rapid and dynamic intracellular patterning of cell-internalized magnetic fluorescent nanoparticles

8/12/2019 Rapid and Dynamic Intracellular Patterning of Cell-Internalized Magnetic Fluorescent Nanoparticles

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Rapid and Dynamic IntracellularPatterning of Cell-Internalized MagneticFluorescent Nanoparticles

Peter Tseng,*, Dino Di Carlo,,,|, and Jack W. Judy,,,|,#

Department of Electrical Engineering, Department of Bioengineering, Biomedical

Engineering Interdepartmental Program, California Nanosystems Institute, UniVersity

of California, Los Angeles, Los Angeles, California

Received May 13, 2009; Revised Manuscript Received June 18, 2009

ABSTRACT

Conjugated magnetic nanoparticles have recently demonstrated potential in activating unique and specific activity within cells. Leveraging

microfabrication, we have developed a technique of localizing nanoparticles to specific, subcellular locations by a micropatterned ferromagnetic

substrate. Controlled patterns of nanoparticles were assembled and dynamically controlled with submicrometer precision within live cells. We

anticipate that the technique will be useful as a compact, simple method of generating localizable, subcellular chemical and mechanical

signals, compatible with standard microscopy.

Magnetic particles have gained wide acceptance in biological

and medical research as a method of selectively controlling

biological environments. Antibody or DNA-conjugated

particles, which have been used for highly specific methods

of sorting cells, proteins and DNA, have also been used in

conjunction with detectors to determine particle conjugation

and size.1-3

More recently, researchers have integratedparticles with additional characteristics,4 including conjugat-

ing particles with quantum dots for ease of detection, and

fabricating porous particles (conjugated to enzymes) to be

used as highly active reaction templates.5,6 Magnetic beads

have been used to remotely generate heat,7,8 control ion

channels, mediate signaling, and probe cell mechanics.9,10

Even with these advances, the potential for this technology

and its use for the cellular localization of signals remains

largely untapped.5,11,12 This is especially important given the

high level of localization and compartmentalization important

for cellular function.

Micro-electromechanical systems (MEMS) technology and

its ability to interface with microenvironments is well suited

as a means of interaction with magnetically coupled biologi-

cal matter. While there has been ample investigation into

microfabrication as a means of sorting and manipulation of

biological material,13-16 its use in generating magnetically

mediated, single cell biological activity is scarce.9,10 The

capability of generating, in a simple fashion, highly localized

chemical and mechanical effects could give biologists a

simple method of probing cellular architecture and biochem-

istry, as well as providing a unique method of studying highly

localized cellular signaling. In this report, we detail the use

of simple micromachined magnetic substrates as a methodof generating and manipulating complex, dynamically con-

trollable, and localized groups of magnetic fluorescent

nanoparticles within single living cells.

The base elements of our substrate are simple ferromag-

netic lines and dots. When combinations of these elements

are placed in an incident magnetic field, unique magnetic-

flux-density maxima will be generated as shown in Figure

1a. Within a cell, these maxima attract and coalesce particles,

generating designed patterns of ensembles of nanoparticles

at high speed. Importantly, the device is engineered for

controllable localization (Figure 1a), as the magnetic potential

minima can span nearly all x-y points of the substratedepending on orientation of the applied magnet field. Incident

fields can be ultimately decomposed into two base modes,

normal and tangential fields, combinations of which can be

generated by a simple magnet oriented below the substrate.

Our substrate design is composed of permutations of ferro-

magnetic arrays with dots that have a diameter varying from

2 to 8 m, and a pitch of approximately 0.4-1 times the

dot size. As an illustration of the arbitrary-patterning

capability of our device, several patterns that spell out letters

and words, both with dots and continuous regions of

permalloy, were included (Figure 1b).

* To whom correspondence should be addressed. Phone: 310-206-3995.Fax: 310-794-5956. E-mail: [email protected].

Department of Electrical Engineering. Department of Bioengineering. Biomedical Engineering Interdepartmental Program.| California Nanosystems Institute. E-mail: [email protected].# E-mail: [email protected].

NANO

LETTERS

2009Vol. 9, No. 8

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Figure 1b shows a schematic diagram and a pair of

scanning electron microscopy (SEM) images of our device

at various stages. The dots themselves are composed of

permalloy (Ni80Fe20, a magnetically soft, high permeability,

and moderate saturation ferromagnetic material), electro-

plated on a seed layer of 40 nm Ti/250 nm Cu/40 nm Ti to

a thickness of 3 m. Upon mold stripping, a thin layer (0.2

m) of low-stress silicon nitride is plasma deposited as a

passivation layer, and a final SU-8 layer planarizes the

surface and acts as an adhesion layer for cells. Right before

the cell-seeding process, the SU-8 surface is modified in an

O2 plasma to encourage cell adhesion to the substrate.The magnetic manipulation force for particles is well

known and is proportional to the magnetic field gradient for

magnetically saturated particles (our case),Fmag) VBsat(B/

0), with volume V, permeability of free space 0, and

saturation magnetization Bsat. Our nanoparticles are super-

paramagnetic, possess a saturation of close to 0.01 T, and

have hydrodynamic diameters of 100 nm (nano-screenMAG-

DX, Chemicell, Berlin, Germany). Given the small volume

and low saturation magnetization of the nanoparticles, which

is common for water-soluble magnetic particles, their ef-

ficient manipulation requires large magnetic gradients and

close proximity to potential minima (both of which are

provided by our design). Essentially, we use ferromagnetic

material to focus magnetic fields (to the point of magneti-

cally saturating the dots and aligning their magnetization with

the surrounding fields) to generate large, highly ordered

magnetic field gradients, as shown in Figure 1c. Large shifts

in the permanent magnet location generate small shifts in

position of the potential minima, and thus the micromachined

substrate displays the ability to dynamically modify the

position of generated nanoparticle ensembles to highly

accurate positions. For future reference, when the positionof the magnet is noted as weak [position], this refers to

the core of the magnet appearing approximately underneath

the substrate, while far [position] refers to the core of the

magnet being offset from underneath the substrate. Because

of the shape anisotropy of the ferromagnetic elements, the

elements will possess a sheared B-H loop, leading to a small

amount of remnance and coercivity in the miniature magnet

elements, even despite the soft nature of our permalloy

(Supporting Information, Figure 1). However, this effect is

relatively minimal and does not affect our technique while

it is actively manipulating nanoparticles.

The focusing effect of the permalloy was numericallysimulated with 3D ANSYS FEA software, by modeling the

permeability as a hyperbolic tangent function of our per-

malloy saturation and permeability, and obtaining solutions

at various heights above the substrate. The thickness of the

SU-8 layer used to planarize our substrate is verified to be

approximately 0.5-1 m above the permalloy dots. Contours

of the magnetic flux density for both normal and tangential

modes of operation are given in Figure 2a for a plane located

1 m above magnetic dots placed in a magnetic flux density

of approximately 0.6 T.

Figure 2b shows the extracted contours (assumed as

radially symmetric) and corresponding magnetic field gra-dients for our normal mode of operation. The peak of the

gradient occurs expectedly at the edge of the dot, suggesting

that the generated nanoparticle patterns will conform to the

underlying ferromagnet definition (this occurs with the

tangential mode too). The forces on our magnetic nanopar-

ticles typically vary from close to 0.1 to 1 pN over its range

of motion.

The response time of a magnetic particle to our base array

from any point can be determined directly by examining the

equation of motion for the magnetic nanoparticles in our

system, m(V/t) ) Fmag- Fdrag, withFdrag ) 3aV, particle

velocity in stagnant fluid is V, hydrodynamic diameter is a,and kinematic viscosity is . Because of the negligibly small

mass of nanoparticles, the velocity will stabilize at a steady

state velocity given by Vss ) Fmag/(3a), which is directly

proportional to the magnetic field gradient at any position.

This equation of motion for the nanoparticles can be solved

to obtain a quick estimate of our response time (or time for

assembled nanoparticle patterns to become noticeable). We

will define this time as the initial formation time constant,

. Ignoring the z-dimension, we obtain an approximate

response time constant of 100 ms in water for a 4 m

diameter dot in 4 m pitch array. Since the cell cytoplasm

has a viscosity that is a complex function of spatial

Figure 1.Ferromagnetic substrates. (a) Diagrams of our magneticarray in its two operation modes, tangential and normal incidentfield. Combinations of these modes generate unique potentialminima spanning the x-y space of the substrate. (b) Schematic ofthe letters U C L A spelled out with our dot-pattern, followed bySEM images of our pattern (1) after permalloy electroplating andmold strip and (2) upon MFC7 breast cancer cell seeding andfixation. (c) The magnetic potential minima as generated by a strongmagnet oriented underneath our substrate.

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dimension, it would yield a value slightly higher than that

for water. While our time constant for water was predicted

for our 100 nm diameter particles, the manipulation speedfor particles half this size (50 nm, which is closing in on the

pore size for the nuclear membrane), would yield speeds only

four times slower (400 ms), which is still fairly rapid.

The magnetic fluorescent nanoparticles (excitation max,

476 nm, blue; emission max, 490 nm, high frequency green)

used in our experiments are composed of a magnetic core

covered first with a lipophilic dye, and subsequently with a

polymer matrix around this dye. Presumably due to the

processing of the particles, each individual particle possesses

a random fluorescent yield. As seen in Figure 3d, a bottom-

oriented magnet applied to the letters U C L A (with

nanoparticles diluted in water above it) would immediately

produce green fluorescing patterns directly above the dots

on the substrate. However, what should be a fairly uniform

cluster of particles generating a relatively smooth signal,

produces instead a clearly punctuated signal at the permalloy

dots (i.e., certain portions will fluoresce significantly stronger

than others). This will also be reflected in our intracellular

experiments, as ensembles of our particles will produce

varying green fluorescing signals. We discovered, however,

that the absorption of the particles in the blue-UV excitation

range of the particles gives an excellent indication ofnanoparticle presence and density, as these results correspond

directly with our expected results. In addition, the nanopar-

ticles were the only object within the cell that absorbed

significantly in this region. As such, in our experiments, both

the emission and excitation wavelengths of the particles are

used to indicate nanoparticle presence and manipulation.

The patterning capabilities of our substrate were verified

in water under a fluorescent microscope with a setup as

shown in Figure 3a, with a 1-T rare-earth magnet providing

the incident magnetic flux. Substrates were inverted over a

diluted solution of the nanoparticles within a Petri dish and

excited under UV and blue light. As in Figure 3d, periodicpotential wells were tuned to various x-y positions above

the micropatterned substrate depending on magnetic orienta-

tion. In addition to basic patterning capability, we tested for

manipulation reversibility (i.e., if the system returns to its

original state upon field removal), and as expected from the

soft magnetic nature of the permalloy elements and magnetic

nanoparticles, the system would convert from dispersed, to

captured upon magnet arrival, and immediately disperse once

the magnet was removed. In water, dependent on the remnant

fluidic motion, near full dispersal occurred within 7 min.

Thus, in general the substrate displays the ability to reversibly

generate a combination of chemical, magnetically mediatedmechanical, and fluorescent signals to engineered locations,

dependent on the orientation and application of the magnet.

Manipulation of nanoparticles internal to live cells was

also demonstrated within MFC7 breast cancer cells. The cells

were grown in Dulbeccos Modified Eagle Media (DMEM)

and incubated with the nanoparticles for 24-48 h. Beyond

48 h, interactions between the endosomes of the particles

would often lead to irreversible aggregation of the nanopar-

ticles.17 After incubation, the cells were then washed multiple

times in phosphate buffered saline (PBS), trypsinized, spun

down, rewashed and sheared, and resuspended in media. For

some experiments, live cells were simultaneously stainedwith a red lipid stain (diL) for improved membrane visual-

ization. Because of the dextran coating and small size of

the particles, the continuous washing resuspends and removes

virtually all noninternalized particles from the system. The

cells were then placed on the magnetic substrate and left

overnight for cell adhesion (Figure 1c). The next day the

media was washed and substrate inverted over a PBS-wetted

Petri dish, so that it could be viewed with a conventional

inverted fluorescent microscope, again as shown in the

schematic diagram given in Figure 3a.

Figure 3b displays a single cell with magnetic particles

patterned by a magnet oriented to the far north and weak

Figure 2.

Simulation of magnetic nanoparticle response. (a)Magnetic-flux-density contours as simulated in ANSYS at 1 mabove the patterned 4 m diameter dots arranged in a 4 m pitcharray. Dashed circles indicate the edge of the ferromagnetic dots.(b) Overlayed plots of the magnetic flux density and correspondingradial gradient as we progress away from the dot midpoint for anormal incident field. The inset graph displays the contours of themagnetic flux density as generated by a best-fit polynomial(assumed radially symmetric). The edge is denoted by the dashedline and coincides with the approximate peak of the magnetic fieldgradient.

Nano Lett., Vol. 9, No. 8, 2009 3055


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east. The image is notable because the magnetic nanoparticlepatterns adjacent to the cell membrane appear modified,

indicating constraint internal to the membrane and intracel-

lular patterning. Confocal microscopy also indicated inter-

nalization of nanoparticles, both with a larger signal in the

particle emission band (490 nm) and the significant presence

of lipids within the cell (stained by diL and which suggests

internalization within endosomes). Figure 3c displays our

patterning results for various permalloy elements and at

different magnet orientations. The various images from this

figure indicate three disparate signals that are clearly view-

able: (1) blue-excited and green-emitting fluorescent particles,

(2) diffuse green autofluorescence of the cells, and (3)reflected short wavelengths from the substrate under the blue

filter that reveals the array of micromachined ferromagnetic

elements, and whose absence indicates the blue absorption

of both the fluorescent dye and magnetic core of the

nanoparticles.

In addition to fluorescence microscopy, we performed

SEM imaging of focused ion beam (FIB) etched cells with

patterned magnetic nanoparticles. Cells were seeded onto our

substrate as in previous experiments, and patterns were

allowed to stabilize over an extended period of time in

incubation (approximately 45 min in order to form a highly

stable group of particles to survive the cell fixation). Cells

were then fixed while the magnet was held in place, driedwith the supercritical dryer, and imaged under the fluorescent

microscope. Shown on the left in Figure 4a is a single cell

(magnet applied to the weak south and weak east) observed

under UV excitation, displaying enhanced cell autofluores-

cence induced by cell fixation, the permalloy posts, and the

patterned, absorbing nanoparticles. Unfortunately, the fixation

process induces significant additional background in the UV

image; despite this, several nanoparticle ensembles are

noticeably patterned according to our expected results. The

substrate was sputtered with a thin layer of AuPd, and imaged

and etched with a SEM/FIB (NOVA 600, FEI, Hillsboro,

Oregon). Figure 1a highlights four generated ensembles and

their correspondences under both top-down SEM and

fluorescence microscopy of a single cell. FIB etching was

initiated at the southern portion of the cell and progressed

north, while sequential images of the cell cross-section were

simultaneously captured (Supporting Information Video 1).

Two of these cuts and the corresponding top-down image

are shown in Figure 4b and display the morphology of the

nanoparticle ensemble. The ensemble forms a type of

hemisphere, as one would expect from the magnetic field

simulations. A close-up of an ensemble is displayed at the

bottom of the Figure 4, and the respective portions of our

Figure 3. Generation of intracellular nanoparticle patterns. (a) Schematic diagram of our experimental setup. A 1-T rare-earth magnet ismounted onto a glass slide, and applied above our inverted substrate in a Petri dish for viewing with an inverted fluorescent microscope.(b) Blue filter and blue/red filter merged images of a single cell stained with red diL containing magnetically patterned nanoparticles. Thenanoparticle absorbance illustrates the modification of patterns at the cell membrane left edge, suggesting intracellular localization. (c)General results indicating the capability of generating various x-y patterns within cells with varying incident magnetic fields. Variousvisible components are noted on the image. Diffuse cell autofluorescence and individual nanoparticle fluorescence can be seen in thegreen-fluorescence image, while permalloy elements and nanoparticle absorption contrasting against UV and blue reflected from the substratecan be seen in the UV-blue image. (d) U C L A patterned by nanoparticles in water with a directly normal magnetic field.

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technique, including the permalloy, SU-8, cell, and nano-particle ensembles are highlighted.

Preliminary statistics for the patterns generated by our

device indicate accurate focusing of nanoparticle clusters.

Figure 5a gives four separate scatter plots of the ensemble

centroids corresponding to differing magnetic orientations,

and include the mean and standard deviation of position. Two

of these plots are scatter plots from groups of cells with

internal patterned nanoparticles excited as in Figure 3c. We

also introduce two more cases: cells above patterns with 4

m diameter dots and arranged in a square array with a 4

m pitch size, and a control situation above unpatterned

portions of the substrate with no permalloy. As one would

expect, the standard deviation of the position of nanoparticle

centroids above the unpatterned substrate is large because

for the time scales of our experiments, they are not

significantly manipulated (for longer manipulation times they

form long chains oriented randomly around the cells). These

data suggest that the particles are scattered approximately

randomly about the cell, as compared to being localized

Figure 4. Combined SEM imaging and focused ion beam (FIB)etching of stimulated cells. (a) Top-down images of the same fixedcell under UV exposure-blue emission and SEM imaging. Fourclear ensembles are noted on each image. (b) Top-down andcoinciding cross-sectional view of generated magnetic nanoparticleensemble at two lines of cuts. The ensemble tends to resemble ahemisphere, as would be suggested from the magnetic potentiallandscape generated by the underlying ferromagnetic elements. Atthe bottom is a close-up of a single created ensemble. Thenanoparticles are densely packed due to the long exposure time ofthe particles to the magnetic field and generate a noticeable bumpin the cell.

Figure 5. Manipulated nanoparticle pattern statistics. (a) Scatterplots of the localization of the centroids of our patterned particleensembles. Four separate cases are given: (1) cells above 4 mdiameter dots arranged in a 4 m pitch array, (2 and 3) cells fromFigure 3c with completed results from additional cells excited bythe same field, and (4) cells above unpatterned portions of thesubstrate without permalloy. Included is the standard deviation,which indicates that the centroids typically occupy around a 600nm to 1 m radius around the mean position, whereas above theunpatterned substrate, the particles appear approximately randomlyaround the cell for the time scales of our experiment. In addition,the orientation of the magnet is notated by the letters F, W andN, S, E, W to represent the orientation of the magnet with respectto the permalloy dots. The image above the unpatterned substratewas contrast enhanced to better illustrate the cell and its encom-

passing diffuse particles. (b) Combined scatter and box plots ofthe fill factor of our particles (defined as the pattern area dividedby the pattern unit cell area). Groups of particles are typicallylocalized to around 15-25% of the area, indicating our ability togather particles to areas significantly smaller than the size of thesubstrate.

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significantly when patterned by our substrate and field. Figure

5b introduces a new, useful value: the pattern fill factor (the

size of the ensembles divided by the area of the unit cell of

the particular corresponding array). This value is useful as a

gauge of how localized our nanoparticle ensembles are in

the x-y plane. Unfortunately, due to the random nature of

cell internalization, cells internalize varying densities of

magnetic nanoparticles. As such, the variance of these

statistics derived from the biology is large, as shown in the

combined scatter and box plots of our data. However, wecan gather that the groups of particles typically appear to

occupy around 15 to 25% of the unit-cell area, indicating

an ability to gather particles into space significantly smaller

than the size of our substrate, even for larger densities of

particles. This would allow us greater control over the

effective imprint of the nanoparticle ensembles within cells.

In addition to basic patterning, we were able to actively

manipulate ensembles of nanoparticles with micrometer-scale

resolution. Displayed in Figure 6a is a single cell with four

noticeable groups of nanoparticles. The leftmost group

conforming to the membrane edge is an irreversible nano-

particle aggregate caused by extended incubation time (asnoted in an earlier paragraph) and undergoes very little

morphology change during the time frame of our manipula-

tion. Interestingly, the three other groups undergo both

morphological and positional changes during magnet reori-

entation, including the rightmost group (flanking the cell

membrane). Images were taken immediately upon magnet

reorientation and subsequent refocusing, indicating the speed

of the transformation is below the 10 s required to acquire

an image (exposure time + refocusing). Upon image capture,

the magnet is immediately reoriented, yielding six images

spaced approximately 10 s apart each. Between images 1-2

and 4-5, we show the difference between that image andthe subsequent image, and the approximate translational shift

to better illustrate changes occurring at each step. The initial

image displays the cell at the first state with magnet located

weak south, and the magnet was progressively manipulated

in order to display both manipulation and merging and

separation of the groups of nanoparticles. Of additional note

is the rightmost group, because it flanks the cell membrane,

its centroid appears significantly modified as compared to

the other two ensembles of particles, again indicating the

intracellular nature of the ensembles. This is particularly

noticeable in images 4-5, while the left two groups

manipulated as expected, the rightmost saw no translationtoward its expected location at all. Notice also in the red

filter image (Figure 6a), as also is suggested by our confocal

data, the nanoparticles colocalize to large signal in the green

excitation/red filter images, which indicate that the nano-

particles enter the cell cytoplasm through an endosomal

pathway (the diL stain targets lipids).18,19 This may also

indicate the potential to dynamically modify the locations

of endosomes internal to single cells.

In summary, we have demonstrated the first engineered,

simultaneous precision control of multiple groups of mag-

netic fluorescent nanoparticles within single cells. Uniquely

aligned patterns within single cells were generated through

Figure 6.Dynamic manipulation of intracellular nanoparticles. (a)UV excitation-blue filter; green excitation-red filter and mergedimages of a single cell with patterned nanoparticles to be manipu-lated. Four groups are strongly visible: a group flanking the leftedge of the membrane, a group flanking the right edge of the

membrane, and two internal, completed groups. (b) Consecu-tive images of the particles taken at 10 s intervals upon shiftingthe permanent magnet. The left group is an irreversible nanoparticleaggregate17 and sees little morphological changes during the timescales of the experiment (these result from extended incubationtime). The rightmost group, from images 1 to 2 and 4 to 5, seeslimited movement as restricted by the cell edge, and its centroid isincapable of reaching its expected potential minima in a manneras suggested by our statistics. The differences between images 1-2and 4-5 are shown between those particular images and clearlyillustrate the shift in position of the nanoparticles during thesemanipulations (for the rightmost group in 4-5 it appears to haveno shift). In addition, during these manipulations, various mergeand separations were accomplished, demonstrating additionalversatility in the technique.

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a lithographically patterned micromagnetic substrate com-

posed of fine ferromagnetic tips and lines and in general can

span much of the x-y space of the array through a

combination of a normal and tangential incident magnetic

fields. The methodology displays potential to dynamically

control intracellular environments and signaling, locally and

with submicrometer accuracy and movement, while simul-

taneously performing rapid operations on nanoparticles

ensembles. Finally, the array and its overhead generates no

heat to the biological sample and is compact enough to be

workable with nearly any microscopy setup. Such tools could

be used to generate highly localized magnetic and biochemi-

cal signals, allowing studies on localizable probing and

actuation in single cells, and expanding on existing micro-

fabricated tools that probe single cell dynamics. Our next

step is to study cell behavior with injected or electroporated

conjugated nanoparticles.

Acknowledgment.The authors acknowledge Eric Tsang

and Hyowon Lee for materials and protocols aide, Andrew

Fung for assistance with confocal microscopy, Noah Bodzin

for assistance with the FIB, and Ira Goldberg for helpful

discussions on magnetic particle manipulation.

Supporting Information Available:Supporting figure of

an M-H loop of our electroplated permalloy and supporting

movie of sequential cross-sectional images generated by our

FIB etching. This material is available free of charge via

the Internet at http://pubs.acs.org.

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rapid and dynamic intracellular patterning of cell-internalized magnetic fluorescent nanoparticles

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