Silicon Photonics Biosensors for Early Cancer Detection

Introduction

Technological advancements have led to the integration of various fields including electronics, medicine, and biology. This has led to the emergence of point-of-care and accurate medical diagnosis devices known as biosensors. Biosensors can detect and convert biological signals into electrical or optical signals, enabling their use in diverse applications including food safety, pharmaceutical research, healthcare, and cancer research.

Optical biosensors that utilize the properties of light for detection have advanced, bringing new possibilities for real-time monitoring, faster response, improved accuracy, and increased sensitivity. The integration of optical technology with emerging silicon photonics (SiPh) technology has resulted in the development of integrated circuits for detecting life-threatening disorders such as cancer.

Malignant cells differ from normal blood cells in their optical characteristics, making them excellent prospects for detection using optical biosensors. This article explores the novel SiPh technology as a technique for utilizing the optical features for early-stage cancer cell detection. Additionally, biosensor characteristics such as ease of use, affordability, and sensitivity are addressed. A comparative analysis of several SiPh designs, including rings, waveguides, photonic crystals (PhCs), integrated chips, and sensor arrays, is presented.

Operating Principle of SiPh Biosensors

Biosensors generally consist of bioreceptors such as cells, nucleic acids, antibodies, or enzymes that react with electrical interfaces known as transducers to provide signals that may be electrical, optical, or in terms of change in mass or pressure. These signals are then amplified, processed, and displayed as results by electronic devices to detect the investigated impurity or pathogen (Fig. 1).

Fig. 1. Types of biosensors: Electrodes based (amperometric, potentiometric, impedimetric, voltammetric), mass-based (piezoelectric, cantilever), and molecular-based (antibody, bacteriophage, DNA, enzyme).

The high refractive index (RI) difference between silicon and silicon dioxide enables the design of many photonic devices, with silicon dioxide used as the upper cladding layer to guide and confine the light in integrated circuits. The working principle of optical biosensors includes total internal reflection (TIR) and resonance. When light propagates through media with a density difference (RI difference) above the critical angle, it reflects entirely through the denser surface, creating an environment of TIR where the light is trapped, providing a resonant wavelength peak for different media.

SiPh biosensors utilize near-infrared light confined in nanometer-scaled silicon waveguides to identify molecular interactions in and around the evanescent field. The binding of target molecules to the receptors on the waveguide surface changes the external RI, disturbing the evanescent field and altering the behavior of the guided light. The desired analytes can be detected in real-time by monitoring the changes in the output light (Fig. 2).

Fig. 2. General schematic of a SiPh-based biosensor

The two major parameters that determine the performance of optical biosensors are sensitivity (S) and quality factor (Q). Sensitivity is the ratio of change in sensor output to change in the quantity measured, while Q is the ratio of the obtained resonant wavelength to the change in the wavelength at full-width at half-maximum (FWHM).

Biosensor Configurations in Silicon Photonics

Various biosensor configurations in SiPh have been explored, including waveguide ring resonators, Bragg gratings, Mach-Zehnder interferometers (MZIs), and photonic crystals (PhCs), as well as their integration with other optical techniques such as strip waveguides, microcantilevers, and porous structures (Fig. 3).

Fig. 3. Optical and mechanical sensors: (a) Bragg grating, (b) Silicon microring modulator, (c) Mach–Zehnder sensor, (d) Microcantilever sensor.

Ring Resonator-Based Biosensors

Ring resonators are widely used to measure dispersion, dielectric constant, and Q factor, and are known for their high sensitivity. They act as transducers, providing results based on the reflectance, transmittance, and absorbance of light at different wavelengths through various materials.

Split Ring Resonator (SRR): An SRR is a pair of concentric loops with a dielectric substrate that is highly sensitive to changes in the dielectric constant of different samples, providing a shift in resonance frequency. Simulations have shown that different cancer cells exhibit a minimum transmission coefficient at slightly different frequencies, enabling their differentiation (Fig. 4).

Fig. 4. Comparison of normal and cancer cells using split ring resonators (SRR): (a) Single SRR showing a 0.02 GHz frequency difference, (b) SRR array with a 20 GHz difference.

Fig. 5. Structure of Split Ring Resonators (SRR): (a) Single SRR cell, sandwiched for array formation, (b) SRR array on a dielectric substrate, (c) Fabricated SRR example.

Cascaded Micro-Ring Sensor: A cascaded micro-ring sensor using the Vernier effect has also been studied for cancer cell detection. A two-ring resonator setup, where the second ring is exposed to the analyte, results in a resonant wavelength shift that can distinguish between gastric cancer cells and normal cells (Fig. 6).

Fig. 6. Example of a two-ring cascaded microring resonator setup where ring two is exposed to an analyte cancer or normal cells.

Chip Integrated SiPh Sensor Array: A multiplexed cancer biomarker detection platform using an array of chip-integrated SiPh sensors has been developed, enabling the simultaneous detection of eight cancer biomarkers in serum within an hour (Fig. 7, Table II) [13]. The combination of active resonance tuning and the nanoscale footprint of the microring resonators (MRRs) allows for highly scalable sensing arrays.

Fig. 7. Silicon microchip with eight microring resonators, each functionalized with a specific antibody for different cancer biomarkers.

Table I. DIELECTRIC CONSTANT AND RI OF DIFFERENT CANCER CELLS VERSUS NORMAL CELLS

Cancer Cell	Dielectric Constant	Refractive Index
Normal Cell	1.822500	1.35
Hela	1.937660	1.39
PCl2	1.946025	1.392
NIDA-MB-231	1.957201	1.395
MCF-7	1.962801	1.399
Jurkat	1.932100	1.402

Table II. BIOMARKERS AND THE CANCER CELLS

Biomarker	Cancer-Related
AFP	Liver and germ cell
ALCAM	Breast
CA15-3	Breast
CA19-9	Pancreatic and Colorectal
CA-125	Ovarian
CEA	Pancreatic and Colorectal
OSTEOPONTIN	Ovarian and Liver
PSA	Prostate

Photonic Ring Resonator with Microcantilever: The examination of PhC nanocavities merged with two silicon-based microcantilevers using the principle of photoelasticity influenced by RI variance is also a promising approach (Fig. 8).

Fig. 8. Ring resonator patch with microcantilever integrated into a light source and monitor with both free and clamped end functioning as a cantilever

Waveguide-Based Biosensors

Optical waveguides are composed of materials with high RI/high permittivity surrounded by materials with lower RI, such as the substrate or media to be sensed. The coupled light is allowed to propagate through the high RI waveguide by the phenomenon of TIR, generating an electromagnetic wave with an exponentially decreasing amplitude as the distance from the surface increases.

Silicon Nitride Photonic MZI Biosensor: Silicon nitride MZI sensor architectures have been studied for cancer cell detection using gradient rib and gradient rib-slot waveguides (Fig. 9, Fig. 10). The long interaction length of the MZI sensing arm with the analyte allows a good response to cancer cells, and the integration of the waveguide enhances the sensitivity.

Fig. 9. Novel rib-slot waveguide with slot geometry of 970 nm width and 400 nm thickness

Fig. 10. MZI and GC silicon nitride biosensor setup

Silicon Nitride Photonic MZI-Based Array Biosensor: The platform introduces the use of silicon nitride (Si3N4) waveguides to form an array of asymmetric-MZI sensors, which can simultaneously analyze two circulating biomarkers (POSTN and TGFBI) overexpressed by cancer stem cells (Fig. 11, Fig. 12).

Fig. 11. Microfluidic system: (a) Cartridge with dual syringes for driving patient sample and buffers through a blood filter and sensor area, controlled by valve actuation. Includes light sensor detection and waste chambers. (b) Final injection molded cartridge.

Fig. 12. (a) Three-dimensional model of the photonic biosensor with a cartridge inserted. (b) Final instrument

Photonic Crystal-Based Biosensors

Photonic crystals (PhCs) have a periodic dielectric framework with an array of air holes in a dielectric slab or the reverse. The path of light through the PhC is interpreted by the solution of the Maxwell equation. Light can be localized within the photonic bandgap (PBG) frequency range by introducing specific defects in the crystal geometry.

Nanocavity-Based Photonic Crystal Waveguide: A nanocavity-coupled photonic crystal waveguide (PCW) biosensor has been proposed for the label-free detection of cancer cells. The introduction of a point defect by missing a central hole creates a coupled nanocavity within the waveguide, leading to a shift in the resonant wavelength that can differentiate normal cells from cancer cells (Fig. 13).

Fig. 13. Generalized schematic of a nanocavity PhC waveguide with defects

Fabrication Technology

Several fabrication processes have been employed and studied for SiPh biosensors, including beam lithography, optical lithography, nanoimprinting, and ultraviolet photolithography. These techniques provide the required accuracy, reliability, resolution, and speed crucial for industrial-scale manufacturing.

Electron beam lithography can achieve higher resolution than light-based techniques but is limited by its ability to write only on small areas. Nanoimprint lithography promises high-throughput patterning of nanostructures by mechanical embossing. UV photolithography, on the other hand, involves the deposition of photoresist, exposure to UV light, and etching to pattern the photonic structures (Fig. 14).

Fig. 14. Schematic showing various stages of lithography. Here, using the photoresist (a special polymer) which becomes soluble in developing substances when exposed to light

The monolithic integration of electronics and photonics on a single chip, known as the electronic-photonic system-on-chip (EPSoC) platform, allows for the implementation of functionalities such as light sources, detectors, and signal processing on a single silicon substrate (Fig. 15).

Fig. 15. Electronic–photonic packaging. This monolithic platform consists of an exposed BOX layer that allows for (a) interrogating dense 2-D MRR sensor arrays simultaneously with multichannel fiber blocks and (b) copackaging of multichannel microfluidics for the analysis of multiple molecules simultaneously.

Challenges and Future Perspectives

While the simulation results of SiPh-based biosensors for cancer cell detection are promising, the field still faces several challenges before practical implementation. These include the integration of suitable light sources, cost-competitiveness with existing devices, temperature sensitivity, the need for additional modulation, lower detection limits compared to other biosensors, and the difficulty of integrating sensing arrays onto a chip.

Researchers are working to address these challenges, such as by introducing off-chip light sourcing, photon light, fluid barriers for sensor array integration, and utilizing the refractive index differences of biomarkers relative to cancer cells. Further integration of SiPh technology with other fields, such as HIV detection and the use of nanomaterials like silicon oxynitride, could provide even greater accuracy and sensitivity for various medical diagnostic applications.

Conclusion

SiPh-based biosensors have emerged as a promising technology for the early detection of cancer cells, leveraging the optical properties of malignant cells and the advantages of silicon-based integrated circuits. This review has provided an in-depth exploration of various SiPh biosensor configurations, including ring resonators, waveguides, and photonic crystals, along with their working principles, fabrication techniques, and current challenges.

The ability of SiPh biosensors to detect cancer cells with high sensitivity, affordability, and ease of use holds great potential for revolutionizing early-stage cancer diagnosis and improving patient outcomes. As the field continues to evolve, overcoming the existing challenges and further integrating SiPh technology with other emerging fields will be crucial in realizing the full potential of this transformative approach to medical diagnostics.

Reference

[1] S. C. Sajan, A. Singh, P. K. Sharma, and S. Kumar, "Silicon Photonics Biosensors for Cancer Cells Detection—A Review," IEEE Sensors Journal, vol. 23, no. 4, pp. 3366-3375, Feb. 15, 2023.