Power-efficient thermo-optic phase shifters have been demonstrated using 3 mu m thick silicon on insulator ( SOI) waveguides fabricated on cavity-SOI wafers. In cavity-SOI the cavities are premade in the SOI wafer which simplifies the processing of the waveguides with thermally insulated heater structures. Measurement results of asymmetric Mach-Zehnder interferometric TO switches show a 10-fold decrease in required power for alpha pi phase shift in devices fabricated on cavity-SOI when compared to devices fabricated on plain SOI. With the cavities the required heating power for the pi phase shift is only 2.1 mW. Numerical simulations support the experimental results.

Increasing identification of protein-protein interaction (PPI) targets creates opportunities for drug discovery. However, the current drug screening strategies are costly and reagent-consuming, which hinders the progress in PPI modulator drug discovery. The primary obstacle lies in the inability to achieve molecular fishing with existing technology. Herein, we present a novel high-throughput, homogeneous-phase screening assay for PPI modulator discovery called “SERScreen”, based on a magnetic field-amplified surface-enhanced Raman spectroscopy (SERS). Two high-affinity proteins are fixed respectively on the magnetic beads (MBs) and the SERS tags, and the cross-linking of two nanoprobes induced by PPI enables strong SERS signals. Candidate modulators interfere with the PPI according to higher affinity toward one protein, resulting in a significant reduction in SERS intensity above the MBs. We established a potential drug screening platform for PD-1/PD-L1, and demonstrated its feasiblility not only with known inhibitors (Durvalumab and BMS-202), but also with a small-molecule combinatorial library, successfully identifying two new candidate inhibitors via the molecular fishing of SERScreen. Furthermore, the anticancer mechanism of two candidates was discussed. As an ultrasensitive, low reagent consumption (2µL sample solution), high-throughput screening technique in the PPI modulator discovery, SERScreen offers an effective solution for molecular fishing from complex samples and displays high compatibility with automatic measurement equipment.

Single-mode and low-loss operation of optical waveguides is typically limited to a 200-500 nm wide wavelength range. The lower limit is the boundary between single and multi-mode operation, and the upper limit comes from the decreasing confinement of the fundamental mode inside the core, which eventually leads to too large bending radii, waveguide crosstalk and poor integration density. Many interferometric waveguide components, such as grating couplers and multi-mode interference (MMI) couplers, have even narrower wavelength range. This paper demonstrates photonic integrated circuits (PICs) with ultra-broadband operation from 1.2 to 2.4 mu m wavelength based on 3 mu m thick silicon-on-insulator (SOI) waveguides. Such thick waveguides maintain ultra-high mode confinement for over 1 mu m bandwidth, which supports dense integration with low-loss crossings, Euler bends and total internal reflection (TIR) mirrors. While some parts of the PICs are based on multi-moded strip waveguides, mode filters with rib-waveguides allow to keep the PICs effectively single-moded. The focus of the paper is on passive PICs, although the platform also enables active components. Ultra-broadband test results are provided for long waveguide spirals and waveguide-fiber coupling, as well as for echelle gratings, arrayed waveguide gratings (AWGs) and different types of 2x2 couplers. Low-loss operation is demonstrated with continuous transmission spectra measured from 1.25 mu m up to 2.4 mu m wavelength, i.e. up to 1.15 mu m bandwidth. The measured bandwidths are limited by the available measurement setup, rather than the PIC components themselves. Remaining challenges for ultra-broadband operation, such as anti-reflection coatings, are discussed. Applications for broadband operation in communication, imaging and sensing are also presented.

Based on commonly used dielectric materials in Si processing platforms, multiple-layer anti-reflection stacks were designed and fabricated, with the main goal of highly efficient light coupling for Si waveguides over a wide wavelength range. Initial characterization results indicate that a <-20dB light reflection was successfully achieved over 1310-1550 nm wavelength range over the whole 150mm wafer. The fluctuation of reflection spectra over the whole wafer was observed to be only 1-2 dB, which guarantees the high yield and mass production capabilities for further applications.

We have systematically studied multimode interferometer (MMI) splitters made from multiple tapered sections. The goal is to create a library of robust and low-loss splitters covering all splitting ratios (SR) for our silicon photonics platform based on 3 $\mu$m thick waveguides. The starting point is always a non-tapered canonical MMI either with general symmetry (canonical SRs 50:50, 100:0, and reciprocal ratios), with mirror symmetric restricted symmetry (canonical SRs 85:15, 50:50, 100:0, and reciprocal ratios), and with point-symmetric restricted symmetry (canonical SRs 72:28 and 28:72). Splitters of these three types are then divided into one to four subsections of equal length, leading to 12 possible different configurations. In each of these subsections, the width is first linearly tapered either up or down and then tapered back to its starting value ensuring mirror symmetry. For all twelve configurations, we carried out an extensive campaign of numerical simulations. For each given width change, we scanned the splitter length and calculated the power in the fundamental mode at the output as well as its relative phase. We then selected the designs with sufficiently low loss and mapped their SR as a function of either the change in width change or length, therefore creating systematic maps for the design of MMI splitters with any SR. Eventually, we selected and fabricated a subset of designs with SRs ranging from 5:95 to 95:5 in steps of 5% and validated their operation through optical measurements.

We demonstrate for the first time flat-top interleavers based on cascaded Mach-Zehnder interferometers (MZIs) which use only single multimode interferometers (MMIs) as power splitters. Our previous designs were based on 4-stage cascades of MZIs, where we used single MMIs and double MMIs to achieve 85:15 splitting ratio and 31:69 splitting ratio respectively. This time, we propose instead a greatly simplified 2-stage configuration using only single MMIs, including a standard 50:50 MMI, and two tapered MMIs to achieve 71:29 and 92:08 splitting ratios. We have designed the interleaver based on its geometrical representation on the Bloch sphere, then confirmed by efficient 2D simulations of the building blocks and of the whole structure, based on the eigenmode expansion method. We show how important is to take into account the phase relations between the outputs of all MMIs in order to make a working design. We have successfully fabricated devices with different channel spacing on our micron-scale silicon photonics platform, and measurement results confirmed their expected flat-top operation on a broad band. Using only single MMI splitters we can not only greatly outperform the bandwidth achieved by standard directional couplers, but we can also ensure much higher robustness to fabrication errors, also compared to previous demonstrations based on double MMIs. Indeed, when compared to those previous attempts, the new results prove tapered MMIs to be the most robust approach to achieve arbitrary splitting ratios.

Ge photodiodes were integrated on the 3 µm SOI platform, where the 3 µm thick Si waveguides offer ultra-low propagation losses (~0.1 dB/cm), ultra-dense integration (μm-scale bends), small polarization dependency (down-to-zero birefringence) and the ability to tolerate relatively high optical powers (>1W). A horizontal Ge PIN photodiode was monolithically integrated on the 3 µm SOI platform. It reached a 3 dB cutoff frequency of 40 GHz and 1.0 A/W responsivity at -1 V bias and 1.55 µm wavelength. Germanium was selectively grown into cavities in the 3 µm SOI layer and the Ge waveguide detector was patterned with the same hard mask with the Si waveguides to achieve waveguide self-alignment. The development of 40 GHz PDs was an important step in improving the feasibility of the 3 µm SOI platform in high-bandwidth applications.

This paper presents our recent progress on fast germanium photodetector (PD) development for our 3μm silicon-on - insulator (SOI) platform. We have fabricated a horizontal PIN photodiode, which has a 3dB cutoff frequency of 40GHz and responsivity of 1.0 A/W at -1V bias for operation wavelength of 1.55μm. The high bandwidth indicates that the detector speed is limited by the transit time of the carriers over the i-region rather than the junction capacitance. The electric field in the i-region at -1V is high enough to maintain the carrier drift speed close to the maximum velocity of carriers in the Ge. The device is realized using selectively grown germanium with very low amount of stress induced crystal defects. The detector area and the Si waveguides were patterned with a common hard mask, which enables accurate lateral alignment between them. The n- and p-contacts were directly made on the Ge using Ti/Al metallization. The vertical sidewalls of the detector area were implanted in order to create the horizontal PIN structure. The subsequent dopant diffusion was estimated to secure the i-region and the junctions by controlling the thermal budget, as the two dopants have different diffusion mechanism in Ge. One of the advantages of our micron scale waveguides is that due to the high confinement of the optical mode within the Si waveguide they allow light coupling into a short detector. The junction capacitances are therefore small as the detector area is only 1x9μm. In addition, the electrical output pulse shape is not distorted by the slow diffusion current of electrons and holes as the incoming light do not overlap the doped n- and n-regions.

This paper explains and demonstrates the unique properties of micron-size silicon-on-insulator (SOI) waveguides. It gives an overview of the silicon photonics research at VTT, as well as latest R&D highlights. The benefits of high mode confinement in rib and strip waveguides are described, reaching from low losses and small footprint to polarization independent operation and ultra-wide wavelength range from 1.2 to over 4 mu m. Most of the results are from photonic integrated circuits (PICs) on 3 mu m SOI, while a 25 Gbps link with a transceiver on 12 mu m SOI is also reported. Wavelength multiplexing and filtering is demonstrated with some breakthrough performance in both echelle gratings and arrayed waveguide gratings. Lowest losses are below 1 dB and lowest cross-talk is below -35 dB. Progress towards monolithically integrated, broadband isolators is described, involving polarization splitters, reciprocal polarization rotators and nonreciprocal Faraday rotation in 3 lam SOI waveguide spirals. Quick update is presented about switches, modulators and Ge photodiodes up to 15 GHz bandwidth. Hybrid integration of lasers, modulators and photodiodes is also reported. The added value of trimmed SOI wafers and cavity-SOI wafers in Si photonics processing is addressed. Latest results also include up-reflecting mirrors with <0.5 dB loss, which support wafer-level testing and packaging.

This paper gives an overview of the 3-mu m silicon-on-insulator (SOI) platform that is openly available from VTT and suitable for the realization of photonic integrated circuits (PICs) for near and mid-infrared applications. Specific benefits of this thick-SOI PIC platform include low optical losses (similar to 0.1 dB/cm), ultradense integration (mu m-scale bends), small polarization dependency (down-to-zero birefringence), and ability to tolerate relatively high optical powers (>1 W). Fabrication technology is based on an i-line stepper and 150-mm wafer size. Open access to the waveguide platform is supported by design kits, wafer-level testing, multi-project wafer runs, dedicated R&D runs, and small-to-medium volume manufacturing.

This paper presents the latest progress in the development of compact and low-loss photonic integrated circuits on 3-micron silicon-on-insulator platform that covers both near and mid-infrared applications.

The effect of the combination of a recombinant adenovirus (ATV) expressing a specific apoptin protein and cisplatin on human lung cancer cells (A549 cells) was determined. The inhibitory effects of ATV and cisplatin, ATV alone, or cisplatin alone on the migration and invasion of A549 cells were evaluated in vitro using cell proliferation, wound healing, Transwell migration and Matrigel invasion assays. The tumor inhibition effect on A549 cells in vivo was assessed by observing the tumor growth and survival rate of nude mice with subcutaneous tumor xenografts grown from implanted A549 cells after treatment with ATV, cisplatin, or ATV combined with cisplatin. The proliferation (P<0.01), migration (P<0.01), and invasion (P<0.01) on A549 cells was suppressed significantly by ATV, cisplatin, and ATV and cisplatin, in a dose- and time-dependent manner. The inhibition of tumor growth in transplanted nude mice in the ATV combined with cisplatin group was significantly higher than that displayed in the other groups, and the survival rate of the combined treatment group was significantly higher than that of the group treated with cisplatin alone. The results indicated that the combined application of ATV and cisplatin could reduce toxicity and showed a synergistic effect in reducing tumor growth and increasing survival. Thus, there is a potential research value in treating tumors using the combination of ATV and cisplatin, which provides a foundation for future preclinical studies on this antitumor treatment.

We show theoretically and experimentally how a flat-top second-order response can be achieved with a self-coupled single add-drop ring resonator based on two couplers with different splitting ratios. The resulting device is a 1x1 filter, reflecting light back in the input waveguide at resonating wavelengths in the passbands, and transmitting light in the output waveguide at all other non-resonating wavelengths. Different implementations of the filter have been designed and fabricated on a micron-scale silicon photonics platform. They are based on compact Euler bends - either U-bends or Lbends - and Multi-Mode Interferometers as splitters for the ring resonators. Different finesse values have been achieved by using either 50:50 MMIs in conjunction with 85:15 MMIs or 85:15 MMIs in conjunction with 95:05 double MMIs. Unlike ordinary lowest order directional couplers, the MMIs couple most of the power in the cross-port which make them particularly suitable for the topology of the self-coupled ring, which would otherwise require a waveguide crossing. Experimental results are presented, showing good agreement with simulations. The proposed devices can find applications as wavelength-selective reflectors for relatively broad-band lasers or used as 2x2 add-drop filters when two exact replicas of the device are placed on the arms of a Mach-Zehnder interferometer.

We present a photonic integrated circuit of four-channel bidirectional-optical subassembly on micron-scale silicon. Experimental results with loss less than 1.5dB, PDL<0.5dB, and near 30dB isolation, allow for the realization of Class C+ QSFP TDM-PON OLT module.

Integrated circuits based on micron-scale silicon waveguides have the clear advantage of being tolerant to fabrication errors, thanks to the high mode confinement within the guiding core. Here we show how flat-top interleavers can be achieved on a micron-scale silicon photonics platform based on ring-loaded Mach-Zehnder Interferometers (MZIs), without the need for any thermal tuning. Robust designs are also guaranteed by resorting to Multi-Mode Interferometers (MMIs) as power splitters in both the MZIs and the ring resonators. A trade-off between in-band ripple and roll-off can be achieved by changing the ring splitting ratios. In particular rings with different finesse based on MMIs with 50:50, 72:28, and 85:15 splitting ratios have been designed, fabricated and successfully tested. In-band ripples as low as 0.2 dB and extinction ratios exceeding 15 dB have been measured from the fabricated samples. Repeatability of the performances from chip to chip and wafer to wafer is presented to show the tolerance of the devices to fabrication errors. Even though these particular devices have been designed for TE polarization only, polarization insensitive designs can be also achieved. All designs are based on strip waveguides and compact Euler-bends, leading to footprints in the order of 700x300 μm2, also thanks to an optimized configuration. They can find applications as interleavers as such or as stages in cascades of N interleavers to achieve flat-top 1x2N (de)multiplexers.

In this study, we investigated the classical fermentation process in Pichia pastoris based on transcriptomics. We utilized methanol in pichia yeast cell as the focus of our study, based on two key steps: limiting carbon source replacement (from glycerol to methonal) and fermentative production of exogenous proteins. In the former, the core differential genes in co-expression net point to initiation of aerobic metabolism and generation of peroxisome. The transmission electron microscope (TEM) results showed that yeast gradually adapted methanol induction to increased cell volume, and decreased density, via large number of peroxisomes. In the fermentative production of exogenous proteins, the Gene Ontology (GO) mapping results show that PAS_chr2-1_0582 played a vital role in regulating aerobic metabolic drift. In order to confirm the above results, we disrupted PAS_chr2-1_0582 by homologous recombination. Alcohol consumption was equivalent to one fifth of the normal control, and fewer peroxisomes were observed in Δ0582 strain following methanol induction. In this study we determined the important core genes and GO terms regulating aerobic metabolic drift in Pichia, as well as developing new perspectives for the continued development within this field.

Gene associated with retinoid‑interferon‑induced mortality 19 (GRIM‑19) is a novel candidate tumor suppressor gene located on the human chromosome 19p13.1 region. Our previous study demonstrated that the upregulation of GRIM‑19 in human oral squamous cell carcinoma (OSCC) cells significantly inhibited tumor cell growth in vitro and in vivo. In the present study, the combined effects of cationic liposome (LP)‑mediated GRIM‑19 gene (LP‑pGRIM‑19) and the low‑dose chemotherapeutic drug, cisplatin (CDDP), on tumor cell growth in vitro and in vivo were examined, and the molecular mechanism of their mutual action was investigated by cell proliferation, colony formation, apoptosis, migration, invasion and western blotting assays in vitro, and a node nude tumor model. It was demonstrated that cationic LP‑pGRIM‑19 gene therapy sensitized the response of breast cancer cells to CDDP, and that LP‑pGRIM‑19 in combination with CDDP significantly induced apoptosis and inhibited proliferation, colony formation, migration and invasion of the cells, compared with CDDP treatment alone. In addition, systemic treatment with a combination of intravenous injection of LP‑pGRIM‑19 and intraperitoneal injection of low‑dose CDDP into subcutaneous HSC3 human OSCC xenograft mice resulted in a significant inhibition of tumor growth (P<0.05). Further investigations indicated that the enhancement of CPPP‑mediated antitumor effects by GRIM‑19 may be associated with the upregulation of phosphorylated p53 and the downregulation of B cell lymphoma‑2, cyclin D1, vascular endothelial growth factor, matrix metalloproteinase (MMP)‑2 and MMP‑9, the proteins of which are involved in the activation of signal transducer and activator of transcription 3. The results of the present study suggested that the combination of GRIM‑19 gene therapy with low‑dose CPPP‑based chemotherapy may be a potent therapeutic strategy for the treatment of OSCC.

Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) and its upregulation contribute to the progression and metastasis of several different tumor types. The gene associated with retinoid‑interferon‑induced mortality-19 (GRIM-19) is known to functionally interact with STAT3 and inhibit its transcriptional activity. It has been reported that upregulation of genes associated with GRIM-19 can significantly reduce the tumor growth of several types of tumors. However, little is known in regards to its role in oral squamous cell carcinoma (OSCC). In the present study, a recombinant eukaryotic expression plasmid carrying GRIM-19 was constructed to evaluate its effects on OSCC cancer growth. Upregulation of GRIM-19 in OSCC cells significantly inhibited cell proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Moreover, we found that upregulation of GRIM-19 reduced cyclin D1, Bcl-2, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) expression whose protein is involved in STAT3 activation. Taken together, these findings suggest that GRIM-19 plays an inhibitory role in the progression of OSCC, and contribute to the future development of STAT3-based gene therapeutic approaches for OSCC.

OBJECTIVE:To compare the accuracy of whole body diffusion weighted magnetic resonance imaging (WB-DWI) with that of somatostatin receptor scintigraphy (SRS) in the detection and localization of the lesions in patients with oncogenic osteomalacia (OOM). METHODS:Totally 6 patients with clinically suspected oncogenic osteomalacia were enrolled. All of them underwent WB-DWI and SRS within 2 weeks to evaluate the possible presence of tumors that lead to osteomalacia. Surgical and pathological findings were considered as the gold standard. The sensitivity, specificity, and accuracy were calculated. RESULTS:Pathology confirmed the diagnosis of two soft tissue tumors (including 1 angiolipoma and 1 mesenchymal tumor) and one bone tumor of malignant neurofibroma. The sensitivity, specificity, and accuracy in the identification of lesions in patients with oncogenic osteomalacia were 33.33%, 100%, 66.67% for WB-DWI and 33.33%, 66.67%, 50% for SRS (P>0.05). CONCLUSION:For adult patients with osteomalacia, WB-DWI and SRS can provide mutually supportive data and be used for identifying potential oncogenic osteomalacia.

OBJECTIVE:To assess the reproducibility of whole-body diffusion weighted imaging (WB-DWI) technique in healthy volunteers under normal breathing with background body signal suppression.METHODS:WB-DWI was performed on 32 healthy volunteers twice within two-week period using short TI inversion-recovery diffusion-weighted echo-planar imaging sequence and built-in body coil. The volunteers were scanned across six stations continuously covering the entire body from the head to the feet under normal breathing. The bone apparent diffusion coefficient (ADC) and exponential ADC (eADC) of regions of interest (ROIs) were measured. We analyzed correlation of the results using paired-t-test to assess the reproducibility of the WB-DWI technique.RESULTS:We were successful in collecting and analyzing data of 64 WB-DWI images. There was no significant difference in bone ADC and eADC of 824 ROIs between the paired observers and paired scans (P>0.05). Most of the images from all stations were of diagnostic quality.CONCLUSION:The measurements of bone ADC and eADC have good reproducibility. WB-DWI technique under normal breathing with background body signal suppression is adequate.