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Abstract
A label-free biosensor based on a reflective microfiber probe for in-situ real-time DNA hybridization detection is proposed and experimentally demonstrated. The microfiber probe is simply fabricated by snapping a non-adiabatic biconical microfiber through closing the oxyhydrogen flame during fiber stretching. Assisted with the Fresnel reflection at the end of microfiber, a reflective microfiber modal interferometer is realized. The in-situ DNA hybridization relies on the surface functionalization of a monolayer of Poly-L-lysine (PLL) and synthetic DNA sequences that bind to a given target with high specificity. The detection processes of DNA hybridization in various concentration of target DNA solutions are monitored in real-time and the experimental results present a minimum detectable concentration of 10pM with good repeatability. Additionally, the detection specificity is also investigated by immersing the microfiber probe into the non-complementary ssDNA solutions and observing the spectral variation. The proposed biosensor has advantages of high sensitivity, compact size, ease of use and simple fabrication, which makes it has great potential to be applied in a lot of fields such as disease diagnosis, medicine, and environmental science.
© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement
1. Introduction
DNA hybridization is usually used to determine the genetic distance between two organisms. The analysis of specific DNA sequences is essential in various fields such as environmental science, disease diagnosis and pharmaceutical research, which has attracted the increasing interest of researchers. Fiber optic sensors have been implemented for label-free DNA detection in recent years due to their advantages of small size, high sensitivity and good compatibility with modern communication system [1–8]. Actually, the propagation of light in an optical fiber is usually confined in the core of the fiber, which limits its sensing applications due to the non-interaction of light with the surroundings. Therefore, it is essential to exploit novel fiber-optic structure to disturb the light propagation, thereby enabling the direct interaction with the surrounding. Until now, several fiber structures, including side polished fiber [9,10], U-shaped fiber [11], fiber gratings [12,13], as well as microfiber [14], have been proposed to tailor the light propagation and prompt the interaction of light with sensing materials. Among them, microfiber, with the diameter of several micrometers to tens micrometers, is the most advantageous platform for biochemical detection owing to its intrinsic strong evanescent field.
Heretofore, various structures based on microfiber has been proposed and demonstrated for DNA detection. As early as 2011, Zibaii et al. implemented the DNA hybridization detection using fiber taper interferometer [15] and its performance was improved by Huang et al. after a few years [16]. Besides that, many other microfiber-based interferometers including square-microfiber interferometer [17], microfiber-assisted Mach-Zehnder interferometer [18], microfiber Sagnac interferometer [19], microfiber coupler [20] and microfiber-capillary [21] have been employed for DNA or RNA detection. However, their transmission-type structure makes them inconvenient in practice, particularly in narrow and semi-enclosed space. In order to overcome this problem, some reflective microfiber sensors have been proposed. In 2015, Luo et al. reported a microfiber sensor assisted by the Fresnel reflection at the standard single-mode fiber (SMF) end [22]. Using the multimode microfiber interferometer, the sensor realized the simultaneous measurement of refractive index (RI) and temperature. In addition, Zhang et al. proposed and demonstrated a Microfiber Fabry–Perot interferometer (MFPI) for dual-parameter sensing [23]. The MFPI is fabricated by the taper-drawing microfiber at the center of a uniform fiber Bragg grating (FBG). Based on the Fresnel reflection or FBG, these sensors have achieved a reflective structure. However, the sizes of them are also compromised. For realizing the small size and reflective structure simultaneously, researchers have made great efforts to develop the reflective all-microfiber sensors. Recently, Liu et al. proposed and demonstrated a hybrid sensor based on tapered fiber Bragg grating (FBG) combined with a microfiber cavity (TFMC), achieving dual-parameter sensing of RI and temperature [24]. Although the size of this senor is further simplified by cutting a MFPI at the center spot with a sapphire, the fabrication is hard owing to the manual cutting. More recently, Sun et al. reported the applications of microfiber Bragg grating (mFBG) in DNA hybridization detection, which opens up a window of fabricating reflective microprobe biosensor [25]. However, the inscription of FBG is complicated and difficult in such a thin microfiber. The easy-fabrication and user-friendly reflective all-microfiber sensors are still clamored by researchers.
In this paper, we proposed and demonstrated a reflective microfiber probe for DNA hybridization detection. The reflective microfiber probe is simply fabricated by snapping a biconical microfiber through closing the oxyhydrogen flame during fiber stretching. Under the action of axial tension, a reflecting plane with high quality is naturally achieved due to the brittle fracture of microfiber. With the help of Fresnel reflection at the microfiber end, a microfiber modal interferometer for sensing measurement is realized. After functionalized with a monolayer of Poly-L-lysine (PLL) and a single-stranded DNA probe (ssDNA), the microfiber probe presented a high specificity for a given target ssDNA to form the double-stranded DNA(dsDNA). The hybridization processes of the target ssDNA with the various concentrations have been monitored in situ with the lowest concentration of 10pM. The detection process is implemented in a microfluidic chip which allows the trace detection of bio-samples. The proposed microfiber probe biosensors offer an attractive solution for rapid, highly sensitive detection of analytes in biochemistry, medicine, and environmental science.
2. Material and methods
The pristine SMF-28e optical fibers were purchased from YOFC. DNA oligonucleotides, Poly-L-lysine (0.1%w/v in water, the molecular weight = 150,000-300,000g/mol) and TE Buffer (PH = 8, and RI = 1.3332) were purchased from Sangon Biotech. (Shanghai, China). The sequences of customized DNA oligonucleotides are as follows:
Probe ssDNA: 5’>ACC GTA CGT TCA GAA CAG AGT CTT GA < 3’.
Complementary ssDNA: 5’>TCA AGA CTC TGT TCT GAA CGT ACG GT < 3’.
Non-Complementary ssDNA: 5’>ATC GCT CCA GAC TTG CAT CTA GAA TC < 3’.
Target ssDNA was diluted in TE buffer to concentrations of 1 pM, 10 pM, 100 pM, 1 nM, 10nM, 100 nM, and 1 µM, respectively. A probe ssDNA concentration of 10 µM was used.
2.1 The characteristics of microfiber probe
The microfiber probe in this work was fabricated through a flame heating-drawing system. The processes can be described as the two-step method: taper drawing-snapping. Firstly, a multimode microfiber is non-adiabatically tapered from a normal fiber until the waist decreasing into the desired diameter. At the same time, close the oxyhydrogen flame and keep moving one end of microfiber at a uniform velocity (0.15mm/s in this work) through the Motorized Positioning Systems, the waist of microfiber will naturally fracture under the action of axial tension. The generating end face is usually of high quality due to the brittle fracture of silica microfiber [26], which can be utilized as the reflecting plane. This point has been proved by the observed results of microfiber probe and its end face. (see Figs. 1(a) and 1(b)). When the light is guided into microfiber, high orders modes (mainly HE11 and HE12 modes) are excited and transmitted to the end face of microfiber. Then, both modes are reflected back microfiber and generate mode interference at the taper. The high RI sensitivity of reflective microfiber probe has been proved by our previous work [27]. For this work, the interference spectrum of microfiber probe used for DNA detection is exhibited in Fig. 1(c). Random noise induced burr can be can be eliminated through a low-pass filter later. In addition, the extinction ratio of the interference spectrum is about 8dB, which is advantageous to distinguish the spectral variation during measurement.
Fig. 1. (a) The micrograph of microfiber probe, 1(b) The SEM of microfiber probe end face and 1(c) The spectrum of microfiber probe (in TE buffer).
2.2 Surface functionalization of microfiber probe
In order to achieve selective detection of target DNA, microfiber probe needs to be functionalized. The processes are as follows: microfiber probe was firstly cleaned for 45mins in the piranha solution (30% H2O2 v/v in H2SO4). After washed by deionized water, it was immersed into Poly-L-lysine (PLL) with the positive charges of the amino group, processing 45mins. Then, microfiber probe was cleaned by deionized water to remove residue. Usually, the surface of silica microfiber is negatively charged [28]. Therefore, the PLL can be immobilized onto the microfiber surface through the combination of positive and negative ions. Next, microfiber probe was allowed to react with probe ssDNA (at a concentration of 10µM) via NH-NH linkage for 45mins. After cleaned by deionized water and TE buffer, it was ready for the test. The schematic diagram of microfiber probe for DNA hybridization detection is presented in Fig. 2(a). The spectrum after each step of surface treatment (in TE buffer) is also collected and shown in Fig. 2(b). It can be seen that the spectral variation of PLL-coated microfiber probe is very small that it is hard to be distinguished with the spectrum of pure microfiber. Actually, the PLL is used as the adhesive between fiber surface and the probe ssDNA, which is very thin. The spectral variation mainly results from the bonding of probe ssDNA on the fiber surface. The observed phenomenon that the spectrum shifts about 0.87nm to the shorter wavelength when probe ssDNA is immobilized on the microfiber surface also proved this point.
Fig. 2. (a) The schematic diagram of microfiber probe for DNA hybridization and 2(b) The spectra of microfiber after coated by PLL and probe ssDNA
To verify the effect of functionalization, microfiber probes are also tested under the scanning electron microscope (SEM) after coated by PLL and probe ssDNA. The observed pictures are exhibited in Figs. 3(a)–3(c). It is noted that the microfibers were sprayed with palladium before the test to get high quality images. From Fig. 3(a), it can be found that the microfiber surface has some particles that make microfiber look like rough. Actually, these particles mainly come from the uneven coating of palladium due to the convex surface of microfiber. When comparing Figs. 3(b) and 3(c), it can be seen that the surface of microfiber has been covered by a layer of biological substances, which gives powerful support to the bonding effect between PLL and probe ssDNA.
Fig. 3. The microphotographs of microfiber probe. 3(a) bare microfiber probe, 3(b) coated by PLL and 3(c) coated by probe ssDNA.
2.3 Experimental setup and optical configuration
The experimental setup is exhibited in Fig. 4. Microfiber probe is placed into a microchip with an inlet and an outlet, through which the samples can be injected and extracted. The normal end of microfiber is connected with an optical sensing interrogator. The reflective spectra are collected and processed through a personal computer. Here, the interrogator acts as the source of incident light, as well as the data acquisition system for continuous monitoring of interactions of the microfiber sensor with different reagents. For DNA hybridization detection, the target ssDNA solution with low concentration is injected into the microchip firstly, reacting with the probe ssDNA on the surface of microfiber probe for 45mins and the spectral data are acquired every 3mins. The concentration of target ssDNA can be detected by tracking the variation of reflective spectrum induced by the combination of probe ssDNA and target ssDNA. After each measurement, the sample is pumped out and then another sample with higher concentration is injected into the microchip for continuous monitoring.
3. Results and discussion
The reflective spectral responses have been monitored in real-time for the detection process of target ssDNA with different concentrations. The typical spectra in target ssDNA solutions are presented in Fig. 5(a).
Fig. 5. (a) Typical spectra of microfiber probe in target ssDNA solutions with different concentration and 5(b) The RI of different concentration target ssDNA.
It can be seen that the spectrum shifts to shorter wavelength when the microfiber probe is immersed into target ssDNA. According to our previous work [26], the wavelength shift is influenced not only by the variation of surrounding RI (dnSRI) but also by the thickness change of the coating (dt) due that the target ssDNA is bound to the microfiber, which can be expressed as:
In order to get wavelength shift theoretically, the values of G and $\partial ({\varDelta {\textrm{n}_{\textrm{eff}}}} )/\partial \textrm{t}$ need to be processed. Here, the transmission wavelength is set as 1.57µm and the surrounding RI is set as 1.3332. Considering that the RI of target ssDNA solutions continue decreases when the concentration of target ssDNA increases and most of the target ssDNA will be bond on the microfiber surface, the RI of coating is estimated as less than the RI of the measured target ssDNA solution. Hence, the RI of biological coating was set as the upper limit of the valuation, which is 1.3330 in this work. In this case, the G and $\partial ({\varDelta {\textrm{n}_{\textrm{eff}}}} )/\partial \textrm{t}$ can be calculated as -0.026 and 7.008e-5, as a result, the Eq. (2) can be calculated as:
According to the Eq. (3), the resonant wavelength will shift to shorter wavelength with the target ssDNA is bound on the microfiber surface, which is consistent with the observed phenomenon.For observing the stability of spectral variation over time, the wavelength shifts in different concentration target ssDNA solutions at different time are collected and shown in Fig. 7(a). Here, the resonant wavelength is calculated through Gauss fitting and the spectrum of microfiber coated by probe ssDNA (in TE buffer) is used as a reference spectrum. For the target ssDNA solution with the concentration of 1pM, the wavelength shifts fluctuate up and down to the zero axis. It means that the spectral variation is too small to be distinguished. For the other target ssDNA solutions with higher concentration, the spectral variation is obvious. In particular, the wavelength shifts change dramatically in the beginning and then they tend to an equilibrium situation. With the concentration increase, the equilibrium is broken and the wavelength shifts start to change again until they reach a new equilibrium. Owing that the reaction is rapid and nearly completed in 3mins, the wavelength shifts of the spectrum collected at the first 3mins is much larger than the initial value. Therefore, the starting point of each concentration has a jump step in the Fig. 7(a). To get the correlation between wavelength shifts and the concentrations of target ssDNA, the acquired data are averaged and then are presented in the inset of Fig. 7(a). It can be found that the wavelength shifts about 0.31nm for the target ssDNA solution with a concentration of 10pM. With the concentration of target ssDNA continue to increase, the wavelength shifts keep growing. When the concentration is greater than 10nM, the growth of the wavelength shift is also slight. It can be explained by the fact that the combination of target ssDNA and probe DNA has been finished. The higher concentration cannot bring the variation of microfiber surface. Therefore, the spectrum of microfiber remains unchanged.
Fig. 7. (a) The real-time wavelength shift responses of microfiber probe to DNA hybridization process, 7(b) The detection repeatability and 7(c) specificity of microfiber probe-based DNA detector.
For verifying the stability of the proposed sensor, the microfiber probe is immersed into the piranha solution for about an hour to remove the bio-coating on microfiber surface. Then, the functionalization processes and measurements are executed for three times. For saving time, only the sample with the concentration of 10pM is tested. The wavelength shifts are presented in Fig. 6(b). The relative standard deviation (RSD) is calculated as about 9.6%, which indicates that the proposed sensor has good repeatability. Additionally, to evaluate the specificity for hybridization between different ssDNA sequences, the control experiment for non-complementary ssDNA is also carried out. The non-complementary ssDNA with a concentration of 10pM is pumped into the microchip and reacted with the probe ssDNA-functionalized-microfiber probe. The corresponding spectra are presented in Fig. 6(c) and the spectral shift is calculated and exhibited in Fig. 6(b) as well. It can be found that the resonant wavelength shift is minuscule compared with that of complementary target ssDNA, which indicates that our proposed microfiber probe-based DNA detector possesses a good specificity for DNA recognition.
Table 1 gives the sensing performances in comparison with other microfiber-based DNA sensors. It can be found that the structure of current microfiber-based DNA sensor is mostly transmission-type, which makes test system redundant. While the reflective microfiber probe used in this work presented great convenience and the size of the sensor is reduced by about half than existing microfiber taper interferometer. At the same time, the sensitivity is also increased compared with the analogical microfiber-based DNA sensors. The distinguished performance is ascribed that the diameter of the proposed reflective microfiber probe is smaller and closer to the the dispersion turning point. Although the lowest detectable concentration of this work is inferior to graphene oxide coated microfiber taper interferometer, the proposed sensor gives a good specificity, which is also important in some fields, for example, recognizing the criminal suspect.
Table 1. Comparison of sensing performance between different microfiber-based DNA sensors.
4. Conclusions
We proposed and experimentally demonstrated a label-free biosensor based on a reflective microfiber probe for in-situ real-time DNA hybridization detection. In order to achieve the selective detection of ssDNA, the microfiber probe is functionalized by a monolayer of PLL and a single-stranded DNA probe (ssDNA) to bind with the given target. The hybridization processes of the target ssDNA with the various concentrations have been monitored in-situ with a lowest detectable concentration of 10pM. The detection of repeatability and specificity are also investigated and the results indicated that the proposed biosensor has good practicability. It is noted that the reflective structure not only brings great convenience in practice, the size of microfiber-based biosensor is also further reduced. What’s more, the method achieving this structure is very simple and economical. Moreover, replacing interrogator and personal computer with small detector and micro-processor respectively, the proposed sensor can be developed into a portable mobile device for biochemical detection, which has great potential to be applied in fields of environmental science, disease diagnosis and pharmaceutical research.
Funding
National Science Fund for Excellent Young Scholars of China (61922033); Wuhan Morning Light Plan of Youth Science and Technology (2017050304010280); Fundamental Research Funds for the Central Universities (HUST: 2019kfyRCPY095).
Disclosures
The authors declare no conflicts of interest.
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