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Targeted drug delivery and controllable release are particularly beneficial in medical therapy. This work provides a demonstration of nanoparticles targeted delivery and controllable release using a defect-decorated optical nanofiber (NF). By using the NF, polystyrene particles (PSs) (713-nm diameter) suspended in water were successfully trapped, then delivered along the NF at an average velocity of 4.8 µm/s with the assistance of a laser beam of 980-nm wavelength at an optical power of 39 mW, and finally, assembled at the defect. Subsequently, by turning off the optical power, 90% of the assembled PSs can be released in 30 s. This method would be useful in targeted drug delivery and controllable release, and provide potential applications in targeted therapy.
©2011 Optical Society of America
1. Introduction
Optical trapping and delivery enable a targeted and noninvasive means for mesoscopic objects manipulation with extremely high precision [1] and have led to a wide use of optical manipulation on the research of biomolecular [2], such as DNA [3,4], myosin [5], kinesin [6], etc. These tools, offering the convenience for the above researches, are called optical tweezers, which was first introduced by Ashkin [7]. Conventionally optical tweezers use a microscope objective with a high numerical aperture to focus a laser beam, which can produce an optical force exerted on objects, and consequently, can trap and manipulate the objects [8]. Evanescent wave fields, which exist in subwavelength diameter waveguides fabricated on substrates or fibers, can also produce strong optical forces and can be used to manipulate particles within a larger operation region than that of the conventionally optical tweezers [9,10]. Therefore, particles were trapped and/or propelled by the optical forces along the waveguides in the propagation direction of the evanescent wave [10–16]. Compared with the waveguides fabricated on substrates, optical fibers are more convenient and flexible to move. Thereby, optical fiber-based structures such as taper, subwavelength wire, and fiber-ring were used to trap and manipulate single particle [17], microspheres [18], and massive dielectric particles [19,20]. Recent medical therapy makes high requirements on targeted drug delivery and controllable release. However, the above optical fiber-based structures are unable to targeted deliver particle and/or controllably release. In this work, we report a targeted delivery and controllable release of nanoparticles using a defect-decorated optical nanofiber (NF) with the assistance of a laser beam of 980-nm wavelength which has a low absorption coefficient for water and many biological tissues [21].
2. Experiment
The experiment was done in the setup schematically shown in Fig. 1 . It includes a 980-nm wavelength laser source for optical power supply, a microscope for particles observation, and a computer connected charge coupled device (CCD) for real-time monitoring and images capture. In the experiment, a glass slide with a water suspension on it was mounted on an adjustable translation stage. The NF was immersed in the water suspension with two ends fixed by respective microstages. The suspension was prepared by diluting 713-nm diameter polystyrene particles (PSs) into deionized water (volume ratio of particles to water ~1:1,000) with the assistance of ultrasonic.
Fig. 1 Schematic of the experimental setup. Two ends of the NF are fixed by respective microstages and immersed in a water suspension of PSs. The translation stage is adjustable while the NF can be moved by adjusting the two microstages. The microscope is used for experimental process observation while the CCD and the computer are for images and videos capture. The amplification of the microscope is ×1000.
The NF was fabricated by drawing a single mode silica fiber through a flame-heated method, while the defect (as shown in the inset of Fig. 2a ) was created by a sudden impingement of the flame during the fiber drawing process. The shape of the defect is a protuberance, with a width of about 1.2 µm and a height of about 0.2 µm. Figure 2a shows the optical image of the NF (diameter 720 nm, length 4.2 mm) which was immersed in the water suspension of PSs. It can be seen that there are no PSs trapped at the defect indicated by the red dashed line circle. When the 980-nm wavelength laser was launched into the NF with an optical power of 39 mW measured at the output of the laser, the PSs near the NF were trapped firstly by the gradient force induced by the evanescent wave field of the 980-nm wavelength, moved toward the NF, and then were propelled along the NF at an average velocity of 4.8 µm/s because of the scattering force exerted on the PSs by the strong evanescent wave field. The use of 39 mW power is because it can get an effective particle delivery and release while inducing little harm to the biophysical circumstances [22]. Once the propelled PSs were delivered to the defect, they were assembled because of the strong gradient force induced by light scattered out from the defect. Detailed delivery and assembly process is shown in Media 1. It has been found that, maintaining the laser on for t on = 1′30″, there are 16 PSs assembled at the defect (Fig. 2b). As time goes by, more PSs were trapped and delivered along the NF and finally assembled at the defect. Figures 2c and d show that there are 28 and 38 PSs assembled at the defect after 3′00″ and 4′30″, respectively.
Fig. 2 Optical microscope images for different PSs trapping, delivery, assembly and release processes. (a-d) Delivery and assembly process. (a) Without laser launched into the NF, there are no PSs trapped, delivered, and assembled at the defect. The inset shows the SEM image of the 720-nm NF with a protuberance defect. (b) The 980-nm laser launched into the NF for t on = 1′30″, 16 PSs were delivered along the NF and assembled at the defect indicated by the red dashed line circle. (c) t on = 3′00″, 28 PSs assembled. (d) t on = 4′30″, 38 PSs assembled. Detailed delivery and assembly process is shown in Media 1. (e-h) Release process. (e) Laser off (i.e. t off = 0′00″, corresponding t total = 4′35″), assembled PSs started to release. (f) t off = 0′10″ (i.e. t total = 4′45″), 25 PSs released. (g) t off = 0′20″, 30 PSs released. (h) t off = 1′20″, only 2 PSs remained at the defect. Detailed release process is shown in Media 2.
We have further found that, when the laser was turned off, the assembled PSs will be released and diffused in the water very soon. Detailed release process is shown in Media 2. Figure 2e shows the optical image of the laser just turned off (i.e. t off = 0′00″, corresponding t total = 4′35″). It can be seen that the PSs start to release. Figures 2f and g show the optical images of the released PSs at t off = 0′10″ and 0′20″, respectively. It indicates that after the laser turned off for 20 seconds, 30 PSs were released with only 8 remained at the defect (Fig. 2g). At t off = 30 s, about 90% of the assembled PSs were released. After t off = 80 s, there are only 2 PSs remained at the defect (Fig. 2h). The reason of the 2 PSs still remained would be that the PSs are not smooth enough and sticked to the defect.
Figure 3a depicts the number of the assembled PSs at the defect during the whole delivery and release process. The relation between the delivery velocity and input laser power was also investigated by changing the input optical power and showed in Fig. 3b. Experiments results show that a low input power can result in a low but stable delivery velocity, while a relatively higher input power can result in a higher velocity. However, since a higher laser power can result in a fluctuation of the surroundings, thus the velocity is not so stable. Fitted result indicates that the average delivery velocity is nearly linearly increased with the input power. Since the velocities were measured for different particles delivered along the NF at different time, they can be affected by the fluctuation resulted from the optical power, which, as a consequence, result in an offset of the fitted velocities. An estimation of the propelling force was also carried out using Stokes law F = 6πrηv [10], where r = 356.5 nm is the PS radius, η = 8.9 × 10−4 Pa∙s is the dynamic viscosity of water at room temperature, and v is the PSs velocity. Estimated result indicates that the propelling force is nearly linearly increased with input power, which is consistent with the reported results [18].
Fig. 3 (a) The number of assembled PSs at the defect with the time of the optical power applied, red arrows and insets indicate the assembly state at corresponding time, blue arrows indicate the laser on/off. (b) Velocity and estimated propelling force of the PSs delivered as a function of the input laser power. Each data point represents the average velocity and propelling force of a single PS; error bars represent standard deviation of measured velocity and propelling force. The delivery velocity and force are linearly fitted with the input power.
The results indicate that the NF with a designed defect on it is capable of particles trapping, delivery, assembly, and finally released at a designated position just by placing the defect at the designated position. The experiments imply that if place the defect of the NF near a targeted tissue, the particles (e.g. drug) can be controllably released around the tissue by switching off the input optical power. As a result, the targeted tissue such as cancer cells could be killed by the released drug. Since this proposal is a new method for drug delivery and release, some practical obstacles might be appeared in real tissue in vivo. For example, how to put the NF into the body and keep the NF unbroken should be solved. In addition, the complexity of the internal environment may also influence the drug delivery and release. To overcome some practical obstacles, further research based on living tissue is necessary.
3. Discussion
To explain the phenomena, a three-dimensional (3D) finite element simulation (COMSOL Multiphysics 3.5a) has been carried out. The refractive index of the water is set to 1.33, while that of the PS and NF are 1.573 and 1.445, respectively. The gap between the PS and the NF surface is set to be 20 nm, and the power of the 980-nm wavelength light is normalized to be 1 W. Figure 4a shows the longitudinal cross-section view of the total energy density distribution. Figures 4b and c show the transversal cross-section view of the energy density distribution in the NF and the defect, respectively. It can be seen that, a part of the light is leaked outside the NF as an evanescent wave, which acts on the PS (Fig. 4b). Though a defect on the surface of the NF can increase the NF diameter, which may decrease the evanescent field outside the NF, the surface imperfection on the defect can result in a strong scattering of light. Thus, the energy outside the surface of the defect is stronger than that without a defect (Fig. 4c). By calculating the integral of the Maxwell stress tensor along the total external surface of the PS particle, the total optical forces acted on the PS particle for the situation of normal NF surface (without defect) and that with the defect were obtained and indicated in Fig. 4a. The total forces are composed of two components, the scattering force which propels the particles along the NF in the propagation direction of light (F p), and the gradient force which traps particles to the strong optical intensity region near the NF surface (F t). For the normal position (without defect), the calculated trapping force F t,n = 15.2 pN, while the propelling force F p,n = 12.1 pN. For the position with a defect, however, the strong energy outside the NF can generate a strong trapping force F t,d = 37.5 pN, which is much stronger than the propelling force F p,d = 7.6 pN. Therefore, when the particles are delivered to the defect region, they will be assembled at the defect.
Fig. 4 Three-dimensional simulation of total energy distribution around the 720-nm diameter NF with the 980-nm wavelength light propagated at a power normalized to be 1 W, the diameter of the PSs is 713 nm. (a) The longitudinal cross-section view of the total energy density distribution and optical forces, the black circles and the gray outlines represent the surface of the 713-nm PS and the 720-nm NF, respectively, while the black arrows and red arrows represent the trapping force and propelling force, respectively. (b) The transversal cross-section view of the total energy density distribution for the normal position (without defect). (c) The transversal cross-section view of the total energy density distribution for the position with a defect.
To study the delivery and trapping capabilities of different diameter NFs, a series of simulations were carried out and shown in Fig. 5 . It can be seen that, the energy density outside the NF decreases with the distance away from the NF surface (Fig. 5a). For smaller diameter NF, energy density outside the NF will be larger. For example, the normalized energy density on the surface for the 500-nm diameter NF is about 0.75, while that for the 900-nm diameter NF is about 0.39. The energy density distribution indicates that a smaller NF can affect particles in a larger area. The forces exerted on the particles which is 20 nm away from the NFs with different diameters were also calculated (Fig. 5b). The results show that the trapping force (F t) decreases with the increase of the NF diameter, which is consistent with the results shown in Fig. 5a. From Fig. 5b it can be seen that, the propelling force (F p) increases first, and then decreases with the increase of the NF diameter. F p reaches a maximum value of 12.7 pN when the NF diameter is 700 nm for the normal surface (without defect), and thus, particles will be propelled/delivered at a maximum velocity. For that of the surface with a defect, the maximum value of 9.3 pN can be obtained for the 600-nm diameter NF. Though F p increases first, and then decreases with the increase of NF diameter, the resultant (F) of F p and F t decreases with the increase of NF diameter for both the NF with a defect and without a defect. This is consistent with the energy density distribution shown in Fig. 5a. For example, for the 600-nm diameter NF, the F p = 9.3 pN is larger than F p = 3.3 pN for a 500-nm diameter, but F is smaller for the 600-nm diameter (48.9 pN) than the 500-nm one (55.1 pN).The results indicate that a NF with too small diameter is not suitable for particle delivery, but can be a good tool for particles trapping because of the strong trapping force. Though F t is stronger than F p for both the situation of normal surface and that with a defect for NFs with different diameters, the situation for a surface with a defect is much more obvious. F t is more than 5 times of F p for various diameters. For example, for the NF diameter of 500 nm, F t = 55.2 pN, about 17 times of F p (3.3 pN). This result indicates that the NF is an excellent tool for particle trapping, delivery, assembly, and release.
Fig. 5 Simulation results for normalized energy density and force exerted on the 713-nm PSs with different diameter NFs at the 980-nm wavelength light and the power normalized to be 1 W. (a) Normalized energy density with the distance away from the NF surface for different diameter NFs. (b) Trapping force (F t) and propelling force (F p) induced on the surface without defect (without D) with different diameter NFs and the surface with a protuberance defect (with D: width 1.2 µm, height 0.2 µm).
4. Conclusions
We have experimentally demonstrated a method of targeted delivery and controllable release of 713-nm diameter polystyrene particles (PSs) using a protuberance defect-decorated NF (diameter 720 nm). The PSs were successfully trapped and delivered at an average velocity of 4.8 µm/s with the 980-nm laser at an optical power of 39 mW, and then assembled at the defect. Once the laser is turned off, the assembled particles will be released immediately. The phenomenon has also been explained with simulations of total energy distributions and optical forces, and analyzed with different diameter NFs. This method would be useful in targeted particle/drug delivery and controllable release, and have potential applications in targeted therapy.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Grants 60625404 and 10974261).
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