Review
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Challenging nature’s monopoly on the creation of
well-defined nanoparticles
Nature has selected and fine-tuned the physical and chemical properties of natural objects, such as size,
shape, mechanical properties and surface chemistry, at the molecular level in order to modulate biological
functions. A new particle fabrication process, particle replication in nonwetting templates (PRINT®), has
recently begun to attempt to emulate nature’s ability to control those physical and chemical traits. The
PRINT technology, which combines modern soft lithography with the unique properties of perfluoropolyether
molds, enables the production of nanoparticles with unprecedented control of size, shape, chemical
composition, deformability and surface functionality. This scalable ‘top-down’ fabrication process allows
for the generation of well-defined nanostructures without the need for molecular assembly. The ability
to flexibly engineer various matrix materials offers unique opportunities for the development of
nanomedicines with desired functionality. The strength and versatility of PRINT makes it a powerful
platform in nanomedicine for elucidating the role of physical and chemical properties of nanodelivery
vehicles on the behavior and fate at the cellular, tissue and whole organism level. Utilizing the PRINT
technology, we are generating well-defined nanomedicines with tailored properties for preclinical studies
against a variety of human diseases.
KEYWORDS: bottom-up n crosslinking n nanoparticle n perfluoropolyether
n poly(dimethylsiloxane) n PRINT® n roll-to-roll process n self-assembly
n soft lithography n top-down
Wonhee Jeong1,
Mary E Napier1 &
Joseph M DeSimone†1,2,3
Department of Chemistry & Carolina
Center of Cancer Nanotechnology
Excellence, University of North Carolina
at Chapel Hill, Chapel Hill, NC, USA
2
Department of Pharmacology &
Lineberger Comprehensive Cancer
Center, University of North Carolina at
Chapel Hill, Chapel Hill, NC, USA
3
Department of Chemical &
Biomolecular Engineering, North
Carolina State University, Raleigh,
NC 27695, USA
†
Author for correspondence:
Tel.: +1 919 962 2166
Fax: +1 919 962 5467
[email protected]
1
Nature has carefully selected physical and
chemical attributes of biological species for optimized functionality in complex physiological
conditions. Many examples found in cellular
environments, where most basic properties and
functions are defined, suggest that properties
such as size, shape, chemistry, mechanical properties and surface structure form the underlying
building blocks of biological functions [1] . The
size, shape and mechanical flexibility of particles have a profound effect on the pathways of
cellular internalization as well as in vivo biodistribution profiles and clearance [1–4] . The
surface structure and chemistry of cells play a
significant role on cell adhesion and motility.
For instance, normal erythrocytes in the vertebral bodies have a unique size (diameter ~7 µm,
thickness ~2 µm), shape (disk and biconcave
shaped) and mechanical properties (Young’s
modulus ~30 kPa) that define their biological
behavior and function [5] . By contrast, pathological erythrocytes in patients with hereditary
spherocytosis are smaller in size, have a round
shape and a higher modulus, as well as disrupted
surface structures [5] . Another remarkable example found in prokaryotic organisms is the diversity of bacterial sizes and shapes. Bacteria display
a wide array of cell morphologies from simple
spheres, rods and spirals to flat, branched and
tapered shapes [6] . It is well recognized that
both bacterial size and shape are crucial for
the t­ransport, nutrient uptake and survival of
b­acteria [6] .
In nature, clever strategies have been developed to obtain desired structures and properties
at the cellular level. Eukaryotic and prokaryotic
cells utilize a rigid framework, that is, a cytoskeleton, to obtain and maintain a particular size
and shape on the microscopic level. Cytoskeletal
systems consist of a dense network of filamentous proteins that provide cell integrity as well
as the mechanical deformability of cells. The
self-assembly of amphiphiles, primarily lipids,
generates cell membranes that cover the cytoskeletons. At present, it has become clear that a complex interplay exists between the cytoskeleton,
mechanical forces and biochemical signaling networks, and cytoskeletal structures play an important role in controlling cell cycle progression and
fate switching between growth, differentiation
and apoptosis [7] . In the case of erythrocytes,
structural proteins, such as spectrin and actin,
form a cytoskeletal meshwork that contributes to
their unique viscoelastic properties [8] . On their
cellular surfaces, various lipids, proteins and carbohydrates constitute membranes and regulate
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Jeong, Napier & DeSimone
immune recognition. Even prokaryotic bacteria
use a regulated internal cytoskeleton as a scaffold
to generate their complex shapes [9,10] .
Just as nature fine-tunes the physical and
chemical attributes of biological species, there
is a great opportunity to apply biomimetic strategies to generate effective nanomedicines for
complex in vivo systems. A variety of particle
fabrication techniques have been developed to
construct polymer colloids, polyplexes, micelles,
liposomes and crosslinked nanoparticles, some
of which adopted nature’s particle fabrication
principles of self-assembly of amphiphiles or
crosslinking [2] . These ‘bottom-up’ approaches
require the precise design and synthesis of molecules for fine control of physical and chemical
properties [11,12] . Even with tailored materials
generated by advanced modern polymerization techniques, control of particle properties
is limited; the typical shape of self-assembled
micelles and crosslinked nanoparticles is spherical, toroidal or cyrindrical. Analogous to biological membranes, self-assembled systems without
rigid skeleton have a dynamic structure so that
their size, shape and surface chemistry are often
ill-defined and change with environments [13] .
Conversely, ‘top-down’ approaches based on
soft imprint lithography have recently emerged
as an alternative particle fabrication platform to
traditional methods. Soft lithography is chara­
cterized by the convergence of microfabrication strategies developed in the microelectronics industry with unique molding and printing
using elastomeric stamps. These strategies have
many advantages over the conventional particle
fabrication methods, including inherent control
of particle size and shape, low cost and scalability. Using poly(dimethylsiloxane) (PDMS) or
other siloxane-based polymers, in the late 1990s
Whitesides and coworkers pioneered soft lithography techniques, which were quickly adapted
toward the fabrication of microstructures for
biological applications [14–16] . This PDMS-based
soft lithography has been further developed
and applied to the fabrication of microparticles
for drug delivery [14–16] . Later, DeSimone and
coworkers developed the particle replication
in nonwetting templates (PRINT® ; Liquidia
Technologies, NC, USA) technology utilizing
perfluoropolyether (PFPE) polymers [17–19] . The
unique properties of PFPE molds allow for the
generation of nanoparticles with enhanced control of size, shape and chemical composition. In
this article, the PRINT technology and its recent
developments at the University of North Carolina
at Chapel Hill (NC, USA) are briefly described.
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PRINT technology
The term ‘soft lithography’ describes a family
of techniques to fabricate microstructures and
replicate them through elastomeric molds or
stamps. Various fabrication techniques for soft
lithography are often categorized as ‘molding
and embossing’ or ‘transfer printing’ according
to their procedures, and they typically utilize
PDMS molds or stamps [14,16] . However, some
drawbacks of using PDMS in soft lithography
have been noted over the last decade. First, the
pattern resolution in soft lithography is greatly
affected by the characteristics of mold or stamp
materials. Elastomeric PDMS molds are susceptible to distortion owing to their low mechanical modulus [16] . For example, microcontact
printing with PDMS stamps is limited to the
fabrication of micron-sized particles because
PDMS stamps could be distorted during contact with substrate due to a low elastic modulus of PDMS [20] . In nanocontact printing, an
extension of microcontact printing, mechanically stiffer elastomeric stamps are used to print
nanostructures with patterns less than 100 nm
in size [20] . The swelling of PDMS molds by
precursors or solvents to dissolve the precursors
often limits the scope of precursor materials [16] .
Before the development of the PRINT technology, soft lithography referred to molding,
embossing and printing methods using elastomeric PDMS molds or stamps [14] . Similar
to other soft lithographic methods, PRINT
involves the fabrication of a mold from a master template, followed by filling the mold with
a precursor liquid or solution of desired material, solidifying and transferring the molecules
to yield discrete particles (Figure 1) . However,
in order to overcome the limits of PDMS the
PRINT technology utilizes PFPE as the mold
material instead of PDMS, and the use of
PFPEs offers some unique advantages. PFPE is
a photocurable, elastomeric polymer that has a
lower surface tension, better solvent resistance
relative to PDMS, and high gas permeability [21] . In particular, the low surface tension
of PFPE (<25 mN/m) enables complete wetting of the master template, after which it is
photocured to yield a crosslinked elastomeric
mold with size- and shape-specific cavities.
Furthermore, a sufficiently low surface energy
of PFPE (lower than that of PDMS) prevents
wetting the land area between the cavities when
filling the cavities in the mold with many different liquids through capillary action and a
film splitting technique. These distinct characteristics of PRINT present a striking contrast
future science group
Challenging nature’s monopoly on the creation of well-defined nanoparticles
Fabrication of a mold
Cast mold
materials
Master
Solidify and
remove
Master
Review
Mold
Molding and printing
Mold
Substrate
Fill transfer
materials
Mold
Substrate
Solidify and
harvest
Figure 1. Fabrication of a mold (A) and molding and printing (B) in the PRINT® process.
to other soft lithographic methods, enabling
the generation of arrays of micrometer-scale
or nanometer-scale discrete particles that are
free of the interconnecting flash layer. In addition, crosslinked PFPE has a wide range of tunable mechanical moduli, while its maximum
modulus (~90 MPa) is higher than that of high
modulus PDMS (h‑PDMS; ~10 MPa) [22] . The
tunable mechanical properties of PFPE relative
to PDMS render it well suited for molding and
replicating nanostructures of size ranging from
10 nm to 1 µm with high density of cavities on a
mold. Some researchers independently exploited
these advantages of PFPE for soft lithography.
For example, Rogers and coworkers showed that
A
composite PDMS molds with PFPE materials
improved the fidelity and resolution of patterns in soft lithography relative to widely used
h-PDMS [23] .
The combination of modern soft lithography with the unique properties of PFPE molds
enables the PRINT process to produce nanoparticles with unprecedented control of size
and shape. Nanoparticles with a wide variety of
size and shape have been generated by means of
PRINT (Figure 2) [18,24] . Of particular interest is
the fabrication of sub-1-µm ‘scum’-free particles
for biomedical applications, which have been
dominantly generated by traditional bottom-up
approaches [2] . The PRINT process enables the
C
500 nm
B
5 µm
D
2 µm
2 µm
Figure 2. Manipulation of size and shape using PRINT®. (A) 200 nm trapezoidal particles [18] ;
(B) 200 × 800 nm bar particles [18] ; (C) 3 µm arrow particles [18] ; (D) 2.5 × 1 µm2 hexnut particles
with 1 µm holes [24] .
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Jeong, Napier & DeSimone
fabrication of truly monodisperse, shape-specific
sub-1-µm nanoparticles composed of purely
organic molecules or biocompatible materials [18] . Moreover, PRINT allows for the patterning of unique monodisperse features, such as
arrow, hexnut and boomerang shapes, and long
filamentous objects of controlled diameter and
length, which are unprecedented in nature [24] .
Especially when compared with nanoparticles
constructed by ‘bottom-up’ approaches, the
degree of size and shape control obtained by
PRINT is remarkable. As a representative model
system, crosslinked poly(ethylene glycol) (PEG)
hydrogel PRINT 200 nm cylindrical particles
(a diameter of 200 nm and a height of 200 nm)
were generated. Their size, polydispersity and
stability at 37°C were compared with those of
liposomes by means of dynamic light scattering [25] . As shown in Figure 3, the crosslinked
PRINT particles with a narrow distribution
of size (polydispersity <0.01) remain stable,
whereas supramolecularly assembled liposomes
change their size and structures during the time
course of 6 h.
One of the most profound impacts of PRINT
on nanomedicine is extensive flexibility in
engineering nanoparticles with various chemistries. Conventional approaches based on either
supramolecular assembly or crosslinking rely
primarily on a chemical composition to control
particle size and shape. By contrast, PRINT can
generate size- and shape-specific particles independent of matrix materials and their composition. PRINT particles have been successfully
constructed from a wide range of matrices, such
as crosslinked PEG hydrogels [18] , biocompatible polyesters [18] , proteins [26] and soft block
copolymer micelles [27] . In addition, PRINT
is amenable to encapsulating essentially any
desired payload, which may be achieved by dissolving it in a matrix solution, casting a film and
carrying out the PRINT process. The compatibility of PRINT with a wide range of cargos,
including fragile biological payload, has been
verified by incorporating proteins [26] , anticancer drugs [28] and nucleic acids. Remarkably,
PRINT enables the effective control of payload
amount in the delivery vector without polymer–
drug conjugation steps by an appropriate choice
of matrix materials. Reports have included drugcontaining crosslinked PEG hydrogels [28] and
100% pure protein nanoparticles [26] with precise control of size and shape (Figure 4A) . To better
deliver therapeutic agents to cancer cells, some
‘smart’ delivery vectors [29] that pre-engineered
stimulus-responsive functionality were fabricated and used (Figure 4B) [28] . For tissue imaging,
PRINT has been used to generate new classes
PRINT® particles
100
100
100
0h
6h
2h
75
75
75
n 50
n 50
n 50
25
25
25
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0
100
200
Diameter (nm)
Liposomes
300
0
0
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100
200
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2h
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n 50
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6h
75
0
100
200
Diameter (nm)
100
100
100
0
300
0
0
100
200
Diameter (nm)
300
0
Figure 3. Size and size distribution of PRINT® particles (A) and liposomes (B) as a function of time. Data taken from [25] .
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Challenging nature’s monopoly on the creation of well-defined nanoparticles
of nanoparticles, including iron oxides or gadolinium chelates for magnetic resonance imaging
and 64Cu chelates for positron emission tomo­
graphy (Figure 4C) [19] . It was also demonstrated
that nanoscale heterogeneity and distribution of
different chemical components in the particle
matrix can be obtained and controlled by careful engineering of the PRINT process. Particle
fabrication through sequential filling of the
cavity of molds with the distinct components
generates a series of anisotropic, multiphasic
nanoparticles with well-defined size and shape
(Figure 4D) [30] .
In addition to its adaptability to various
chemical components, PRINT can allow for the
control of the mechanical properties of nanoparticles effectively. PRINT enables the capability of fine-tuning the deformability of nanoparticles, which holds considerable promise for
biomedicines as nature selects from a very narrow range of elastic moduli to delegate specific
biological functions [1] . For example, the aforementioned erythrocytes have a specific modulus
of 26 kPa [5] , while tissues of the human body
have very selective mechanical moduli ranging from soft (brain: 0.5 kPa), to moderately
stiff (skin and muscles: 10 kPa) to stiff (bone:
>30 kPa) [1] . These unique mechanical properties are achieved by a complex crosslinked network of filamentous proteins in cytoskeletons [8] .
However, the PRINT process provides a simple and robust platform for controlling particle
moduli with the control of other variables. In the
PRINT process, the matrix materials are solidified or cured within the chemically inert mold.
Thus, mechanical properties of particles can
be tweaked simply by varying crosslink density
regardless of particle size and shape. A PRINT
mimic of an erythrocyte has been achieved
with highly similar size, shape and mechanical
properties, and are being investigated to determine the impact of modulus on circulation and
c­learance [31] .
The power and versatility of the PRINT
technology has been expanded through surface
modification to effectively communicate with
cells and biological environments. Nature uses
dynamic, selectively permeable biomembranes
as a barrier to regulate the passage of molecules
or particles through cell membranes. The surface chemistry and structures of biomembranes
affect all communication among cells and the
interaction between cells and environments. A
great deal of research effort has been directed
toward the design and development of surface
chemistries and structures to engineer targeted
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5 min 20 min 1 h
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1.5 h
2h
Figure 4. Well-defined PRINT® nanoparticles with distinct chemical
attributes. (A) 200 nm pure Abraxane® particles [26] ; (B) 2 µm pH-responsive
doxorubicin-loaded particles [28] ; (C) in vivo PET Imaging with 64Cu-DOTA
particles [17] ; (D) triphasic particles [30] .
and stealth-like nanoparticles. In particular,
strategies based on postfunctionalization of
nanoparticles have been largely exploited to
attain desirable surface properties. PRINT
has been employed with various postfunctionalization strategies to functionalize surfaces
with functional groups for bioconjugation [28] ,
fluorophores [30] , PEGs for long circulation and
targeting moieties on the surface of PRINT particles. In parallel, analytical methods are being
developed to quantitatively characterize the
PRINT particle surface.
In order to fully realize the impact of the
PRINT breakthrough in nanomedicine, some
technical innovations have been integrated into
the PRINT process over the last few years. The
PRINT technology has evolved from a batch
mode process to an automated roll-to-roll process (Figure 5) . The manufacturing paradigm has
Figure 5. Technical innovations in the PRINT® technology. (A) Low-cost thin
mold manufacturing [19] and (B) continuous roll-to-roll PRINT technology.
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Jeong, Napier & DeSimone
shifted to a single-pass, continuous roll-to-roll
line utilizing low-cost thin molds to produce
a range of nanoparticles in large quantities for
in vivo studies. These engineering advancements
in the PRINT technology are expected to provide the critical infrastructure for supporting
preclinical research and clinical trials.
The goal of the PRINT technology is to provide a versatile toolbox for independent design
and control of all of the physical and chemical attributes mentioned previously, and better
understanding of the impact of the attributes
on biological functions. As critically highlighted by Mitragotri and Lahann [1] , studying the effect of a physical or chemical factor
on biological outcomes requires total control
of all the design parameters; therefore, rigorous particle characterizations are needed to
ensure that the observed biological effects are
dictated only by a factor of concern rather than
an interplay of multiple factors. In this regard,
PRINT offers unique opportunities to better
elucidate the relationships between the particle
design parameters and the biological functions.
Indeed we have recently reported the effects of
particle size and shape on cellular internalization pathways, revealing their mechanistic
dependence on particle dimensionality [32] .
At present, we are systematically investigating the influence of the physical and chemical
attributes of particles on important biological
processes in nanomedicine, such as cellular
internalization, biodistribution and pharmacokinetics of nanoparticles. The authors envisage that exploring and understanding particle
design parameters and their relationships with
biological consequences through PRINT will
provide stepping stones for establishing truly
engineered drug therapies.
Conclusion & future perspective
It is becoming increasingly evident that control of the physical and chemical properties
of nanoparticles is crucial for the design and
development of successful nanomedicines.
Researchers in the field of nanomedicine
clearly see that nanostructures can actively
mediate molecular processes for cell functions,
and truly ‘active’ nanomedicines in addition
to their current role as passive nanocarriers
will emerge [33] . This new design concept was
experimentally supported by the recent work
by Chan and coworkers [34] . They showed
that metallic nanoparticles of different sizes
even without effective cargos can affect certain pathways that are essential for cell growth
and apoptosis [34] . Needless to say, the importance of controlling the physical and chemical
properties of nanoparticles in nano­medicine
motivates the development of versatile particle
fabrication platforms.
PRINT technology is a powerful particle
fabrication process that enables the generation
of nanoparticles with total control over numerous physical and chemical properties. With the
development and optimization of the PRINT
particle fabrication technique, we have developed a variety of unique nanoparticles, and are
investigating their potential for applications in
biomedicines. Precise control of the particle
properties through PRINT attempts to emulate nature’s particle engineering. In particular,
independent design of all of the physical and
chemical attributes allows for the elucidation of
their role in complex biological processes, and
bestows PRINT with unlimited possibilities for
generating nanoparticles with unique functions.
We expect that the PRINT technology will permit simultaneous control of key particle design
parameters to yield engineered nanomedicines
for complex in vivo systems.
Financial & competing interests disclosure
The PRINT® technology has been licensed to a venture
capital-backed company, Liquidia Technologies. The
research reported herein received partial financial support
from Liquidia Technologies that Joseph M DeSimone cofounded. Currently, he is on the board of directors and has
a personal financial interest in Liquidia Technologies. The
authors have no other relevant affiliations or financial
involvement with any organization or entity with a financial interest in or financial conflict with the subject matter
or materials discussed in the manuscript apart from
those disclosed.
No writing assistance was utilized in the production of
this manuscript.
Executive summary
ƒƒ The PRINT® technology enables the production of nanoparticles with unprecedented control of size,
shape, chemical composition, deformability and surface functionality.
ƒƒ PRINT allows for the generation of well-defined nanomedicines with tailored properties.
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