In a liquid environment, optical trapping and multifunctional manipulation of biological cells, in a noncontact, noninvasive, and high-precision way, have become one of the research focuses in the field of integrated optics, biophotonics, and clinical medicine. However, it still faces great challenges to perform multifunctional manipulation in very narrow spaces with high flexibility, including stable retaining, controllable deformation, and precise regulation of a cell chain. Therefore, in this chapter, we introduce the multifunctional manipulation for biological cells based on the elaborately designed fiber probes. With the probes, the sequential organization, precise regulation, and bidirectional transportation of the cell chain were performed. We also discuss the potential applications of fiber probes on the endocytosis and exocytosis purpose, which will play an important role in the detection and treatment of complex disease.
- optofluidic manipulation
- fiber probe
- cell chain
- fiber tweezers
In the field of endocytosis and exocytosis, a precise manipulation of a cell was required, especially for the nanomedicine injection, intracellular signaling pathway, and pathogenic research, which holds a great potential in the detection and treatment of complex diseases . Thus, increasing attentions have been paid to the dynamic manipulation of cells in a fluid, which has been proved to be crucial in cell growth [2, 3], differentiation [4, 5, 6], drug delivery [7, 8, 9], mechanical force transduction [10, 11], etc. Up to now, diverse techniques have shown invaluable performance in the multifunctional manipulation of cells, including dielectrophoretic [12, 13], magnetic field [14, 15], and mechanical force [4, 16, 17]. Nevertheless, these strategies face the challenges of potential sample heating and high power consumption and required attachment of electric/magnetic nanoparticles [18, 19]. Besides, the cells were required to be confined on an elaborated substrate, which was usually not reusable in these techniques [20, 21].
Since first introduced by A. Ashkin, optical tweezers have motivated many intriguing advances in interdisciplinary applications, such as micro/nanophotonics, biphotonics, and biomedicine [22, 23, 24]. The most commonly used optical manipulation tool is the conventional optical tweezers (COTs), which uses high numerical aperture objectives to focus the free-space laser beam [25, 26]. After the transfer of photon momentum, the cell will suffer from the optical force, which can be divided into optical scattering force and gradient force, with the direction pointed to the optical propagating direction and beam focus, respectively. The magnitude of optical force was ranged from femtonewton to nanonewton, and thus, it was the ideal chose to measure the response of biological and macromolecular system . Compared to other microscopic techniques, for example, electric filed, magnetic field, and acoustic method, optical tweezers have the great potential of high precision, high flexibility, noncontact, and wide manipulation range. However, COTS faces certain challenges, such as bulky structure, limited integration, and diffraction for nanoparticles . Thus, researchers have developed various schemes of optical tweezers to extend the potential application scenario, including holographic optical tweezers (HOTs), surface plasmon-based optical tweezers (SPOTs), and fiber probe-based optical tweezers (FP).
For HOTs, the optical tweezer system was inserted with a diffractive beam splitter. Then the beam wavefront can be further sculptured, which can manipulate multiple cells simultaneously [29, 30, 31]. Nevertheless, appropriate algorithms are required to be elaborately designed for achieving a specific pattern of cells. In addition, the complicated optical system was consisted of dichroic mirrors, spatial light modulators, and high-numerical-aperture focusing objectives. The working distance of objectives limits the depth at which cells can be manipulated in the cell suspensions. Besides HOTs, surface plasmon-based optical tweezers (SPOTs) have also been developed to manipulate cells with high trapping stability and retaining ability, especially for the sub-microsized cells and biological molecules [32, 33]. However, once the substrates designed, the cell pattern is fixed without a flexibility to adjust and transport the cell chain dynamically. Moreover, the organization of cell pattern is also limited at a specific depth of cell suspension. Thus, there is a great need of developing a new strategy to perform the multifunctional manipulation of cells.
2. Fiber probe-based optical tweezers
First, we will give a detailed introduction about the fiber probe-based optical tweezers. As for optical tweezers, a focused laser beam was essential for the stable trapping and dynamic manipulation of cells. To realize a focused laser beam, the fiber probe was designed into a tapered tip, for which the laser beam will be focused by the paraboloid end. After one cell approached the beam focus, it will suffer from the optical gradient force and then attracted into the optical axis. After that, it will be pushed away from the probe tip or attracted into the focus, which depends on the struggling of optical scattering force and gradient force along the optical axis direction. After the cell was trapped one by one, a specific organization of cell pattern can be achieved with the fiber probe. Further, the organized cell pattern can be shifted dynamically in the three dimensional direction. The FPs were fabricated by drawing commercial single-mode optical fibers with a flame-heating technique. By adjusting the stretch parameters, various parabolic ends can be achieved to conduct the multifunctional manipulation of the cell. With the high flexibility, ease fabrication, and compact size, fiber probe-based optical tweezers have been widely used for the trap of dielectric microparticles and cells , the shift of fluorescent particles , and organelles in the cell . Besides, it is free from the limitation on the depth of cell manipulation in the suspensions and does not require any elaborated substrates, providing a flexible platform that can be easily integrated with microfluidics.
In this chapter, we will discuss the multifunctional manipulation of cells with the designed optical fiber probes (FPs). We will show the precise regulation and bidirectional transport of the cell chain with the FPs. Furthermore, it can also conduct the dynamic rotation and deformation of human red blood cells. With the further combination into the microfluidic technique, FPs have enabled the precise control of cell and further applied into the noninvasive analysis for the endocytosis and extrocytosis behaviors.
3. Optical fiber probe-based manipulation of cells
3.1 The regulation of the cell chain
Figure 1 schematically shows the formation and regulation process of an
To demonstrate the operation mechanism, a dynamic regulation of the cell chain was experimentally conducted. After the laser beam injected into FP 1 (
To quantitatively interpret the above experiment, the optical torques (
Further, the numerical simulations show that the method can be used for the regulation of cell chains consisted of cells with different sizes and shapes (e.g., spherical). After the FPs incorporated into lap-on-chip platforms, the presented regulation method is expected to enable a new opportunity for the investigation of cell growth, intercellular singling pathway, and pathogenic processes.
3.2 Optofluidic organization and transport of the cell chain
Except for the precise regulation, the organized cell chain can also be dynamically transported with an optofluidic strategy, by implanting a large-tapered-angle fiber probe (LTAP) into the microfluidic technique. As shown in Figure 4a, when an
Then, the experiment was conducted to demonstrate the bidirectional transportation of the cell chain (Figure 4b). The flow velocity was fixed at
In addition, spherical eukaryotes (e.g., yeast cells) can also be organized and transported with the proposed optofluidic technique (Figure 5a). The flow velocity and laser power were set to be
3.3 Optical rotation and deformation of human red blood cells
Except for the bidirectional transportation of the RBC chain, FPs were also investigated to conduct the multifunctional rotation and deformation of human red blood cells, which were of great physiological and pathological significance. As shown in Figure 6, one RBC was bound to the tip of TFP 1 at
To quantitatively analyze the above rotation process,
Further, a stretch of single or multiple RBCs can also be realized by using two TFPs. As schematically shown in Figure 7a, after the laser beams injected into both TFPs 1 and 2, three RBCs are trapped and then stretched along the optical axis of TFPs. The experiments were then conducted to demonstrate the above stretch mechanism. At
Similarly, the simultaneous stretch of three RBCs was also conducted, as shown in Figure 7c. The diameters of RBCs 1, 2, and 3 were 6.7, 5.7, and 6.9 μm, respectively. At
From the above analysis, it can be seen that the multifunctional trap and manipulation can be conducted with the fiber probe-based optical tweezers. As we know, a precise control of cell behavior was essential in the research of the endocytosis and exocytosis process, especially for nanomedicine injection, intracellular signaling pathway, and pathogenic progress. After cells manipulated in a controlled manner, various microparticles or viruses can be brought into contact with the targeted cells at specific well-defined time points and positions. Meanwhile, the spatiotemporal effect can be quantitatively investigated of different extracellular cues on the endocytosis and exocytosis process.
Then the potential application and advantages were discussed for fiber probe-based tweezers on the endocytosis and exocytosis purpose. As for the nanomedicine injection, the cells can be located at a different distance to the medicine with the assistance of fiber probes, providing a great way to study the diffusion and transportation process. Further, the nanomedicine can be adjusted to approach various sites of the cell membrane. Then, the endocytosis efficiency on the interaction sites can be quantitatively investigated. Meanwhile, various nanomedicines can approach the targeted cell simultaneously with controlled sites, providing an insight into the study of selective phagocytosis progress. While for the intracellular signaling pathway, spatial manipulation will be beneficial to analyze the effect of contact distance on the cell interaction. As we know, the cell can interact with each other through the exchange of soluble signaling molecules or direct cell-cell contact, which can vary in both time and space continuously. Thus, it is of great importance in dynamically adjusting the cell-cell interaction distance and contact sequence, which can be conducted by using the fiber-probe tweezers. Further, the detailed pathway for the intracellular signaling can be individually investigated with the proposed technique. Besides, in the pathogenic progress, the specific infection site can be decided by using fiber probes to manipulate pathogenic bacterium and targeted cell simultaneously. Thus, the dependence of the contact site on the infection performance can be investigated, which opens up the possibility for analyzing pathogenic dynamics not accessible through passive observation.
In this chapter, the fiber probe has been demonstrated to conduct the multifunctional manipulation of cell chains, including the sequential organization, precise regulation, and bidirectional transportation. Besides, the dynamic rotation and deformation of the human red blood cell were also realized using the fiber probes. With the advantage of ease integration, high flexibility, and noninvasive, the proposed technique can provide a great perspective in the investigation of the endocytosis and exocytosis purpose. The targeted cells and pathogenic bacterium can be dynamically manipulated simultaneously, which is anticipated to be useful in the analysis, diagnosis, and treatment of cell diseases. By incorporating the FPs into lap-on-chip platforms, the presented technique is expected to enable a new opportunity for the investigation of the nanomedicine injection, intracellular signaling pathway, and pathogenic process.
This work was supported by the National Natural Science Foundation of China (No. 11774135, 11874183, and 61827822), the Tip-top Scientific and Technical Innovative Youth Talents of Guangdong Special Support Program (No. 2015TQ01X267), the Fundamental Research Funds for the Central Universities (No. 21618301), and the PhD Start-up Fund of Natural Science Foundation of Guangdong Province (No. 2018A030310501).
Conflict of interest
The authors declare no competing financial interests.
Oh N, Park JH. Endocytosis and exocytosis of nanoparticles in mammalian cells. International Journal of Nanomedicine. 2014; 9:51-63. DOI: 10.2147/IJN.S26592
Aoki SK, Pamma R, Hernday AD, Bickham JE, Braaten BA, Low DA. Contact-dependent inhibition of growth in Escherichia coli. Science. 2005; 309:1245-1248. DOI: 10.1126/science.1115109
Aoki SK, Diner EJ, Roodenbeke CK, Burgess BR, Poole SJ, Braaten BA, et al. A widespread family of polymorphic contactdependent toxin delivery systems in bacteria. Nature. 2010; 468:439-442. DOI: 10.1038/nature09490
Tang J, Peng R, Ding J. The regulation of stem cell differentiation by cell-cell contact on micropatterned material surfaces. Biomaterials. 2010; 31:2470-2476. DOI: 10.1016/j.biomaterials.2009.12.006
Charest JL, Jennings JM, King WP, Kowalczyk AP, Garcia AJ. Cadherin-mediated cell-cell contact regulates keratinocyte differentiation. The Journal of Investigative Dermatology. 2009; 129:564-572. DOI: 10.1038/jid.2008.265
Krauss RS, Cole F, Gaio U, Takaesu G, Zhang W, Kang JS. Close encounters: Regulation of vertebrate skeletal myogenesis by cell-cell contact. Journal of Cell Science. 2005; 118:2355-2362. DOI: 10.1242/jcs.02397
Castillo J, Dimaki M, Svendsen WE. Manipulation of biological samples using micro and nano techniques. Integrative Biology. 2009; 1:30-42. DOI: 10.1039/b814549k
Wlodkowic D, Cooper JM. Microfabricated analytical systems for integrated cancer cytomics. Analytical and Bioanalytical Chemistry. 2010; 398:193-209. DOI: 10.1007/s00216-010-3722-8
Saltzman WM, Olbricht WL. Building drug delivery into tissue engineering. Nature Reviews. Drug Discovery. 2002; 1:177-186. DOI: 10.1038/nrd744
Chen CS, Tan J, Tien J. Mechanotransduction at cell-matrix and cell-cell contacts. Annual Review of Biomedical Engineering. 2004; 6:275-302. DOI: 10.1146/annurev.bioeng.6.040803.140040
Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B, et al. Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nature Cell Biology. 2011; 13:49-58. DOI: 10.1038/ncb2133
Kirschbaum M, Guernth-Marschner CR, Cherré S, Peña AP, Jaeger MS, Kroczek RA, et al. Highly controlled electrofusion of individually selected cells in dielectrophoretic field cages. Lab on a Chip. 2012; 12:443-450. DOI: 10.1039/c1lc20818g
Hamdi FS, Français O, Subra F, Dufour-Gergam E, Pioufle BL. Microarray of non-connected gold pads used as high density electric traps for parallelized pairing and fusion of cells. Biomicrofluidics. 2013; 7:044101. DOI: 10.1063/1.4813062
Kimura T, Sato Y, Kimura F, Iwasaka M, Ueno S. Micropatterning of cells using modulated magnetic fields. Langmuir. 2005; 21:830-832. DOI: 10.1021/la047517z
Sakar MS, Steager EB, Kim DH, Kim MJ, Pappas GJ, Kumar V. Single cell manipulation using ferromagnetic composite microtransporters. Applied Physics Letters. 2010; 96:043705. DOI: 10.1063/1.3293457
Khademhosseini A, Yeh J, Jon S, Eng G, Suh KY, Burdick JA, et al. Molded polyethylene glycol microstructures for capturing cells within microfluidic channels. Lab on a Chip. 2004; 4:425-430. DOI: 10.1039/b404842c
Théry M. Micropatterning as a tool to decipher cell morphogenesis and functions. Journal of Cell Science. 2010; 123:4201-4213. DOI: 10.1242/jcs.075150
Huang NT, Zhang HL, Chung MT, Seo JH, Kurabayashi K. Recent advancements in optofluidics-based single-cell analysis: optical on-chip cellular manipulation, treatment, and property detection. Lab on a Chip. 2014; 14:1230-1245. DOI: 10.1039/c3lc51211h
Yi CQ, Li CW, Ji SL, Yang MS. Microfluidics technology for manipulation and analysis of biological cells. Analytica Chimica Acta. 2006; 560:1-23. DOI: 10.1016/j.aca.2005.12.037
Schmidt BS, Yang AH, Erickson D, Lipson M. Optofluidic trapping and transport on solid core waveguides within a microfluidic device. Optics Express. 2007; 15:14322-14334
Psaltis D, Quake SR, Yang CH. Developing optofluidic technology through the fusion of microfluidics and optics. Nature. 2006; 442:381-386
Dholakia K, Reece P, Gu M. Optical micromanipulation. Chemical Society Reviews. 2008; 37:42-55. DOI: 10.1039/b512471a
Daly M, Sergides M, Chormaic SN. Optical trapping and manipulation of micrometer and submicrometer particles. Laser & Photonics Reviews. 2015; 9:309-329. DOI: 10.1002/lpor.201500006
Phillips DB, Padgett MJ, Hanna S, Ho YD, Carberry DM, Miles MJ, et al. Shape-induced force fields in optical trapping. Nature Photonics. 2014; 8:400-405. DOI: 10.1038/NPHOTON.2014.74
Rodríguez-Sevilla P, Rodríguez-Rodríguez H, Pedroni M, Speghini A, Bettinelli M, Solé JG, et al. Assessing single upconverting nanoparticle luminescence by optical tweezers. Nano Letters. 2015; 15:5068-5074. DOI: 10.1021/acs.nanolett.5b01184
Kim K, Yoon J, Park YK. Simultaneous 3D visualization and position tracking of optically trapped particles using optical diffraction tomography. Optica. 2015; 2:2334-2536. DOI: 10.1364/OPTICA.2.000343
Grier DG. A revolution in optical manipulation. Nature Photonics. 2003; 424:21-27. DOI: 10.1038/nature01935
Xin HB, Xu R, Li BJ. Optical trapping driving, and arrangement of particles using a tapered fibre probe. Scientific Reports. 2012; 2:1-8. DOI: 10.1038/srep00818
Padgett M, Leonardo RD. Holographic optical tweezers and their relevance to lab on chip devices. Lab on a Chip. 2011; 11:1196-1205. DOI: 10.1039/c0lc00526f
Kirkham GR, Britchford E, Upton T, Ware J, Gibson GM, Devaud Y, et al. Precision assembly of complex cellular microenvironments using holographic optical tweezers. Scientific Reports. 2015; 5:8577. DOI: 10.1038/srep08577
Akselrod GM, Timp W, Mirsaidov U, Zhao Q, Li C, Timp R, et al. Laser-guided assembly of heterotypic three-dimensional living cell microarrays. Biophysical Journal. 2006; 91:3465-3473. DOI: 10.1529/biophysj.106.084079
Righini M, Ghenuche P, Cherukulappurath S, Myroshnychenko V, Abajo FJ, Quidan R. Nano-optical trapping of Rayleigh particles and Escherichia colibacteria with resonant optical antennas. Nano Letters. 2009; 9:3387-3391. DOI: 10.1021/nl803677x
Juan ML, Righini M, Quidant R. Plasmon nano-optical tweezers. Nature Photonics. 2011; 5:349-356. DOI: 10.1038/nphoton.2011.56
Decombe JB, Valdivia-Valero FJ, Dantelle G, Leménager G, Gacoin T, Francs GC, et al. Luminescent nanoparticle trapping with far-field optical fiber-tip tweezers. Nanoscale. 2016; 8:5334-5342. DOI: 10.1039/c5nr07727c
Li YC, Xin HB, Liu XS, Li BJ. Non-contact intracellular binding of chloroplasts in vivo. Scientific Reports. 2015; 5:10925. DOI: 10.1038/srep10925
Fazal FM, SM B. Optical tweezers study life under tension. Nature Photonics. 2011; 5:318-321. DOI: 10.1038/nphoton.2011.100
Gross SP. Application of optical traps in vivo. Methods in Enzymology. 2003; 361:162-174. DOI: 10.1016/S0076-6879(03)61010-4
Liu XS, Huang JB, Zhang Y, Li BJ. Optical regulation of cell chain. Scientific Reports. 2015; 5:11578. DOI: 10.1038/srep11578
Liu XS, Huang JB, Li YC, Zhang Y, Li BJ. Optofluidic organization and transport of cell chain. Journal of Biophotonics. 2017; 10:1627-1635. DOI: 10.1002/jbio.201600306
Liu XS, Huang JB, Li YC, Zhang Y, Li BJ. Rotation and deformation of human red blood cells with light from tapered fiber probes. Nano. 2017; 6:309-316. DOI: 10.1515/nanoph-2016-0115