedance probe,’’ Ann. New York Acad. Sci., vol. 873, no. 1, pp. 313–321, include bioimpedance measures and analysis, sig- Apr. 1999, doi: 10.1111/j.1749-6632.1999.tb09479.x. [20] B. H. Brown, J. A. Tidy, K. Boston, A. D. Blackett, nal processing, and data science. She is interested R. H. Smallwood, and F. Sharp, ‘‘Relation between tissue structure in machine learning and data science. and imposed electrical current flow in cervical neoplasia,’’ Lancet, vol. 355, no. 9207, pp. 892–895, Mar. 2000, doi: 10.1016/ S0140-6736(99)09095-9. [21] C. Gabriel, S. Gabriel, and E. Corthout, ‘‘The dielectric properties of biological tissues: III. Parametric models for the dielectric spec- trum of tissues,’’ Phys. Med. Biol., vol. 41, no. 11, pp. 2271–2294, 2000. [Online]. Available: http://iopscience.iop.org/article/10.1088/0031- LEXA NESCOLARDE received the Ph.D. degree 9155/41/11/003/pdf in biomedical engineering from the Universitat [22] B. Sanchez, G. Vandersteen, I. Martin, D. Castillo, A. Torrego, P. J. Riu, Politècnica de Catalunya (UPC), Barcelona, Spain, J. Schoukens, and R. Bragos, ‘‘in vivo electrical bioimpedance characteri- in 2006, under the supervision of Professor Javier zation of human lung tissue during the bronchoscopy procedure. A feasi- Rosell. Since January 2001, she has been a mem- bility study,’’ Med. Eng. Phys., vol. 35, no. 7, pp. 949–957, Jul. 2013, doi: ber of the Electronic and Biomedical Instrumen- 10.1016/j.medengphy.2012.09.004. tation Group (IEB) and the Centre for Research [23] P. J. Riu, G. Company, R. Bragos, J. Rosell, V. Pajares, and in Biomedical Engineering (CREB-UPC). She is A. Torrego, ‘‘Minimally invasive real-time electrical impedance currently an Associate Professor with UPC. Since spectroscopy diagnostic tool for lung parenchyma pathologies,’’ 2002, she has been participating in 22 research in Proc. 42nd Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. projects and has led three research and technology transfer contracts of (EMBC), Jul. 2020, pp. 5077–5080, doi: 10.1109/EMBC44109.2020. special relevance and two of which are still valid. Her current research 9175860. interests include use of non-invasive localized bioimpedance measurement [24] J.-Z. Bao, C. C. Davis, and R. E. Schmukler, ‘‘Impedance spectroscopy (L-BIA) for muscle assessment in high-performance athletes, body compo- of human erythrocytes: System calibration, and nonlinear modeling,’’ sition analysis, and data analysis. IEEE Trans. Biomed. Eng., vol. 40, no. 4, pp. 364–378, Apr. 1993, doi: 10.1109/10.222329. [25] J. F. Murray, ‘‘The structure and function of the lung,’’ Int. J. Tuberc. lung Dis. Off. J. Int. Union Against Tuberc. Lung Dis., vol. 14, no. 4, pp. 391–396, Apr. 2010. [26] G. Amorós-Figueras, E. Jorge, C. Alonso-Martin, D. Traver, M. Ballesta, R. Bragós, J. Rosell-Ferrer, and J. Cinca, ‘‘Endocardial VIRGINIA PAJARES was born in Girona in infarct scar recognition by myocardial electrical impedance is not 1979. She received the Ph.D. degree in medicine influenced by changes in cardiac activation sequence,’’ Heart Rhythm, vol. 15, no. 4, pp. 589–596, Apr. 2018, doi: 10.1016/j.hrthm.2017. and surgery from the Universitat Autónoma de 11.031. Barcelona, in 2015. She has been a Medical Doctor [27] A. Keshtkar, ‘‘Design and construction of small sized pencil and a Respiratory Specialist, since 2008. More- probe to measure bio-impedance,’’ Med. Eng. Phys., vol. 29, over, she is a Consultant with the Respiratory no. 9, pp. 1043–1048, Nov. 2007, doi: 10.1016/j.medengphy.2006. Department, Hospital Santa Creu i Sant Pau of 10.010. Barcelona. She is part of the Bronchosocopy Unit [28] A. Keshtkar, Z. Salehnia, M. H. Somi, and A. T. Eftekharsadat, ‘‘Some Staff, and also works as a Respiratory Residents’ early results related to electrical impedance of normal and abnormal Mentor. As of 2021, she is an author of 20 sci- gastric tissue,’’ Phys. Medica, vol. 28, no. 1, pp. 19–24, Jan. 2012, doi: entific articles in PubMed. Her research interests include interventional 10.1016/j.ejmp.2011.01.002. pulmonology, lung cancer, and pleural diseases. [29] R. Baghbani, ‘‘Small-sized probe for local measuring electrical proper- ties of the tissues inside of human body: Design, modelling and simula- tion,’’ IET Nanobiotechnol., vol. 13, no. 9, pp. 946–951, Dec. 2019, doi: 10.1049/iet-nbt.2019.0040. [30] M. B. Garcia, Evaluation of New Methods to Assess Infarcted Myocardial Tissue by measuring electrical Impedance. Barcelona, Spain: Polytechnic Univ. Catalonia (UPC), 2017. ALFONS TORREGO was born in Barcelona, [31] A. Piccoli, B. Rossi, L. Pillon, and G. Bucciante, ‘‘A new method Spain, in 1971. He has been a Medical Doc- for monitoring body fluid variation by bioimpedance analysis: The tor and a Respiratory Specialist, since 2000, and RXc graph,’’ Kidney Int., vol. 46, no. 2, pp. 534–539, Aug. 1994, doi: a Consultant with the Respiratory Department, 10.1038/ki.1994.305. Hospital Santa Creu i Sant Pau of Barcelona, [32] K. R. Foster and H. C. Lukaski, ‘‘Whole-body impedance-what does it Spain. He is also the Bronchosocopy Unit Coor- measure,’’ Amer. J. Clin. Nutr., vol. 64, no. 3, pp. 388S–396S, Sep. 1996, dinator at the Hospital Santa Creu i Sant Pau of doi: 10.1093/ajcn/64.3.388S. Barcelona. Moreover, he is an Associate Profes- [33] D. F. Morrison, Multivariate statistical Methods. New York, NY, USA: McGraw-Hill, 1967. sor of medicine at the Universitat Autònoma de [34] V. Ambrosini, S. Nicolini, P. Caroli, C. Nanni, A. Massaro, M. C. Marzola, Barcelona and a Former Chairperson of the Span- D. Rubello, and S. Fanti, ‘‘PET/CT imaging in different types of lung can- ish Respiratory Society Scientific Committee. As of 2021, he is an author cer: An overview,’’ Eur. J. Radiol., vol. 81, no. 5, pp. 988–1001, May 2012, of more than 60 scientific articles in PubMed. His research interests include doi: 10.1016/j.ejrad.2011.03.020. interventional pulmonology, lung cancer, and severe asthma. 7366 VOLUME 10, 2022 G. Company-Se et al.: Minimally Invasive Lung Tissue Differentiation Using Electrical Impedance Spectroscopy PERE J. RIU (Senior Member, IEEE) received RAMON BRAGÓS received the degree in elec- the M.Sc. degree in telecommunication engineer- trical engineering (major in telecommunications ing and the Ph.D. degree in electronic engineer- engineering) and the Ph.D. degree in electronic ing from the Universitat Politecnica de Catalunya engineering from the Technical University of Cat- (UPC), Barcelona, Spain, in 1986 and 1991, alonia (UPC), in 1991 and 1997, respectively. respectively. He was a Visiting Associate Profes- Since 1998, he has been an Associate Profes- sor with the Department of Bioengineering, Uni- sor with the Electronic Engineering Department, versity of Pennsylvania, Philadelphia, PA, USA, UPC. He belongs to the Electronic and Biomedical in 1997. He is currently a Full Professor of elec- Instrumentation Research Group and the Centre tronics with the Department of Electronic Engi- for Research in Biomedical Engineering (CREB). neering, UPC. His research interests include electromagnetic compatibility, His research interests include design of methods and systems for the char- computational electromagnetics, the interaction of electromagnetic fields acterization of biological materials and systems using minimally invasive with biological tissues, and biomedical instrumentation design with empha- methods, mainly electrical impedance spectroscopy. sis on electrical bioimpedance techniques, including electrical impedance tomography (EIT). These activities are performed within the Centre for Research on Biomedical Engineering (CREB, UPC) and the Institut de Recerca Sant Joan de Déu (IRSJD). He is a member of the Committee on Man and Radiation (COMAR) (IEEE-BMES) and the Vice President of the International Society for Electrical Bio-Impedance. JAVIER ROSELL (Senior Member, IEEE) was born in Barcelona, Spain, in June 1959. He received the Ingeniero de Telecomuni- cación and Doctor Ingeniero de Telecomuni- cación degrees from the Polytechnic University of Catalunya (UPC), Barcelona, in 1983 and 1989, respectively. He is currently a Full Profes- sor with the Department of Electronic Engineer- ing, UPC, and the Head of the Research Group, Centre for Research in Biomedical Engineering (CREB-UPC). His current research interests include non-invasive and non- obtrusive measurement methods in sports and medical and biological fields, particularly based on bioelectrical impedance spectroscopy and magnetic induction spectroscopy. 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