Applications and developments of on-chip biochemical sensors based on optofluidic photonic crystal cavities

Abstract

Photonic crystal (PC) cavities, which possess the advantages of compactness, flexible design, and suitability for integration in a lab-on-a-chip system, are able to distinguish slight variations in refractive index with only a small amount of analyte. Combined with the newly proposed optofluidic technology, PC-cavity devices stimulate an emerging class of miniaturized and label-free biochemical sensors. In this review, an overview of optofluidic PC cavities based biochemical sensors is presented. First, the basic properties of the PC, as well as the sensing principle of the PC cavity, are discussed. Second, the applications of the sensors in detecting gas, liquid, and biomolecule concentrations are reviewed, with a focus on their structures, sensing principles, sensing properties, advantages, and disadvantages. Finally, the current challenges and future development directions of optofluidic PC-cavity-based biochemical sensors are discussed.

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Ya-nan Zhang

Ya-nan Zhang was born in Anhui, China, in June 1989. She received her B.A. and M.A. degrees, respectively, in 2010 and 2012 from the College of Information Science and Engineering, Northeastern University, Shenyang, China, where she is currently working toward the Ph.D. degree. Her research interests include fiber optical sensors, photonic crystal sensors, and slow light technology and its sensing applications. She has authored and co-authored more than 15 scientific papers and conference presentations.

Yong Zhao

Yong Zhao is currently a Full Professor with the Northeastern University, Shenyang, China. In 2014, he was awarded by the National Science Foundation for Distinguished Young Scholars of China. In 2015, he was honored as the Yangtze River Scholar Distinguished Professor by the Ministry of Education of China. His current research interests include development of fiber-optic sensors and device, photonic crystal sensors, novel sensor materials and principles, slow light and sensor technology, and optical measurement technologies. He has authored or coauthored more than 160 scientific papers and conference presentations, 15 patents, and 5 books.

Tian-min Zhou

Tian-min Zhou was born in Jiangxi, China, in June 1992. He received the B.S. degree in the Electric Engineering College, Yanshan University, Hebei, China in 2016. Now he is currently pursuing the M.S. degree in the College of Information Science and Engineering, Northeastern University, Shenyang, China. His current research interests include biosensors and whispering-gallery-mode resonator sensors.

Qi-lu Wu

Qi-lu Wu was born in Sichuan, China, in October 1993. He received his B.A. degree in 2016 from the College of Information Science and Engineering, Northeastern University, Shenyang, China, where He is currently studying for a Ph.D. degree. His research interests include fiber optical gas sensors, photonic crystal waveguide sensors, optical detection of ocean parameters.

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1. Introduction

Detection of biochemical molecule concentration is necessary in many fields, including food and environment protection, health care, basic biology, and clinical diagnostics.¹ At present, the most urgent task is to develop biochemical sensors that are miniature, highly sensitive, simple to use, inexpensive, and that show high precision. To realize this aim, some novel methods that take full advantage of advanced microfabrication technology, optical theory, and materials science to integrate biochemical sensors in a lab-on-a-chip system have flourished over recent years.^2,3 Such methods include surface plasmon (SPR) resonator,⁴ optical resonator,^5–7 optical grating,⁸ laterally-illuminated photonic crystal (PC) cavity,^9–12 and normally-illuminated PC slab.¹³ Some commercial products based on the above technologies are listed in Table 1. These products inherit the favorable characteristics of optical sensors, including safety in flammable and explosive environments, immunity to electromagnetic interference, remote monitoring, and rapid response. In particular, due to the prominent advantages of PCs, such as their ultra-compact size (of the order of tens to hundreds of microns squared), small amount of analyte required, high spectral sensitivity, and integration capability, considerable attention has been devoted to the PC in relation to biochemical sensing applications.¹⁴ In comparison, the normally-illuminated PC slab sensor, with a PC resonant reflector surface as the sensor head, can be illuminated/detected at a normal incidence.¹⁵ By introducing an optical fiber-coupled traveling-wave semiconductor amplifier as the gain media, it enables a high degree of multiplexing, a high-quality factor, and high refractive-index sensitivity.¹¹ A detailed introduction of biochemical sensors based on a normally-illuminated PC slab can be found in ref. 16. In contrast, in laterally-illuminated PC-cavity sensors, the sensing heads are connected with two optical fibers at the lateral sides of the PC, and they feature a high degree of compactness. Furthermore, different PC-cavity sensors can share one simple optical source and set of detection instruments, thus offering the possibility of integrating several sensors on one chip. In this review, the use of laterally-illuminated PC cavities as the biochemical sensing platforms will be discussed, mainly concerning their applications in lab-on-a-chip systems.

Table 1 Examples of commercial optical biosensor products

Technology	Manufacturer	Instruments	Integration	Response time	Website
SPR	Biosensing Instruments	BI-4500	5 channels	4 ms	http://www.biosensingusa.com
	GE Healthcare/Biacore	Biacore 8K	8 channels (384 well microplates)	2–15 min	http://www.proteins.gelifesciences.com
	NanoSPR	NanoSPR9	2 channels	0.2 s	http://www.nanospr.com
	Reichert Analytical	Reichert4SPR	4 channels	—	http://www.reichertspr.com
	BioNavis	420A ILVES	4 (96 well microplates)	—	http://www.bionavis.com
PC	Cunningham Group and SRU Biosystems	—	1536 well microplates	—	http://www.nano.ece.illinois.edu
Optical grating	Axela	DotLab	—	—	http://www.axelabiosensors.com
Resonant gratings	Corning	EPIC system	384 well microplates	15 s	http://www.corning.com
Ring resonator	Genalyte	Maverick	128 rings	15 min	http://www.genalyte.com

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In contrast with the conventional optical cavity that has a closed structure with its cavity layer sandwiched between two high-reflected surfaces,¹⁷ the PC configuration forms a unique open cavity, which allows its cavity layer (sensing layer) to be easily functionalized and directly exposed to microfluidics for sensing.¹⁸ It has been demonstrated that the strong confinement of light in the PC defect cavity might incur some very narrow resonant modes, both in the transmission and reflection spectrum of the PC cavity, which yields heavy perturbation when chemical- or biomolecules are captured on the cavity surface. Therefore, both a low detection limit and a high measurement sensitivity can be obtained for such a PC-cavity-based biochemical sensor.¹⁹

On the other hand, optofluidic has become a new photonic branch in biochemical sensing,²⁰ which integrates nanophotonic on the manipulation of photons at the scale of an optical wavelength, with microfluidic on the control of fluids at the micron scale.²¹ In addition, the large fraction of air holes in the PC cavity is a natural candidate for storing fluids. Therefore, the combination of the PC cavity and the optofluidic can further promote the sensing applications of the on-chip integrated PC cavity,^22,23 and make it possible for the optofluidic PC-cavity-based sensor to be sensitive to external chemical- or bio-stimuli, such as gas, bulk liquid concentration, protein, DNA, avidin, nanoparticles, and cancer cells.

In this work, an overview of the on-chip biochemical sensors based on the optofluidic PC cavity is given in detail. The rest of this paper is organized as follows: in section 2, the theoretical background behind the PC cavity is analyzed. In section 3, a discussion of the way in which PC cavities are used as biochemical sensors, along with their structures, sensing principles, and sensing properties, is presented. In section 4, the existing challenges and future research directions of the optofluidic PC cavity for biochemical sensing applications are put forward. Finally, in section 5, we draw a brief conclusion and discuss future prospects.

2. Basic properties and sensing principle of the PC cavity

A PC is usually formed by periodically arranging air holes in high-refractive-index dielectric materials (e.g. glass or silicon). The periodicity of the PC can be classified into one, two, and three spatial dimensions. The pattern in which the dielectric materials are distributed is called a lattice. The constructive and destructive interferences that are generated from the various reflections and refractions of photons within these contrasting dielectric materials, and more importantly at the boundaries between them, give rise to some photonic pass and stop bands, similar to the electronic band gaps in semiconductors. The propagation of light within the wavelength range of the photonic band gap (PBG) is forbidden.²⁴ A small perturbation of the refractive index distribution (or arrangement) of dielectric materials in the PC can provide an impressive amount of control over the propagation of light, and thus enable the development of PC sensing technologies.²⁵ By applying electromagnetic perturbation theory, the influence of the refractive-index variation can be given as:²⁶where ε, n, and ω are the dielectric constant, refractive index, and optical frequency, respectively; Δε, Δn, and Δω are the variations of the dielectric constant, refractive index, and optical frequency, respectively; f represents the filling fraction, which quantifies the proportion of electric field energy in the region where the refractive index is perturbed, and 0 ≤ f ≤ 1.

From this equation, it is clear that the frequency change of an optical mode in the PC depends linearly on both the refractive-index variation and the filling fraction. Since the change in refractive index can typically reflect the properties of the analyte being detected, researchers have sought to enhance the sensing sensitivity of the PC by localizing the electric field energy only to the region where analyte interrogation will occur.²⁷ It is well known that once defects are introduced into a PC, the periodicity of its dielectric function will be broken, making it possible to guide and manipulate the way that the light interacts with the artificial PC at the scale of an optical wavelength. In particular, when certain point defects are introduced in the orderly arranged lattices of the PC, a PC cavity that is potentially surrounded by reflecting walls may be formed. As long as this new space supports an optical mode whose frequency is located inside the PBG, light can be “trapped” there for an extended number of field oscillation cycles, thus bringing strong spatial and temporal light confinement and long photon lifetime (namely, high-quality factor Q) in the PC cavity.²⁸

As shown in Fig. 1, the typical point defected structures of the PC cavity can be classified into four types: 1) Hm-typed: modifying one or more lattice points to create a small space that is potentially surrounded by reflecting walls;^29,30 2) Ln-typed: removing some lattice points in one line to form a cavity;^31–33 3) ring-typed: removing some lattice points to form one or more ring-typed defects and generate some localized optical modes that resonated in these rings;^34,35 4) hetero-typed: spanning a large number of lattice points with different lattice constants, holes sizes, holes locations, or shapes to generate resonant modes.^36,37 In many cases, the PC waveguide, which is formed by removing a row of air holes, enables a transmission spectrum to be recorded after light is transmitted through the PC cavity. In general, the straight waveguide is used for routing light to an Ln-typed, ring-typed, or hetero-typed cavity, and side-coupling light to an Hm-typed or Ln-typed cavity.

Fig. 1 Schematic structures of different PC cavities. (a) H0 cavity, (b) L4 cavity, (c) hetero cavity and (d) ring cavity.

As for sensing applications, the enhanced interaction effect gives rise to an optical mode of the PC cavity whose resonant wavelength is highly sensitive to the local refractive-index variation in its surrounding medium. This, in turn, makes it useful for highly sensitive sensing purposes, since the analyte of interest within the PC cavity can greatly change the local refractive index. In this regard, PC cavities are widely utilized to develop sensing platforms for multiple applications in chemical sensing and biosensing. Briefly, a biochemical interaction (e.g., binding) on the PC cavity may cause a change in the effective refractive index of air holes in the PC cavity, which will then result in a shift of the resonant wavelength that is proportional to the concentration of the biochemical target. To obtain the wavelength shift, almost all the published biosensor configurations based on the PC cavity share the same detection instrument configurations, in which a low-cost broadband source and a coupling lens are used to couple light into the PC waveguide, with an optical spectrum analyzer or a power meter on the other side of the PC waveguide to obtain the resonant spectrum. In particular, different PC cavities can be integrated on one chip, and each PC cavity will independently shift its resonant wavelength in response to corresponding changes in measurement signals, without perturbing the others. As a result, all the wavelength shifts of the different PC cavities that carried the information of different measurement signals can be interrogated simultaneously by using one optical spectrum analyzer, which provides an ideal platform for realizing ultra-compact lab-on-a-chip applications with dense arrays of functionalized spots for multiplexed sensing.^18,38

3. Sensing applications

Recent advances in optofluidics technology hold promise for providing compact and portable platforms in biochemical sensing applications to realize rapid, highly sensitive, label-free, and on-chip detection of biochemical molecules. The PC cavity has been used to detect changes in the refractive index of liquids or gases and also changes in the refractive index of the sensor surface induced by adsorption of either chemical or biological molecules. Combined with the considerable benefits of the PC-cavity-based sensor, optofluidic PC-cavity sensors have been broadly employed to detect multiple biochemical targets, such as protein, DNA, avidin, nanoparticles, and cancer cells. Here, we summarize the typical applications of the optofluidic PC cavity in on-chip biochemical sensors. For each sensing application, the structural configuration, sensing principle, sensing properties, advantages and disadvantages will be reviewed in detail.

3.1 On-chip detection of gas concentration

With the increasing depletion of coal, oil, and other fossil fuels, measurement of gas concentration has assumed increasing importance.³⁹ In particular, some trace gases need to be measured in a narrow space, which immediately invalidates most gas sensors. The periodic air hole microstructure of a PC cavity is a natural candidate for housing gas analytes, so it is easy to think that the refractive index of the air hole, as well as the resonant wavelength of the PC cavity, will change with the concentration variation of an infiltrated gas. In comparison with traditional gas sensors, PC-cavity-based gas sensors exhibit the merits of both PC-cavity sensors and optical gas sensors, and the volume can be drastically reduced. By using this measurement principle, Sünner et al. proposed a hetero-typed PC cavity by modulating the radii of the first row of air holes adjacent to the waveguide.⁴⁰ While this sensor structure could be used to identify vacuum, nitrogen, and SF₆, its refractive-index sensitivity was only 80 nm per refractive-index units (RIU). Based on this, Jágerská et al. improved the sensitivity by introducing an air slot in a hetero-typed PC cavity.⁴¹ An experimental sensitivity up to 510 nm RIU⁻¹ and a detection limit higher than 1 × 10⁻⁵ RIU were demonstrated. However, to obtain high-quality factor and high sensitivity, the structure of the hetero-typed PC cavity needs to be carefully optimized and finely tuned, resulting in a low tolerance to fabrication deviation. To resolve this problem, Li et al. recently proposed an Ln-slot PC cavity for gas-sensing applications,⁴² as shown in Fig. 2. Beyond the simple structure and high fabrication tolerance of this PC cavity, a quality factor exceeding 30 000 and sensitivity up to 421 nm RIU⁻¹ were experimentally demonstrated, potentially greatly extending its application in gas sensors. However, it should also be mentioned that the refractive index of gas is relatively low (∼1.0 RIU) and the corresponding refractive-index variation due to the gas concentration change is usually lower than 10⁻⁴ RIU. Furthermore, the variations of any other gases or environmental parameters can all result in the refractive-index variation of the air hole in the PC cavity. Therefore, the above proposed gas sensors based on PC cavity remain conceptual, making them unsuitable for identifying the concentration of target gas, and creating very poor sensitivities compared with other conventional gas sensors.

Fig. 2 Microscopic structure (a) and gas sensing properties (b) of Ln slot PC cavity.⁴²

In order to address these problems and capitalize on the advantages of the ultra-compact and high refractive-index sensitivity of the PC-cavity sensor, our group first proposed a gas concentration sensor using a cryptophane-E-infiltrated PC cavity,⁴³ as shown in Fig. 3. The refractive index of the cryptophane-E would only change with variation in the concentration of methane, which would then induce a resonant wavelength shift of the PC cavity. By combining the selective adsorption property of the cryptophane-E to methane and the excellent resonant properties of the PC cavity, the resonant spectrum of the PC cavity would sharply shift with the change in concentration of methane, allowing high precision and highly sensitive measurement of methane concentration. Finally, a theoretical detection limit of 697.35 ppm for sensing of methane concentration was achieved. This technology provides a new direction for the gas sensor based on PC cavity. Next, we further proposed a gas-sensing system based on the fiber loop ring-down technique to realize the high-precision demodulation of the output resonant spectrum of the PC cavity. In particular, slow light was introduced to enhance the refractive-index sensitivity of the PC cavity.⁴⁴ For this design, the detection limit was improved to 2.37 ppm. However, it should be mentioned that the sensing properties of this sensor are also not as good as some conventional gas sensors, whose detection limit may be as low as 1 ppb.⁴⁵ At the same time, Liapis et al. proposed a compact and high-resolution on-chip spectrometer by using a thermally tuned PC cavity, as shown in Fig. 4. This chip-scale spectrometer could be used to measure the absorption spectra of both acetylene and hydrogen cyanide in the 1550 nm spectral band.⁴⁶ However, the detection limit of gas concentration was not given. From the above schemes, it is found that the PC cavity can be used for on-chip detection of gas concentration, which behaves in miniaturized size. However, the sensitivity and precision of concentration measurement still need to be improved.

Fig. 3 Schematic structure (a) and gas sensing properties (b) of a cryptophane E infiltrated PC cavity. Adapted from ref. 43, copyright 2015.

Fig. 4 Schematic structure (a) and resonant properties (b) of thermally tuned PC cavity. Adapted from ref. 46, copyright 2016.

3.2 On-chip detection of liquid concentration

The detection of liquid concentration also utilizes the refractive-index variation of the air hole, by infiltrating the test liquid into certain holes of the PC cavity. As a result, the resonant wavelength of the PC cavity will change with variations in the liquid concentration. To increase the measurement sensitivity, many types of PC cavity structures have been proposed.

The first proposal is the hetero-typed PC cavity. In 2009, Di Falco et al. fabricated a hetero-typed PC cavity by gradually adjusting the width of the air slot,⁴⁷ as shown in Fig. 5. This peculiar cavity possesses a high-quality factor of about 50 000, and enables the detection of a slight refractive-index change with high sensitivity up to 1538 nm RIU⁻¹. However, the gradual adjustment of slot width is very difficult, which will increase the complexity and cost of PC-cavity fabrication.

Fig. 5 Schematic structure (a) and liquid concentration-sensing properties (b) of one hetero-typed PC cavity. Adapted from ref. 47, copyright 2009.

The second proposal is the ring-typed PC cavity. In 2012, Hosseinibalam et al. proposed another PC cavity, which was composed of a half-ring cavity that was side-coupled to an optofluidic slow light PC waveguide,⁴⁸ as shown in Fig. 6. Simulation results demonstrated that the sensitivity to refractive-index change could be increased from 77 nm RIU⁻¹ to 293 nm RIU⁻¹ when slow light was introduced.

Fig. 6 Schematic structure (a) and liquid concentration sensing properties (b) of one optofluidic based ring-typed PC cavity. Adapted from ref. 48, copyright 2012.

Coincidentally, Lai et al. have demonstrated experimentally that in a side-coupled cavity-waveguide configuration, group velocity of the propagating mode in the coupled waveguide plays an important role in enhancing the sensitivity.⁴⁹ Taking a linear L13 PC cavity for example, the sensing sensitivity would increase from 57 nm RIU⁻¹ to 66 nm RIU⁻¹ when the group index in the coupled waveguide was increased from 10.2 to 13.2, with nearly the same quality factor of 7000. However, engineering for the highest sensitivity in such a planar-integrated sensor requires careful design of the PC structure to enhance the group index of slow light, which still needs to be researched in the future.

On the basis of the half-ring cavity, Ho et al. investigated another PC cavity which comprised three hexagonal nano-rings.⁵⁰ It was demonstrated that the symmetrical resonance output of the three PC cavities could be used for simultaneous sensing of three variables at same input frequency.

The third proposal is the Ln-typed PC cavity. In 2013, Olyaee et al. proposed a PC cavity by introducing waveguides and a cavity into the periodic PC structure.⁵¹ The waveguides were obtained by eliminating two groups of air holes, and the cavity was formed by changing the dimensions of the air holes. The simulation results showed that the resonant wavelength of the PC cavity would shift to longer wavelengths with trapping of biochemical molecules, with a sensitivity of 63.1 nm RIU⁻¹. This kind of PC cavity has relatively high transmissivity, but its refractive-index sensitivity is low.

Then, in 2014, Najafgholinezhad et al. proposed another shoulder-coupled PC cavity, which was created by eliminating a row of holes and substituting a hole with a different radius.⁵² As a result, the designed structure had a high-quality factor of about 15 000 and a sensitivity of approximately 141.67 nm RIU⁻¹. Furthermore, the presence of fluid with a negative thermo-optic coefficient could balance the thermal drift of the main material of the PC cavity, such as silicon, resulting in a low-temperature sensitivity of about −0.0142 nm °C⁻¹.

In the same year, Zhou et al. also improved this structure by modifying the number and sizes of the air holes nearest to the PC cavity,⁵³ as shown in Fig. 7. Simulation results demonstrated that the refractive-index sensitivity could be up to 131.70 nm RIU⁻¹. In addition, through changing the number of functionalized holes, the sensitivity could also be increased.

Fig. 7 Schematic structure (a) and liquid concentration sensing properties (b) of one Ln-typed PC cavity.⁵³

On this basis, Huang et al. proposed a ring-slot PC cavity, whose resonant properties could be controlled by adjusting the width of the ring-slot.⁵⁴ Simulation results demonstrated that a refractive-index sensitivity of 160 nm RIU⁻¹ and detection limit of 8.75 × 10⁻⁵ RIU could be obtained, when the width of the ring-slot was 0.28a. The width and refractive index of the ring-slot have a great influence on the resonant properties of the PC cavity. Besides, the ring-slot is eminently suitable for housing the liquid to be measured. Therefore, this ring-slot PC cavity can be applied well in sensing the concentration of the liquid.

The fourth proposal is the Hm-typed PC cavity. In 2009, Yang et al. presented nanoscale PC sensor arrays on a monolithic substrate, which could be used as an optofluidic architecture for performing highly parallel detection of liquid concentration.⁵⁵ The architecture consisted of arrays of lattice-shifted resonant cavities side-coupled to a single PC waveguide, as shown in Fig. 8. Each resonant cavity was formed by shifting the positions of two air holes. Simulation results demonstrated that a refractive-index sensitivity of 115.60 nm RIU⁻¹ could be achieved and the refractive-index detection limit was approximately 8.65 × 10⁻⁵ RIU for this device. Besides, by setting different cavity spaces, the resonant peaks of the different PC cavities were different, and each independent resonant peak would shift with the refractive-index change of the corresponding cavity. The fabrication is relatively simple, but the detection sensitivity still needs to be increased.

Fig. 8 Schematic structure (a) and liquid concentration sensing properties (b) of one Hm-typed PC cavity. Adapted from ref. 55, copyright 2011.

Then, in 2014, Liu et al. proposed radius-graded PC sensor arrays applied on a nanoscale optical platform for refractive-index sensing.⁵⁶ Two L3 cavities and two H1 cavities were multiplexed and interlaced on both sides of a PC W1 waveguide. In response to the refractive-index changes of air holes surrounding the PC cavities, four interlaced and symmetrical cavities were shown to independently shift their resonant wavelength without crosstalk. The simulation results demonstrated that the refractive-index sensitivity of the sensor array could vary from 66.67 to 136.67 nm RIU⁻¹ when the number of functionalized air holes was changed from 4 to 21. This design allows different cavities multiplexed on both sides of the waveguide. Meanwhile, the radius-graded PC with more symmetrical and interlaced cavities is better for large integration in the sensor arrays.

By utilizing this structure, we have proposed a new method for the simultaneous measurement of liquid concentration and temperature.⁵⁷ In this design, two cascaded cavities (H0 cavity and H1 cavity) were separately located adjacent to one waveguide. A standard liquid with a fixed and known concentration was infiltrated in the defected holes of the H1 cavity, and the measured liquid with unknown concentration was infiltrated in the defected holes of the H0 cavity. The two cavities had two different and independent resonant dips, which could be simultaneously observed at the output spectrum of the waveguide. Furthermore, the variation of the test liquid concentration and the variation of temperature could all cause the wavelength shifts of the two resonant dips. However, the shift sensitivities are different. Therefore, according to the dual-wavelength matrix method, the liquid concentration measurement with a resolution of 9.4322 ppm and the temperature measurement with a resolution of 0.0136 °C were simultaneously obtained by measuring the shifts of the two resonant dips.

3.3 On-chip detection of biomolecule concentration

3.3.1 Sensing of protein. By chemically modifying and subsequently immobilizing special recognition materials on the hole surface of the PC, the interaction effect between biomolecules and the recognition material can lead to refractive-index variation, shifting the resonant wavelength.

In 2007, Lee et al. reported that an H0-typed PC cavity with only one spot defect (see Fig. 9) was able to detect a protein molecule as small as 2.5 fg, while the active sensing volume could be as low as 0.15 μm².⁵⁸

Fig. 9 Schematic structure of H0-typed PC cavity for protein concentration measurement. Adapted from ref. 58, copyright 2007.

Then, in 2009, Dorfner et al. proposed an L3-typed PC cavity (see Fig. 10) for the sensing of bovine serum albumin.⁵⁹ The cavity was coupled to a ridge waveguide that allowed the introduction of a fluid flow cell on a chip. A response of ∂λ/∂c = (4.54 ± 0.66) × 10⁵ nm M⁻¹ was measured, which lead to a detection limit as good as ∂m = 4.0 ± 0.6 fg or ∂m/∂A = (4.9 ± 0.7) × 10² pg mm⁻² in the sensitive area.

Fig. 10 Schematic structure (a) and liquid concentration sensing properties (b) of one Hm-typed PC cavity. Adapted from ref. 59, copyright 2009.

Later in 2011, Pal et al. proposed a point-defect PC cavity for label-free and error-corrected detection of human immunoglobulin (IgG) molecules.⁶⁰ Experimental results showed that the structure had a refractive-index detection limit of 10⁻² RIU and a biosensing sensitivity of 2.3 ± 0.24 × 10⁵ nm M⁻¹, with an achievable lowest detection limit of 1.5 fg for the human IgG molecule. Additionally, the experimental results demonstrated that the PC cavity was specific in IgG detection and provided a concentration-dependent response consistent with Langmuir behavior. This PC-cavity device shows outstanding potential as a microscale label-free error-correcting sensor, and may have future utility in ultrasensitive multiplex devices.

In 2012, Lai et al. experimentally demonstrated that an Ln-type PC-cavity-based resonant sensor coupled to a PC waveguide could be used for protein sensing.⁶¹ It was demonstrated that increasing the length of the PC cavity could enhance the quality factor of the resonance by an order of magnitude and increase the resonant wavelength shift, while retaining compact device characteristics. As a result, a high-quality factor of Q ∼26 760 and a detection limit down to 15 ng ml⁻¹ and ∼110 pg mm⁻² in protein sensing were experimentally demonstrated.

Then, in 2015, Yang et al. fabricated a high sensitive L13-type PC cavity with nanoholes, and measured its sensitivity to pancreatic cancer biomarkers in patient serum samples.⁶² As a result, a sample with 0.03 pM concentration was experimentally detected, which was 10-times lower than the dilution achieved with enzyme-linked immunosorbent assay (ELISA).

3.3.2 Sensing of DNA. A PC cavity has also been used for the detection of DNA. In 2010, Hsiao et al. theoretically proposed a PC nano-ring cavity by removing holes of a hexagon from a 2-dimensional (2D) PC slab in a hexagonal lattice (see Fig. 11).⁶³ Biomolecules (e.g., DNAs) trapped in a hole would be functionalized with the molecule probes, and then shift the wavelength of the resonant peak derived in the output terminal. The minimum detectable DNA weights in a sensing hole for a nano-ring resonator of two-hole and three-hole coupling distances were derived as 0.23 fg and 0.2 fg, respectively. This technique shows promising applications in situations which demand detection of biomolecules down to the level of a single copy of DNA. In addition, when two ring PC cavities were cascaded together, it would be possible to detect two kinds of target DNA molecules or realize a temperature-compensated biosensor.⁶⁴ A major advantage of this structure is that it allows the measurement of multiple biomolecules at the same input port through the use of appropriate sensing holes, and offers the possibility to implement the corroboration mechanism by exchanging the input and output ports.⁵⁰

Fig. 11 Schematic structure (a) and sensing property (b) of ring-typed PC cavity for DNA weight measurement. Adapted from ref. 63, copyright 2010.

In 2013, Olyaee et al. proposed an H1-typed PC cavity (see Fig. 12) for the detection of biomaterials such as DNA molecules and proteins.⁶⁵ A quality factor and sensitivity of about 4000 and 1.63 nm fg⁻¹, respectively, were obtained. Furthermore, the bulk refractive-index sensitivity for this structure was about 165.45 nm RIU⁻¹. Besides, to enhance the number of detected target molecules, a multichannel biosensor was designed by lattice shifting a single hole around the cavity. Each channel had a different resonant cavity wavelength and the filling of analyte in selected holes independently caused a resonant wavelength shift.

Fig. 12 Schematic structure (a) and sensing property (b) of H1-typed PC cavity for DNA weight measurement. Adapted from ref. 65, copyright 2013.

Then, in 2015, these researchers further presented a diamond-shaped sensor based on a PC nano-ring cavity.⁶⁶ The ring cavity with two end waveguides on both sides, were placed in the middle of the PC structure, as shown in Fig. 13. Simulation results demonstrated that the resonant wavelength shift was linearly proportional to the refractive-index variation in the refractive-index range of 1.33–1.54. The quality factor and the sensitivity of the biosensor were obtained at about 3700 and 3.4 nm fg⁻¹, respectively. The minimum detectable biomolecule weight in a sensing hole for a diamond-shaped nano-ring resonator was derived as 0.029 fg.

Fig. 13 Schematic structure (a) and sensing property (b) of ring-typed PC cavity for protein concentration measurement. Adapted from ref. 66, copyright 2015.

3.3.3 Sensing of avidin. In 2009, Zlatanovic et al. reported the first demonstration of the sensitive detection of avidin to a surface-immobilized biotinylated bovine serum albumin (BSA), by using a PC cavity with only one spot.⁶⁷ The proposed sensor could able to detect the avidin with a concentration of 20 pM (corresponding to less than 4.5 fg of bound material on the sensor surface and fewer than 80 molecules in the modal volume of the cavity).

By combining the spatial confinement of the optical field provided by a slot waveguide with the temporal confinement of the optical field in a PC cavity, Scullion et al.⁶⁸ first demonstrated the possibility of the slot PC cavity (see Fig. 14, lattice constant 490 nm, cavity period 460 nm, hole radius 135 nm, and slot width 120 nm) in the detection of dissolved avidin concentration as low as 15 nM or 1 μg ml⁻¹, with a sensing area of only 2.2 μm². The high sensitivity over an extremely small area is due to the strong modal overlap with the analyte enabled by the slotted waveguide cavity geometry.

Fig. 14 Microscopic structure (a) and sensing property (b) of slot PC cavity for avidin concentration measurement. Adapted from ref. 68, copyright 2011.

Then, in 2012, Chakravarty et al. proposed an L13-typed PC cavity as shown in Fig. 15, in which resonance showed a high-quality factor ∼9300 in the bio-ambient phosphate buffered saline (PBS) and high sensitivity.⁶⁹ Experimental results demonstrated that an antibody mass sensitivity of 8.8 atto-grams with a sensitivity per unit area of 0.8 pg mm⁻² could be achieved.

Fig. 15 Microscopic structure (a) and sensing property (b) of L13-typed PC cavity for antibody concentration measurement. Adapted from ref. 69, copyright 2012.

Upon this structure, Zou et al. demonstrated that 1 pM (67 pg ml⁻¹) and 50 femto-molar (3.35 pg ml⁻¹) concentrations of avidin binding to biotin in PBS could be detected for the L21 and L55 PC microcavities respectively.⁷⁰

At the same time, Chakravarty et al. gave detailed analyses of quality factor, fill fraction, and group index of this PC device, to the detection limit for bulk chemical sensing and the minimum detectable biomolecule concentration in biosensing. Slow light in a two-dimensional PC provided the opportunity for significant reduction of the detection limit below 1 × 10⁻⁷ RIU, which enabled a highly sensitive sensor in diverse application areas. It was experimentally demonstrated that a concentration of 1 fM (67 fg ml⁻¹) for the binding between biotin and avidin could be detected.⁷¹

3.4 On-chip detection of nanoparticle

The ultra-small mode volume of the PC cavity plays an important role in single nanoparticle detection. When a nanoparticle falls in the vicinity of the strongly localized optical field (sensitive region), the resonant wavelength will undergo a gentle shift. Based on the perturbation theory, the resonant shift caused by the nanoparticle is determined by:⁷²where ε_p is the permittivity of the nanoparticle, ε_s is the permittivity of the surrounding environment, V_p is the volume of the nanoparticle, E_p is the optical field where the nanoparticle allocates, and is the overall optical energy inside the cavity, which is proportional to the mode volume.

From the equation shown above, a larger wavelength shift is generated as long as the mode volume is smaller on a condition of the same particle size. As previously mentioned, PC cavity can confine the electric field to a very small volume, of the order of a few cubic wavelengths. If a particle is delivered to this high-field region (sensitive region) on the sensor surface, single-particle sensitivity may be achieved. Therefore, there is a significant interest in developing a PC cavity for the ultrasensitive detection of nanoparticles such as viruses.

In 2007, Lee et al. demonstrated that the PC cavity can be used for the detection of a single latex particle that has a diameter of 50 nm.⁷³ The slab-PC consisted of a 685 nm diameter microcavity (see Fig. 16) where a significant amount of electric field was confined. The resonant redshift would increase as the latex sphere diameter increased. A particle that has a diameter of 370 nm would induce a redshift of 4.2 nm. Further, the authors reported that the electric field was concentrated close to the edge of the central hole, which made this region more sensitive to a particle diameter change than the center of the hole.

Fig. 16 Microscopic structure (a) and sensing property (b) of PC cavity for nanoparticle diameter measurement. Adapted from ref. 73, copyright 2007.

Then, in 2010, Baker et al. utilized a defect-free slab-PC design to demonstrate sensitive and size-selective detection of the biological particle.⁷⁴ In their experiments, the infiltrations of latex particles with diameters of 260 and 320 nm into the PC lattice holes of 280 nm in diameter were investigated. A significant redshift in the band-edge of the PC was observed for the infiltration of smaller particles, thus demonstrating a size-selective particle detection. With this PC structure, it is possible to detect low numbers (<200) of randomly bound virus-sized particles.

In 2013, Descharmes et al. demonstrated a resonant optical trapping mechanism based on a PC cavity (see Fig. 17).⁷⁵ The PC cavity was implemented in a 30 mm × 12 mm optofluidic chip, which consisted of a patterned silicon substrate and an ultrathin microfluidic membrane for particle injection and control. It was demonstrated that the particle induced a large resonant shift of the cavity mode, amounting to several linewidths. This shift was exploited to detect the presence of a particle within the trap and to retrieve information on the trapped particles.

Fig. 17 Microscopic structure (a) and sensing property (b) of H1-typed PC cavity for nanoparticle detection. Adapted from ref. 75, copyright 2013.

3.5 On-chip detection of cancer cell

Cancer has become one of the leading diseases world-wide, which results in increased morbidity and mortality. Developing a fast, efficient, and accurate method for the detection and diagnosis of cancer in the early stages can contribute to better treatment outcomes and significantly increase the quality of life for cancer patients. The refractive-index ranges of normal cells and cancerous cells are reported as 1.35–1.37 and 1.39–1.401 respectively. Therefore, many PC cavity sensors have been widely employed in the refractive-index detection of cancerous cells.

In 2013, Chakravarty et al. proposed a label-free PC cavity biosensor to detect the epithelial-mesenchymal transition (EMT) transcription factor, ZEB1, in lysates from NCI-H358 lung cancer cells.⁷⁶ By using a L13 PC cavity, an estimated concentration of 2 cells per μL was demonstrated. Multiplexed sensors permit simultaneous detection of many binding interactions with specific immobilized antibodies from the same bio-sample at the same instant of time.

Later, in 2016, an H1-typed PC cavity was proposed for diseased cell detection.⁷⁷ It was observed that the resonant wavelength of the PC cavity would redshift on increasing the refractive index of the nanocavity imposed by the presence of a cancer cell. This system was able to differentiate a slight change in resonant peak in the transmission spectra when Jurkat and HeLa cell lines were introduced (refractive-index difference of 0.002 RIU).

As for the cell study, it should be mentioned that PC-enhanced microscopy, a new form of optical microscopy that uses a PC surface to dynamically detect and visualize biomaterial-surface interactions, has the ability to make high-resolution images of attached cells, thus enabling us to study cell functions (including cell adhesion, migration, apoptosis, and differentiation).^78,79

3.6 Summary and comparison

From the above examples, we can find that with an appropriate choice of receptor to infiltrate the air holes of the PC cavity, a PC cavity sensor could be used for biochemical sensing. The properties of such as system can be further improved by designing PC cavities with higher quality factors and by localizing the target molecular recognition processes in the defect region. The small size of the device, combined with the strong integration of multiple PC cavities, provides a promising potential for large arrays of independent sensors on a centimeter-sized chip. It should be noted that the electromagnetic fields distributions and the sensing properties of the PC cavity are related to the refractive index of the air holes. As different analytes have different refractive indices, the structural design of the PC cavity is not common to all measurement parameters. Specially, for PC-cavity sensors that operate in a liquid environment, the covering of liquid will vastly change the refractive index of the air holes, which will then influence the quality factor and bulk refractive-index sensitivity of the PC-cavity. Therefore, the structural design and fabrication of the PC cavity need to consider the refractive-index range of the target analyte under different concentrations. The aim is to ensure that the PC-cavity sensor can work well with liquid infiltration and exhibit good sensing properties under different liquid concentrations. Table 2 summarizes the structures and corresponding properties of optofluidic PC cavities that are used for biochemical sensing.

Table 2 Structures and corresponding properties of biochemical sensors based on optofluidic PC cavity

Sensing parameter	Structure type	Sensitivity	Detection limit	Quality factor	Ref.
Gas concentration	Hetero	80 nm RIU^−1	1 × 10^−5 RIU	40 000	40
	Hetero	510 nm RIU^−1	1 × 10^−5 RIU	26 000	41
	Ln-slot	421 nm RIU^−1	1 × 10^−5 RIU	30 000	42
	Ring	363.8 nm RIU^−1	697.35 ppm	12 923	43
	Shoulder-coupled	450 nm RIU^−1	2.37 ppm	1105	44
Liquid concentration	Hetero	1538 nm RIU^−1	7.8 × 10^−6 RIU	4000	47
	Half-ring	293 nm RIU^−1	—	950	48
	L13	66 nm RIU^−1	—	7000	49
	Ln	61.3 nm RIU^−1	0.006 RIU	5248	51
	Shoulder-coupled	141.67 nm RIU^−1	—	15 000	52
	Ring-slot	160 nm RIU^−1	8.75 × 10^−5 RIU	11 477	54
	Hm	115.6 nm RIU^−1	8.65 × 10^−5 RIU	2761	55
	L3 + H1	136.67 nm RIU^−1	6.5 × 10^−3 RIU	2000	56
	H0 + H1	620 nm RIU^−1	9.4322 ppm	2480	57
Protein	H0	—	2.5 fg	—	58
	L3	24.7 nm pg^−1	4.0 fg	—	59
	Point defect	2.3 × 10^5 nm M^−1	1.5 fg	500	60
	Ln	—	110 pg mm^−2	26 760	61
	L13	—	3.35 pg mL^−1	15 000	62
DNA	Nano-ring	0.5 nm fg^−1	0.2 fg	3200	63
	H1	1.63 nm fg^−1	0.061 fg	4000	65
	Nano-ring	3.4 nm fg^−1	0.029 fg	3700	66
Antibiotic	H0	176 nm RIU^−1	20pM	690	67
	Slot	—	15 nM	3000	68
	L13	—	0.8 pg mm^−2	9300	69
	L55	—	50 fM	14 000	70
	L55	—	1 fM	10 000	71
Nanoparticle	Microcavity	—	≤50 nm	2000	73
	Point defect	—	50 nm	2000	75
Cancer cell	L13	—	2 cells	26 760	76
	Shoulder-coupled	388.57 nm RIU^−1	—	4857	77

---

4. Challenges and future research directions

At present, the integration of PC-cavity structures with emerging technologies is promising for the on-chip sensing of biochemical molecules, owing to the compact, flexible, and easy-to-use platforms. However, the field of PC-cavity-based, on-chip biochemical sensors is still at an early stage, and some challenges remain that need to be resolved.

4.1 High-precision fabrication and infiltration of PC cavity

The PC cavities presented above are mainly fabricated on a silicon-on-insulator (SOI) substrate by using an electron beam lithography method. Considering the current technology of PC fabrication, the position and size of the critical hole can only be maintained within 1 nm (ref. 80) and 2–4 nm,⁸¹ respectively, thus resulting in low reproducibility of these PC structures. However, these fabrication errors have a large influence on the properties of the PC. It was estimated that a 1% fluctuation in hole size would cause the transmission attenuation of 15 dB mm⁻¹.⁸² Further, to maintain the transmission of a PC with a length of 1 mm above 90%, the position error should be below 0.3% and the size error should be below 0.5%. In particular, the fabrication errors of the cavity region of the PC cavity will have a more significant influence on the resonant properties of the PC cavity, due to the fact that the interaction strength between the optical field and the materials of the defected region is relatively strong. Hagina et al.⁸³ demonstrated that the quality factor of a hetero-typed PC cavity would be reduced to one eighth of the ideal value when only a 1 nm hole size error was introduced. However, due to the particular micro-nano and porous structure of the PC, the fabrication errors of the PC cavity are still complicated, random, unpredictable, and immeasurable. Therefore, simplification of the fabrication complexity and realization of the high-precision fabrication of the PC cavity are major challenges in the future.

As for biosensing, which relies on the binding of the target molecule and receptor antibody/protein, the PC-cavity-based sensor can sense only the analytes that land in the high-field region/sensitive region/defected region of PC cavity, but not those that land in all the other places. The vast majority of molecules on the non-sensitive region do not contribute to a wavelength shift of the resonant spectrum. In other words, a biosensor may be sensitive to a single virus or single nanoparticle only if this virus or nanoparticle was landed in the high-field region/sensitive region/defected region of the PC cavity. Therefore, it is necessary to infiltrate the analyte to land on the specific holes of the PC cavity, and not all the other places where the sensor lacks sensitivity. Besides, the sensing properties of the PC cavity are inescapably affected by the precision of the infiltration process. At present, some infiltration methods for PC devices have been proposed, by using an integrated optofluidic circuit that is bonded onto the PC chip⁸⁴ or lithographic masking,⁸⁵ a modified confocal laser scanning microscope equipped with a micro-infiltration system,⁸⁶ a computer-controlled micro-tip,⁸⁷ or micro-pipette⁸⁸ whose size is comparable to the air holes to be infiltrated. These technologies are able to achieve local filling of one or more nanometer holes in the specific location of the PC with high precision and good reproducibility. However, during biosensing experiments, after each measurement of a certain concentration of target molecule, the PC device should be washed a number of times before the effective resonant wavelength shift is measured. This will require considerable time, resulting in a low throughput of the PC cavity-based biosensor. Therefore, methods of infiltrating certain air holes of the PC cavity with high precision and high speed is also a major challenge in the future work.

4.2 Integrating sensing platform

Most biochemical sensors based on a PC cavity operate as a point or single mode, whose throughputs are low due to the necessity to measure each detected region separately with an individual detector, and thus also increase the sample volume needed for measurement. To overcome these drawbacks, an ideal method is to detect multiple targets in one integrated biochemical sensing platform. This feature will provide a wide window to comprehensively evaluate many biomolecules, such as proteins, DNA molecules, small molecules, or virus particles. For this reason, many integrated sensing platforms based on cascaded PC cavities have been developed.^60,78–85

In 2011, Pal et al.⁶⁰ demonstrated an integrated lgG sensor, in which three PC cavities were cascaded in series. However, the sensor volume was too large and not suitable for sensing applications. Then, in 2012, Wang et al.⁸⁹ built a theoretical model of an integrated parallel self-collimation sensor array. However, only three sensors could be integrated on the monolithic platform, resulting in a low integration density. At the same time, Yang et al.⁹⁰ theoretically investigated the integrated properties of the H0-typed PC cavity for multi-point refractive-index sensing. Then, in 2014, Yang et al.⁹¹ designed a PC beam-splitter, which consisted of parallel output waveguides. It was demonstrated that some H0-typed PC cavities could be side-coupled to any waveguides, and allowed the implementation of a simple but functional sensor array. At the same time, Liu et al.⁵⁶ proposed a radius-graded PC sensor array, where two L3 cavities and two H1 cavities were multiplexed and interlaced on both sides of a PC waveguide. In addition, Olyaee et al.⁶⁵ have demonstrated that the sensor array could also be realized when some H1-typed PC cavities were side-coupled to a PC waveguide. Later, in 2016, to enhance the measurement sensitivity, the integrated slot the PC cavity was introduced (see Fig. 18) by Fu et al.⁹² and Yang et al.⁹³

Fig. 18 Schematic structure of integrated slot PC cavity.⁹²

However, the main drawback of these side-coupled resonant cavity arrays was that the greater the number of PC cavities integrated on the monolithic platform, the narrower the spacing of the adjacent resonant peaks. For sensing application, the resonant peak might cross with each other if the variation of one resonant signal caused by the target parameter change is too large, which will result in difficulties in recognizing the sensing signals from different cavities.

To effectively increase the integrated density of the sensor array and avoid crosstalk of adjacent PC cavities, Huang et al.⁹⁴ proposed a low crosstalk ring-slot array structure for label-free multi-parameter sensing. The structure was based on an array of three ring-slot and input/output line defect coupling waveguides (see Fig. 19(a)). Each ring-slot cavity had a slightly different cavity spacing and a different resonant frequency. Then, in 2016, to further enhance the sensitivity of each sensor, Zhou et al.⁹⁵ proposed a new integrated structure using a well-designed 1 × 3 PC waveguide splitter and an elaborate single-slot PC cavity (see Fig. 19(b)).

Fig. 19 Schematic structure of integrated PC cavity with (a) three ring-slot and (b) PC waveguide splitter. Adapted from ref. 94, copyright 2014, and ref. 95, copyright 2016.

Although the above cascaded PC cavities can improve the integration degree of PC-cavity-based sensor and then achieve simultaneous multi-element detection, the surface of each PC cavity in the array should be immobilized with a specific binding material to detect the corresponding element in the mixture, which severely limits the sensing flexibility and requires massive external equipment and complex device packaging. In comparison with the normally-illuminated PC biosensors that have a very high degree of multiplex,^11,16 the multiplexing throughput of the PC-cavity-based biosensors should also be improved. Recently, Zhang et al.⁹⁶ proposed another integrated scheme, by using the real and imaginary parts of the refractive index. Experimental results demonstrated that both the resonant wavelength and linewidth changed linearly with the real and imaginary parts of the refractive index, respectively. Therefore, two mutually independent physical quantities were obtained during the detection, and the concentration composition of a ternary mixture, which had two unknown parameters, could be determined without any surface immobilizations; thus providing an effective solution to resolve the limitations in multiplexing throughput of PC-cavity-based biosensors.

4.3 Response time

A PC-cavity-based biosensor can detect a single biomolecule, but it should be mentioned that the diffusion velocity of a biomolecule from microfluidic will limit the minimum detectable analyte concentration.⁹⁷ For ease of measurement and device portability, a common method is to deliver the measured sample to the biosensor by using on-chip streams of fluid, which is driven by pressure or electrokinesis.^68,96 The microfluidic channel layer that is placed on the top of the PC layer can be fabricated by soft lithography using a silicon template, and then bonded onto the PC chip after undergoing an oxygen plasma treatment. Then, in the detection process, molecules flowing above the sensor will diffuse down to the sensor surface, near the PC cavity. However, the detection should also take a few minutes in terms of practical measurement. In particular, in some filtration-typed sample preparation steps, it is required to concentrate targets in the sample, which also increases the device complexity and detection time. Considering the practical application perspective, biochemical sensors need to be fabricated with inexpensive materials and simple production techniques. Therefore, it is necessary to provide rapid, inexpensive, and multiplexed infiltration solutions.

4.4 Novel smart sensitive materials

In a biochemical sensor, the introduction of smart sensitive materials, such as hydrogels, polyionic liquids, graphene, and carbon nanotubes, is significant due to the fact that their physical or chemical properties will be modified along with surrounding responsive substances.^98–101 In particular, their incorporation with PC structures holds considerable promise for rapid, sensitive, and reliable biochemical sensing.^102–106 For instance, PC structures comprised of hydrogel materials can be used as biosensors for detection of DNA, proteins, antibodies, and enzymes by monitoring the changes in lattice spacing or refractive index.^102,103 In this respect, hydrogel-based PC structures provide quantitative spectral results of target biomolecule concentrations. Taking advantage of flexible (e.g., hydrogels) and smart (e.g., carbon nanotubes and graphene) materials, PC-based sensors will be an alternative to the current wearable continuous monitoring tools and sensors.¹⁰⁷

5. Conclusions

In this paper, the most typical on-chip biochemical sensors based on optofluidic PC cavities over recent years were reported, with specific focuses on their structures, development processes, sensing principles, advantages, and disadvantages. Besides, the existing challenges and future research directions were noted. The review of these reported works and their corresponding results demonstrates that PC cavities combined with optofluidic technologies have played very important roles in the biochemical sensing fields and will produce a significant industrial value. Clearly, readers who are interested in this field can not only see the special properties and flexibilities in the structural design of optofluidic PC cavity, but can also broaden their thoughts and innovate with new solutions to further exploit more novel biochemical sensors. In addition, more design schemes involving optofluidic PC cavities will be proposed and better on-chip biochemical sensing properties will be presented, along with technology developments of PC fabrication and microfluidic infiltration, which will then inspire a promising future for PC-based sensors.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported in part by the National Science Foundation for Distinguished Young Scholars of China under Grant 61425003, the National Natural Science Foundation of China under Grant 61703080, 61273059 and 61371200, the Fundamental Research Funds for the Central Universities under Grant N160404012 and N150401001, the Liaoning Province Natural Science Foundation under Grant 20170540314, and State Key Laboratory of Synthetical Automation for Process Industries under Grant 2013ZCX09.

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