Micro-biosensor integrated medical needle towards teal-time tissue analysis during medical procedure

Abstract

Minimally invasive procedure is a procedure with minimal incision on patient’s body by inserting small medical tools in order to treat a lesion. Because of minimal incision, recovery of patient is faster than open surgery, which is most important advantage of the minimally invasive procedure. A medical needle, which is one of representative medical tools in minimally invasive procedure, has been widely utilized in biomedical field such as drug delivery, biopsy, and tissue treatment. In case of a conventional image-guided biopsy procedure to get a specimen for histological assessment, some cancerous tissues cannot be distinguished from normal tissues due to limited image resolution and imaging contrast in the medical imaging tools, which causes inaccurate biopsy procedure. In order to overcome this limitation, we developed a biopsy needle that can discriminate the type of tissue around the needle tip during biopsy procedure by integrating multi-modal physical/chemical biosensors on the surface of biopsy needle. Specifically, we aimed to develop a sensor integrated biopsy needle that can discriminate between cancerous and normal tissues. Therefore, as possible indicators for cancer discrimination, electrical conductivity (cancer=1.5 - 4.5 times higher or lower than normal tissue), pH (normal= pH 7.3-7.4, cancer= pH 6.5-7.0), glucose concentration (normal= 1.5-3.3 mM, cancer = less than 1 mM), and lactate concentration (normal= 2-4.5 mM, cancer = 5-17 mM) were selected. In this research, a multi-modal physical/chemical sensor array with a sensing capability of the above-mentioned parameters was fabricated on the surface of biopsy needle based on two approaches. We could overcome the limitations of previously reported sensor integrated biopsy needles such as limited sensor types and measurement error induced by limited number of electrodes.

Firstly, we developed a biopsy needle integrated with stainless steel (STS) microwires with a capability of electrical impedance spectroscopy (EIS) by assembling STS microwires onto the surface of biopsy needle. However, in this case, it was difficult to fabricate sensor electrodes uniformly. Therefore, it was utilized only as an EIS sensor because the measurement error can be calibrated using conventional calibration techniques. The fabricated biopsy needle with EIS sensor could measure an electrical conductivity in range of physiological condition (0.0125 S/m – 1.0370 S/m) in AC frequency range from 1 kHz to 1 MHz within $\pm8 %$ error range. Furthermore, we proposed the calibration method to correct the above-mentioned error by utilizing a relation between the conductivity of sample and the cell constant of EIS sensor. Numerical simulation and receiver operating characteristics (ROC) were utilized to analyze a diagnostic performance as a medical tool, and the fabricated sensor could discriminate between cancerous and normal tissues with a high accuracy (Area under curve > 0.9). In addition, a usefulness of the developed biopsy needle was demonstrated using a liver cancer mimicking hydrogel, a porcine meat, and a fatty-liver mouse model. Secondly, a biopsy needle with a capability of multi-modal physical/chemical sensing was developed by assembling a biosensor array with sensor electrodes on a flexible polymeric substrate. Au electrodes were fabricated on a polyimide substrate using conventional microfabrication method and various patterning methods such as screen printing and electrodeposition were utilized to form various sensing materials on Au electrodes. Four types of sensors such as an electrical conductivity sensor, an iridium oxide (IrOx) based pH sensor, a glucose concentration sensor, and a lactate concentration sensor were integrated onto a single sensor platform with a maximum width of 1.8 mm. A saline solution, a phosphate buffer solution, a glucose solution, and a lactate solution were utilized for the characterization of individual sensors. With the electrical conductivity sensor, conductivities from 0.0265 S/m to 1.027 S/m could be measured within 12% error range in AC frequency range of 10 kHz - 1 MHz. Furthermore, because of improved uniformity between sensors based on microfabrication method, cell constants of different sensors were almost similar (5.8% of standard deviation from averaged cell constant in five sensor samples). In IrOx based pH sensor, we utilized additional electrochemical treatment method to minimize the deviation between sensors and the IrOx based pH sensor could measure pH differences in the range of pH 6.6 – pH 7.4 with a sensitivity of -69.3 mV/pH. In case of glucose sensor, a glucose oxidase was immobilized using both drop-casting and electropolymerization methods. In both cases, glucose differences in glucose range between 2 mM and 12 mM could be successfully measured. Also, the sensitivities of glucose sensor were -4.47 nA/mM and -13.3 nA/m by drop-casting and electropolymerization methods, respectively. For a lactate sensor, electropolymerization method was used for the enzyme immobilization and differences of lactate concentrations in the range between 1 mM to 5 mM weres successfully measured with sensitivity of -10.3 nA/mM. In addition to the sensor characterization, a capability of multi-modal sensing was demonstrated using a hydrogel based phantom, a solution sample, and a porcine liver with exchanged internal liquid environment.

We expect that more accurate biopsy procedure can be performed using the developed biopsy needle integrated with sensor. Based on this, it is also expected that safer and more accurate biopsy procedure can be realized by providing information of tissue to a surgeon in real-time. Furthermore, the proposed method for the sensor integration can be also applied to other medical tools, which can improve the accuracy of medical procedure by in-situ analysis of the properties of tissues near the sensor integrated medical tools.