Red blood cell-based microlens: application to single-cell membrane

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Red blood cell-based microlens: application to single-cell membrane imaging and stretching Xiaoshuai Liu, Yuchao Li, Xiaohao Xu, Yao Zhang, and Baojun Li ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.9b00274 • Publication Date (Web): 16 May 2019 Downloaded from http://pubs.acs.org on May 18, 2019

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ACS Applied Bio Materials

Red blood cell-based microlens: application to single-cell membrane imaging and stretching Xiaoshuai Liu, Yuchao Li, Xiaohao Xu, Yao Zhang*, and Baojun Li Institute of Nanophotonics, Jinan University, Guangzhou 511443, China *Corresponding Author: E-mail: [email protected]

ABSTRACT: Red blood cell (RBC)-based microlens has attracted extensive insights in biological applications due to its intrinsic advantages of total biocompatibility. Most of the currently available RBC microlenses are fixed on a substrate and cannot be moved in a flexible manner, which limits its applications to optical imaging. Here we present an RBC microlens assembled by launching a 980-nm laser beam into a tapered fiber probe. The RBC microlens was then used to scan a singlecell membrane in three dimensions for optical imaging with a magnification factor of 1.7. Moreover, the microlens was employed to stretch the cell membrane with an enhancement factor of 1.5 in a noncontact and noninvasive manner.

KEYWORDS: red blood cells, cell microlens, fiber probe, membrane stretching, optical tweezers

INTRODUCTION Natural biomaterials have been desired to construct miniaturized and biocompatible structures for biological imaging, as the biomedical applications of conventional microscopes constructed of a series of optical components are generally limited by the difficulty of implantation and the low

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biocompatibility. As a naturally abundant and fully biocompatible material, cells can focus and guide light in biosystems and act as the “bio-microlenses”1-3. As one of the candidates for biomicrolens4-6, red blood cells (RBC) have recently emerged with the intrinsic elastic properties and congenital advantage for the real-time detection and imaging in vivo7-10. For applications to the scanning imaging and dynamic stretching of cell membranes, a precise control of multiple RBCs has been required in the integration of RBC microlenses11. Substantial efforts have been devoted to develop diverse manipulation techniques for the RBCs, such as dielectrophoretic12, acoustic tweezers13 and microfluidic systems14-18 et al. However, the engineering fabrication of electrodes, interdigital transducer and microfluidic channel requires complex crafts and inaccessible for nonprofessionals. Besides, the modification requirement of the cell’s native state also set unavoidable damage for the cell bioactivity. Recently, huge steps have been taken to trap RBCs using conventional optical tweezers (COTs), which can shift cells in a contactless and label-free way19-21. Nevertheless, due to the limited flexibility, it faces great challenges to manipulate multiple RBCs in three dimensions (3D), especially for the case of various cell shapes in very narrow spaces. Here we propose an optical method that enables the precise manipulation of multiple RBCs. By using a tapered fiber probe (TFP), RBCs can be assembled and then manipulated to conduct the scanning imaging for the single cell membrane. The imaging capability was quantitatively investigated for different cell shapes. Meanwhile, the laser beam from TFP suffers from the refocus by RBC microlens, yielding an enhanced stretching for the cell membrane, which holds great promises for investigating cancer metastasis and drug delivery. RESULTS AND DISSCUSSION Experimental Schematic


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Figure 1a schematically shows the scanning imaging and enhanced stretching mechanism with the RBC microlens. The 980-nm laser beam was chosen to manipulate RBCs due to the low absorption for the biological sample22. After the laser beam injected into TFP, one RBC near the tip will be attracted into the optical axis, and then trapped stably under the action of optical force. Meanwhile, the RBC can be shifted with TFP along the 3D direction and remained at the probe tip. Note RBC was mainly composed of hemoglobin without a three dimensional polymer skeleton throughout the cytoplasm, and lack any internal organelles. Thus, a microscopic magnifying lens can be assembled, in which the TFP and RBC act as operation handle and microlens, respectively. The scanning imaging can be conducted by dynamically manipulating RBC microlens in a controlled manner. Further, more RBCs can be trapped one after another, and then organized into a cell chain at the probe tip. That is, multiple RBC microlenses can be assembled simultaneously, and conduct the line scanning with the advantage of wide-field and fast imaging. Besides, the laser beam from TFP can be refocused by the RBC microlens along the x direction, i.e., the optical axis direction. Then an enhanced stretch of cell membrane can be expected with the larger trap capacity exerted on the K562 cell, which was located in front of RBC microlens (Figure 1a). Further, the stretch direction can be adjusted dynamically by manipulating TFP. Figure 1b-d shows the optical microscopic images of TFP, RBC and K562 cells, respectively. TFP was fabricated with a flame-heating technique (see Section 1 of the Supporting Information for fabrication details). It has a gradual tapered tip with the diameter decreased from 9.2 m to 1 m in a distance of 12 m (Figure 1b). In the blood solution (see Section 1 of the Supporting Information for preparation details), RBC was biconcave and in disk-like shape with the average diameter of 6.5 m (Figure 1c), while K562 cell was spherical with a diameter of 14.5 m (Figure 1d).


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Figure 1. (a) Schematic of the assembled RBC microlens. (b-d) Optical microscopic images for TFP (b), RBC (c) and K562 cell (d), respectively. Scale bar: 5 m.

Manipulation of RBCs in the 3D direction Firstly, the dynamic manipulation of RBCs was experimentally achieved. The 980-nm laser beam was injected into TFP with a power of P  50 mW. As shown in Figure 2a1, one RBC was trapped at the probe tip at t  0 s. After that, the RBC will rotate under the action of optical torque and orientate itself horizontal to the TFP, i.e., the cell plane in the x-y plane (Figure 2a2). Note for a normal RBC in a disk-like shape, there exist some differences when the RBC is horizontal or vertical to the beam (see Figure S1 in Section 2 of the Supporting Information). Since the scanning imaging was conducted for the objects in the x-y plane, the cell plane and side facet was applied to magnify the targeted cell at the case of the RBC horizontal and vertical to the beam, respectively. Nevertheless, the side facet of RBC was considered as a much more complex optical component and it cannot contribute to a clear imaging of magnification with a significant optical aberration. Note that the fabrication efficiency of RBC microlens, i.e. the percentage of times of successful fabrication, was dependent on the designed TFP to stably trap the RBC. In our experiment, the


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TFP was adjusted to approach a specific RBC, and was then injected with the laser beam at the wavelength of 980 nm. In most cases, the RBC will be trapped at the probe tip, with a fabrication efficiency of 95%. Once the RBC microlens was assembled, it will remain at the probe tip until the laser was switched off. In a minority of cases, the RBC escapes due to the adhering to the glass slide or the disturbance induced by the microflow. After trapped, the RBC was shifted with TFP along x and y direction, with a distance of 38 and 20 m, as Figure 2a3 and 2a4 shown, respectively. Further, RBC can be shifted along x direction by a distance of 30 m (Figure 2a5 and 2a6). The shift velocity in the x (Vx) and y (Vy) direction was also achieved to quantitatively interpret the above experiment (Figure 2b). From t  0 s to 2 s, Vx was increased from 0 to 47 ms, and then decreased to be 0 ms at t  2 s. The RBC remained to be stationary from t  2 s to 4.5 s. After that, with RBC shifted along y direction, Vy was rapidly decreased to be 22 ms from t  4.5 s to 6.5 s. Then the RBC was pulled back along x direction with Vx decreased to be 35 ms. Further, the controllable release of RBC was also demonstrated. From t  0 s to 3 s, one RBC was trapped at the probe tip (Figure 2c). After the laser off at t  4 s, the RBC was escaped free from the trap, and gradually flowed into the cell solution, indicating the cell can be released controllably by turning off the laser at specific location. Meanwhile, more RBCs with different shapes can be manipulated simultaneously. As Figure 2d shown, the RBCs were exposed into the hypotonic solution, and gradually swollen to the spherical shape. The 980-nm laser beam was injected into TFP at a power of 60 mW. After that, four spherical RBCs were trapped one by one, and organized into a cell chain at the probe tip (Figure 2d1). The cell chain can be shifted along y, x, x and y direction with a distance of 16, 21.5, 24 and 12.8 m, as Figure 2d2, 2d3, 2d4 and 2d5 shown, respectively. Further, by shifting the TFP


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Figure 2. (a) Optical microscopic images for one RBC shifted in the x-y plane (a1-a6). (b) The calculated velocity as a function of t. (c) The trapped RBC (c1-c4) escaped from the probe after the laser was switched off (c5, c6). (d) Optical microscopic images of the manipulation of four spherical RBCs in 3D (d1-d8). Scale bar: 10 m.

along z direction from t  38 to 41 s, the RBCs were also shifted along the same direction and kept trapped at the probe tip (Figure 2d6). After remained stationary for 2 s, they were shifted along z direction and adjusted to the original position (Figure 2d7 and 2d8), indicating the potential 3D manipulation flexibility of TFP for the RBC chains. The cell viability was further investigated to indicate the biological safety for the proposed technique, and the results show that the cells survived without any damages at the case of P  120 mW (see Section 3 of the Supporting Information for the characterization details). The scanning imaging of targeted cell The imaging performance was then investigated with the assembled RBC microlens. Figure 3a shows the schematic of imaging cell membrane with one RBC microlens. Individual RBC was


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trapped and then acted as a biological microlens. After it positioned above one targeted cell, a distinct edge can be observed to investigate the cell membrane. The experiment was conducted to interpret the above operation schema. As shown in Figure 3b, the RBC microlens was assembled at the probe tip, and one cell can be observed with a fuzzy edge. By manipulating the TFP, the RBC microlens was positioned above the targeted cell. Meanwhile, a distinct edge emerged, indicating that an enhanced imaging can be expected with the RBC microlens. Note that the cell was observed with a magnified image. The magnification can be defined as: M  N1  N2, for which N1 and N2 indicates the pixel number for the same viewing zone. By obtaining the pixel numbers from the microscope images, a magnification of M  1.7 was achieved for the spherical RBC microlens. Note that the distance between the microlens and targeted cell was adjusted manually through the six-axis microstages (KOHZU FH9-10, step resolution: 50 nm) to achieve the clearest edge of targeted cell. An automatical regulation can be achieved through the electrical driven microstages with the assitance of LabVIEW software to induce a real-time feedback loop. Besides, the RBC microlens was adjusted above the targeted cell in the z direction, and the illumination light, rather than the trapping laser, was applied into the cell imaging. Thus, the targeted cell remained at its original location and cannot be pushed or trapped by the optical force. Further, the scanning imaging was demonstrated with the proposed technique. As Figure 3c shown, one RBC microlens was assembled at the probe tip, and then adjusted to be above the targeted cell in the z direction. By shifting RBC microlens along the counterclockwise direction, a distinct image can be achieved for the various edge of cell. The detailed process of the scanning imaging was shown in Movie S1 in Supporting Information. Note the scanning period was 4.5 s, which can be further improved by manipulating TFP. Besides, the RBC with normal shapes was also investigated for the dynamic scanning to image the targeted cells. As shown in Figure 3d1, one


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Figure 3. (a) Schematic for the membrane imaging. (b) Optical microscopic images for imaging membrane without (b1) and with RBC microlens (b2), respectively. (c, d) Scanning imaging using one RBC microlens with the spherical shape (c1-c8) and the normal shape (d1-d8), respectively. Scale bar: 10 m.

normal RBC was trapped at the probe tip and then assembled as a microlens. After adjusted to be above targeted cell, a distinct cell edge can be achieved with a magnification of M 1.1 (Figure 3d2). Further, the various edges can be under an enhanced imaging by manipulating TFP (Figure 3d3-8), indicating the normal RBCs can also be applied into the scanning imaging in a controlled manner. Notably, the imaging performance of spherical RBCs were better than that of normal RBCs, which was due to the larger focus capability.


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The enhanced stretch of leukemia cell membrane Except for the cell imaging, an enhanced stretch was also conducted for the cell membrane with the assembled RBC microlens. For the cancer cells, the membrane elasticity, especially along the different directions, was an important indicator for the biomechanical and physiological features, which was essential for investigating cancer development, metastasis, diagnose and drug delivery23-25 et al. Notably, the controllable stretch with TFP was a valuable approach to quantitatively study the membrane elasticity in a non-contact and non-invasive way26. However, it faces great challenges to stretch the leukemia cell due to the weak stretch capability. Though the stretch capability can be enhanced using the laser beam with a higher power, it will induce a detective optical damages and should be avoided in the study of cell biology. Note for the assembled RBC microlens, the laser beam from TFP was refocused by the RBC microlens in the optical axis direction (i.e., x direction), resulting in a larger laser gradient which can be expected to conduct the enhanced stretch of cell membrane. Then the experiment was conducted to demonstrate the above theoretical analysis. Figure 4a schematiclly shows the enhanced stretch of cell membrane with one RBC microlens. The stretch direction, indicated by azithmul angle , can be varied by manipulating the TFP. After one RBC microlens assembled, it was adjusted to approach one K562 cell. The laser power injected into TFP was set as 100 mW. The left side of the cell membrane was then stretched along the optical axis (Figure 4b), and the stretching direction can be dynamically adjusted by shifting RBC microlens along the y direction. The K562 cell was stretched at the direction of   15, 0, 30, 15, 30 and 50, as Fig. 4b1, 4b2, 4b3, 4b4, 4b5 and 4b6 shown, respectively. The detailed process of membrane stretching was shown in Movie S2 in Supporting Information. Notably, the stretch degree was dependent on the azimuthal angle, and decreased with the larger . To compare


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Figure 4. (a) Schematic for stretching the membrane of K562 cell. (b, c) Optical microscopic images for the stretch of K562 cell membrane with (b1-b6) and without RBC microlens (c1-c6), respectively. (d) Calculated shear strain  as functions of  at x  0 m (d1) and x at   0 (d2), respectively. Scale bar: 10 m.

the enhanced capability, a stretch of same cell membrane was conducted without RBC microlens at the probe tip (Figure 4c). Note the cell can also be stretched along the various direction while the deformation degree was less than that in Figure 4b. For a quantitative comparison, the influences of azimuthal angle () and distances (x) on the shear strain  were separately investigated. x indicates the distance between the targeted cell and the RBC microlens or the TFP tip for the case with or without the RBC microlens. Figure 4d1 shows the calculated  as a function of  at x  0 m. The strains were dependent on the stretch


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direction and the maximum values of the strain max, which emerge at   0, were 0.24 and 0.16 for the case with and without the microlens, respectively. The results indicate that an enhanced factor of 1.5 can be achieved with the assistance of RBC microlens. Moreover, as indicated by the function of x at   0 (Figure 4d2),  decreased with x due to the further divergence of laser beam and consequently a weakened stretching of the membrane of the K562 cell. Further, a series of theoretical simulations were performed to interpret the above experiment by a 3D finite-element method with the COMSOL Multiphysics 5.3. The refractive index of TFP, RBC and solution was set as 1.445, 1.40227 and 1.33, respectively. The laser beam was injected into TFP at the 980-nm wavelength with a power of 50 mW. Figure 5a1 shows the simulated electric field (E-field) distribution with one cell at the probe tip. After the cell irradiated by the laser beam, it suffered from the optical force and moved toward the optical axis. The optical force along the y (Fy) and x (Fx) direction were further achieved28 (see Section 4 of the Supporting Information for calculation details). The values of Fy and Fx were set to be positive along y and x direction, respectively. In the y direction, it can be seen Fy was positive and negative for y  0 and y  0 m, respectively. Then the cell will be attracted toward the optical axis whether the cell center was located above or below the fiber probe (Figure 5a2). Note Fx was negative at x  7 m, and then the RBCs will be attracted toward the tip (Figure 5a3). While at x  7 m, Fx was positive and then RBC will be transported along the x direction. That is, only the RBC near the tip can be trapped while the others will be pushed away from TFP. Note that the output electric field distributions were dependent on the probe shapes for the fiber tweezers29, 30. When the beam focus was near the probe tip (within 2 m), a strong optical potential was generated by the fast decay of electric field and can be applied into a stable trapping of the smaller cells, i.e. E. colis. For the larger RBCs, they suffer from a positive optical force and will be pushed away along the optical axis. Thus, a


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specific electric filed distribution was required with a larger focal length to conduct the stable trapping of the RBCs. In this work, for the designed TFP, the beam focus was far away from the probe tip (Fig. 5c1), and the calculated focal length was 7.5 m, comparable to the diameter of the RBCs. Meanwhile, the calculated optical force was negative, i.e. a pulling force, to the RBC and the cell will be trapped at the probe tip rather than pushed away. As mentioned above, the scanning image was dependent on the focus flexibility of visible light along the z direction, i.e., vertical to the cell surface. Then the imaging performance of RBCs were investigated by analyzing the focus length with different cell shapes. The beam at the wavelength of 550 nm, which was most sensitive for human eyes, was chosen to be irradiated at the cell surface along the z direction. As Figure 5b shown, the normal RBC acts as a concave lens with a negative focus at x  2.9 m. While for the ellipsoid RBC, it acts as a biconvex lens with the focus length of 2.8 m. Further, by using the spherical cell, the beam was further focused with the focus length changed to be 11.6 m. Thus, as the RBC was gradually swollen to the spherical, the focus length was varied from negative to be positive. Notably, the spherical cell has the optimal focus performance, which has the potential application into the super-solution imaging. However, the enhanced stretch were affected by the focus flexibility of 980-nm laser beam in the x direction, i.e., the optical axis direction. As Figure 5c1 shown, the outputted laser beam can be refocused by the RBC microlens in the x direction. Then a series of numerical simulations were conducted to investigate the focus capability of cells with various shapes. For TFP without RBC microlens, the E-field distribution was shown in Figure 5c1 with the focus plane at x  7.5 m. While for one normal RBC at probe tip (Figure 5c2), the focus plane was shifted toward the probe tip and changed to be x  5 m. Meanwhile, the peak value of E-field was also increased, indicating a refocus due to the RBC microlens. Further, the focus capability was also investigated for spherical cells. As


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Figure 5. (a) Simulated 3D electric field distribution with one RBC at the probe tip (a1) and the calculated Fy (a2) and Fx (a3) as a function of y and x, respectively. (b) Simulated focus capability of RBC microlens with normal (b1), ellipsoid (b2) and spherical shape (b3), respectively. (c) Simulated electric field distribution of TFP (c1), normal RBC (c2) and spherical RBC (c3), respectively. The electric field along the yellow dashed line were calculated (c4).

shown in Figure 5c3, the laser beam was strongly focused by the RBC microlens and the focus plane was shifted to be x  10 m. Further, the electric field along the optical axis, as the yellow dashed lines shown, was quantitatively investigated in Figure 5c4. The blue, black and red curve


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indicates the E-field intensity for TFP, normal RBC and spherical RBC, respectively. Note the maximum value of E was increased from 3.47106 to 3.83106 and 4.74 Vm, with an increasement of 9.4 and 36.6%, respectively. The increased electric filed gradient will induce a larger optical potential to trap cells. Thus, an enhanced stretch can be expected with the RBC microlens, and the spherical RBC has the best enhancement flexibility. It should be pointed out that the RBC microlens can resist complex system infections. In the experiment, the RBC microlenses were manipulated for 30 minutes to conduct the scanning imaging and they maintained their original shapes and showed a stable imaging performance. The RBC microlens was also applied to image cells in the different culture media, without observable cell infection and rupture. For the RBC microlens, the imaging performance was mainly dependent on the cell shapes. The cell shapes were affected by the osmotic pressure of culture media which may gradually increase due to the liquid evaporation. Therefore, a long time process with the RBC microlens may induce a bit changes of cell shapes, which affects the imaging performance. Such an impact can be avoided by using a coverslip to build a sealed microchamber or supplementing culture media in time.

CONCLUSION An optical method was proposed and demonstrated to conduct the assembly and manipulation of RBCs. With the assistance of a TFP, individual or multiple RBCs with different shapes were manipulated in three dimensions. An RBC microlens was assembled to conduct the scanning imaging and enhanced stretching of the cell membrane. With the features of ease in integration and total biocompatibility, the RBC microlens can be further incorporated into biophotonic chips to provide a great perspective in the bio-imaging and clinical diagnose of blood disease.


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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsabm.XXXXXX. Fabrication of the TFP, preparation of the blood solution, assemble states of the RBC biomicrolens, cell viability characterization and calculation of optical force (PDF). Scanning imaging with a spherical RBC microlens (MP4). The membrane stretch with an RBC microlens (MP4).

AUTHOR INFORMATION Corresponding Author: Yao Zhang: *E-mail: [email protected] ORCID Xiaoshuai Liu: 0000-0001-5665-7421 ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 61827822, 11874183, and 11774135), the PhD Start-up Fund of Natural Science Foundation of Guangdong Province (No. 2018A030310501), the Science and Technology Program of Guangzhou (No. 201904010411) and the Fundamental Research Funds for the Central Universities (No. 21618301). Notes The authors declare no competing financial interest.


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Red blood cell-based microlens: application to single-cell membrane

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