RapidET: a MEMS-based platform for label-free and rapid demarcation of tumors from normal breast biopsy tissues

Abstract

The rapid and label-free diagnosis of malignancies in ex vivo breast biopsy tissues has significant utility in pathology laboratories and operating rooms. We report a MEMS-based platform integrated with microchips that performs phenotyping of breast biopsy tissues using electrothermal sensing. The microchip, fabricated on a silicon substrate, incorporates a platinum microheater, interdigitated electrodes (IDEs), and resistance temperature detectors (RTDs) as on-chip sensing elements. The microchips are integrated onto the platform using a slide-fit contact enabling quick replacement for biological measurements. The bulk resistivity (ρ _B ), surface resistivity (ρ _S ), and thermal conductivity (k) of deparaffinized and formalin-fixed paired tumor and adjacent normal breast biopsy samples from N = 8 patients were measured. For formalin-fixed samples, the mean ρ _B for tumors showed a statistically significant fold change of 4.42 (P = 0.014) when the tissue was heated from 25 °C to 37 °C compared to the adjacent normal tissue, which showed a fold change of 3.47. The mean ρ _S measurements also showed a similar trend. The mean k of the formalin-fixed tumor tissues was 0.309 ± 0.02 W m^-1 K^-1 compared to a significantly higher k of 0.563 ± 0.028 W m^-1 K^-1 for the adjacent normal tissues. A similar trend was observed in ρ _B, ρ _S, and k for the deparaffinized tissue samples. An analysis of a combination of ρ _B , ρ _S , and k using Fisher's combined probability test and linear regression suggests the advantage of using all three parameters simultaneously for distinguishing tumors from adjacent normal tissues with higher statistical significance.

Keywords: Biosensors; Electrical and electronic engineering.

Fig. 1. Summary of the workflow of the RapidET system for rapid label-free phenotyping of breast biopsy tissue.

a Extraction of breast biopsy tissue from breast excisional biopsy sample, b photograph of extracted breast biopsy tissue, c frozen section preparation from the biopsy tissue using a microtome in the pathology laboratory, d extraction of fine section for staining and examination, e examination of the morphology of the tissue under the microscope by the pathologist, f image of stained tumor tissue section under the microscope, g schematic of the RapidET system for rapid electrothermal phenotyping, and h the summary of resistivity and thermal conductivity readout from the system for delineating between normal and tumor tissue

Fig. 2. Temperature-dependent bulk and surface resistivity measurements using the RapidET system.

a Bulk resistivity measurements from the deparaffinized normal and tumor FFPE samples at two different tissue temperatures of 25 °C and 37 °C, (b) bulk resistivity measurements from the formalin-fixed normal and tumor tissue samples, and (c) and (d) surface resistivity measurements from the deparaffinized FFPE and formalin-fixed normal and tumor samples at the two tissue temperatures

Fig. 3. Thermal conductivity measurement using the RapidET system.

a Thermal conductivity (k) of normal and tumor FFPE samples measured at 25 °C and 37 °C and b thermal conductivity (k) of formalin-fixed normal and tumor samples

Fig. 4. Regression analysis for the combination of measurement parameters.

a Scatter plot showing the correlation between bulk resistivity and thermal conductivity for the measured samples. The plot demonstrates a clear demarcation between tumor and normal samples. b Correlation plot between surface resistivity and thermal conductivity and c correlation plot between surface and bulk resistivity

Fig. 5. Microchip for electrothermal phenotyping: design and fabrication.

a Process flow for the fabrication of the microchip for electrothermal phenotyping of the breast biopsy tissues, b design of the microchip showing the different functional components used for sensing, c optical photograph of the microchip fabricated on a silicon substrate, d scanning electron micrograph of the active area of the microchip, e optical profilometry of the active area of the sensor showing the elevated platinum film, and f a close-up scanning electron microscope image with a 20° tilt angle showing the thermal isolation trench

Fig. 6. RapidET system design.

a 3D schematic of the platform showing the various subsystems, b photograph of the fabricated system interfaced with a tablet PC running the graphical user interface for control and data acquisition, c sample loaded between the two indenter subsystems, d the indenter subsystem with the PCBs, microchip attached to slide-fit contacts, and FFC connector cable going into the electronic modules in the system, e close-up view of the microchip packaged into the sensor holder structure through slide-fit contacts, f and g rendered and actual image of the microchip connected to the slide-fit contacts, eliminating the need for wire-bonding