Needle-compatible miniaturized optoelectronic sensor for pancreatic cancer detection

Abstract

Pancreatic cancer is one of the deadliest cancers, with a 5-year survival rate of <10%. The current approach to confirming a tissue diagnosis, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), requires a time-consuming, qualitative cytology analysis and may be limited because of sampling error. We designed and engineered a miniaturized optoelectronic sensor to assist in situ, real-time, and objective evaluation of human pancreatic tissues during EUS-FNA. A proof-of-concept prototype sensor, compatible with a 19-gauge hollow-needle commercially available for EUS-FNA, was constructed using microsized optoelectronic chips and microfabrication techniques to perform multisite tissue optical sensing. In our bench-top verification and pilot validation during surgery on freshly excised human pancreatic tissues (four patients), the fabricated sensors showed a comparable performance to our previous fiber-based system. The flexibility in source-detector configuration using microsized chips potentially allows for various light-based sensing techniques inside a confined channel such as a hollow needle or endoscopy.

Fig. 1. Design concept of a miniaturized needle-compatible OE sensor.

(A) Illustration depicts an application scenario of 19-gauge needle–compatible miniaturized sensor through a commercial EUS-FNA device for enlarged optical interrogation volume with multiple sensing units. (B) Mean normalized reflectance spectra acquired from our previous ex vivo DRS measurements on human pancreatic tissues (a total of 22 patients and 105 sites including normal tissue, CP, and PDAC) establish that the spectral shape of each tissue type is different. The wavelengths showing the maximum (blue shaded) and minimal (red shaded) difference between different tissues can be selected for a ratiometric analysis. (C) The reflectance ratios (R₄₆₀/R₆₅₀ nm) computed from DRS are significantly different between three pancreatic tissues (*P < 0.001, Wilcoxon rank sum test). Error bars are SEs. (D) Three-dimensional (3D) design concept of the miniaturized OE sensor.

Fig. 2. Computational design analysis.

Computational design tools perform engineering analysis and confirm feasibility of optical sensing and thermal safety of the miniaturized sensor. (A) MC simulation visualizes the path traveled by photons (blue, 460 nm; red, 650 nm) collected by the phototransistor inside a pancreatic tissue model. (B) 3D model of the integrated sensor for heat transfer analysis given the heat dissipation from two LEDs and the heat capacitance of each component. (C and D) Side view of temperature distribution after (C) 1 s of LED illumination and (D) in equilibrium after about 10 s shows that the maximum temperature increase is only 1° right on the LEDs and the temperature increase in adjacent pancreatic tissues is minimal. (E) Time series maximum temperature profile shows that the temperature stabilizes after 10 s with continuous LED illumination.

Fig. 3. Fabricated OE devices and characterization of their basic performance.

The 19-gauge needle–compatible miniaturized OE sensor has been successfully developed for a proof-of-concept study of pancreatic cancer detection. Basic electrical and optical performance of the assembled OE sensor has been characterized. (A) The handheld sensor module consists of a 19-gauge needle and a fabricated μPCB, which the OE components are assembled on. The μPCB is connected to another large-scale PCB to provide electrical connection to the control electronics. (B) Photo of the sensor module held by hand (C) size comparison with a U.S. dime. (D) A zoomed-in photo (scale bar, 1 mm) displays one type of the sensing unit, consisting of one phototransistor and three LEDs that are shown through a side-cut window of the hollow needle (internal diameter, 850 μm) in the commercial EUS-FNA unit. (E to G) LED light emission from different types of the fabricated sensors. (E) Single-unit type 1: 460- and 650-nm LEDs located on either side of a single phototransistor; (F) single-unit type 2: 460-nm LED located on one side, and 650-nm LED and NIR LED located on the other side of a single phototransistor; (G) dual unit: two single units (type 1) with a distance of ~5 mm between two phototransistors. (H) Forward voltage versus forward current curves of three assembled LEDs (n = 5 for 460- and 650-nm LEDs and n = 1 for 785-nm LED) (I) Linear relationship between forward current and optical power of three assembled LEDs. (J) Emission wavelengths of three LEDs measured by spectrophotometer. (K) The voltage detected by the phototransistor under constant LED power increases with the increase of the scatterer [Intralipid (IL)] concentrations for both the blue and red LEDs. The error bars represent SDs. Photo credit: Seung Yup Lee and Brandon Baier, University of Michigan.

Fig. 4. Results of the bench-top experiments with tissue-simulating phantom.

(A) The developed OE sensing system has been verified using a set of liquid phantoms with varying hemoglobin concentrations ([HbT]) in comparison with our DRS system. (B) The measured relative reflectance at both wavelengths by DRS (solid lines) and the OE sensing system (diamond markers) are comparable across the different [HbT]. a.u., arbitrary units. (C) The reflectance ratios R₄₆₀/R₆₅₀ decrease as [HbT] increases in all of three single sensing units: Two units (OE D1 and OE D2) are from the same dual-unit sensor; the third one (OE S) is from a single-unit sensor. (D) The averaged R₄₆₀/R₆₅₀ measured by three OE units and DRS-measured R₄₆₀/R₆₅₀ are linearly correlated (Pearson’s correlation r = 0.96). Error bars represent SDs of the values from three units. Photo credit: Seung Yup Lee, University of Michigan.

Fig. 5. Results of the pilot study on human tissues.

The developed OE sensing system has been validated in ex vivo measurements on resected human pancreas (a total of four patients and 48 sites) during pancreatic surgery. The freshly excised human pancreas is measured by our fabricated dual-sensing-unit OE probe [(A) pancreatic cancer; (B) normal; (C) CP]. (D) Scatter plot of reflectance ratios (R₄₆₀/R₆₅₀) acquired using the subunit 1 from all the sites and all the patients. (E) The differences in the measured reflectance ratios R₄₆₀/R₆₅₀ between normal, CP, and PDAC are statistically significant (*P < 0.001 and **P = 0.007, Wilcoxon rank sum test). The error bars represent SEs. Photo credit: Seung Yup Lee, University of Michigan.