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Photopolymerization in Microfluidic crosslinker-concentration profile. Materials with gradients in

crosslinker concentration that extend over several centimeters
Gradient Generators: Microscale or millimeters can be generated easily using a gradient ma-
Control of Substrate Compliance to ker.[6] The gradient profile is dependent on the dimensions of
Manipulate Cell Response** the gradient maker. Therefore, to create chemical gradients
on the length-scale of a single cell (10±100 lm), systems capa-
ble of manipulating fluids on this length-scale are essential.
By Nadia Zaari, Padmavathy Rajagopalan,
Such technologies have only been very recently realized
Sooyoung K. Kim, Adam J. Engler, and
through the development of microfluidic networks,[7,8] with
Joyce Y. Wong*
which one can easily generate solution (e.g., cytokine)[9] and
surface (e.g., adhesive protein) gradients.[10]
In the design of biomaterial interfaces to control cell re-
Motivated by the power of creating microscale gradients
sponse, efforts have predominantly focused on tuning surface
with microfluidic networks, and a recent study that demon-
chemistry and/or topography. Recently, studies in which the
strated the photopolymerization of hydrogels in microchan-
mechanical properties of elastic substrates were systematically
nels,[11] we describe here a method that integrates microfluidic
varied have revealed that cell behavior is also dependent on
gradient technology with photopolymerization to create nov-
the mechanical compliance of the substrate.[1±5] It is important
el, microgradient-compliance substrates. We demonstrate this
to recognize that most of these studies compared cell re-
concept by using a microfluidics gradient generator[7] to
sponses on different substrates, each characterized by a single
photopolymerize a hydrogel precursor solution with a defined
mechanical compliance. However, certain cellular phenomena
gradient in the crosslinker concentration. Previously, we re-
may not be detected on substrates with uniform mechanical
ported the idea and basic methodology of this approach,[5,12]
properties. For example, ªdurotaxisº, i.e., migration guided by
but here we correlate the local mechanical properties of the
substrate rigidity, was discovered for fibroblasts on substrates
gradient gel to the cellular responses on these substrates. For
with step-gradients in their mechanical compliance.[1] We re-
cells cultured on these gradient-compliance substrates, we ob-
cently showed that vascular smooth muscle cells (VSMCs)
served a sharp increase in the range of spread-area above a
also exhibit durotaxis and accumulate in the stiffer regions of
threshold value of elastic modulus. Thus, we show that micro-
a gradient-compliance substrate.[4] However, the methods
fluidics, combined with photopolymerization, is a very promis-
used to generate compliant gradients in both of these studies
ing system to generate gradient-compliance substrates which
lacked precise control of the gradient profiles. In order to ex-
can be used to investigate the role of substrate mechanics on
plore fully the role of substrate mechanics on cell behavior,
cell response.
there is a need for methodologies to generate substrates with
We chose polyacrylamide (PAAM) to validate our system
mechanical-compliance profiles that are tunable on the micro-
because its mechanical properties can be easily tuned over a
scale.
wide range of elastic moduli by varying the monomer/cross-
The most straightforward way to create substrates with vari-
linker ratio. PAAM hydrogels can also be polymerized using a
ations in mechanical compliance is to control the crosslinking
variety of initiators, including photoinitiators, which enable
density of the substrates. This can be achieved by tuning the
photopolymerization of the gradient gels in the microfluidic-
gradient generator. We also chose PAAM in order to compare
our results directly with the numerous studies that have used
± PAAM to investigate the effects of substrate stiffness on cell
[*] Prof. J. Y. Wong, N. Zaari, Dr. P. Rajagopalan,[+] S. K. Kim
Department of Biomedical Engineering behavior.[1±4,13] We note that a recent study employed micro-
Boston University fluidics and photopolymerization to generate gradient gels by
44 Cummington Street, Boston, MA 02215 (USA) injecting poly(ethylene glycol) (PEG) diacrylate macromono-
E-mail: jywong@bu.edu
mers of differing molecular weights. However, in this case, the
A. J. Engler
Biophysical Engineering Lab study focused on generating gradients of immobilized-ligand
University of Pennsylvania concentration and did not measure the elastic moduli of the
112 Towne Building gradient gels.[14] Furthermore, there were limitations on the
Philadelphia, PA 19104 (USA)
achievable gradients due to the large differences in viscosity
[+] Present address: Center for Engineering in Medicine, Harvard
Medical School, Massachusetts General Hospital, Boston, MA 02114, among the PEG diacrylate macromonomer solutions, which is
USA. not the case for PAAM.
[**] The authors thank N. L. Jeon, H. Baskaran, and J. Jacot for helpful As illustrated in Figure 1, gradient-compliant polyacrylam-
discussions; P. Mak and the Boston University Photonics Center for
ide hydrogels were formed by photopolymerizing the precur-
access and support for microfabrication facilities; and D. E. Discher
for support and use of atomic force microscopes in the Biophysical sor solution in the outlet channel that contained a gradient of
Engineering Lab at the University of Pennsylvania. JYW acknowledg- bis-acrylamide (bis), which was generated by flowing different
es financial support from the Whitaker Foundation (RG-98±0506; concentrations of bis into the inlets of a microfluidics gradient
TF 02±0026), NSF CAREER Award (BES-9985338), NIH grant (R01
HL072900±01 A1) and a Clare Boothe Luce Professorship from the generator using a syringe pump. The gradient generator de-
Henry Luce Foundation. vice was fabricated from poly(dimethylsiloxane) (PDMS), but

Adv. Mater. 2004, 16, No. 23±24, December 17 DOI: 10.1002/adma.200400883  2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 2133
COMMUNICATIONS
Figure 1. Schematic diagram of the microfluidic gradient device used for
photopolymerization of hydrogels. Top view: the device consists of a pat-
terned PDMS mold attached to an activated glass slide. The width,
length, and height of the outlet are 2.8 mm, 2 cm, and 100 lm, respec-
tively. All of the inlets are filled with a solution containing 8 % acrylamide
and the photoinitiator, 2,2¢-azobis(2-methylpropionamide) dihydrochlor-
ide (AIBN). To generate a gradient in the crosslinker concentration,
0.04 % bis was added to two adjacent inlets, and 0.48 % bis to the third
inlet. Upon attaining stable flow in the outlet channel, the device was ex-
posed to radiation from a UV lamp for 5 min (side view). After the first
10 s of UV exposure, the flow was turned off.
can also be constructed from glass or oxidized silicon. The ad-
vantage of using PDMS is the rapid turn-around time from
conception to fabrication.[15] We found several factors to be
essential to the successful fabrication of the microgradient
gels. First, plasma treatment of the PDMS microdevice was
used to form an irreversible seal between the microchannels
and the glass substrate. While this prevented fluid leakage
and allowed one to use high flow rates, a reversible seal was
required for the outlet channel in order to access the hydrogel
formed to perform mechanical testing and cell studies. We
therefore applied different plasma treatments (see Experi-
mental) to the microchannels (static water contact angle
~ 64, compared to ~ 105 for untreated PDMS) and the outlet
channel (contact angle ~ 8). With the reversible seal, we ob-
served leaking only when the flow rate exceeded 10 lL min±1.
Furthermore, we determined that the optimal flow rate for
hydrogel formation was < 5 lL min±1, which agrees with find-
ings by Jeon et al.,[7] who demonstrated that smooth gradients
were obtained under these flow conditions.
We formed a gradient in the bis concentration in the outlet
channel by introducing acrylamide solutions containing
0.04 % bis to two adjacent inlets, and 0.48 % bis to the remain-
ing inlet. Fluorescein-isothiocyanate-conjugated polystyrene
(FITC-conjugated PS) beads were added to the solution con-
taining 0.48 % bis in order to visualize the gradient using fluo-
rescence microscopy (Fig. 2A). The tiled fluorescent images
of the PS-bead distributions obtained at different positions
2134  2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PAAM Film Width (2.8 mm)
PAAM Film Width (mm)
E
PAAM Film Width (mm)
Figure 2. A) Fluorescent image showing the distribution of FITC-polysty-
rene beads across the width of a PAAM film photopolymerized in the gradi-
ent generator. Here, fluorescent beads were added only to the inlet contain-
ing the solution with 0.48 % bis (Fig. 1). B) Measured fluorescence
intensity of entrapped FITC-dextran (MW = 20 kDa) (r) across the width of
a PAAM film. FITC-dextran was added only to the inlet containing the solu-
tion with 0.48 % bis (Fig. 1). Theoretical prediction (solid line) obtained
using the method described by Dertinger et al. [8]. The diffusion coefficient
of FITC-dextran is 3 ” 10±7 cm2 s±1 in phosphate buffered saline (at 25 C).
[23] C) Measured elastic modulus of the PAAM film using AFM. The elastic
modulus values for control gels made with one concentration of bis are rep-
resented by solid triangles and indicated by arrows. Elastic modulus values
for the gradient gel are represented by open circles and are plotted as aver-
age and standard deviation of multiple measurements at the same position
along the width of the gel, but at different positions along the length of the
gel. At least three measurements were made and in many cases, they num-
bered 12. AFM data is fitted (dashed line) to the following polynomial curve:
y = ± 3.28x3 + 13.85x2 ± 0.05x + 2.9 with R2 = 0.99.
across the width of the PAAM gel clearly show a significantly
higher concentration of beads on one side of the gel (denoted
the ªstiffer regionº in Fig. 2A). The bead density decreased
across the width of the gel and dropped to a much lower level
at the opposite end (denoted the ªsofter regionº in Fig. 2A).
Note also that the bead density was uniform along the length
of the gel: this demonstrated that the solutions were well-
mixed in the gradient generator, but the gradient profile was
maintained in the outlet channel.
The gradient profile could be varied by changing the config-
uration of the microfluidic channels and the monomer/cross-
linker ratios of the inlet solutions. Moreover, one could pre-
http://www.advmat.de Adv. Mater. 2004, 16, No. 23±24, December 17

dict the concentration profile using the finite-differences mod-
el of diffusion described by Dertinger et al.[8] We tested our
design by comparing the experimental and theoretical gradi-
ent profiles. In order to measure the actual gradient profile,
we added FITC-dextran to the inlet solution containing
0.48 % bis, and quantified the fluorescence intensity of the
FITC-dextran molecules entrapped in the photopolymerized
PAAM microgradient gel. Note that the normalized fluores-
cence intensity was flat at the outer edges of the gel and was
approximately linear in the middle region (Fig. 2B). Thus, the
experimentally obtained concentration profile of the FITC-
dextran agreed quite well with the theoretically predicted pro-
file.
We also directly measured the elastic modulus across the
width of the microgradient gel using atomic force microscopy
indentation (AFM indentation) (Fig. 2C). Note that there was
very little variation in the modulus along the length of the gel,
as indicated by the low values of the standard deviations: that
is, the gradient is only in one dimension. The modulus varied
over a large range (~ 3±40 kPa), and the elastic moduli at the
outer edges and center (Fig. 2C, filled triangles and arrows,
respectively) matched the values obtained for uniform com-
pliant gels prepared using the same concentrations of input
solutions (0.04 and 0.48 % bis, as well as an intermediate
0.26 % bis) well. We also confirmed, as has been previously
shown,[3] that the elastic moduli of uniform compliant gels, as
determined by standard tensile tests, are similar to the values
obtained from AFM microindentation. For the uniform com-
pliant gels, there was a strong correlation between the elastic
modulus and the bis concentration for bis concentrations be-
tween 0.04 and 0.48 %. This relationship is readily apparent if
one draws a line through the values obtained for uniform-
compliance gels with bis concentrations indicated by the ar-
rows in Figure 2C, which yields a gradient of ~ 12 Pa lm±1.
Note, however, that the bis concentration in the hydrogel
formed by the gradient generator is not exactly linear, but is
fit by a polynomial curve instead. We expect that the final spa-
tial distribution of bis is modulated by its diffusion and rate of
reaction during the crosslinking process, and therefore, one
must verify the elastic moduli of the gradient gel through di-
rect measurement.
To promote cell adhesion, the hydrogels must first be modi-
fied covalently with adhesive proteins. It is important to note
that we and others have reported that the amount of protein
covalently attached does not vary with substrate compli-
ance.[1,3,4] Here, we used a bifunctional linker to attach type I
collagen, but in other studies[12,16] we have also copolymerized
into the hydrogel an acrylic acid N-hydroxy succinimide ester
(NHS-ester) to which adhesive molecules could be attached.
We observed striking differences in cell morphology on the
different regions of the microgradient-compliance substrate
(Fig. 3A). Most notably, cells located on the stiffer region
were well-spread and appeared to be well-adhered to the un-
derlying substrate. In contrast, cells located on the softer re-
gion of the substrate were not well-spread and appeared to
have a more rounded morphology. A closer look at individual
Adv. Mater. 2004, 16, No. 23±24, December 17 http://www.advmat.de
COMMUNICATIONS
Increasing Elastic Modulus
Figure 3. VSMC spreading increases and F-actin becomes more well-de-
fined with increasing PAAM stiffness. The arrow shows the direction of
increasing elastic modulus. A) Phase contrast image of VSMCs on the
gradient gel modified with type I collagen; the scale bar is 500 lm. Indi-
vidual panels (B±E) show representative fluorescent images of F-actin
stained with rhodamine-phalloidin. B is from the softer region of the gel
(i.e., the leftmost 0.7 mm portion of the gel). (C,D) are from the inter-
mediate regions (i.e., the middle 1.4 mm portion of the gel), and (E) is
from the stiffer region of the gel (i.e., the rightmost 0.7 mm portion of
the gel). The scale bar is 50 lm.
cells on specific regions (Figs. 3B±E) revealed that the cyto-
skeletal organization was also quite different, depending on
whether the cells were on the stiffer or softer region. Specifi-
cally, F-actin organization in the cells was well-defined on the
stiffer region, but was diffused on the softer region. We ob-
served similar behavior for BALB/c 3T3 fibroblasts (data not
shown).
Our observation of the dependence of cell spreading on
the elastic modulus of the substrate corresponds well with
what has been reported previously for NIH 3T3 fibroblasts.[2]
We also found that a higher percentage of cells attached to
the stiffer region of the gradient-compliance gel (Fig. 4A),
and this trend was statistically significant (p < 0.05). More im-
portantly, our gradient-compliant substrates have revealed an
interesting property, previously unreported for cultures on
uniform-compliance substrates: there appears to be a thresh-
old value of the modulus (~ 30 kPa), above which there is a
sharp increase in cell spreading for VSMCs (Fig. 4B). This
trend, that the highest spread area is observed on regions of
the gel with the highest elastic modulus, is statistically signifi-
cant (p < 0.05) (Fig. 4B). We verified these results using uni-
form-compliant gels with several different values of elastic
modulus (data not shown); however, the data was more strik-
ing for the gradient gel because there was a continuous
increase in elastic modulus. Also note that above 30 kPa, the
distribution of cell areas is much larger than below 30 kPa.
We also observed a large distribution of VSMC spread areas,
which was similar to that observed for the gradient gel, on
uniform-compliant gels. At this point, the implication of a
threshold modulus that leads to increased cell spreading is
unclear.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 2135
COMMUNICATIONS
Figure 4. A) The number of attached cells increases with stiffness along
the gradient. The film was divided into 0.7 mm regions across the width
of the gel, and each bar represents the fraction of the total number of ad-
hered cells for each region. The data is the average of two independent
experiments. Statistically significant differences were found between the
percentage of cells adhering to the area with the highest moduli com-
pared to that with the lowest (p < 0.05). B) Cell spreading increases with
stiffness along the gradient. Each point represents the spread area of a
single cell at a specific position on the gradient gel. The elastic modulus
values for each position on the PAAM gradient gel was calculated using
the fitted line given in Figure 2C.
The basis for a correlation between the elastic modulus of
the substrate and cell spreading is supported by previous stud-
ies, which show that the rigidity of the matrix strengthens the
linkages between cell surface receptors and the matrix.[17]
Thus, one could imagine that there is a minimum value of
modulus required for the cell spreading to attain a specific
area. This brings up an important issue: that of the physiologi-
cally relevant values for the spread-areas of the VSMCs. To
put these values into context, a typical spindle-shaped con-
tractile VSMC has a projected cell area of ~ 2500 lm2.[18]
However, cells can spread over either lower or much higher
areas than 2500 lm2 (Fig. 4A): others have observed similar
spread areas for VSMCs (~ 5000 lm2)[19] and areas even as
large as 12 000 lm2.[3] While this data clearly indicates that
the elastic modulus of the underlying substrate affects the cell
spread area, further investigation is needed to determine the
correlation between substrate elastic modulus, spread area,
and, perhaps most importantly, cell function.
2136  2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim http://www.advmat.de
We have demonstrated that the integration of microfluidics
and photopolymerization can effectively generate substrates
with well-controlled gradient-compliance profiles on the mi-
croscale. Our approach is general and can be used to test the
response on microgradient-compliance substrates of other cell
types, which have been shown to respond to differences in
substrate mechanics using uniform-compliant substrates (see
review[5]). To date, microfluidics applications have primarily
focused on the manipulation of fluids. However, by incorpo-
rating traditional materials-processing techniques, one can
create new material systems with tunable properties on the
microscale, to reveal novel, biological phenomena that would
otherwise be undetected.
Experimental
Microfluidic Gradient Generator: PDMS (Sylgard 184, Dow Corn-
ing) microfluidic gradient generators were fabricated as described by
Jeon et al. [20] and sealed to glass coverslips (Fig. 1). The outlet was
sealed reversibly by using high-power plasma treatment (5 min); the
inlets and gradient-mixer microchannels were irreversibly sealed
using medium-power plasma treatment (40 s). Before the sealing pro-
cess, the coverslips were activated with (3-aminopropyl)trimethoxysi-
lane (Sigma) and glutaraldehyde, to promote adhesion of the hydrogel
[2].
Generation of Microgradient-Compliance Hydrogels: All concentra-
tions are v/v. Photopolymerization of acrylamide (8 %) in the micro-
fluidics gradient generator was initiated with (AIBN; Aldrich). A bis
gradient was achieved by adding 0.04 % bis to two adjacent inlets and
0.48 % bis to the third inlet. After stable flow (5 lL min±1) was estab-
lished in the outlet channel, photopolymerization was initiated by
exposure to UV light (350 nm, 1.8 mW cm±2) for 5 min. The flow was
turned off after the first 10 s of UV light exposure.
Gradient Characterization: Fluoresbrite carboxylate microspheres
(0.75 lm, Polysciences) or FITC-dextran (20 kDa, Sigma) were added
only to the third inlet, and the acrylamide was photopolymerized as
described above. Fluorescent images (Zeiss Axiovert S100) were ob-
tained and the fluorescence intensities were analyzed using Meta-
morph software.
Mechanical Characterization: An atomic force microscope (Asylum
1D, Asylum Research) with a pyramid-tipped cantilever (spring con-
stant ~ 60 pN nm±1, Veeco) was used to determine the mechanical
properties of the gradient compliant hydrogel. Blunted AFM tips with
a half-open angle of 35 were used to minimize penetration depth. A
Hertz-cone model was used to fit tip deflections of up to 2 lm in the
force±indentation curves [21,22] for multiple samples and numerous
(152) force±indentation curves. Samples were indented at a rate of ap-
proximately 2 lm s±1, which is generally sufficient to explore the elas-
tic, rather than the viscoelastic, properties of the substrates [23].
Cell Studies: Bovine aortic VSMCs (Coriell Cell Repositories) were
maintained in Dulbecco's modified Eagle's medium (DMEM) (Invi-
trogen) supplemented with 50 lg mL±1 penicillin, 50 U mL±1 strepto-
mycin, 200 mM L-glutamine, and 10 % bovine calf serum (Hyclone).
Type I collagen (0.2 mg mL±1) was covalently immobilized onto the
gradient gels via the bifunctional linker, N-sulfosuccinimidyl-6-[4¢-azi-
do-2¢-nitrophenylamino] hexanoate (sulfo-SANPAH; Pierce). Cells
were seeded onto the hydrogels covalently modified with type I col-
lagen at a density of 1000 cells cm±2. After 18 h of incubation, the cells
were fixed and stained for F-actin with rhodamine phalloidin. The
cells were observed under phase-contrast and fluorescence microsco-
pies. The entire gel width was imaged by tiling four adjacent pictures,
each 0.7 mm wide by 0.68 mm long, and defined as a ªfield of viewº.
Ten such fields of view were randomly chosen per experiment. Each
field of view was divided into four 0.7 mm intervals, and the percent-
Adv. Mater. 2004, 16, No. 23±24, December 17

age of attached cells was calculated by counting the number of cells
per interval and dividing by the total number of cells attached in the
entire field of view.
Statistical Analysis: We performed Student t tests to determine the
statistical significance of the differences between results. A signifi-
cance level of p < 0.05 was used as the cut-off (i.e., p values were
reported only for cases in which p < 0.05).
Received: June 4, 2004
Final version: October 8, 2004
± applications ranging from multi-gas detection to wavelength
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______________________
Adv. Mater. 2004, 16, No. 23±24, December 17 DOI: 10.1002/adma.200400033
COMMUNICATIONS
Soft-Lithographically Embossed,
Multilayered Distributed-Feedback
Nanocrystal Lasers**
By Vikram C. Sundar,* Hans-Jürgen Eisler, Tao Deng,
Yinthai Chan, Edwin L. Thomas, and
Moungi G. Bawendi
Operational multiple-wavelength lasers are sought after for
division multiplexing.[1,2] Three key requirements for such de-
vices include broad bandwidths, gain media that can operate
at room temperature, and resonators that can be tuned to dif-
ferent wavelengths across the broad bandwidth.[3] We present
a novel strategy for satisfying all these requirements by com-
bining the processing ease afforded by semiconductor nano-
crystals (NCs) with soft lithography. Spin-coating NC±titania
films and in-situ embossing with elastomeric stamps yielded
gain media that were patterned with distributed-feedback
(DFB) grating structures. Not only did these individual layers
function as DFB lasers, but sequential assembly of multiple
layers with well-matched gain and feedback windows resulted
in a multiple-wavelength DFB laser that oscillated simulta-
neously at multiple wavelengths at room temperature. These
ªbottom±upº-assembled composite structures highlight the
flexibility inherent in NC-based gain media, especially when
they are combined with non-traditional lithographic tech-
niques.
Early theoretical work predicted that the peak material
gain in zero-dimensional structures, or quantum dots (QDs),
should be larger and less temperature sensitive than that of
the corresponding bulk semiconductor.[4,5] In the case of wet-
chemically synthesized cadmium selenide (CdSe) nanocrys-
±
[*] Dr. V. C. Sundar,[+] Dr. H.-J. Eisler,[++] Dr. Y. Chan,
Prof. M. G. Bawendi
Department of Chemistry and
Center for Material Science and Engineering
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sundarv@us.ibm.com
Dr. T. Deng,[+++] Prof. E. L. Thomas
Department of Materials Science and Engineering and
Institute of Soldier Nanotechnologies
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
[+]Present address: IBM Watson Research Center, Yorktown Heights,
NY 10546, USA.
[++]Present address: Nano-optics Group, Institute for Physics, Univer-
sity of Basel, Klingelbergstrasse 82, CH-4056 Basel, Switzerland.
[+++]Present address: GE Global Research Center, One Research Circle,
Niskayuna, NY 12309, USA.
[**]We thank M. Walsh and H. I. Smith for the original Si DFB gratings.
H.-J. Eisler acknowledges funding from the DFG. This research was
funded in part through the NSF MRSEC program at MIT (DMR-
0213282), by the NSF funded Harrison Spectroscopy Laboratory
(NSF-011370-CHE), by the Packard Foundation, and by the U.S. De-
partment of Energy (DE-DFG02-02ER45974).
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 2137