Optical Fiber Tweezers: a Versatile Tool for Optical Trapping and Manipulation

micromachines

Review Optical Fiber Tweezers: A Versatile Tool for Optical Trapping and Manipulation

Xiaoting Zhao †, Nan Zhao †, Yang Shi, Hongbao Xin * and Baojun Li Institute of Nanophotonics, Jinan University, Guangzhou 511443, China; [email protected] (X.Z.); [email protected] (N.Z.); [email protected] (Y.S.); [email protected] (B.L.) * Correspondence: [email protected]; Tel.: +86-20-3733-6704 These authors contributed equally to this work. † Received: 7 December 2019; Accepted: 16 January 2020; Published: 21 January 2020

Abstract: Optical trapping is widely used in different areas, ranging from biomedical applications, to physics and material sciences. In recent years, optical fiber tweezers have attracted significant attention in the field of optical trapping due to their flexible manipulation, compact structure, and easy fabrication. As a versatile tool for optical trapping and manipulation, optical fiber tweezers can be used to trap, manipulate, arrange, and assemble tiny objects. Here, we review the optical fiber tweezers-based trapping and manipulation, including dual fiber tweezers for trapping and manipulation, single fiber tweezers for trapping and single cell analysis, optical fiber tweezers for cell assembly, structured optical fiber for enhanced trapping and manipulation, subwavelength optical fiber wire for evanescent fields-based trapping and delivery, and photothermal trapping, assembly, and manipulation.

Keywords: optical fiber tweezers; optical trapping and manipulation; optical force; photothermal effect; evanescent fields; cell trapping and assembly

1. Introduction Optical forces have been widely used for optical trapping and manipulation of particles while using laser beams since 1970, when Arthur Ashkin used two counter-propagating and continuous wave focused beams to trap particle [1]. In 1986, Ashkin and co-workers used a single tightly focused laser beam, which realized the stable trapping of particles. They then named the optical-trapping technique as optical tweezers [2], which we refer to conventional optical tweezers (COTs). Over the years that followed, Ashkin and co-workers carried out a series of studies, which not only realized the capture of particles ranging from tens of nanometers to tens of microns with a single focused beam, but also realized the capture of viruses and bacteria [2,3]. After nearly 50 years of development, optical trapping and manipulation via COTs have made great progresses in both methods and applications, with manipulated samples ranging from different dielectric particles to biological cells and biomolecules [4,5]. However, a high numerical aperture (NA) objective is necessary for the light focusing via COTs. In addition, different optical components for beam expanding and steering are also essential. This bulky structure makes it lack manipulation and control flexibility. Alternatively, in 1998, holographic optical tweezers (HOTs) that can realize multiple traps with complex structured light fields have been developed [6]. These multiple traps can be achieved by means of computer generated holograms via the modulation of spatial light modulators. Such HOTs greatly increase the manipulation and control degrees, and they are also widely used for multiple particle trapping and manipulation [7–10]. However, it is difficult for the stable trapping of particles in the nanometer scale due to the diffraction limit. In the late 2000s, surface plasmon-based optical tweezers (SPOTs) [11,12] have been created, which can realize the stable

Micromachines 2020, 11, 114; doi:10.3390/mi11020114 www.mdpi.com/journal/micromachines Micromachines 2019, 10, x 2 of 26 trapping of nanoparticles, even single molecules with a few nanometer scale, to realize the nanoscale trapping and manipulation [13,14]. Though with the ability for the trapping of nanoscale particles, the SPOTs necessitate carefully designed and elaborate nanostructures. These nanostructures also limit the manipulation flexibility. Techniques, such as COTs, HOTs, and SPOT, involve complex devices and components with inflexible control. Therefore, it is particularly important to seek a simple and flexible control and manipulation tool. The development of optical fiber tweezers (OFTs) Micromachines 2020, 11, 114 2 of 27 [15,16] makes it a versatile candidate for optical trapping and the manipulation of different samples. OFTs possess exceptional advantages in the manipulation flexibility due to the simple structure with onlytrapping optical of nanoparticles,fibers. The fiber even can single be inserted molecules into with thick a few samples nanometer and turbid scale, to media, realize which the nanoscale greatly increasestrapping andthe sample manipulation applicability. [13,14]. In Though addition, with OFTs the abilitymake optical for the manipulation trapping of nanoscale a low cost particles, technique the dueSPOTs to necessitatethe easy fabrication carefully designedprocedures. and OFTs elaborate can nanostructures.also be integrated These into nanostructures small devices, also such limit as optofluidicthe manipulation channels flexibility. and chips Techniques, [17]. OFTs such were as fi COTs,rst presented HOTs, andin 1993, SPOT, where involve two complex aligned devicessingle- modeand components optical fibers with were inflexible used for control. optical Therefore,trapping [18]. it is While particularly tiny particles important and tocells seek can a simplebe directly and capturedflexible control and manipulated and manipulation using tool. the The optical development scattering of opticalforce generated fiber tweezers by two (OFTs) fibers [15, 16[19],] makes the manipulationit a versatile candidate flexibility for is limited optical by trapping the two and fibers. the manipulationIndeed, a single of optical different fiber samples. can also OFTs be used possess for particleexceptional trapping advantages and manipulation. in the manipulation In 1997, flexibility the first optical due to themanipulation simple structure using witha single only tapered optical opticalfibers. Thefiber fiber was canreported be inserted [20]. These into thick single samples fiber-based and turbid OFTs media,greatly whichincrease greatly the manipulation increases the flexibility.sample applicability. The end of In a single addition, fiber OFTs for light make focusing optical manipulation is similar to that a low in costCOTs technique after being due drawn to the easyinto afabrication lenticular procedures.shape, which OFTs creates can alsoa stronger be integrated gradient into force small on devices,the particle such and as optofluidic makes it easier channels for opticaland chips trapping [17]. OFTs [21–23]. were Both first dual presented and single in 1993, fibers where can two be alignedused for single-mode stable trapping, optical as fibers shown were in Figureused for 1. optical trapping [18]. While tiny particles and cells can be directly captured and manipulated usingOFTs the optical can be scattering divided into force two generated categories, by two accord fibersing [19 to], their the manipulation working principles: flexibility photothermal is limited by effectthe two and fibers. optical Indeed, force. aThe single former optical generates fiber can trap alsoping be usedforce forby particlelaser-induced trapping thermal and manipulation. and acoustic gradientsIn 1997, the in firstthe surrounding optical manipulation medium usingof the a partic singleles tapered [24], while optical the fiber latter was has reported been traditionally [20]. These decomposedsingle fiber-based into two OFTs components: greatly increase the scattering the manipulation force in flexibility.the direction The of end light of apropagation single fiber forand light the gradientfocusing force is similar in the to direction that in COTs of the after optical being intensity drawn intogradient a lenticular [25]. shape, which creates a stronger gradientFor the force purpose on the of particle this review, and makes we will it easierfocus on for the optical OFTs trapping and summarize [21–23]. their Both recent dual and advances single infibers the trapping can be used and for manipulating stable trapping, of tiny as shownobjects, in especially Figure1. for cells.

Figure 1. TheThe overview overview figure figure of of optical optical fiber fiber tweezer tweezerss (OFTs) (OFTs) for for particle and cell trapping and manipulation. ( (II)) Dual Dual fiber fiber tweezers tweezers for for trapping trapping and and mani manipulation;pulation; single single optical optical fiber fiber tweezers tweezers for for (II) cell cell trapping trapping and and single single cell cell analysis, analysis, and and ( (IIIIII)) cell cell assembly; assembly; ( (IVIV)) structured structured optical optical fiber fiber tweezers tweezers forfor trapping and manipulation; ( (VV)) subwavelength subwavelength optical optical fiber fiber wire wire for evanescent fields-based fields-based trappingtrapping andand delivery; delivery; and, and, (VI) optical(VI) optical fiber-based fiber-based massive photothermalmassive photothermal assembly and assembly manipulation. and manipulation. OFTs can be divided into two categories, according to their working principles: photothermal effect and optical force. The former generates trapping force by laser-induced thermal and acoustic gradients in the surrounding medium of the particles [24], while the latter has been traditionally decomposed into two components: the scattering force in the direction of light propagation and the gradient force in the direction of the optical intensity gradient [25]. For the purpose of this review, we will focus on the OFTs and summarize their recent advances in the trapping and manipulating of tiny objects, especially for cells. Micromachines 2020, 11, 114 3 of 27

2. Theoretical Analysis of Optical Forces Exerted on Particles Optical force will be exerted on the particles near the focal point by the momentum transfer from the scattering of incident photons when a high intensity laser beam is irradiated on dielectric particles. The resulting optical force traditionally consists of two components: a scattering force and a gradient force. The Rayleigh scattering condition will be satisﬁed when the wavelength of laser beam is much longer than the size of trapped particle [25]. With the above condition, the optical force can be obtained by treating particles as point dipoles. For a particle of radius a, this force is given by

I σn F = 0 m (1) scatt c

!2 128π5a6 m2 1 With σ = − (2) 3λ4 m2 + 2 where I0 is the intensity of the incident light, σ is the scattering cross section of the particle, nm is the refractive index of the surrounding medium, c is the speed of light in vacuum, m is the ratio of the refractive index of the particle to that of the medium (np/nm), and λ is the wavelength of the trapping laser. The scattering force is in the same direction as the incident light and it is proportional to the intensity of the light. The optical gradient force is generated by the interaction between the induced dipole and the non-uniform ﬁeld, as given by

2πα F = I (3) grad 2 0 cnm ∇

2 ! 2 3 m 1 with α = nm a − (4) m2 + 2 However, for many cases, the size of the trapped particles is comparable to the wavelength of the trapping laser beam. In this situation, the point-dipole approach is invalid. More complete electromagnetic theories are necessary for the force calculation. Fortunately, numerical simulation and calculation methods that are based on electromagnetic theories, such as the finite element method and finite difference time domain method, can be used for the calculation of optical forces. The total optical force (FO) exerted on the particle can be calculated by calculating the integral of the time-independent Maxwell stress tensor () along the total external surface of the particle. can be expressed as

T = DE∗ + HB∗ 1/2(D E∗ + HB∗)I (5) h Mi − · where D and H are the electric displacement and magnetic field, respectively; E* and B* are the complex conjugates of the electric field E and magnetic flux field B, respectively; and, I is the isotropic tensor. F can be expressed as O I FO = ( TM n)dS (6) s h i · where n is the surface normal vector.

3. Dual Fiber Tweezers for Trapping and Manipulation The dual fiber tweezers mainly use the scattering force to trap particles cooperatively by two optical fibers. It can form a large enveloping area and easily accommodate large objects due to its beam divergence. In addition, the dual fiber tweezers do not use focused light, resulting in minimal radiation damage to living cells [26]. Jess et al. used a fiber arm with an output power of 800 mW to trap a 100 µm polymer sphere [27] (Figure2a). Decombe et al. achieved the capture of a 1 µm polystyrene sphere at an optical power of 2 mW by using optical tweezers with the tips of two chemically corroded fibers [28]. Micromachines 20202019,, 1110,, 114x 44 ofof 2726

The rotation of the trapped particles can also be achieved by the dual fiber tweezers. For example,The rotationa fiber ofspanner the trapped tool particles[29], which can also was be formed achieved by by two the dualtransversely fiber tweezers. offset Forfibers example, with acounterpropagating fiber spanner tool [ 29laser], which beams was that formed can rotate by two part transverselyicles, like a ospannerffset fibers tool, with was counterpropagating used to introduce laserthe lateral beams offset that canbetween rotate the particles, two back-propagating like a spanner tool, divergent was used beams to introduce from the the single-mode lateral offset fiber. between The thecenter two of back-propagating the fiber is laterally divergent biased and beams the optica froml thefiber single-mode is used to trap fiber. and Therotate center the human of the smooth fiber is laterallymuscle cell biased (hSMC) and the(Figure optical 2b). fiber If there is used is a to zero trap offset, and rotate the object the human can remain smooth in muscle a static cell state. (hSMC) The (Figureobject begins2b). If to there rotate is a when zero otwoffset, fibers the objecthave a can relative remain displacement in a static state. [29]. TheThe objectrotation begins of living to rotate cells whencan be two performed fibers have in a adual-beam relative displacement optical fiber [trap29]. integrated The rotation into of a living modular cells laboratory can be performed chip system in a dual-beam[30]. optical fiber trap integrated into a modular laboratory chip system [30]. Alternatively, thethe cellscells cancan bebe stretchedstretched afterafter beingbeing capturedcaptured withwith aa doubledouble beam.beam. Guck et al. constructedconstructed aa devicedevice andand namednamed itit anan opticaloptical stretcherstretcher [[31].31]. The principle ofof the optical stretcher isis asas follows:follows: when placing the dielectric object in thethe middle of two opposed, non-focused laser beams, thethe totaltotal forceforce actingacting onon thethe objectobject isis zero,zero, butbut thethe surfacesurface forcesforces areare additive,additive, whichwhich causescauses thethe objectobject toto bebe stretchedstretched alongalong thethe beambeam axis.axis. As shown in FigureFigure2 2c,c,Müller Müllercell cellcan can be be trapped, trapped, aligned, aligned, and and stretchedstretched outout by two counter-propagating near-infrarednear-infrared laser beams diverging from the optical fibers, fibers, wherewhere thethe incidentincident laserlaser wavelengthwavelength isis 10641064 nmnm [[32].32]. The cell stretching results from thethe additiveadditive surfacesurface forceforce onon the the cell cell membrane membrane due due to to momentum momentum changes changes of photonsof photons [31 ].[31]. The The red red blood blood cells cells can alsocan bealso stretched be stretched using dual-trapusing dual-trap optical optical tweezers tw aftereezers placing after themplacing in thethem suspension in the suspension and expanding and intoexpanding a sphere into [33 a]. sphere [33].

Figure 2.2. DualDual fiberfiber tweezerstweezers forfor cell cell trapping trapping and and manipulation. manipulation. (a ()a A) A 100 100µm µm polymer polymer is trappedis trapped by theby the dual dual fibers. fibers. Adapted Adapted with with permission permission from from Jess Jess et al.et al. [27 [27].]. (b )(b The) The human human smooth smooth muscle muscle cell cell is capturedis captured and and rotated rotated by by optical optical fiber fiber at at the the center center of of two two horizontally horizontally biased biasedfibers fibers (20(20 mWmW inin eacheach arm).arm). Adapted with permission from Black et al. [[29].29]. ( c) The Müller cell isis captured,captured, aligned,aligned, andand stretchedstretched byby twotwo near-infrarednear-infrared laserlaser beamsbeams thatthat propagatepropagate backwardsbackwards fromfrom thethe fiber.fiber. AdaptedAdapted withwith permissionpermission fromfrom FranzeFranze etet al.al. [[32].32].

The use of dual fiber fiber tweezers tweezers also also allows allows for for mo morere precise precise control control of of the the nanoscale nanoscale particles particles in inaddition addition to tothe the manipulation manipulation of ofparticles particles and and cells cells with with a arelatively relatively large large size size (micrometer scale). Figure3 3aa showsshows thethe schematic schematic depictiondepiction ofof aa dual-fiber-nanotip dual-fiber-nanotipmethod methodfor forthe the manipulation manipulation ofof multiwalled carboncarbon nanotubes nanotubes (MWCNTs) (MWCNTs) with with an an outer outer diameter diameter of onlyof only 50 nm50 nm and and a length a length of 0.9 ofµ 0.9m. Theµm. positionThe position and orientation and orientation of the of MWCNT the MWCNT can be can adjusted be adjusted by changing by changing the distance the distance between between the two nanotipsthe two nanotips and the inputand the power input of power each nanotip. of each nanotip. When P1 When(optical P1 power(optical from power the from left fiber) the left remains fiber) unchangedremains unchanged and P2 (optical and P2 power (optical from power the rightfrom fiber) the right power fiber) increases, power theincreases, orientation the orientation and position and of theposition MWCNT of the change MWCNT accordingly change accordingly [34]. Xu et al. [34]. realized Xu et al. the realized three-dimensional the three-dimensional (3D) optical (3D) trapping optical of silvertrapping nanoparticles of silver nanoparticles and nanowires and while nanowires using while dual focusedusing dual coherent focused beams coherent [35] (Figurebeams [35]3c). (Figure As the distance3c). As thed (thedistance gap betweend (the gap two between fiber probes, two fiber FPs) probes, increases, FPs) theincreases, initial stablethe initial trap stable state oftrap the state silver of nanowiresthe silver nanowires (diameter: (diameter: 330 nm, length: 330 nm, 2.1 µlength:m) is destroyed 2.1 µm) is and destroyed the transverse and the Poynting transverse vector Poynting points outward,vector points which outward, causes which the particle causes to the escape particle (Figure to escape3d-I,II). (Figure The 3d-I,II). nanowires The arenanowires rotated are clockwise rotated byclockwise increasing by theincreasing transverse the distancetransverse between distance FP1 between and FP2 FP1 to formand FP2 an asymmetric to form an fieldasymmetric distribution field (Figuredistribution3e). Additionally,(Figure 3e). Additionally, Liu et al. proved Liu et thatal. proved the inclined that the dual-fiber inclined opticaldual-fiber tweezers optical have tweezers the abilityhave the of 3Dability trapping, of 3D which trapping, is related which to the is inclinationrelated to anglethe inclination of the fiber angle [36]. Theof the combination fiber [36]. of The 3D printedcombination Fresnel of 3D lenses printed on dual Fresnel fiber lenses surface on dual was fi reportedber surface to bewas an reported excellent to method be an excellent to increase method the to increase the trapping efficiency and stability [37]. In this scenario, the trap stiffness is increased by a substantial factor of 35–50.

Micromachines 2020, 11, 114 5 of 27 trapping eﬃciency and stability [37]. In this scenario, the trap stiﬀness is increased by a substantial factorMicromachines of 35–50. 2019, 10, x 5 of 26

FigureFigure 3.3. ((aa)) SchematicSchematic depictiondepiction ofof thethe orientationorientation andand displacementdisplacement ofof aa singlesingle multiwalledmultiwalled carboncarbon nanotubesnanotubes (MWCNT)(MWCNT) controlled controlled using usin a dual-fiber-nanotipg a dual-fiber-na method.notip method. (b) Dark-field (b) opticalDark-field microscope optical imagesmicroscope of MWCNT images at of di MWCNTfferent output at different power. Adaptedoutput power. with permission Adapted fromwith Xinpermission et al. [34]. from (c) Schematic Xin et al. depiction[34]. (c) Schematic of three-dimensional depiction of (3D) three-dimensional optical trapping (3D) of silver optical nanostructures. trapping of silver (d) Optical nanostructures. traps images (d) atOptical different traps distances. images at (e different) Continuous distances. microscopic (e) Continuous images of microscopic silver nanowires images trapped of silver by nanowires rotation. Adaptedtrapped by with rotation. permission Adapted from with Xu et permission al. [35]. from Xu et al. [35]. 4. Single Optical Fiber Tweezers for Trapping and Single Cell Analysis 4. Single Optical Fiber Tweezers for Trapping and Single Cell Analysis 4.1. Single Optical Fiber Tweezers for Particle/Cell Trapping 4.1. Single Optical Fiber Tweezers for Particle/Cell Trapping Dual fiber tweezers still lack simplicity, so it is very important to realize the optical trapping and manipulationDual fiber based tweezers on a still single lack fiber, simplicity, i.e., single so it optical is very fiber important tweezers. to realize In general, the optical single trapping optical fiber and tweezersmanipulation are tweezers based on that a single resulted fiber, from i.e., a single single op opticaltical fiber fiber. tweezers. Figure4a In shows general, the workingsingle optical principle fiber tweezers are tweezers that resulted from a single optical fiber. Figure 4a shows the working principle of particle trapping while using a single tapered fibre probe (TFP) [38], where DA indicates the axial of particle trapping while using a single tapered fibre probe (TFP) [38], where DA indicates the axial distance (x direction) of the particles to the tip of the TFP and DT indicates the transverse distance (distancein y direction (x direction)) of a particle of the to particles the axis. to Once the tip a laser of the beam TFP isand launched DT indicates into the the TFP, transverse the light distance emerging (in fromy direction) the TFP of after a particle focusing to the will axis. exert Once an optical a laser force beam on is thelaunched particles. into Optical the TFP, force the consistslight emerging of two from the TFP after focusing will exert an optical force on the particles. Optical force consists of two parts—the gradient force Fg and the scattering force Fs. Fg tends to attract particles, while Fs pushes away,parts—the and thegradient resultant force force Fg and of themthe scattering together force dominates Fs. Fg tends the motion to attract of theparticles, particles. while The Fs opticalpushes forceaway, on and the the particle resultant can force be calculated of them together by integrating domina thetes the Maxwell motion stress of the tensor particles. around The optical the particle. force on the particle can be calculated by integrating the Maxwell stress tensor around the particle. Figure Figure4b-I shows the calculated force Fx exerted on the particle along the TFP axis as a function of 4b-I shows the calculated force Fx exerted on the particle along the TFP axis as a function of DA (i.e., DA (i.e., DT = 0). When the particle is close to the TFP tip (DA < 13 µm), Fx is negative, which means DT = 0). When the particle is close to the TFP tip (DA < 13 µm), Fx is negative, which means that there is a trapping force towards the tip. In this region, the gradient force Fg dominates the motion of particles and the particle can be trapped. When the particle is away from the TFP tip, Fx is positive, which means that there is a driving force in the direction of light propagation. In this region, the scattering force Fs dominates the motion of particles and the particle can be pushed away. This

Micromachines 2020, 11, 114 6 of 27

that there is a trapping force towards the tip. In this region, the gradient force Fg dominates the motion of particles and the particle can be trapped. When the particle is away from the TFP tip, Fx is positive, which means that there is a driving force in the direction of light propagation. In this region, Micromachines 2019, 10, x 6 of 26 the scattering force Fs dominates the motion of particles and the particle can be pushed away. This didifferentfferent opticaloptical force-based force-based manipulation manipulation mechanism mechanis resultsm results from from the lightthe light distribution distribution near thenear fiber the tip.fiber For tip. a For clearer a clearer description, description, Figure Figure4c shows 4c shows the light the light distribution distribution near near the fiberthe fiber tip [ tip39]. [39]. It can It can be seenbe seen that that the laserthe laser beam beam is focused is focused at the at fiber the tip.fiber At tip. the At tip the of thetip fiber,of the the fiber, optical the intensityoptical intensity reaches thereaches highest the and,highest therefore, and, therefore, there is athere strong is opticala strong gradient optical gradient force near force the tip,near which the tip, can which be used can for be trapping.used for trapping. The gradient The ofgradient intensity of inintensity the converging in the converging beam pulls beam small pulls objects small towards objects the towards focal point, the whilefocal thepoint, radiation while pressurethe radiation tends topressure push them tends away to push along them the optical away axis. along With the gradient optical forceaxis. beingWith dominated,gradient force a particle being dominated, can be trapped a particle in three can dimensions be trapped nearin three the dimensions focal point bynear the the optical focal gradientpoint by forcethe optical [40]. gradient force [40].

Figure 4. The principle for the single optical fiber tweezers trapping of particles. (a) Schematic Figure 4. The principle for the single optical fiber tweezers trapping of particles. (a) Schematic illustration for particle trapping and manipulation with light launched into the tapered fibre probe illustration for particle trapping and manipulation with light launched into the tapered fibre probe (TFP). (b) Calculation result of the optical force: (I) axial force exerted on particles along the TFP axis (TFP). (b) Calculation result of the optical force: (Ι) axial force exerted on particles along the TFP axis as a function of DA, (II) transverse force (Fy), and trapping potential (U) received by the particles at as a function of DA, (II) transverse force (Fy), and trapping potential (U) received by the particles at DA DA = 4.5 µm. Adapted with permission from Xin et al. [38]. (c) Optical intensity distribution near the = 4.5 µm. Adapted with permission from Xin et al. [38]. (c) Optical intensity distribution near the fiber fiber tip. Adapted with permission from Liu et al. [39]. tip. Adapted with permission from Liu et al. [39]. The requirement to trap a particle is the light focusing at the fiber end, so that an optical gradient forceThe can requirement be exerted on to the trap particles a particle near is the the light fiber focusi end. Additionally,ng at the fiber theend, main so that eff ectsan optical are the gradient optical forces.force can The be trapping exerted mechanismon the particles for optical near the fiber fiber tweezers end. Additionally, is the same as the that main in COTs, effects both are are the resulted optical fromforces. the The optical trapping force (opticalmechanism gradient for forceoptical for fiber trapping). tweezers For is the the COTs, same light as isthat focused in COTs, by a highboth NAare objectiveresulted from and thethe particleoptical force is trapped (optical near gradient the focus force by for optical trapping). gradient For force.the COTs, In single light OFTs,is focused light by is focuseda high NA by theobjective end surface and the of the particle fiber andis trapped the optical near gradient the focus force by also optical traps gradient the particle. force. The In abilitysingle OFTs, light is focused by the end surface of the fiber and the optical gradient force also traps the particle. The ability of OFTs to trap particles highly depends on the shape of the end of the fiber, which directly affects the light focusing at the fiber end. For an optical fiber with a flat end surface, the light is difficult to focus and, thus, the particle is difficult to be trapped. Instead, it will be pushed away by the optical scattering force. For a tapered optical fiber with a parabolic or convex surface, light will be focused at the fiber end, and particles can be trapped by the generated optical gradient

Micromachines 2020, 11, 114 7 of 27 of OFTs to trap particles highly depends on the shape of the end of the fiber, which directly affects the light focusing at the fiber end. For an optical fiber with a flat end surface, the light is difficult to focus and, thus, the particle is difficult to be trapped. Instead, it will be pushed away by the optical scattering force. For a tapered optical fiber with a parabolic or convex surface, light will be focused at the fiber end, and particles can be trapped by the generated optical gradient force. Light is highly Micromachines 2019, 10, x 7 of 26 focused near the fiber tip, as shown in Figure4c. This highly focused light will generate a strong opticalforce. gradient Light is force highly for focused particle near trapping. the fiber Actually, tip, as shown Xin etin Figure al. calculated 4c. This highly the trapping focused e lightfficiency will of a 10-µmgenerate polystyrene a strong particle optical in gradient both OFTs force and for COTsparticle [38 trapping.]. The calculated Actually, Xin effi ciencyet al. calculated is 0.227 andthe 0.12 for OFTstrapping and COTs,efficiency respectively. of a 10-µm That polystyrene means thatparticle the trappingin both OFTs efficiency and COTs for OFTs [38]. isThe not calculated weaker than COTs.efficiency The main is 0.227 difference and 0.12 between for OFTs the and FOTs COTs, and respectively. the COTs is That that means the COTs that realizethe trapping a truly efficiency non-contact trapping,for OFTs while is particlenot weaker might than be COTs. contacted The main with differ theence fiber between surface the after FOTs trapping and the in COTs OFTs. is Bythat changing the COTs realize a truly non-contact trapping, while particle might be contacted with the fiber surface the shape of tapered fiber end so that the focal point is a few microns away from the tip of the optical after trapping in OFTs. By changing the shape of tapered fiber end so that the focal point is a few fiber,microns we can realizeaway from a non-contact the tip of the optical optical trapping fiber, we [can41]. realize The fundamental a non-contact limitationoptical trapping for the [41]. trapping The is the difundamentalffraction limit. limitation For particles for the withintrapping the is ditheff ractiondiffraction limit, limit. it isFor di particlesfficult to within trap. the diffraction Opticallimit, it is fiber difficult tweezers to trap. can be used to trap particles and cells of different sizes, which range from few hundredsOptical of fiber nanometers tweezers tocan tens be used of micrometers. to trap particle Figures and cells5 shows of different the optical sizes, trappingwhich range of from di fferent particlesfew/ cellshundreds from of small nanometers to large. to tens The of main micrometers. influence Figure factor 5is shows Brownian the optical motion trapping anddi offf differentraction limit for theparticles/cells trapping of from small small particles. to large. As The shown main influe in Figurence factor5a, the is Brownian SiO 2 sphere motion was and 1.1 diffractionµm away limit from the for the trapping of small particles. As shown in Figure 5a, the SiO2 sphere was 1.1 µm away from the optical fiber tip at t1 = 0 s, and it was trapped at the tip at t1 = 1 s. Likewise, Escherichia coli (E. Coli) was optical fiber tip at t1 = 0 s, and it was trapped at the tip at t1 = 1 s. Likewise, Escherichia coli (E. Coli) was 1.3 µm away from the optical fiber tip at t1 = 0 s, and trapped at the tip at t1 = 1 s [38]. Figure5c shows 1.3 µm away from the optical fiber tip at t1 = 0 s, and trapped at the tip at t1 = 1 s [38]. Figure 5c shows a tapered optical fiber with abruptly tapered twin-core, which is fabricated by fusing and drawing the a tapered optical fiber with abruptly tapered twin-core, which is fabricated by fusing and drawing twin-corethe twin-core fiber [42 fiber]. The [42]. twin-core The twin-core fiber fiber extends extend thes functionalitythe functionality of of the the fiber fiber optical optical tweezers,tweezers, and allowsand for allows the particle for the trappingparticle trapping with orientation. with orientation. The single The single optical optical fiber tweezersfiber tweezers can evencan even be used be for the trappingused for ofthe cells trapping larger of than cells 10largerµm. than Figure 10 µm.5d showsFigure the5d shows trapping the oftrapping a mammalian of a mammalian cell with cell a size of aboutwith 15 a sizeµm of [43 about]. 15 µm [43].

FigureFigure 5. Single 5. Single optical optical ﬁber fiber tweezers tweezers are are able able toto traptrap pa particlesrticles and and cells cells with with different diﬀerent sizes. sizes. Optical Optical trappingtrapping of ( aof) ( aa) 0.7-a 0.7-µm-diameterµm-diameter SiO22 particles.particles. Adapted Adapted with permi withssion permission from Xin from et al. Xin[38], et(b) al. E. [38], (b) E.coli coli. .AdaptedAdapted with with permission permission from from Xin et Xin al. et[38], al. ( [c38) yeast], (c) cell. yeast Adapted cell. Adapted with permission with permission from Grier from Grieret et al. al. [42], [42 ],(d ()d Chinese) Chinese hamster hamster ovary ovary cell. Adapted cell. Adapted with permission with permission from Mohanty from Mohanty et al. [43]. et al. [43].

SingleSingle OFTs OFTs are widelyare widely used used for opticalfor optical trapping trapping and and manipulation manipulation due due toto thethe easyeasy fabricationfabrication and simpleand structure. simple structure. Without theWithout need the of high-NAneed of high objective-NA objective for light for focusing light focusing and the opticaland the elements optical for laserelements beam expanding for laser beam and lightexpanding steering and that light are steerin necessaryg that are in necessary COTs, the in OFTs COTs, have the OFTs the advantages have the of advantages of compactness and high manipulation flexibility. By simply moving the fiber, the compactness and high manipulation flexibility. By simply moving the fiber, the trapped particles can trapped particles can be flexibly manipulated accordingly. Figure 6 shows some examples for the be flexiblyflexible manipulated manipulation accordingly. and moving Figureof trapped6 shows partic someles and examples bacteria for[38,44]. the flexibleBy simply manipulation moving the and movingfiber, of the trapped trapped particles particles and can bacteria be manipulated [38,44]. Byin three simply dimensions moving theflexibly. fiber, Such the trappedmanipulation particles enables the pick-up action for further precise arrangement of particles into designed patterns (Figure 6a). The manipulation can also be applied in flowing environment (Figure 6b,c) [44]. In addition, a single optical fiber can be inserted into the sample with any angles and any depth, which greatly

Micromachines 2020, 11, 114 8 of 27 can be manipulated in three dimensions flexibly. Such manipulation enables the pick-up action for further precise arrangement of particles into designed patterns (Figure6a). The manipulation can also be applied in flowing environment (Figure6b,c) [ 44]. In addition, a single optical fiber can be inserted into theMicromachines sample 2019 with, 10 any, x angles and any depth, which greatly increases the manipulation8 flexibility. of 26 Therefore, the single optical fiber tweezers can be used in many different environments, where COTs increases the manipulation flexibility. Therefore, the single optical fiber tweezers can be used in many cannot be achieved. By cooperating with aspheric lens, optical trapping, and cooling of particles in different environments, where COTs cannot be achieved. By cooperating with aspheric lens, optical vacuum has also been demonstrated [45]. For a direct comparison, Table1 shows some features of trapping, and cooling of particles in vacuum has also been demonstrated [45]. For a direct comparison, singleTable OFTs 1 shows when some compared features with of single COTs. OFTs when compared with COTs.

FigureFigure 6. 6.Images Images of of usingusing OFTs for for flexible flexible manipula manipulationtion of trapped of trapped particles particles and bacteria. and bacteria.(a) (a) ArrangementArrangement ofof sixsix particlesparticles into into a a hexagon. hexagon. Th Thee particles particles are arepicked picked up and up andplaced placed into intothe the designateddesignated postion postion after after trapping trapping by by flexible flexible moving moving the fiber fiber (yellow (yellow arrow arrow indicated). indicated). Adapted Adapted with with permission from Xin et al. [38]. (b,c) Flexible manipulation of a trapped E. coli bacterium in flowing permission from Xin et al. [38]. (b,c) Flexible manipulation of a trapped E. coli bacterium in flowing environment. The yellow solid arrow indicates the fiber, the blue arrows indicate the flowing environment. The yellow solid arrow indicates the fiber, the blue arrows indicate the flowing direction. direction. Adapted with permission from Xin et al. [44]. Adapted with permission from Xin et al. [44]. Table 1. Comparison of single optical fiber tweezers (OFTs) with the conventional optical tweezers Table 1. Comparison of single optical fiber tweezers (OFTs) with the conventional optical (COTs). tweezers (COTs). Items Single OFTs COTs Items Single OFTs COTs Laser source Laser sourcehighhigh NA objective NA objectivea number of Key components Laser source, tapered optical fiber Key components Laser source, tapered opticala fibernumber ofoptical optical components for for beam beam expanding expanding and steeringand steering Easy, simply fabricate a taperedCarefully designCarefully the beam design path the via beam the adjusting path via of the FabricationFabrication and and Easy, simply fabricate a tapered optical fiber with beam expandingadjusting and of beamsteering expanding components and are steering construction optical fiber with different methods different methods componentsnecessary are necessary Integration HighlyHighly compact, compact, can be integrated can be integrated Integration capability Not compactNot compact capability into microfluidicinto microfluidic platform platform Less flexible, trapped particles can only be Highly flexible, trapped particles can Less flexible, trapped particles can only be Highly flexible, trapped particles Manipulation manipulated manipulatedby controlling bythe controllingfocus through the beam focus be deliveredcan be delivered to any designated to any designated Manipulationflexibility flexibility steering andthrough modulation beam elem steeringents incorporated and modulation with positions bypositions simply moving by simply the fiber moving theelements high-NA incorporated objective with the the fiber Wide, the fiber can be inserted into high-NA objective Suspension suspensions with any different Suspension depth and direction is limited due to the Wide, the fiber can be inserted into Suspension depth and direction is limited applicability directionssuspensions and depths for with trapping any di fferent focus generated by the high-NA objective. Suspension applicability due to the focus generated by the directionsand manipulation and depths for trapping high-NA objective. and manipulation

MicromachinesMicromachines2020 2019, ,11 10,, 114 x 99 of of 27 26

4.2. Single Optical Fiber Tweezers for Cell Analysis 4.2. Single Optical Fiber Tweezers for Cell Analysis In addition to the trapping of particles and cells, the single optical fiber tweezers are also widely usedIn for addition single tocell the labelling trapping and of particlesanalysis andafter cells, the cell the is single trapped. optical For fiber example, tweezers a single are also bacterium widely usedcan be for labelled single cell via labelling the cotrapping and analysis of a aftersingle the bacterium cell is trapped. and upconversion For example, nanoparticles a single bacterium (UCNPs) can be[46]. labelled Figure via 7a,b the provide cotrapping a clear of description a single bacterium of how anda tapered upconversion fiber probe nanoparticles (TF) traps a (UCNPs) single UCNP [46]. Figureand briefly7a,b provide labels the a clearbacterium. description A single of howUCNP a tapered(≈120 nm) fiber undergoing probe (TF) Brownian traps a single motion UCNP is trapped and brieflyat the tip labels of the the TF, bacterium. with a 980 A nm single wavelength UCNP ( 120lase nm)r beam. undergoing It is difficult Brownian to observe motion uncaptured is trapped UCNPs at the ≈ tipbecause of the TF,of the with small a 980 size nm of wavelength UCNPs. When laser are beam. UCNPs It is diis ffitrappedcult to observeto the tip, uncaptured it emits green UCNPs light because excited ofby the the small 980 nm size laser of UCNPs. and could, When therefore, are UCNPs be isdire trappedctly observed. to the tip, After it emits the greentrapping light of excited the UCNP, by the a 980bacterium nm laser can and be could, further therefore, trapped, be directlyand another observed. UCNP After can the be trappingcotrapped of theat the UCNP, end a face bacterium of the canbacterium. be further The trapped, emitting and green another light provides UCNP can a direct be cotrapped way for the at thelabeling end face and ofobservation the bacterium. of a single The emittingbacterium green that light is otherwise provides impossible a direct way in fordark the envi labelingronments. and observation Figure 7b shows of a single the images bacterium of labelled that is otherwiseindividual impossible bacteria with in dark different environments. lengths. The Figure labelling7b shows also the allows images for of the labelled single individual bacterium bacteria analysis withvia optical different signals. lengths. Figure The labelling7c shows alsothe reflection allows for signal the single of labeled bacterium bacteria analysis with vialengths optical of signals.1.8, 2.4, Figureand 3.27c µm, shows respectively. the reflection signal of labeled bacteria with lengths of 1.8, 2.4, and 3.2 µm, respectively.

FigureFigure 7. 7.( a(a)) Schematic Schematic and and (b ()b experimental) experimental images images of bacterialof bacterial cotrapping cotrapping and labelling.and labelling. (c) Real-time (c) Real- reﬂectedtime reflected optical optical signal fromsignal the from trapping the trapping and labeling and labeling of single of bacteria single withbacteria diﬀerent with sizes.different Adapted sizes. withAdapted permission with permission from Xin et from al. [ 46Xin]. et al. [46].

InIn addition addition to to the the analysis analysis of of single single bacteria bacteria from from thethe opticaloptical signals,signals, opticaloptical trappingtrapping viavia singlesingle OFTsOFTs also also allows allows for for the the energy energy analysis analysis of of motile motile bacteria. bacteria. Xin Xin et et al. al. usedused aa modifiedmodified taperedtaperedfiber fiberto to traptrapE. E. coli coliin in solution solution and and studied studied the the kinematics kinematics of of single single bacteria bacteria [ 41[41].]. FigureFigure8 a8a shows shows the the dynamic dynamic ofof aa motilemotile bacterium bacterium in in the the trapping trapping potential. potential. At Att 1t1= = 1.71.7 s,s, thethe motilemotile bacteriumbacterium waswas stablystablytrapped trapped µ atat a a distance distance of of 1.9 1.9 µmm away away from from the the fiber fiber tip tip and and kept kept halted halted for for about about 0.2 0.2 s (Figure s (Figure8a-I). 8a-I). At tAt1 = t11.9 = 1.9 s, thes, the bacteria bacteria began began to struggleto struggle in thein the trapping trapping potential potential after after the the stored stored energy energy release release (Figure (Figure8a-II). 8a- Later,II). Later, it was it trappedwas trapped back back toward toward the fiber the (Figurefiber (Figure8a-II). 8a-II). At t1 =At2.3 t1 s,= 2.3 the s, bacterium the bacterium was trapped was trapped back withback a with gap ofa gap 1.5 µ ofm 1.5 to theµm fiber to the tip. fiber Figure tip.8 bFigu canre analyze 8b can andanalyze explain and the explain phenomenon the phenomenon of bacteria of back-and-forth.bacteria back-and-forth. In solution, In solution, the motile the bacterium motile bacterium is swimming. is swimming. When near When the fibernear tip,the itfiber was tip, first it was first trapped by the OFTs, and then halted for about 0.1–1 s. After that, the energy that was stored

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Micromachines 2019, 10, x 10 of 26 trapped by the OFTs, and then halted for about 0.1–1 s. After that, the energy that was stored in the bacteriumin the bacterium was released was released and converted and converted into kinetic into kine energy.tic energy. If the If trapping the trapping potential potential is smaller is smaller than bacteriumthan bacterium energy, energy, the bacterium the bacterium can be can released. be releas Otherwise,ed. Otherwise, the bacteriumthe bacterium can can be struggling be struggling in the in trappingthe trapping potential. potential. Further, Further, the the bacterium bacterium can can further further escape escape from from the the trap trap if if thethe storedstored energyenergy is further released, and is larger than the trapping po potential.tential. Otherwise, Otherwise, the ba bacteriumcterium can be constantly constantly trapped. This This method method provides a simple meth methodod for the analysis of bacterium dynamics.

Figure 8. DynamicDynamic analysis analysis of of motile motile bact bacteriaeria via via non-contact non-contact optical optical trapping trapping of single of single bacteria. bacteria. (a) (Opticala) Optical microscope microscope images images capture capture and and struggle struggle with with the the process process of of E.E. coli coli bacterium.bacterium. ( (bb)) Schematic Schematic of the bacterium dynamics in the non-contact trapping.trapping. Adapted with permission from Xin et al. [[41].41].

5. Optical Fiber Tweezers for Cell Assembly In addition to the trapping and manipulation of of a single particle, OFTs can also be used for the cell assembly, whichwhich isis veryvery importantimportant forfor thethe studystudy ofof cell-cellcell-cell interactioninteraction andand communication.communication. In addition, the assembly of randomly distributed cells into regular shaped structures and arrays also plays anan importantimportant role role in in many many other other biomedical biomedical and an bio-opticald bio-optical ﬁelds, fields, such such as tissue as tissue engineering engineering [47], drug[47], drug delivery, delivery, and targeted and targeted therapy therapy [48,49 [48,49].].

5.1. Cell Assembly by the Optical Binding Tam et al. used multiple optical fibers fibers to form dense optical wells to capture and arrange parallel microspheres [50]. [50]. However, However, this approach is too cumbersome and it would be nice to capture and arrange particles with a single fiber.fiber. Figure9 9aa schematicallyschematically showsshows thethe mechanismmechanism ofof particleparticle chainchain formation while using a single optical fiber fiber probe (TF) [[51].51]. When a 980 nm laser beam is launchedlaunched into thethe TF,TF, thethe resulting resulting optical optical force force will will act act on on the the particles. particles. Firstly, Firstly, the the scattering scattering force force will will drive drive the firstthe first particle particle away away along along the TFtheaxis. TF axis. Subsequently, Subsequently, the particlesthe particles beside beside the TFthe axis TF axis and nearand near thefirst the particlefirst particle can be can trapped be trapped to the to TF the axis TF resulting axis resulting from transverse from transverse gradient gradient force. Under force. theUnder action the of action axial gradientof axial gradient force of theforce tail of particle,the tail particle, the particle the isparticle closely is bound closely to bound the former to the and, former therefore, and, therefore, multiple particlesmultiple andparticles cells and are assembledcells are assembled together bytogether the cooperation by the cooperation of optical of scattering optical scattering force and force gradient and force.gradient By force. using theBy aboveusing principle,the above theprinciple, particles the can particles be arranged can be into arranged a one-dimensional into a one-dimensional particle chain (Figureparticle9 chainb) or even(Figure a two-dimensional9b) or even a two-dimensiona graphic particlel graphic array particle (Figure 9arrayc). The (Figure binding 9c). abilityThe binding also worksability onalso cells works in theon cells same in manner. the same Figure manner.9d showsFigure the9d shows yeast cell the chainyeast cell formed chain by formed optical by binding. optical Thisbinding. method This canmethod even can be usedeven forbe used the assembly for the assembly of organelles of organelles inside a inside living a cell. living For cell. example, For example, Li et al. investigatedLi et al. investigated the noncontact the noncontact intracellular intracellular binding bi andnding controlled and controlled manipulation manipulation of chloroplasts of chloroplastsin vivo whilein vivo using while optical using fiber optical probes fiber [52 probes]. Figure [52].9e Figure shows the9e shows optical the binding optical of binding chloroplasts of chloroplasts in plant cells in usingplant cells optical using fiber optical probe fiber (OFP), probe which (OFP), is above which a plant is above leaf witha plant an approximatelyleaf with an approximately 3-µm gap between 3-µm gap between the fiber tip and the leaf. Figure 9f shows the arranged one-dimensional (1D) and two- dimensional (2D) chloroplast structures.

Micromachines 2020, 11, 114 11 of 27 the ﬁber tip and the leaf. Figure9f shows the arranged one-dimensional (1D) and two-dimensional (2D)Micromachines chloroplast 2019, 10 structures., x 11 of 26

FigureFigure 9.9. ((a)) SchematicSchematic ofof opticaloptical assemblyassembly ofof particlesparticles andand cellscells viavia opticaloptical binding.binding. MicroscopicMicroscopic imagesimages ofof ((bb)) one-dimensionalone-dimensional (1D)(1D) patternedpatterned particleparticle chainschains andand ((c)) two-dimensional (2D)(2D) patterningpatterning ofof particleparticle arrays. ( (dd)) Microscopic Microscopic images images of of yeast yeast cell cell chains chains.. Adapted Adapted with with permission permission from from Xin Xin et etal. al. [51]. [51 (].e- (Ιe)- ISchematic) Schematic of ofan an optical optical fiber ﬁber probe probe (OFP)(OFP) whichwhich isis aslantaslant placedplaced aboveabove thethe plantplant leafleaf withwith aa laserlaser atat 980980 nmnm launched.launched. The inset shows a living plant (Hydrilla verticillata) on a glass slide. ((ee--IIII)) SchematicSchematic of of optical optical binding binding of chloroplasts of chloroplasts inside inside a plant a cell, plant which cell, shows which a row shows of chloroplasts a row of

confinedchloroplasts in theconfined optical in axis the optical and bound axis and to each bound other, to each resulting other, fromresulting the cooperationfrom the cooperation of Fg and ofF Fsg. (andf) Microscopic Fs. (f) Microscopic images of theimages arranged of the chloroplast arranged chain chlo androplast rectangle. chain Adaptedand rectangle. with permission Adapted fromwith Lipermission et al. [52]. from Li et al. [52]. 5.2. Cell Assembly by Extended Optical Gradient Force 5.2. Cell Assembly by Extended Optical Gradient Force Multiple cells can also be assembled solely by optical gradient force in addition to the cooperation Multiple cells can also be assembled solely by optical gradient force in addition to the between optical scattering force and gradient force for cell assembly. Xin et al. reported an extended cooperation between optical scattering force and gradient force for cell assembly. Xin et al. reported optical gradient force-based method for cell assembly [53]. In general, a cell is first trapped at the tip of an extended optical gradient force-based method for cell assembly [53]. In general, a cell is first an ATF (abrupt tapered optical fiber) by optical gradient force, light can propagate along the cell, and trapped at the tip of an ATF (abrupt tapered optical fiber) by optical gradient force, light can refocused at the cell end surface, as shown in Figure 10a. This refocused light can generate an optical propagate along the cell, and refocused at the cell end surface, as shown in Figure 10a. This refocused light can generate an optical gradient force on other cells. In this regard, the optical gradient force is extended. Multiple cells are then assembled via the extended optical gradient force, and light can propagate along the multiple cells, Figure 10b shows the energy density distribution of the captured E. coli of (I) N = 0, (II) N = 3, (III) N = 10. It is can be seen that light is highly concentrated at the tip of the fiber, which provides a higher trapping efficiency to E. coli. Using this phenomenon, Xin et al.

Micromachines 2020, 11, 114 12 of 27 gradient force on other cells. In this regard, the optical gradient force is extended. Multiple cells are then assembled via the extended optical gradient force, and light can propagate along the multiple cells, Figure 10b shows the energy density distribution of the captured E. coli of (I) N = 0, (II) N = 3, (III) N = 10. It is can be seen that light is highly concentrated at the tip of the fiber, which provides a Micromachines 2019, 10, x 12 of 26 higher trapping efficiency to E. coli. Using this phenomenon, Xin et al. constructed biological optical constructedwaveguides biological (bio-WGs) optical based onwaveguidesE. coli bacteria, (bio-WGs) as shown based in Figureon E. coli 10 c.bacteria, This all as cell-based shown in bio-WGs Figure 10c.opens This the all door cell-based for the fabricationbio-WGs opens of biological the door waveguides for the fabrication using cells. of Becausebiological all waveguides of the materials using of cells.the bio-WGs Because areall biologicalof the materials cells, these of the waveguides bio-WGs are are biological highly biocompatible, cells, these waveguides when compared are highly with biocompatible,conventional optical when waveguides compared with that areconventional based on silica optical and waveguides other organic that/inorganic are based materials. on silica Based and otheron this organic/inorganic idea, Li et al. made materials. a bio-nanospear Based on in this which idea, the Li “handle” et al. made was madea bio-nanospear of a tapered in fiber which and the the “head”“handle” was was assembled made of witha tapered a yeast fiber cell and and the a chain “head” ofnanosized was assembledLactobacillus with a acidophilusyeast cell and(L.acidophilus a chain of) nanosizedcells [54], asLactobacillus schematically acidophilus shown ( inL. acidophilus Figure 10d.) cells At first,[54], anas schematically 808 nm laser beamshown was in Figure launched 10d. into At first,the tapered an 808 nm fiber laser to trap beam a yeastwas launched cell at the into tip the and ta thenpered to fiber trap atoL. trap acidophilus a yeast cellbehind at the the tip yeast. and then The tospherical trap a L. yeast acidophilus focused behind the laser the beamyeast. and The exerted spherical a strongyeast focused optical forcethe laser on thebeamL. acidophilusand exertedcell a strongthat was optical trapped force behind on the L. the acidophilus yeast. Figure cell that 10 ewas is thetrapped image behind of the the biological yeast. Figure spear. 10e With is the precise image ofmanipulation, the biological the spear. formed With bio-nanospear precise manipulati can guideon, the the formed input light bio-nanospear to a specific can location guide and the detectinput lightoptical to signalsa specific from location biological and detect cells, such optical asindividual signals from leukemia biological cells cells, in human such as blood. individual In addition, leukemia the cellsgroup in stably human trapped blood. a In bio-microlens addition, the (yeast group or stably a human trapped cell)on a bio-microlens a compact fiber (yeast probe or by a opticalhuman force,cell) onthe excitationa compact light fiber was, probe therefore, by optical confined force, in a subwavelengththe excitation region,light was, which therefore, resulted inconfined the enhanced in a subwavelengthup-conversion fluorescenceregion, which [55 resulted]. in the enhanced up-conversion fluorescence [55].

Figure 10. 10. OpticalOptical assembly assembly via via extended extended optical optical gradient gradient force. force. (a) Schematic (a) Schematic of optical of optical assembly assembly and biologicaland biological optical optical waveguides waveguides (bio-WGs) (bio-WGs) formation. formation. (b) (bThe) The distribution distribution of of energy energy density density in in ATF ATF when different diﬀerent numbers of E.E. coli were captured ( c) Images Images of of formed formed bio-WGs bio-WGs with with different diﬀerent lengths. lengths. Adapted withwith permission permission from from Xin Xin et al. et [ 53al.]. [53]. (d) Schematic (d) Schematic illustration illustration of the assembled of the assembled bio-nanospear. bio- nanospear.(e) Optical image(e) Optical of the image bio-nanospear of the bio-nanosp assembledear from assembled a yeast andfromL. a acidophilus yeast andcells. L. acidophilus Adapted cells. with Adaptedpermission with from permission Li et al. [ 54from]. Li et al. [54].

5.3. Cell Cell Separation Separation after after Assembly Assembly The separation and screeningscreening ofof particlesparticles can can also also be be realized realized by by OFTs OFTs after after cell cell assembly. assembly.Liu Liu et et al. al.proposed proposed a compact,a compact, miniaturized miniaturized optofluidic optofluidic chip chip integrated integrated with with OFTOFT inin aa T-type microfluidic microfluidic channel [56] [56] (Figure 11a)11a) for the selective capture of cells and bacteria. It It was was verified verified that that the the OFTs OFTs can capture capture and assemble E. coli cells,cells, and and it it can can drive drive red red blood blood cells cells (RBCs), (RBCs), to to experimentally experimentally verify verify the OFTs' selective capture capability. It is reported that the focusing characteristics of the fiber tip will change with its shape, which results in different optical forces. Taking advantage of this feature, a special fiber tip was used to provide push force to the red blood cells and trapping force to the E. coli cells, thus achieving cell sorting. Figure 11b experimentally verified the OFTs' selective trapping, which realized the trapping and delivery of E. coli and the push of RBCs. When the laser was turned off, the E. coli and RBCs were mixed together in the channel 1. Once laser was on, the E. coli were trapped and assembled, while the RBCs were immediately pushed away (Figure 11b-I). Finally, the

Micromachines 2020, 11, 114 13 of 27 the OFTs' selective capture capability. It is reported that the focusing characteristics of the fiber tip will change with its shape, which results in different optical forces. Taking advantage of this feature, a special fiber tip was used to provide push force to the red blood cells and trapping force to the E. coli cells, thus achieving cell sorting. Figure 11b experimentally verified the OFTs' selective trapping, which realized the trapping and delivery of E. coli and the push of RBCs. When the laser was turned off, the

E.Micromachines coli and RBCs 2019, 10 were, x mixed together in the channel 1. Once laser was on, the E. coli were trapped13 of and 26 assembled, while the RBCs were immediately pushed away (Figure 11b-I). Finally, the trapped and trappedassembled andE. assembled coli were sentE. coli to were channel sent2, to while channel the 2, RBCs while were the RBCs left in were channel left in 1, channel achieving 1, achieving the 100% purethe 100% separation pure separation (Figure 11 (Figureb-II–IV). 11b-II–IV).

Figure 11. ((aa)) Schematic Schematic of of E.E. coli coli trappingtrapping and and arrangement arrangement at at the the ti tipp of of the the OFTs OFTs with red blood cells (RBCs) pushed away. (b-I) Laser OFF. In channel 1, the E. coli and RBCs are mixed together. ( (bb--IIII––IVIV)) Laser ON. The The E.E. coli coli isis attracted attracted and and the the RBCs RBCs are are released. released. Adapted Adapted with with permission permission from from Liu Liu et al. et [56].al. [56 ].

6. Structured Optical Fiber for Trapping and Manipulation 6. Structured Optical Fiber for Trapping and Manipulation The trappingtrapping andand manipulation manipulation of of di ffdifferenterent objects objects make make a high a high requirement requirement on structured on structured OFTs, OFTs,although although single OFTssingle have OFTs been have successfully been successfully used in manyused studiesin many [57 studies–59]. These [57–59]. structured These structured OFTs will provideOFTs will a newprovide platform a new for platform optical for manipulation, optical manipulation, especially especially for the trapping for the oftrapping nanosized of nanosized particles particlesthat need that to overcome need to overcome the diffraction the diffraction limit. Structured limit. Structured OFTs will serveOFTs aswill a newserve candidate as a new with candidate much withmore much powerful more trapping powerful and trapping manipulation and manipulation capabilities capabilities [4,60,61]. [4,60,61]. 6.1. Internal Structured Optical Fiber Tweezers for Non-contact Trapping 6.1. Internal Structured Optical Fiber Tweezers for Non-contact Trapping 6.1.1. Fiber-based Total Internal Refection Lens 6.1.1. Fiber-based Total Internal Refection Lens There are many ways to achieve contactless capture, and the fiber-based total internal refection lens isThere one ofare them. many In ways one to case, achieve a bundle contactless of optical capture, fiber was and encapsulatedthe fiber-based in total a quartz internal capillary refection and lensfixed is with one epoxyof them. resin In one [62]. case, The a end bundle surface of opti of opticalcal fiber fiber was is encapsulated properly processed in a quartz to make capillary the light and fixed with epoxy resin [62]. The end surface of optical fiber is properly processed to make the light propagation between the optical fiber and the surrounding medium in a total internal reflection form, so as to achieve the high numerical aperture focusing and realize the purpose of capture particles that are far away from the fiber end (Figure 12a). Moreover, the direction of light propagation is inclined to the z axis in this structure, and the exerted scattering force is therefore greatly weakened. A 3D optical trap that is constructed by the optical fiber with special internal structure can capture and manipulate objects in a non-contact and non-invasive manner. Different functions of this structure can be achieved and multiple potential wells can be implemented at different or same distances from

Micromachines 2020, 11, 114 14 of 27 propagation between the optical fiber and the surrounding medium in a total internal reflection form, so as to achieve the high numerical aperture focusing and realize the purpose of capture particles that are far away from the fiber end (Figure 12a). Moreover, the direction of light propagation is inclined to the z axis in this structure, and the exerted scattering force is therefore greatly weakened. A 3D optical trap that is constructed by the optical fiber with special internal structure can capture and manipulate objects in a non-contact and non-invasive manner. Different functions of this structure can be achieved andMicromachines multiple 2019 potential, 10, x wells can be implemented at different or same distances from the fiber.14 of By 26 changing the angle of the light, the trapped particles can be slightly moved when simultaneously the fiber. By changing the angle of the light, the trapped particles can be slightly moved when collecting optical signals (Figure 12b). simultaneously collecting optical signals (Figure 12b).

Figure 12.12. Fiber-based total internal refectionrefection lenslens forfor non-contactnon-contact trapping.trapping. (a) ScanningScanning electronelectron microscope (SEM)(SEM) imageimage ofof thethe opticaloptical fiberfiber probe.probe. TheThe gradient inclined hole is obtained by shaping thethe endend ofof thethe fiber.fiber. ((bb)) DiDifferentfferent functionsfunctions cancan bebe achievedachieved byby usingusing opticaloptical fiberfiber bundles.bundles. AdaptedAdapted withwith permissionpermission from Liberale et al. [[62].62]. (c-I) The profileprofile view of the annular core fiber,fiber, thethe externalexternal diameter of annular fiberfiber is 78.5 µµmm whilewhile thethe internalinternal diameterdiameter is 74.174.1 µµm,m, andand thethe surroundingsurrounding cladding diameterdiameter isis 125125 µµm.m. (c-II) The lateral view of the annular core fiber. fiber. ( c-III) Schematic diagram of the optical path. (d) Images of oil droplets captured byby thethe annular core fiberfiber opticaloptical tweezers.tweezers. The diameters ofof the oil droplets areare ((dd--II)) 3.83.8 µµm;m; (d--IIII)) 16.4 µµm;m; (d--IIIIII)) 40.1 µµm.m. Adapted with permission fromfrom LiuLiu etet al.al. [[63].63].

InIn another method, an annular core fiber fiber is used to make a a new new type type of of OFTs OFTs (Figure 12c-I)12c-I) [63]. [63]. TheThe endend faceface ofof thethe annularannular corecore fiber fiber is is made made into into a a special special frustum frustum cone cone shape, shape, which which can can generate generate a stronga strong optical optical force force to to capture capture droplets droplets in in a a non-contact non-contact form. form. TheThe lightlight beambeam isis completelycompletely reflectedreflected at the edge of the the cone, cone, and and then then deflected deflected away away from from the the end end of of the the fiber. fiber. Therefore, Therefore, objects objects can can be becaptured captured and and manipulated manipulated in ina anon-contact non-contact manner manner (Figure (Figure 12c-II,III). 12c-II,III). The The special special OFTs OFTs with a magnetic ringring structurestructure can can capture capture a a wide wide range range of of objects objects and and droplets droplets ranging ranging from from three three microns microns to 40to 40 microns microns in diameter.in diameter. The The shape shape ofthe of the trapped trapped droplets droplets can can be perfectly be perfectly maintained maintained while while using using this non-contactthis non-contact method method (Figure (Figure 12d). 12d).

6.1.2. Graded-Index Lens Graded-index fiber can also achieve the non-contact capture and manipulation of objects. Developing adjustable OFTs can improve the operating ability and range of applications, which is conductive to its application of optical tweezers in more fields [44,64]. For example, the combination of OFTs and microfluidics can realize the adjustable working distance of optical tweezers [65,66]. Graded-index fiber taper has been proved to own a strong focus effect [66], and it enables optical trapping with adjustable working distances in liquid flow, combined with an optical microcavity (Figure 13). In this situation, the graded-index fiber and single-mode fiber are aligned in the capillary

Micromachines 2020, 11, 114 15 of 27

6.1.2. Graded-Index Lens Graded-index fiber can also achieve the non-contact capture and manipulation of objects. Developing adjustable OFTs can improve the operating ability and range of applications, which is conductive to its application of optical tweezers in more fields [44,64]. For example, the combination of OFTs and microfluidics can realize the adjustable working distance of optical tweezers [65,66]. Graded-index fiber taper has been proved to own a strong focus effect [66], and it enables optical trapping with adjustable working distances in liquid flow, combined with an optical microcavity (FigureMicromachines 13). 2019 In this, 10, situation,x the graded-index fiber and single-mode fiber are aligned in the capillary15 of 26 to form an air microcavity, the length of which can be adjusted by shifting the platform, and then to form an air microcavity, the length of which can be adjusted by shifting the platform, and then directly affects the focusing ability. By adjusting the light focus or the balance between optical force and directly affects the focusing ability. By adjusting the light focus or the balance between optical force drag force, the adjustable OFTs are realized while improving the working range and operating ability and drag force, the adjustable OFTs are realized while improving the working range and operating (Figure 13b). The tip of graded-index fiber has lower transmission loss and the stronger transverse ability (Figure 13b). The tip of graded-index fiber has lower transmission loss and the stronger gradient force, which can enhance the operating range of OFTs. The graded-index OFTs are adjustable transverse gradient force, which can enhance the operating range of OFTs. The graded-index OFTs for non-contact trapping of particles with controllable working distance by changing the input power are adjustable for non-contact trapping of particles with controllable working distance by changing of light, flow rates, length of the micro-cavity, and other factors (Figure 13c). the input power of light, flow rates, length of the micro-cavity, and other factors (Figure 13c).

Figure 13. (a) OptofluidicOptofluidic tunable manipulation of microparticlesmicroparticles by changing the laser power, flowflow rate and shape of the tapered fiber.fiber. (b) The operating range of OFTs cancan be adjusted by changing the length ofof thethe opticaloptical microcavity.microcavity. The The optical optical microcavity microcavity is is the the air air cavity cavity inside inside the the fiber, fiber, as as marked marked in aquain aqua green green and indicatedand indicated by the dashedby the arrow.dashed (c )arrow. Optofluidic (c) Optofluidic tunable manipulation tunable manipulation of microparticle of withmicroparticle different with working different distance. working Adapted distance. with Ad permissionapted with from permission Gong et al.from [65 Gong]. et al. [65].

6.2. Surface Structured OFTs forfor NanomanipulationNanomanipulation The latest demand for nanotechnologynanotechnology is that itit cancan preciselyprecisely andand noninvasivelynoninvasively manipulatemanipulate nanoscale objectsobjects [[67].67]. However,However, trappingtrapping of of objects objects with with nanometer nanometer scale scale is is of of great great challenge challenge due due to theto the diff diffractionraction limit limit and and the strongthe strong Brownian Brownian motion motion [68,69 [68,69].]. Therefore, Therefore, the nanomanipulation the nanomanipulation of OFTs of hasOFTs become has become the focus the of researcher focus of' sresearcher's attention [70 ].attention Until now, [70]. diff erentUntil OFTs-based now, different nanomanipulation OFTs-based techniquesnanomanipulation have been techni developed,ques have such asbeen plasmonic developed, nanostructure-based, such as plasmonic photonic nanostructure-based, nanojet-based, and connectedphotonic nanojet-based, fiber/nanoject and combined connected forms. fiber/nanoject combined forms.

6.2.1. Plasmonic Nanostructure-based Fiber Tweezers A plasmonic nanostructured-based fiber tweezers can be used for nanomanipulation. In this case, a metal coating is applied to the tapered fiber and a bowtie plasmonic aperture is designed to capture and manipulate the nanoparticles (Figure 14a) [71]. The plasmonic nanostructures at the fiber end surface plays the key role in this technique, providing a powerful way of dealing with individual atoms that are attached to surfaces. The trapping mechanism of this optical fiber structure is based on the self-induction back-action, which can reduce the influence of the photothermal effect on the captured object [72]. The trapped specimens play an active role in the trapping mechanism, and the required field strength is several orders of magnitude weaker than traditional optical fiber tweezers. This technique works as a scanning optical microscope probe and nano-optical tweezers for nanomanipulation in three dimensions. The end of the probe is used to manipulate and detect objects, while the object is captured and detected while using optical fibers [70,73,74]. Using this plasmonic

Micromachines 2020, 11, 114 16 of 27

6.2.1. Plasmonic Nanostructure-based Fiber Tweezers A plasmonic nanostructured-based fiber tweezers can be used for nanomanipulation. In this case, a metal coating is applied to the tapered fiber and a bowtie plasmonic aperture is designed to capture and manipulate the nanoparticles (Figure 14a) [71]. The plasmonic nanostructures at the fiber end surface plays the key role in this technique, providing a powerful way of dealing with individual atoms that are attached to surfaces. The trapping mechanism of this optical fiber structure is based on the self-induction back-action, which can reduce the influence of the photothermal effect on the captured object [72]. The trapped specimens play an active role in the trapping mechanism, and the required field strength is several orders of magnitude weaker than traditional optical fiber tweezers. This technique works as a scanning optical microscope probe and nano-optical tweezers for nanomanipulation in Micromachines 2019, 10, x 16 of 26 three dimensions. The end of the probe is used to manipulate and detect objects, while the object is nanostructuredcaptured and detected fiber tweezers, while using sub-100-nm optical fibers partic [70,73les,74 can]. Using be trapped this plasmonic and manipulated nanostructured in three fiber dimensionstweezers, sub-100-nm (Figure 14b). particles can be trapped and manipulated in three dimensions (Figure 14b).

Figure 14. (a(a) )SEM SEM image image of ofsurface surface structured structured fiber ﬁber with with a plasmonic a plasmonic bowtie bowtie aperture. aperture. Adapted Adapted with withpermission permission from fromPang Panget al. [71]. et al. ( [b71) Structure]. (b) Structure diagram diagram for nanoparticle for nanoparticle trapping trapping on the onbowtie the bowtie nano- aperturenano-aperture structure. structure.

6.2.2. Photonic Photonic Nanojet-based Fiber Tweezers Currently, the selective capture of nanoscale targetstargets and the simultaneous capture of multiple targets are are facing facing huge huge challenges challenges [67,75]. [67,75 ].With With high high focusing focusing characteristics, characteristics, photonic photonic nanojet nanojet can effectivelycan effectively reduce reduce the critical the critical size of size the ofcaptured the captured object object[76,77]. [ 76Since,77]. being Since first being reported first reported by Chen byet alChen [78], et photonic al. [78], photonic nanojets nanojetshave been have applied been appliedin many in fields many [79,80]. fields [These79,80]. photonic These photonic nanojets nanojets can be usedcan be for used optical for optical trapping trapping and nano and nanomanipulationmanipulation when when integrated integrated into into a fiber a fiber end. end. In In this this case, case, a microsphere thatthat isis positivelypositively charged charged is is attached attached to to the the end end of aof tapered a tapered optical optical fiber fiber (Figure (Figure 15a) 15a) [35]. [35].Light Light is highly is highly focused focused at the at the end end of theof the sphere sphere due due to to the the photonic photonic nanoject nanoject mechanismmechanism ofof the microsphere (Figure 1515b).b). This light focusing can ex exertert enhanced optical force on the nanoobject, and the shadow of the photonic nanojet surface forms a potential well for capturing nanoparticles in a non-contact wayway (Figure(Figure 15 15a).a). Therefore, Therefore, this this structure structure can can be be used used for for the the trap trap of nanoparticles of nanoparticles as well as wellas biomolecules, as biomolecules, such assuch DNA. as DNA. Combining Combining the three-dimensional the three-dimensional optical optical manipulation manipulation with signal with signalenhancement, enhancement, this technique this technique can also becan used also for be the used detection for ofthe nanoparticles detection of and nanoparticles biomolecules. and biomolecules.

Figure 15. Photonic nanojet-based fiber tweezers. (a) Schematic of photonic nanojet-based trapping of nanoparticles. (b) Microscopic image (I) and simulation results of the photonic nanojet (II). Adapted with permission from Li et al. [81]. (c) Schematic of a parallel photonic nanojet array for selective trapping and manipulating of nanoparticles and cells in blood solution. (d) Images for photonic nanojet array trapping and separation of different particles and cells. Adapted with permission from Li et al. [82].

Micromachines 2019, 10, x 16 of 26 nanostructured fiber tweezers, sub-100-nm particles can be trapped and manipulated in three dimensions (Figure 14b).

Figure 14. (a) SEM image of surface structured fiber with a plasmonic bowtie aperture. Adapted with permission from Pang et al. [71]. (b) Structure diagram for nanoparticle trapping on the bowtie nanoaperture structure.

6.2.2. Photonic Nanojet-based Fiber Tweezers Currently, the selective capture of nanoscale targets and the simultaneous capture of multiple targets are facing huge challenges [67,75]. With high focusing characteristics, photonic nanojet can effectively reduce the critical size of the captured object [76,77]. Since being first reported by Chen et al [78], photonic nanojets have been applied in many fields [79,80]. These photonic nanojets can be used for optical trapping and nanomanipulation when integrated into a fiber end. In this case, a microsphere that is positively charged is attached to the end of a tapered optical fiber (Figure 15a) [35]. Light is highly focused at the end of the sphere due to the photonic nanoject mechanism of the microsphere (Figure 15b). This light focusing can exert enhanced optical force on the nanoobject, and the shadow of the photonic nanojet surface forms a potential well for capturing nanoparticles in a non-contact way (Figure 15a). Therefore, this structure can be used for the trap of nanoparticles as well as biomolecules, such as DNA. Combining the three-dimensional optical manipulation with Micromachinessignal enhancement,2020, 11, 114 this technique can also be used for the detection of nanoparticles17 ofand 27 biomolecules.

Figure 15. Photonic nanojet-based fiber ﬁber tweezers. ( a) Schematic Schematic of photonic nanojet-based trapping of nanoparticles. ( b) Microscopic image ( I) and simulation results of the photonic nanojet (II). AdaptedAdapted with permissionpermission from LiLi etet al.al. [[81].81]. (c) Schematic of aa parallelparallel photonicphotonic nanojetnanojet arrayarray forfor selectiveselective trapping and manipulatingmanipulating ofof nanoparticlesnanoparticles andand cellscells inin bloodblood solution.solution. ( d) Images for photonicphotonic nanojet array trapping and separation of didifferentﬀerent particlesparticles andand cells.cells. Adapted with permission from Li et al. [[82].82].

In addition, multiple dielectric microparticles can be arranged onto the surface of a fiber end to form photonic nanojet array [82]. The back of microparticles produces a highly focused beam because of the high refractive index and low light absorption of dielectric particles, which serves as photonic nanojet array, and can thus manipulate and detect nanoparticles and subwavelength cells. The photonic nanojet array assembled with microspheres can form tens to hundreds of nanowells and then manipulate and detect multiple nanoparticles or subwavelength cells simultaneously at low power (Figure 15c). The device owns a strong capture ability, while the optical power is far lower than the COTs, it therefore will not easily generate a photothermal effect. In addition, the optical signal that is transmitted through the front end of the optical fiber can also be detected through the same fiber in reflection. This can be used for the detection of different particles and cells. For different cells, the exerted force is different due to the different sizes. Scattering forces cause the large particles to move in the direction of light propagation, while the smaller bacteria cells can be trapped. This can be used for the selective trapping and separation of different cells (Figure 15d).

6.2.3. Connected Fiber/Nanojet Combined Fiber Tweezers The connected fiber with combined nanojet at the surface can also be used for the manipulation of nanoparticles in addition to the solely surface modification of optical fiber end [83]. In this case, the single-mode fiber (SMF) and multi-mode fiber (MMF) are connected together to generate Bessel beam, which produces a narrow output laser, and a glass microsphere (GMS) is attached to the surface of the MMF to form a photonic nanojet (Figure 16a). At the tip of the optical fiber, the narrow laser beam is further focused into a nanoscale point by the glass spheres at high magnification (Figure 16b). This technique can thus be used for the trapping and manipulation of nanoparticles in a non-contact manner. Micromachines 2019, 10, x 17 of 26

In addition, multiple dielectric microparticles can be arranged onto the surface of a fiber end to form photonic nanojet array [82]. The back of microparticles produces a highly focused beam because of the high refractive index and low light absorption of dielectric particles, which serves as photonic nanojet array, and can thus manipulate and detect nanoparticles and subwavelength cells. The photonic nanojet array assembled with microspheres can form tens to hundreds of nanowells and then manipulate and detect multiple nanoparticles or subwavelength cells simultaneously at low power (Figure 15c). The device owns a strong capture ability, while the optical power is far lower than the COTs, it therefore will not easily generate a photothermal effect. In addition, the optical signal that is transmitted through the front end of the optical fiber can also be detected through the same fiber in reflection. This can be used for the detection of different particles and cells. For different cells, the exerted force is different due to the different sizes. Scattering forces cause the large particles to move in the direction of light propagation, while the smaller bacteria cells can be trapped. This can be used for the selective trapping and separation of different cells (Figure 15d).

6.2.3. Connected Fiber/Nanojet Combined Fiber Tweezers The connected fiber with combined nanojet at the surface can also be used for the manipulation of nanoparticles in addition to the solely surface modification of optical fiber end [83]. In this case, the single-mode fiber (SMF) and multi-mode fiber (MMF) are connected together to generate Bessel beam, which produces a narrow output laser, and a glass microsphere (GMS) is attached to the surface of the MMF to form a photonic nanojet (Figure 16a). At the tip of the optical fiber, the narrow laser beam is further focused into a nanoscale point by the glass spheres at high magnification (Figure Micromachines16b). This technique2020, 11, 114 can thus be used for the trapping and manipulation of nanoparticles in a18 non- of 27 contact manner.

Figure 16.16.( a)(a Schematic) Schematic of the of ﬁber the probe fiber with probe a glass with microsphere a glass (GMS)microsphere attached. (GMS) (b)(I),( attached.II)Simulation (b) results(I),(II)Simulation of light distribution; results of (III light) Microscopic distribution; image (III of) theMicroscopic probe. (IV image) Optical of trappingthe probe. of nanoparticles(IV) Optical withtrapping diameters of nanoparticles of 200 nm. with Adapted diameters with permissionof 200 nm. Adapted from Tang with et al. permission [83]. from Tang et al. [83].

7. Subwavelength Optical Fiber Wire for EvanescentEvanescent Fields-based Trapping andand DeliveryDelivery Optical tweezers capture and manipulate particles with the optical force that is generated by a highly focusedfocused laserlaser [ 84[84].]. TheThe di diffractionffraction limit limit and and focusing focusing depth depth of of optical optical tweezers tweezers in spacein space limit limit the applicationsthe applications of optical of optical tweezers tweezers in the in manipulation the manipu oflation particles of particles and continuous and continuous delivery delivery of particles of inparticles a long in range. a long This range. problem This problem can be solvedcan be solved when usingwhen ausing subwavelength a subwavelength optical optical fiber wirefiber withwire evanescentwith evanescent fields fields at the at surface,the surface, which which can can capture capture and and manipulate manipulate particles particles in in a a longlong range [85]. [85]. Similar to the optical waveguides, optical forces that are generated by the evanescent field around the subwavelength fiber wire can also be used for the capture and delivery of particles [86–88]. For the subwavelength optical fiber wire, as shown in Figure 17a, near the optical fiber surface, evanescent fields decay exponentially away from the surface. At the fiber surface, the optical intensity is the maximum, and field gradient exists along the direction of the exponential decay, which is perpendicular to the fiber wire. With this field gradient, optical gradient force is generated perpendicular to the fiber surface, which can be used for particle trapping. Figure 17a also shows the calculated optical gradient force. Accordingly, the particle is stably trapped at the fiber surface by the optical gradient force. Along the fiber, there is an optical scattering force, which delivers the particles along the fiber surface in direction of light propagation [89]. Size dependent trapping and delivery of polystyrene spheres was achieved while using a 600 nm diameter fiber wire (Figure 17a). The optical force exerted on the polystyrene sphere increased with the increase of the diameter, and the delivery speed of the larger sphere was also higher than that of the smaller sphere. At low input laser power, the larger sphere was more likely to be captured on the surface of the fiber and then delivered along the propagation direction [90]. This subwavelength optical fiber wire can also be used for the manipulation of biological cells in addition to the manipulation and delivery of particles. For example, E.coli can be stably trapped on the surface of the fiber by optical gradient forces (Figure 17b) [91], and the trapped E. coli can further be delivered along the fiber, even in microfluidic environment. In addition to the delivery in a straight trajectory along a straight fiber wire, particles can also be delivered along a bent optical fiber wire. For example, Li et al. demonstrated the delivery of nanoparticles along an arbitrary bent fiber wire (Figure 17c) [92]. The relationship between bending loss, bending radius, and center angle were studied. For a specific input power, the light capture and transmission had a corresponding minimum bending radius. The delivery of nanoparticles was Micromachines 2019, 10, x 18 of 26

Similar to the optical waveguides, optical forces that are generated by the evanescent field around the subwavelength fiber wire can also be used for the capture and delivery of particles [86–88]. For the subwavelength optical fiber wire, as shown in Figure 17a, near the optical fiber surface, evanescent fields decay exponentially away from the surface. At the fiber surface, the optical intensity is the maximum, and field gradient exists along the direction of the exponential decay, which is perpendicular to the fiber wire. With this field gradient, optical gradient force is generated perpendicular to the fiber surface, which can be used for particle trapping. Figure 17a also shows the calculated optical gradient force. Accordingly, the particle is stably trapped at the fiber surface by the optical gradient force. Along the fiber, there is an optical scattering force, which delivers the particles along the fiber surface in direction of light propagation [89]. Size dependent trapping and delivery of polystyrene spheres was achieved while using a 600 nm diameter fiber wire (Figure 17a). The optical Micromachinesforce exerted2020 on, 11 the, 114 polystyrene sphere increased with the increase of the diameter, and the delivery19 of 27 speed of the larger sphere was also higher than that of the smaller sphere. At low input laser power, the larger sphere was more likely to be captured on the surface of the fiber and then delivered along firstthe demonstratedpropagation direction by using 650[90]. nm This red subwavelength light propagating optical along fiber a 600-nm wire diametercan also optical be used fiber for wire. the Themanipulation nanoparticles of biol canogical be captured cells in by addition the optical to the gradient manipulation force when and the delivery power ofof incidentparticles. light For wasexample, increased E.coli to can 12 be mW, stably and trapped then delivered on the surface along the of the bent fiber fiber by in optical the direction gradient of forces light propagation (Figure 17b) direction[91], and bythe the trapped scattering E. coli force can further caused be by delivered evanescent along field. the fiber, even in microfluidic environment.

FigureFigure 17.17. EvanescentEvanescent field-basedfield-based capturecapture andand deliverydelivery alongalong opticaloptical fiberfiber wire.wire. ((aa)) SimulationSimulation distributiondistribution ofof evanescentevanescent wavewave fieldfield aroundaround aa fiberfiber wirewire withwith didifferentfferent sizedsized particlesparticles trapped.trapped. AdaptedAdapted with with permission permission from from Xu Xu et al. et [ 90al.]. [90]. (b) Trapping (b) Trapping of E.coli ofalong E.coli an along optical an fiber optical wire. fiber Adapted wire. withAdapted permission with permission from Xin et from al. [91 Xin]. (c )et Delivery al. [91]. of(c nanoparticles) Delivery of nanoparticle along bent opticals along fiber bent wire. optical Adapted fiber withwire. permission Adapted with from permission Li et al. [92 from]. Li et al. [92].

InIn additionaddition to to the the delivery delivery of in particles a straight in onetrajectory direction along along a straight the fibre, fiber bidirectional wire, particles manipulation can also ofbe particles delivered can along also bea bent realized optical while fiber using wire. optical For ex fiberample, wire Li [ 93et, 94al.]. demonstrated In this case, two the laser delivery beams of Micromachines 2019, 10, x 19 of 26 werenanoparticles transmitted along in reversean arbitrary direction bent intofiber the wire fiber (Figure to realize 17c) bidirectional[92]. The relationship manipulation between of particles. bending Theloss, magnitude bending radius, and direction and center of the angle scattering were studied. force can For be a changed specific input to control power, the the delivery light capture direction and of The magnitude and direction of the scattering force can be changed to control the delivery direction thetransmission particles by had changing a corresponding the laser power minimum of the bending input fiber radius. (Figure The delivery18)[82]. of nanoparticles was first of the particles by changing the laser power of the input fiber (Figure 18) [82]. demonstrated by using 650 nm red light propagating along a 600-nm diameter optical fiber wire. The nanoparticles can be captured by the optical gradient force when the power of incident light was increased to 12 mW, and then delivered along the bent fiber in the direction of light propagation direction by the scattering force caused by evanescent field. In addition to the delivery of particles in one direction along the fibre, bidirectional manipulation of particles can also be realized while using optical fiber wire [93,94]. In this case, two laser beams were transmitted in reverse direction into the fiber to realize bidirectional manipulation of particles.

FigureFigure 18.18. BidirectionalBidirectional transportationtransportation andand controllablecontrollable positioningpositioning ofof nanoparticles.nanoparticles. AdaptedAdapted withwith permissionpermission fromfrom LeiLei etet al.al. [[93].93].

8. Optical Fiber-based Massive Photothermal Assembly The photothermal effect due to light absorption can also be used for the trapping and manipulation of particles, in addition to the trapping and manipulation of particles by optical force using optical fiber tweezers. The light absorption of surrounding medium and particles can induce different photothermal effects. For the medium absorption, the main effect is the thermophoresis, where the temperature gradient that is induced by the light absorption can result in the particle migration responsive to temperature gradient by the Soret effect [95]. While for the particle absorption, photophoresis will induce the particle migration. The uneven photothermal phenomenon of light-irradiated particles can keep the high-absorptive particles away from the light-induced hot point [96,97], while the low-absorptive particles tend to the hot point, and the photothermal effect can, therefore, manipulate the large-scale particles [98]. For the photophoresis, one of the important parameters is the asymmetrical factor of heat distribution J, which can directly represent the heat flow [97]. The J factor is given by: 6 | ( )| , = ⋅ ⋅ ⋅ (7) || where is the refractive index of the particle, is the absorption rate of the particle, is the refractive index of the solution, R is the radius of the particle, λ is the wavelength of incident light,

(,) is the local electric field intensity within the particle, and is the electric field intensity of incident light. For particles in the liquid medium, the expression formula of the photophoretic velocity is expressed, as follows [97]: 3 + 4(3 − 1) =− (8) 18 +21+2 where is the thermal expansion coefficient of solvent, A is Hamaker constant, is the radius of the solvent molecules, and is the viscous coefficient of liquid, is the solvent the characteristics of the molecular volume, is the thermal conductivity solvent, I is light intensity, is particle relative to the slip length of water, is the thermal conductivity particles, and R is the particle radius. For a given solution and a particle of the same material, the photophoretic velocity can be () expressed, as follows (C is a constant, =− ) [99]:

Micromachines 2020, 11, 114 20 of 27

8. Optical Fiber-based Massive Photothermal Assembly The photothermal effect due to light absorption can also be used for the trapping and manipulation of particles, in addition to the trapping and manipulation of particles by optical force using optical fiber tweezers. The light absorption of surrounding medium and particles can induce different photothermal effects. For the medium absorption, the main effect is the thermophoresis, where the temperature gradient that is induced by the light absorption can result in the particle migration responsive to temperature gradient by the Soret effect [95]. While for the particle absorption, photophoresis will induce the particle migration. The uneven photothermal phenomenon of light-irradiated particles can keep the high-absorptive particles away from the light-induced hot point [96,97], while the low-absorptive particles tend to the hot point, and the photothermal effect can, therefore, manipulate the large-scale particles [98]. For the photophoresis, one of the important parameters is the asymmetrical factor of heat distribution J, which can directly represent the heat flow [97]. The J factor is given by:

2 Z R Z π 6πnpκp E(r, θ) J = r3cosθsinθ dθ dr (7) 2 3 2 n R λ · 0 0 E · · f | 0| where np is the refractive index of the particle, κp is the absorption rate of the particle, nf is the refractive index of the solution, R is the radius of the particle, λ is the wavelength of incident light, E(r, θ) is the local electric field intensity within the particle, and E0 is the electric field intensity of incident light. For particles in the liquid medium, the expression formula of the photophoretic velocity VP is expressed, as follows [97]: L β Ar2 ln3 + 4(ln3 1) S T 0 − r0 VP = IJ (8) −18µv k kp L 0 f + 2 1 + 2 S kf R where βT is the thermal expansion coefficient of solvent, A is Hamaker constant, r0 is the radius of the solvent molecules, and µ is the viscous coefficient of liquid, v0 is the solvent the characteristics of the molecular volume, kf is the thermal conductivity solvent, I is light intensity, LS is particle relative to the slip length of water, kp is the thermal conductivity particles, and R is the particle radius. For a given solution and a particle of the same material, the photophoretic velocity VP can be expressed, as follows L 2 + ( ) S βTAr ln3 4 ln3 1 r = 0 − 0 (C is a constant, C 18µv k kp )[99]: − 0 f +2 kf

CIJ VP = (9) LS 1 + 2 R

In many situations, the photothermal effect is the combination of both the thermophoresis and the photophoresis. When compared with optical force, the force that is induced by photothermal effect is much stronger and, thus, can be used for massive particle trapping and assembly. For example, Lei et al. demonstrated the photothermal assembly of particles and E. coli while using a subwavelength diameter fiber (SDF) [100]. When the 1550 nm laser is launched into the fiber, the leaking light radiates the object and creates a negative photophoresis that pulls the object toward the fiber. The SDF functions as a linear “light source” and particles or other small objects around the SDF are exposed to the radiation. The energy of the leaking light will be absorbed by the particles and converted into a local heat distribution. The uneven heat distribution inside each sample causes the photothermal effect to drive the particles (Figure 19a). When suspended in medium, the particles will also move along the temperature gradient, usually from hot to cold. Particles move towards the strong region and gather in the center of the region, where the negative photophorsis force and the temperature gradient force are balanced, due to the combination effect of the photophoresis and thermophoresis. By moving the SDF, the assembled particles and bacteria can be migrated along the moving direction. Alternatively, Micromachines 2019, 10, x 20 of 26

= (9) (1 + 2 ) In many situations, the photothermal effect is the combination of both the thermophoresis and the photophoresis. When compared with optical force, the force that is induced by photothermal effect is much stronger and, thus, can be used for massive particle trapping and assembly. For example, Lei et al. demonstrated the photothermal assembly of particles and E. coli while using a subwavelength diameter fiber (SDF) [100]. When the 1550 nm laser is launched into the fiber, the leaking light radiates the object and creates a negative photophoresis that pulls the object toward the fiber. The SDF functions as a linear "light source" and particles or other small objects around the SDF are exposed to the radiation. The energy of the leaking light will be absorbed by the particles and converted into a local heat distribution. The uneven heat distribution inside each sample causes the photothermal effect to drive the particles (Figure 19a). When suspended in medium, the particles will also move along the temperature gradient, usually from hot to cold. Particles move towards the strongMicromachines region2020 and, 11 ,gather 114 in the center of the region, where the negative photophorsis force and21 ofthe 27 temperature gradient force are balanced, due to the combination effect of the photophoresis and thermophoresis. By moving the SDF, the assembled particles and bacteria can be migrated along the movinga tapered direction. optical fiberAlternatively, can also be a tapered used for optical the massive fiber can photothermal also be used assemblyfor the massive of particles photothermal [98]. As assemblyshown in Figureof particles 19b, particles[98]. As shown can be assembledin Figure 19b, to the particles end of thecan fiber be assembled with a distance to the of end several of the tens fiber of withmicrons a distance due to theof several photothermal tens of emicronsffect. By due moving to the the photothermal fiber, the assembled effect. particlesBy moving can the be fiber, migrated the withassembled an effi particlesciency up can to 95%.be migrated with an efficiency up to 95%.

Figure 19.19.( a)(a Massive) Massive photothermal photothermal assembly assembly and migration and migration of particles of and particlesE.coli using and subwavelength E.coli using subwavelengthdiameter ﬁber. (diameterb) Assembly fiber. and (b) migrationAssembly ofand particles migration using of particles a tapered using optical a tapered ﬁber. Adapted optical fiber. with Adaptedpermission with from permission Xin et al. from [98]. Xin et al. [98].

9. Opto-Thermophoretic Opto-Thermophoretic Fiber Tweezers In addition to the optical force and photothermal ef efffect,ect, the electric fields fields can also contribute to the trapping and manipulation [[101–104].101–104]. Kotnala et al. demonstrated demonstrated an an opto-thermophoretic opto-thermophoretic fiber fiber tweezer (OTFT) [105], [105], which combined combined the the photothermal photothermal effect effect and and electric electric field field effect effect into the fiber fiber tweezers. TheseThese fiberfiber tweezers tweezers are are a newa new strategy strategy for thefor lowthe powerlow power manipulation manipulation of nanoscale of nanoscale objects. objects.In OTFT, In a OTFT, layer of a layer porous of goldporous film gold was film deposited was deposited on the fiber on the tip fiber to form tip ato thermoplasmonic form a thermoplasmonic fiber tip, whichfiber tip, converts which converts photons intophotons phonons. into phonons. The charged The charged molecules molecules were adsorbed were adsorbed onto particle onto particle surface surfaceto form to a form charged a charged molecular molecular layer, layer, which which forms forms into positiveinto positive micelles, micelles, and and Cl− Clmolecules− molecules work work as ascounterions. counterions. With With light light irradiation, irradiation, the the photothermal photothermal e effectffect induced induced thermophoresisthermophoresis resultsresults in the migration of particles. The positive micelles and Cl− ionsions were were separated, separated, inducing inducing an an electric field field between the fiber fiber tip and the particles due to the didifffferenterent SoretSoret coecoefficient,fficient, whichwhich isis givengiven byby [[105]:105]:

P∑ = kBT T i ZiniSTi ET= 5 (10)(10) e P∑ 2 i Zi ni where i is the ionic species, kB is the Boltzmann constant, T is the environmental temperature, T is the 5 temperature gradient, e is the elemental charge, Zi is the chrage number, ni is the concentration, and STi is the Soret coefficient of i species. An electric field ET pointing toward the fiber tip is generated, due to the higher molecular mass and larger Soret coefficient of the positive micelle. The resulting thermo-electric field results into the trapping of the positively charged particles (Figure 20a). OTFT uses opto-thermoelectric force to capture particles, which have the unique advantages as compared with normal OFTs: it can be used to capture wide range of nanoparticles with low power consumption (less than 1 mW). By increasing the power, the increased convective flow and thermophoretic force can be used for particle assembly and concentration (Figure 20b, power: 10 mW). By manipulating the fiber, the trapped nanoparticles can also be used for multifunction applications. For example, it can be used for the delivery of a single nanoparticle to a lipid vesicle membrane (Figure 20c). Micromachines 2019, 10, x 21 of▽ 26 where i is the ionic species, is the Boltzmann constant, T is the environmental temperature, T is the temperature gradient, e is the elemental charge, is the chrage number, is the concentration, and is the Soret coefficient of i species. An electric field ET pointing toward the fiber tip is generated, due to the higher molecular mass and larger Soret coefficient of the positive micelle. The resulting thermo-electric field results into the trapping of the positively charged particles (Figure 20a). OTFT uses opto-thermoelectric force to capture particles, which have the unique advantages as compared with normal OFTs: it can be used to capture wide range of nanoparticles with low power consumption (less than 1 mW). By increasing the power, the increased convective flow and thermophoretic force can be used for particle assembly and concentration (Figure 20b, power: 10 mW). By manipulating the fiber, the trapped nanoparticles can also be used for Micromachinesmultifunction2020 applications., 11, 114 For example, it can be used for the delivery of a single nanoparticle22 ofto 27a lipid vesicle membrane (Figure 20c).

Figure 20. Opto-thermophoretic fiber ﬁber tweezer (OTFT) for nanoparticle trapping and manipulation. Adapted withwith permissionpermission fromfrom Kotnala Kotnala et et al. al. [ 105[105].]. ( a(a)) Schematic Schematic of of OTFT, OTFT, opto-thermoelectric opto-thermoelectric force force is usedis used for for nanoparticle nanoparticle trapping. trapping. (b) Schematic(b) Schematic for nanoparticle for nanoparticle assembly assembly and concentration and concentration using OTFT.using (OTFT.c) and ( (cd)) and OTFT (d) serves OTFT asserves a nanopipette as a nanopipette for single for nanoparticle single nanoparticle delivery. delivery.

10. Conclusions In conclusion,conclusion, this this review review presents presents recent recent development development of optical of optical fiber-based fiber-based tweezers tweezers for optical for trappingoptical trapping and manipulation. and manipulation. Different typesDifferent of OFTs types were of discussed,OFTs were including discussed, their including corresponding their principlescorresponding and applications.principles and Single applic OFTsations. enable Single the OFTs targeted enable trapping the targeted and flexible trapping manipulation and flexible of particlesmanipulation and cellsof particles while using and opticalcells while force, using and enable optical single force, cell and analysis. enable Evanescent single cell field analysis. from subwavelengthEvanescent field optical from fibersubwavelen wire enablesgth optical the long-range fiber wire manipulation enables the and long-range delivery manipulation of different targets. and Thedelivery photothermal of different e fftargets.ect of diThefferent photothermal fiber forms effect can of be different used for fiber massive forms assembly can be used and for migration. massive Theassembly opto-thermalphoretic and migration. fiberThe tweezersopto-thermalphoretic are able to multifunctional fiber tweezers trapping are able and to manipulationmultifunctional of nanoparticlestrapping and manipulation with low power of nanoparticles consumption with when low combing power consumption the electric field. when Fiber combing optical the tweezers electric willfield. provide Fiber optical many tweezers new possibilities will provide for di manyfferent new applications possibilities in the for near different future applications due to the advantagesin the near offuture easy due fabrication, to the advantages compact size, of easy and fabrication, flexible manipulation. compact size, and flexible manipulation. Although great great progress progress has has been been made made in inOFTs, OFTs, there there are are still still many many open open challenges, challenges, but also but alsoopportunities. opportunities. First, First, the thedirect direct contact contact between between the the sample sample and and fiber fiber end end surface surface might induce mechanical damage on the samples. Therefore, thethe non-contact and damage-freedamage-free trapping technique based on OFTs isis necessary to develop. Second, stable trapping and flexible flexible manipulation of samples with sizes in the nanometer scale to overcome the diffraction diffraction limit while using OFTs is still a big challenge. In In particular, particular, stable trapping of single biomolecules is is very difficult, difficult, but will be of great importance for single molecular analysis. Third, optical trapping and manipulation of cells and biological structures and the subsequent biosensing in vivo will be a new trend in the following few years. However, the OFTs may induce mechanical damage when inserting the fiber into living samples. Therefore, the construction of biocompatible OFTs is of great importance, and maintains great application potential. Living biophotonic waveguide via the assembly of living bacteria or cells in vivo will provide new possibilities for the formation of biocompatible optical fibers [53,54]. Trapping, manipulation, sensing, and diagnostics in vivo will be possible with such optical fibers.

Author Contributions: H.X. supervised the project; X.Z. and N.Z. wrote the original draft and prepared the ﬁgures; Y.S., H.X., and B.L. reviewed and edited the ﬁnal manuscript. All authors have read and agreed to the published version of the manuscript. Micromachines 2020, 11, 114 23 of 27

Funding: This work was funded by the by the National Natural Science Foundation of China (61975065, 11904132), Guangdong Basic and Applied Basic Research Foundation (2019B151502035), the Fundamental Research Funds for the Central Universities (21619323). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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