Extracellular vesicles (EVs) have great potential as biomarkers since their composition and concentration in biofluids are disease state dependent and their cargo can contain disease-related information. Large tumor-derived EVs (tdEVs, >1μm) in blood from cancer patients are associated with poor outcome, and changes in their number can be used to monitor therapy effectiveness. Whereas, small tumor-derived EVs (<1μm) are likely to outnumber their larger counterparts, thereby offering better statistical significance, identification and quantification of small tdEVs are more challenging. In the blood of cancer patients, a subpopulation of EVs originate from tumor cells, but these EVs are outnumbered by non-EV particles and EVs from other origin. In the Dutch NWO Perspectief Cancer-ID program, we developed and evaluated detection and characterization techniques to distinguish EVs from non-EV particles and other EVs. Despite low signal amplitudes, we identified characteristics of these small tdEVs that may enable the enumeration of small tdEVs and extract relevant information. The insights obtained from Cancer-ID can help to explore the full potential of tdEVs in the clinic.

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We realized integrated photonics multi-waveguide devices for optical trapping and Raman spectroscopy of particles in a fluid. In these devices, multiple beams directed towards the device center lead to a local field enhancement around this center and thus counteract the effect of light concentration near the facets, which is a disadvantage of dual-waveguide traps. Thus, a trapping region is created around the center, where a single particle of a size in a wide range can be trapped and studied spectroscopically, free from the influence of surfaces. We report the design (including simulations), fabrication and performance demonstration for multi-waveguide devices, using our Si₃N₄ waveguiding platform as the basis. The designed ridge waveguides, optimized for trapping and Raman spectroscopy, emit narrow beams. Multiple waveguides arranged around the central microbath result from fanning out of a single input waveguide using Y-splitters. A second waveguiding layer is implemented for detection of light scattered by the trapped particle. For reliable filling of the device with sample fluid, microfluidic considerations lead to side channels of the microbath, to exploit capillary forces. The interference of the multiple beams produces an array of hot spots around the bath center, each forming a local trap. This property is clearly confirmed in the experiments and is registered in videos. We demonstrate the performance of a 2-waveguide and a 16-waveguide device, using 1 and 3 pm polystyrene beads. Study of the confined Brownian motion of the trapped beads yields experimental values of the normalized trap stiffness for the in-plane directions. The stiffness values for the 16-waveguide device are comparable to those of tightly focused Gaussian beam traps and are confirmed by our own simulations. The Raman spectra of the beads (in this work measured via an objective) show clear peaks that are characteristic of polystyrene. In the low-wavenumber range, the spectra have a background that most likely originates from the Si₃N₄ waveguides.

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We report a highly sensitive ultrasound sensor based on an integrated photonics silicon Mach-Zehnder interferometer (MZI). One arm of the MZI is located on a thin membrane, acting as the sensing part of the device. Ultrasound waves excite the membrane's vibrational mode, thus inducing modulation of the MZI transmission. The measured sensor transfer function is centered at 0.47 MHz and has a -6 dB bandwidth of 21.2%. For 1.0 mW optical input power, we obtain a high sensitivity of 0.62 mV/Pa, a low detection limit of 0.38 mPa/Hz^1/2 at the resonance frequency and a large dynamic range of 59 dB. In preliminary ultrasound imaging experiments using this sensor, an image of a wire phantom is obtained. The properties of this sensor and the generated image show that this sensor is very promising for ultrasound imaging applications.

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A highly sensitive ultrasound sensor based on an integrated photonics Mach–Zehnder interferometer (MZI) fabricated in silicon-on-insulator technology is reported. The sensing spiral is located on a membrane of size 121 μm × 121 μm. Ultrasound waves excite the membrane’s vibrational mode, which translates to modulation of the MZI transmission. The measured sensor transfer function is centered at 0.47 MHz and has a −6 dB bandwidth of 21.2%. The sensor sensitivity is linear in the optical input power and reaches a maximum 0.62 mV/Pa, which is limited by the interrogation method. At 0.47 MHz and for an optical power of 1.0 mW the detection limit is 0.38 mPa∕Hz ¹ ∕ ² and the dynamic range is 59 dB. The MZI’s gradual transmission function allows a wide range of wavelength operation points. This strongly facilitates sensor use and is promising for applications.

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We propose a design method for silicon ring resonators (RRs) with a free spectral range (FSR) insensitive to fabrication variations. Two waveguide-core widths are used in the RR, with opposite signs of the group-index derivative with respect to the width. This results in cancellation of the width-dependent FSR changes. The systematic deviation of the realized width from the design width is determined and is used for calibrating the calculated relation of group index versus width. This enables a more accurate FSR value and well-aimed robust performance. We present two robust design examples. Experimental results match well with the predictions. For the deliberately introduced ±10 nm core-width change, the FSR variation of the robust designs is only about 30% of the value measured from the RR with a single core width. This design method can be used to improve the performance of photonic integrated circuits using multiple RRs. As the FSR of a RR is not easily tunable, the robust design is beneficial to applications where an accurate FSR is required, such as in microwave photonics.

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We present a compact integrated photonics interrogator for a ring-resonator (RR) ultrasound sensor, the so-called MediGator. The MediGator consists of a special light source and an InP Mach-Zehnder interferometer (MZI) with a 3 × 3 multi-mode interferometer. Miniaturization of the MZI to chip size enables high temperature stability and negligible signal drift. The light source has a −3 dB bandwidth of 1.5 nm, a power density of 9 dBm/nm and a tuning range of 5.7 nm, providing sufficient signal level and robust alignment for the RR sensor. The mathematical procedure of interrogation is presented, leading to the optimum MZI design. We measure the frequency response of the sensor using the MediGator, giving a resonance frequency of 0.995 MHz. Further, high interrogation performance is demonstrated at the RR resonance frequency for an ultrasound pressure range of 1.47 − 442.4 Pa, which yields very good linearity between the pressure and the resulting modulation amplitude of the RR resonance wavelength. The measured signal time traces match well with calculated results. Linear fitting of the pressure data gives a sensor sensitivity of 77.2 fm/Pa. The MediGator provides a low detection limit, temperature robustness and a large measurement range for interrogating the RR ultrasound sensor.

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The application of on-chip optical trapping and Raman spectroscopy using a dual-waveguide trap has so far been limited to relatively big synthetic and biological particles (e.g., polystyrene beads and blood cells). Here, from simulations, we present the capabilities of dual-waveguide traps built from composite SiO₂-Si₃N₄ waveguides for optical trapping of extracellular vesicles (EVs). EVs, tiny cell-derived particles of size in the range 30−1000 nm, strongly attract attention as potential biomarkers for cancer. EVs are hard to trap, because of their smallness and low index contract w.r.t. water. This poses a challenge for on-chip trapping. From finite-difference time-domain simulations we obtain the narrow beam emitted from the waveguide facet into water, for λ = 785 nm. For a pair of such beams, in a counter-propagating geometry and for facet separations of 5, 10 and 15 µm, we derive the inter-facet optical field, which has a characteristic interference pattern with hot spots for trapping, and calculate the optical force exerted on EVs of size in the range 50−1000 nm, as a function of EV position. We use two refractive index models for the EV optical properties. Integration of the force curves leads to the trapping potentials, which are well-shaped in the transverse and oscillatory in the longitudinal direction. By applying Ashkin’s criterion, the conditions for stable trapping are established, the central result of this work. Very small EVs can be stably trapped with the traps by applying a power also suitable for Raman spectroscopy, down to a smallest EV diameter of 115 nm. We thus argue that this dual-waveguide trap is a promising lab-on-a-chip device with clinical relevance for diagnosis of cancer.

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We experimentally demonstrate an interrogation procedure of a ring-resonator ultrasound sensor using a fiber Mach-Zehnder interferometer (MZI). The sensor comprises a silicon ring resonator (RR) located on a silicon-oxide membrane, designed to have its lowest vibrational mode in the MHz range, which is the range of intravascular ultrasound (IVUS) imaging. Ultrasound incident on the membrane excites its vibrational mode and as a result induces a modulation of the resonance wavelength of the RR, which is a measure of the amplitude of the ultrasound waves. The interrogation procedure developed is based on the mathematical description of the interrogator operation presented in Appendix A, where we identify the amplitude of the angular deflection Φ0 on the circle arc periodically traced in the plane of the two orthogonal interrogator voltages, as the principal sensor signal. Interrogation is demonstrated for two sensors with membrane vibrational modes at 1.3 and 0.77 MHz, by applying continuous wave ultrasound in a wide pressure range. Ultrasound is detected at a pressure as low as 1.2 Pa. Two optical path differences (OPDs) of the MZI are used. Thus, different interference conditions of the optical signals are defined, leading to a higher apparent sensitivity for the larger OPD, which is accompanied by a weaker signal, however. Independent measurements using the modulation method yield a resonance modulation per unit of pressure of 21.4 fm/Pa (sensor #1) and 103.8 fm/Pa (sensor #2).@en