RESUMEN
BACKGROUND: Technologies for quick and label-free diagnosis of malignancies from breast tissues have the potential to be a significant adjunct to routine diagnostics. The biophysical phenotypes of breast tissues, such as its electrical, thermal, and mechanical properties (ETM), have the potential to serve as novel markers to differentiate between normal, benign, and malignant tissue. RESULTS: We report a system-of-biochips (SoB) integrated into a semi-automated mechatronic system that can characterize breast biopsy tissues using electro-thermo-mechanical sensing. The SoB, fabricated on silicon using microfabrication techniques, can measure the electrical impedance (Z), thermal conductivity (K), mechanical stiffness (k), and viscoelastic stress relaxation (%R) of the samples. The key sensing elements of the biochips include interdigitated electrodes, resistance temperature detectors, microheaters, and a micromachined diaphragm with piezoresistive bridges. Multi-modal ETM measurements performed on formalin-fixed tumour and adjacent normal breast biopsy samples from N = 14 subjects were able to differentiate between invasive ductal carcinoma (malignant), fibroadenoma (benign), and adjacent normal (healthy) tissues with a root mean square error of 0.2419 using a Gaussian process classifier. Carcinoma tissues were observed to have the highest mean impedance (110018.8 ± 20293.8 Ω) and stiffness (0.076 ± 0.009 kNm-1) and the lowest thermal conductivity (0.189 ± 0.019 Wm-1 K-1) amongst the three groups, while the fibroadenoma samples had the highest percentage relaxation in normalized load (47.8 ± 5.12%). CONCLUSIONS: The work presents a novel strategy to characterize the multi-modal biophysical phenotype of breast biopsy tissues to aid in cancer diagnosis from small-sized tumour samples. The methodology envisions to supplement the existing technology gap in the analysis of breast tissue samples in the pathology laboratories to aid the diagnostic workflow.
RESUMEN
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.