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Self-Assembly of Block Copolymers

Article in Chemical Society Reviews · July 2012

DOI: 10.1039/c2cs35115c · Source: PubMed

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Cite this: Chem. Soc. Rev., 2012, 41, 5969–5985

www.rsc.org/csr TUTORIAL REVIEW

Self-assembly of block copolymerswz
Yiyong Mai and Adi Eisenberg*
Received 2nd April 2012
DOI: 10.1039/c2cs35115c

Block copolymer (BCP) self-assembly has attracted considerable attention for many decades
because it can yield ordered structures in a wide range of morphologies, including spheres,
Published on 09 July 2012 on http://pubs.rsc.org | doi:10.1039/C2CS35115C

cylinders, bicontinuous structures, lamellae, vesicles, and many other complex or hierarchical
assemblies. These aggregates provide potential or practical applications in many fields. The
present tutorial review introduces the primary principles of BCP self-assembly in bulk and in
solution, by describing experiments, theories, accessible morphologies and morphological
transitions, factors affecting the morphology, thermodynamics and kinetics, among others.
As one specific example at a more advanced level, BCP vesicles (polymersomes) and their
potential applications are discussed in some detail.
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1. Introduction soaps are used, originate from the self-assembly of small-

Molecular self-assembly is ubiquitous in nature and in daily
life. Membranes of living cells are formed by the self-assembly
of phospholipids. Soap bubbles, which are encountered when
Department of Chemistry, McGill University,
801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada.
E-mail: adi.eisenberg@mcgill.ca
w Part of a themed issue on supramolecular polymers.
z Electronic supplementary information (ESI) available: Derivations
of some equations and relevant discussions. See DOI: 10.1039/
c2cs35115c
molecule surfactants. All of these molecules consist of one or
more hydrophobic tails and a hydrophilic head group. The desire
to understand molecular self-assembly and to explore potential
applications motivates the studies including those on molecular
self-assembly principles, theories, structures and properties of the
assemblies, etc. The self-assembly of small- molecule
amphiphiles has been studied for many decades, and various
morphologies have been observed in bulk and in aqueous
solutions.1,2 The morphologies include spherical micelles (spheres),
cylindrical micelles (cylinders), bicontinuous structures, lamellae and
vesicles, among others. It is primarily the packing

Yiyong Mai received his PhD Adi Eisenberg received his

from Shanghai Jiao Tong
University in 2007 under the
co-supervision of Professors
Deyue Yan and Yongfeng
Zhou, working on synthesis and
self-assembly of hyper-
branched polymers. His thesis
was awarded ‘‘The Outstanding
Doctoral Dissertation in
Shanghai’’. Other awards
include, among others, the
Outstanding Postgraduate in
Shanghai (2004 and 2007),
the BOC Scholarship (2004),
and the National Scholarship
Yiyong Mai
of China (2005). He joined the group of Professor Adi Eisenberg
at McGill University as a Postdoctoral Fellow in September 2008,
where he is currently a Research Associate. His present research
interests involve synthesis and self-assembly of block copolymers,
as well as exploration of block copolymer aggregates containing
inorganic nanoparticles and their potential applications.
MA and PhD in 1959 and
1960, respectively, from
Princeton University, under
the direction of A. V. Tobolsky.
He has been a Professor of
Chemistry at McGill University
since 1967, where he is
currently Otto Maass Emeritus
Professor. His research inter-
ests include, among others, the
exploration of block copolymer
aggregates and their potential
applications. He published over
Adi Eisenberg 400 papers and 11 books; his
H-index is 78. He is a fellow of
the Royal Society of Canada, the Chemical Institute of Canada
(CIC), and the American Physical Society. His awards include the
MSED Award of the CIC (1988), the Killam Research Fellowship
(1987–1989), the E.W.R. Steacie Award (1998), the Urgel
Archambault Prize, ACFAS (2004), the Humboldt Award
(2005/6), and the CIC Medal (2011). He is among the top 100
chemists by citation impact scores for 2000–2010.

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2012 5969

parameter, p = v/aolc, that determines the morphology of the
aggregates, where v is the volume of the hydrophobic segment, ao
is the contact area of the head group, and lc is the length of the
hydrophobic segment.1 When p o 1/3, spheres are formed; when
1/3 o p o 1/2, cylinders; when 1/2 o p o 1, flexible
lamellae or vesicles; finally, when p = 1, planar lamellae are
obtained. If p > 1, inverted structures can be observed.
Morphologies analogous to those of the small-molecule
aggregates were also found in the self-assembly of block
copolymers (BCPs) in bulk3–6 or in solution,3,7–9 based on
principles quite similar to those of small-molecule amphiphile
self-assembly. Compared to small-molecule aggregates, polymer
aggregates exhibit higher stability and durability due to their
mechanical and physical properties. Therefore, polymer self-
assembly has attracted considerable attention, not only out of
academic interest but also because of their potential applications in
many fields, such as biomedicine, biomaterials, micro-
electronics, photoelectric materials, catalysts, etc.3,10
Advances in polymer synthesis have given rise to a wide
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range of controlled polymerization techniques, e.g. anionic or
living radical polymerization, for the preparation of polymers of
various architectures, including linear BCPs, graft copolymers,
dendritic polymers, star-like polymers, and cyclic polymers,
among others.10 It has been found that all of these types of
polymers of different structures can self-organize into aggregates of
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diverse morphologies under certain conditions.10 Among these,
the BCPs, which are the most extensively studied system, consist
of two or more chemically distinct and frequently
immiscible blocks that are covalently bound together. Fig. 1
illustrates schematically the different structures of BCPs
containing two types of blocks, A and B. The AB diblock
copolymers have been the focus of a very large number of studies.
Self-assembly of BCPs is a very broad and active area. BCP
self-assembly in bulk has been studied extensively since the
1960s, and is well understood. Books and reviews are available
on this topic and the relevant applications.3,6,11 BCP self-assembly in
solution, which can also produce multiple morphologies,
exhibits a higher level of complexity; it has been studied actively
only since 1995.7–9 As a part of the themed issue on super-
molecular polymers, this tutorial review introduces the basic
principles of self-assembly of synthetic BCPs in bulk and in
solution, with emphasis on AB diblocks in solution. Topics
covered by other reviews in this issue, such as polymeric films,
stimuli-responsive assemblies, the self-assembly of non-covalent or
biopolymer-based copolymers, characterizations of BCP
aggregates, etc., are not included in this article. Following the
introduction, Section 2 describes briefly some fundamental
Fig. 1 Typical structures of block copolymers containing two types
of blocks, A and B.
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aspects of BCPs in bulk, including theoretical and experimental
studies, morphologies and mechanism of morphological transitions.
Section 3 discusses BCP self-assembly in solution, focusing on
accessible morphologies, major factors affecting the morphologies,
thermodynamics and kinetics, among others. Section 4 presents an
overview of studies on BCP vesicles; this topic is selected owing to
the high level of activity in this area as well as a range of potential
applications. The final section gives a summary of the review.
2. Block copolymers in bulk
2.1. Diblock copolymers
Generally, in bulk, BCPs with immiscible blocks can micro-
phase separate as a function of composition into a variety of
morphologies, including spheres (S), cylinders (C), bicontinuous
gyroids (G), lamellae (L), etc., as shown in Fig. 2a.6 The self-
assembly process is driven by an unfavorable mixing enthalpy
coupled with a small mixing entropy, with the covalent bond
connecting the blocks preventing macroscopic phase separa- tion.
The microphase separation of diblock copolymers depends on
three parameters:6 (1) the volume fractions of the A and B
blocks (fA and fB, with fA + fB = 1), (2) the total
degree of polymerization (N = NA + NB), and (3)
the
Flory–Huggins parameter, wAB . The w-parameter specifies
the degree of incompatibility between the A and B blocks,
which drives the phase separation. The relationship between
wAB and temperature.(T) is given in eqn (1):5,6 .
z .. 1
wAB ¼ ðeAA þ eBB Þ ð1Þ
eAB —
kB T 2
where z is the number of nearest neighbours per repeat unit in the
polymer, kB is the Boltzman constant, kBT is the thermal
energy, and eAB, eAA, and eBB are the interaction energies per
repeat unit of A–B, A–A, and B–B, respectively. For diblock
copolymers, e.g. polyisoprene-block-polystyrene (PI-b-PS), in
which there are no strong specific interactions, such as hydrogen
bonding, or ionic charges, wAB is generally positive and small,
and varies inversely with temperature. The degree of micro-
phase separation of diblocks is determined by the segregation
product, wN. With increasing temperature or decreasing wN, the
incompatibility between the constituent blocks decreases, while the
combinatorial entropy increases, the copolymers show order-
to-disorder transition (ODT) and become disordered (i.e.
homogeneous). The temperature, at which the ODT occurs, is
referred to as TODT. The phase behaviour of BCPs in bulk is well
understood both theoretically and experimentally.3,6,11
2.1.1. Theoretical phase diagram. A number of theories
have been developed dealing with the phase behaviour of diblock
copolymers in bulk.12–15 In terms of wN, the so-called weak
segregation limit (WSL) (wN o 10) and the strong
segregation limit (SSL) (wN c 10) were introduced. To span
the range, the self-consistent mean-field (SCMF) theory has
been developed.14,15 Fig. 2b shows the phase diagram of diblock
copolymers predicted by the SCMF theory.6,15 With increasing fA
at a fixed wN above the ODT (wN > B10.5), the order-to-
order transition (OOT) starts from closely packed spheres (CPS,
which separates the disordered state and S phase), passing
through body-centered cubic spheres (S), hexagonally packed
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Fig. 2 (a) Equilibrium morphologies of AB diblock copolymers in bulk: S and S 0 = body-centered-cubic spheres, C and C 0 = hexagonally
packed cylinders, G and G 0 = bicontinuous gyroids, and L = lamellae.6 (b) Theoretical phase diagram of AB diblocks predicted by the self-
consistent mean-field theory, depending on volume fraction (f) of the blocks and the segregation parameter, wN, where w is the Flory–Huggins
segment–segment interaction energy and N is the degree of polymerization; CPS and CPS 0 = closely packed spheres.6 (c) Experimental phase
portrait of polyisoprene-block-polystyrene copolymers, in which fA represents the volume fraction of polyisoprene, PL = perforated lamellae.6
Reproduced with permission from ref. 6.

cylinders (C) and bicontinuous gyroids (G), to lamellae (L).
Morphological inversion takes place when the composition is
inverted (L - G 0 - C 0 - S 0 - CPS 0 - disordered). The
morphologies and their transitions have been verified experi-
mentally, as described below.
2.1.2. Experimental phase diagram. The preparation of the
samples for morphological studies usually starts with heating
and annealing the polymer sample at a temperature higher
than the glass transition temperature (Tg) of the polymers for a
certain period, in order to allow equilibrium to be reached.16
Then, the sample
polymers with lowis quenched
Tg, the to a temperature
sample below
is usually Tg. For to
quenched
temperatures near that of liquid nitrogen and then allowed to warm
to room temperature. When the sample is at the annealing
temperature, the structure of the polymers can be (and frequently is)
under thermodynamic control. When the sample is cooled below
its Tg, the structure of the sample is kinetically frozen because of
the extremely low mobility of the chains. Thus, the morphology
observed is characteristic of the material at the annealing
temperature.16 Fig. 2c shows an experimental phase diagram of
PI-b-PS copolymers reported by Bates and co-workers.6,16
The resemblance to the theoretical diagram in Fig. 2b is
remarkable with only a few discrepancies.6
2.1.3. Mechanism of morphological transitions. The formation of
the various morphologies is attributed to two competing
factors: interfacial energy between the two blocks (an enthalpic
contribution), and chain stretching (an entropic contribution). As
microphase separation occurs, the two blocks separate
from each other in such a way as to minimize interfacial area
in order to lower the total interfacial energy. Phase separation
induces chain stretching away from the preferred coiled polymer
chain conformation; the degree of stretching depends on the volume
fraction of one block relative to that of the diblock. Fig. 3 shows the
well-known cone—column mechanism for morpho- logical
transitions. When the diblocks are highly asymmetric, i.e. the
volume fraction of one block such as block A is small, the A
blocks prefer to aggregate into spherical microdomains, leaving
the B blocks to surround them as ‘‘coronas’’ (Fig. 3a). This
way affords the system the lowest interfacial area and increased
configurational entropy relative to other morpho-
logies, and thus is energetically favourable. 6 As fA increases at a
fixed temperature, the corona volume fraction (or the effective volume
fraction of block B) decreases and less curved interfaces are formed
(Fig. 3b and c), the polymer chains have to adopt new arrangements
to reduce their stretching, leading to a morphological transition from
spheres to cylinders and to lamellae.
2.2. Multiblock copolymers
An increase in the number of blocks in BCPs leads to an
increased level of complexity for self-assembly in bulk. For
example, ABC linear triblock copolymers contain three different
blocks (A, B, and C); the phase behaviour of the ABC triblocks
depends on the three different w-parameters (wAB, wAC, and wBC), the
total degree of polymerization (N), the volume fractions of the three
blocks (fA + fB + fC = 1), and the sequences of the three segments
(ABC, BCA, or CAB). A wide range of ordered structures have
been discovered experimentally, with theory suggesting the existence of
30 different morphologies.17 One can imagine the much higher

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2012 5971

Fig. 3 Schematic illustration of the possible polymer chain arrange-
ments in different morphologies of AB diblocks changing from sphere (a)
to cylinder (b) and to lamella (c), as the volume fraction (fA) of the A
block (black) increases to B0.5. The dash curve in each morphology
represents a part of the interface between A and B domains. The concept of
Published on 09 July 2012 on http://pubs.rsc.org | doi:10.1039/C2CS35115C
this figure originates from ref. 24. This reference contributes to BCP self-
assembly in solution, and is cited accordingly in Section 3.1.
level of complexity in the phase behaviour of BCPs with more
than three blocks.
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3. Block copolymers in solution
The introduction of solvent increases the level of complexity for
BCP self-assembly in solution, compared with BCP self-assembly in
bulk. For example, the self-assembly of polystyrene-b- poly(acrylic
acid) (PS-b-PAA) copolymers in dioxane–water or other solvent–
nonsolvent mixtures involves six w-parameters, namely wAB, wAS,
wAN, wBS, wBN, wSN, where A and B represent the two blocks, S
expresses the good solvent for both blocks, and N denotes water or
the nonsolvent (selective solvent) for one of the blocks. The more
components are present in the solution, the more complex is the
self-assembly process.
The discussion in Section 3 focuses on BCP self-assembly in
aqueous solutions, since water has been extensively applied as a
selective solvent in the self-assembly of a wide range of materials.
Depending on the solubility of the blocks in water, diblock
copolymers can be categorized into amphiphilic,3,8,9 double hydro-
philic,18 and double hydrophobic systems.19 The amphiphilic
BCPs have been studied most extensively and are the focus of
the following discussion. In the early stage of the studies on the
self-assembly of amphiphilic diblocks, such as PS-b-PAA or PS-
block-poly(ethylene oxide) (PS-b-PEO), it was found that systems, in
which the hydrophobic blocks are much longer than the hydrophilic
segments, generate various morphologies, in which the coronas
are much smaller than the hydrophobic regions. Such
‘‘crew-cut’’ aggregates have received extensive attention over the
last 15 years.8,9,20–22 By contrast, aggregates (usually spherical
micelles) in which the coronas are much larger than the core
regions are frequently referred to as ‘‘star-like’’ aggregates.21
The present section starts with a description of accessible
morphologies, followed by introductions of aggregate prepara- tion,
major factors affecting the morphology, thermodynamics and
kinetics in the formation of aggregates, ‘‘permanent’’
morphologies, and finally theoretical studies.
3.1. Accessible morphologies
Diverse morphologies have been obtained by BCP self-assembly in
solution. For example, a wide range of crew-cut aggregates
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of different morphologies have been prepared from asymmetric
amphiphilic BCP systems since 1995.8,9,20–22 The aggregates include
spherical micelles, rods, bicontinuous structures, lamellae, vesicles,
large compound micelles (LCMs), large compound vesicles
(LCVs), tubules, ‘‘onions’’, ‘‘eggshells’’, baroclinic tubules,
pincushions, etc. Overall, more than 20 morphologies have been
identified, some of which are thermodynamically induced, while
others are kinetically controlled (thermo- dynamics and kinetics
will be discussed in Section 3.4). For instance, working with PS-
b-PAA under different conditions, one can observe a spectrum
of thermodynamically controlled morphologies ranging from
spheres through rods, bicontinuous rods, bilayers (lamellae and
vesicles), to inverse rods (HHHs) and large spheres (LCMs), as
shown in Fig. 4. These aggregates will be discussed further in the
following paragraphs. Other morphologies, such as LCVs, tubules,
etc., are mostly produced under kinetic control. Due to space
limitations, most of these structures will not be described further.
Two reviews are avail- able describing the morphological
versatility of the crew-cut aggregate families, based on PS-b-PAA,
PS-b-PEO, and PS-block- polyvinylpyridine (PS-b-PVP)
systems.21,22 Other diblock systems, which also produce
multiple morphologies, include polybutadiene-block-PEO (PB-b-
PEO),23 poly(lactic acid)- block-PEO (PLA-b-PEO),24
polycaprolactone-block-PEO (PCL-b-PEO),24 poly(2-
cinnamoylethyl methacrylate)-b-PAA (PCEMA-b-PAA),25 and
poly(butylene oxide)-block-PEO (PBO-b-PEO),26 among others.
Simple spherical micelles consist of a spherical core surrounded by
coronal chains (Fig. 4a).8,22 A restriction for simple spherical
micelles is that the radius of the core cannot exceed the longest
hydrophobic chains in their planar zigzag configuration. The
spherical micelles are usually the first aggregates to form, for
example, under the frequently-used preparative conditions for crew-
cut systems such as addition of water to solutions of
diblocks in N,N0 -dimethylformamide (DMF), tetrahydrofuran
(THF), or dioxane. Thus, they can be considered as the starting
morphology for other aggregates. The hydrophilic coronas
afford the spherical micelles solubility in water, while the hydro-
phobic cores provide an ideal location for encapsulation of, for
example, hydrophobic drugs,10,27–29 fluorescence probes,29 and a
range of other species such as genes or proteins.27–29 Therefore,
spherical micelles are under extensive study for applications in
drug/gene delivery and biological imaging.10,27–29 Spherical
micelles have been developed considerably beyond simple core–
corona structures, such as polyionic complex (PIC) micelles,28
zwitterionic micelles,30 Janus micelles with two distinct
hemispheres,31 multi-compartmental micelles,32 e.g. ‘‘hamburger’’
(Fig. 5a),33 etc.
Rods (cylindrical or wormlike micelles) are composed of a
cylindrical core and a corona surrounding the core (Fig. 4b).8,22
They are characterized by diameters of the same order of
magnitude as those of primary spheres (ca. 30 nm) but can be of
widely variable length that can exceed tens of micrometers.
Since rods provide an excellent template for alignment of metal,
semiconductor, or magnetic nanoparticles,34 control of the rod
length has been an active topic. A recently developed ‘‘living
self-assembly’’ strategy, based on polyferrocenyldimethylsilane
(PFS)-containing BCPs, achieved excellent control of the rod
length.35 Current self-assembly techniques have generated more
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Fig. 4 Transmission electron microscopy (TEM) micrographs and corresponding schematic diagrams of various morphologies formed from amphiphilic PSm-b-
PAAn copolymers.22 Note: m and n denote the degrees of polymerization of PS and PAA, respectively. In the schematic diagrams, red represents hydrophobic
PS parts, while blue denotes hydrophilic PAA segments. HHHs: hexagonally packed hollow hoops; LCMs: large compound micelles, in which inverse
micelles consist of a PAA core surrounded by PS coronal chains. Generally, the hydrophilic segments (e.g. coronas) of the crew-cut aggregates cannot
be seen in TEM images if they are not stained. Pictures are reproduced with permission from ref. 22.

sophisticated cylindrical structures, including Janus,31 segmen- ted
(Fig. 5b),36 helical (Fig. 5c),37 etc.
Bicontinuous rods consists of three-dimensional networks of
interconnected branched rods (Fig. 4c),22,38 which are similar to
the bicontinuous gyroids in the bulk. This morphology is not
seen frequently, and where it is seen, it is only over a very
narrow range of experimental parameters.
Bilayers (lamellae and vesicles) represent the next step in the
arrangement of copolymer chains as block or environmental
parameters change. Lamellae are flat or slightly curved
bilayers. Fig. 4d shows small lamellae coexisting with some
vesicles, whereas Fig. 4e presents the layering of large lamellae.22,39
Vesicles are closed bilayers, namely hollow spheres with a8,22,40 bilayer
wall sandwiched by internal and external coronas (Fig. 4f).
They are more frequently seen than lamellae owing to their
higher thermodynamic stability (to be discussed in Section 3.4.4).
Besides the unilamellar vesicles in Fig. 4f, other different types of
vesicles were also obtained; examples often observed are given in
Fig. 5d and e.39,41 The studies on vesicles will be reviewed
separately in Section 4. It should be mentioned here that bilayers are
mostly formed from diblock copolymers; for triblock or multiblock
copolymers, monolayers or multilayers are usually obtained.42 For
example, ABC triblock copolymers can form monolayers composed
of B blocks along with A and C blocks located on each side.
Hexagonally packed hollow hoop (HHH) structures are the
phase-inverted counterpart of rods (Fig. 4g).22,43 In rods the
PS forms the cores while PAA forms the coronas, but in HHH
aggregates the PS and PAA phases are inverted, with PAA
(possibly in solution) forming the hoop ‘‘cores’’ and PS the
coronas (i.e. the continuous phase). The HHH structure is depicted
in a computer visualization (inset of Fig. 4g), and

Fig. 5 Representative morphologies formed from block 36copolymers,

(a) ‘‘hamburger’’ micelles,33 (b) segmented cylindrical micelles, (c) helical
micelles, (d) large compound vesicles (LCVs),39 (e) multilamellar vesicles.41
37

Pictures are reproduced with permission from ref. 33, 36, 37, 39 and 41.

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2012 5973
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consists of an arrangement of multiple ‘‘hollow’’ concentric
hoops packed on a hexagonal lattice. The word ‘‘hollow’’ is
used because the ‘‘core’’ (internal phase) of the hoops consists
of short water-soluble PAA chains. Surrounding the hollow
hoops is the ‘‘bulk’’ PS, and the hollow hoops are thus
embedded in a PS matrix.43
Large compound micelles (LCMs) consist of an aggregation of
inverse micelles, the outer surface of which is stabilized in
solution by a thin layer of hydrophilic chains (Fig. 4h).8,22 This
morphology is similar to inverse spheres in bulk. For LCMs
formed from PS-b-PAA, islands of PAA chains are located in a
continuous hydrophobic PS phase, which is surrounded by the
solvent-soluble PAA corona (inset of Fig. 4h). LCMs are
frequently seen in many polymer systems, their sizes are much
larger than those of simple spherical micelles, and are usually
highly polydisperse.
3.2. Preparation of block copolymer aggregates
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interactions among corona-forming chains.20,21 The morphologies can
therefore be controlled by factors affecting any of the three
contributions, e.g. through variations in copolymer composition and
concentration, water content in the solution, nature of the
common solvent, presence of additives such as ions or homo-
polymers, etc.20,21 The present section discusses some of the
major factors that influence the morphology of the aggregates,
and gives the possible reasons for their effectiveness, focusing
on PS-b-PAA systems.
3.3.1. Copolymer composition. Paralleling BCP self-assembly in
bulk, copolymer composition (or block content) also affects the self-
assembly in solution. Table 1 shows morphological transitions of PS-
b-PAA aggregates from spheres, through cylinders and vesicles, to
LCMs, as the molar percentage of the PAA block deceases. One
can refer to the cone—column transition mechanism in Fig. 3 for the
morphological transitions. In this subsection, the influence of
copolymer composition on the morphology of the aggregates is
discussed in more detail.

Several popular methods utilized in the preparation of BCP
aggregates in solution are introduced here. Generally, for
BCPs with a glassy hydrophobic block at room temperature,
such as PS-b-PAA or PS-b-PEO (Tg,PS E 100 1C in bulk), a
co-solvent method (or solvent switch) is frequently used.20,21
Typically, the amphiphilic BCPs are dissolved in a common
solvent, such as DMF, dioxane, or THF, which are good
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Usually, PS-b-PAA copolymers with a relatively long PAA
block form spherical micelles. In terms of the three contribu-
tions mentioned above, three key parameters which should be
considered include the number-average core radius (Rcore), the
degree of stretching of PS chains (Sc), and the area per corona
chain on the core surface (Ac), all of which are functions of the
chain lengths (degrees of polymerization) of both the PS block

solvents for all blocks. Then a selective solvent, such as water
(which is a nonsolvent for the hydrophobic block), is slowly
added to the solution. The water addition is continued until the
water content (generally 25–50 wt%) is much higher than that
at which aggregation starts (the effect of water addition will be
discussed in Sections 3.3.3 and 3.4). Then the aggregates are
usually quenched in an excess of water to freeze the kinetic
processes and morphologies. Finally, the common solvent is
removed by dialysis of the resulting solution against water. For
BCP systems with a relatively flexible hydrophobic block, such
as PB-b-PEO (Tg,PB E —90 1C), aggregates can be formed by
direct hydration techniques, e.g. a so-called film rehydration
approach (or solvent-free).23,24,42 Generally, this approach
involves the rehydration of a BCP film in a selective solvent
with or without an assistance of mechanical mixing, sonication,
extrusion, or electrical fields.42 This method is particularly useful for
the generation of giant vesicles of micrometer sizes.
Other techniques, especially for the preparation of vesicles,
include electroformation,44 layer-by-layer assembly,45 micro-
fluidic techniques,46 among others. Recent developments in
microfluidics have opened fascinating ways to prepare mono-
disperse vesicles of controlled size.46 Another recently developed
strategy is the formation of aggregates during synthesis of BCPs in
solution.47 A continuous increase in one block length of the
copolymers during a living/controlled polymerization may induce a
successive morphological transition of the resulting assemblies.
(NPS) and the PAA block (NPAA).20 For example, for spherical
micelles formed from PS-b-PAA copolymers in DMF–water
mixtures, the dependences of Rcore, Sc, and Ac on the copolymer
composition are given by eqn (2)–(4), respectively, based on
experimental data:20
—0.15
Rcore B N0.4
PS NPAA (2)
0.1 —0.15
Sc B N—
PS NPAA (3)
Ac B N0.6 0.15
PS NPAA (4)
In the micelle core, some of the PS blocks must be stretched
from the core–corona interface to the core center. For micelles
formed from copolymers with a constant PS block length, the
stretching of the PS chains in the core increases as the core size
increases. This also applies to cylinders, lamellae, and vesicles.
Table 2 gives some typical data, showing parameters of PS
dimension, Sc, and Ac of the aggregates formed from PS200-b-PAAn
copolymers in DMF–water solutions. As the aggregates
change from spheres to cylinders and to vesicles with decreasing
PAA block length, the dimension of the PS region, Sc, and Ac
decrease progressively. The discussion of the decreases in these
three parameters as the morphology changes is given in the ESI.z
Table 1 Aggregates formed from PS-b-PAA copolymers in DMF–water
solutions

3.3. Major factors affecting the morphology PS-b-PAA PAA (mol%) Morphology
The formation of thermodynamically stable BCP aggregates of
various morphologies is governed by three contributions to the 410-b-46 10.1 Spheres
free energy of the system: the degree of stretching of the 200-b-21 9.5 Spheres
core-forming blocks, the interfacial tension between the micelle 200-b-15 7.0 Rods
core and the solvent outside the core, and the repulsive 410-b-25 5.9 Rods
410-b-20 4.7 Vesicles
200-b-8 3.8 Vesicles
200-b-4 2.0 LCMs

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Table 2 Parameters of the aggregates formed from PS200-b-PAAn in
DMF–water solutions
PS dimensiona/
PAA Ac c /
b 2
PS-b-PAA
200-b-21 (mol%)
9.5 Morphology
Spheres nm
26 S1.41
c nm
8 discussed in Section 3.3.3). CMC usually decreases as the
200-b-15 7.0 Rods 23 1.26 5.8
200-b-8 3.8 Vesicles 18 0.99 4.2
200-b-4 2.0 LCMs —d —d —d
a
Average diameter of the spherical and cylindrical micelles or wall
thickness of the vesicles. b Degree of stretching of the PS blocks in the
core or wall; for the spherical and rod-like micelles, it is defined as a
ratio of the radius to the end-to-end distance of the PS block in thec
unperturbed state; for the vesicles, half of the wall thickness is used.
Surface area per corona chain at the core/corona interface calculated from
the dry aggregates. If the PS core or wall is swollen by solvent, the Ac
values of thed swollen aggregates should be higher than those of the dry
aggregates. Not applicable, because LCMs consist of a large number
of reverse micelles with polar PAA cores in a PS matrix.
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It should be noted that the PS chains in spherical micelles are
usually more stretched than in cylindrical micelles, in which
they are more stretched than in lamellae or vesicles.
(NFor spherical micelles, an increase in the aggregation number
agg, the average number of polymer chains in an aggregate)
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yields larger core dimensions. This process is energetically
favourable because the larger core sizes result in a smaller
number of aggregates, and therefore a smaller total interfacial area
and a lower total interfacial energy between the core and
the nonsolvent. However, the increase of Nagg, and consequently
of the core dimension, is opposed by increases of both the PS
chain stretching and the repulsion among the corona chains. The
strength of the interactions among the corona chains is related to
coil dimensions of the corona-forming blocks. For copolymers
with a constant PS block length, when the PAA blocks are
relatively long, the coil dimensions of corona chains are large
and the interchain repulsion can be more important than the
stretching of the PS blocks during the micelle formation. Nagg
is limited more strongly by the interchain repulsion than by
the stretching of the core blocks. As the length of the PAA
blocks decreases, the repulsion among the corona chains also
decreases. Accordingly, Nagg and the core size increase
(eqn (2)), the stretching of the PS chains in the core also
increases (eqn (3)) and becomes more important in restricting
the growth of the core. The stretching cannot increase indefinitely
owing to the increased penalty from the decreased entropy of
the PS chains in the core. At some point, in order to minimize
the total free energy of the system by reducing the stretching
of the PS chains, the aggregates change from spheres, through
cylinders and lamellae/vesicles, to LCMs, as the corona chain
length decreases.
3.3.2. Copolymer concentration. The morphology of aggregates
also depends on copolymer concentration. For example, the
PS190-b-PAA20 aggregates in DMF–water mixtures change
from spheres to rods and to vesicles as the concentration
increases from 1 to 3.5 wt%.38
The effect of copolymer concentration on the morphology of the
aggregates can be explained by the fact that Nagg is a function
of copolymer concentration. An equation from a theory for
small-molecule surfactant micelles,1 namely Nagg = 2(C/CMC)1/2,
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2012
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can be used to illustrate the trend of Nagg as a function of
copolymer concentration (C). In the equation, CMC represents the
critical micellization concentration, which is also the copolymer
concentration at the critical water content (CWC, to be
water content in solution increases due to the increase of
the Flory–Huggins interaction (w-parameter) between the
hydrophobic blocks and water,48 thus Nagg increases. Besides,
Nagg increases with increasing copolymer concentration, which
leads to an increase in the sizes of micelle cores, and
consequently an increase in the degree of stretching of the
core-forming blocks, when the mobility of the polymer chains is
still high. Therefore, increasing copolymer concentration can
have a morphogenic effect on the aggregates similar to that
of decreasing corona chain length, as discussed above.
3.3.3. Water content. It is found that independent of the
nature of the common solvent (DMF, THF, or dioxane), the
copolymers always form spherical micelles first during water
addition. The amount of added water at which the micellization
starts is defined as the critical water content (CWC), which can be
obtained from the sudden change in the intensity of scattered
light as water is added.48 As the water content increases
progressively from the CWC, the aggregates may change from
spheres to rods and to vesicles. An example is shown in Fig. 6a,
which presents a morphological phase diagram of PS310-b-PAA52 in
dioxane–water mixtures as functions of copolymer concentration
and water content. 40,49
The morphogenic effect of water content can be ascribed to
a change of Nagg.49 When the copolymer chains start to form
micelles during water addition, Nagg is small in the early stages
of micellization because the system is under weak segregation
conditions. Although the degree of swelling of the core may be
high, the degree of stretching of the PS chains in the core need
not be high because only a small number of chains are present.
Thus, no matter which common solvent is used, spherical
micelles appear in the early stages. As the water content
increases, the mobility of the PS chains in the core decreases
but if it is high enough, Nagg and consequently the core
dimensions increase, while decreasing the total number of
the aggregates. This process reduces the total interfacial energy
between the core and water, but increases the stretching of the
PS chains in the core as well. At some critical value of the
water content, the spheres may change to rods and then to
vesicles, so as to minimize the free energy by reducing the
stretching penalty of the PS chains. If the mobility of the PS
chains has slowed down sufficiently before Nagg reaches the
critical point, the spherical structure will be frozen over the
experimental time scale. The effect of water addition on chain
mobility and the kinetics in the formation of various morphologies
are discussed in Section 3.4.
3.3.4. Nature of the common solvent. The nature of the
common solvent can play a crucial role in the formation of
various aggregates, since the common solvent directly affects
the dimensions of both hydrophobic domains and hydrophilic
corona chains of the aggregates.50,51 For example, PS200-b-PAA18
yields spheres when the common solvent is DMF, but gives LCMs
with THF. The intermediate morphologies, rods and vesicles,
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Fig. 6 (a) Phase diagram of PS310-b-PAA52 in dioxane–water as functions of
copolymer concentration and water content. The colored regions
between sphere and rod phases and between rod and vesicle phases
correspond to coexistence regions.40 (b) Phase diagram of PBO-b-PEO in
water as functions of molecular weight and copolymer concentration.26
Pictures are reproduced with permission from ref. 26 and 40.
can be obtained by using DMF–THF mixtures with increased
THF contents as the common solvent.50
During water addition, the common solvent is present in the
hydrophobic regions of the aggregates, such as the micelle
cores. Dissolution of polymers is optimal when the values of
the solubility parameters (d) for the polymer and the solvent are
similar. As these values diverge, the polymer chain dimensions
decrease.50,51 For PS-based copolymers, because the d value of
PS (d = 16.6–20.2) is closer to those of THF (d = 18.6) and
dioxane (d = 20.5) than to that of DMF (d = 24.8), the degree
of swelling of the PS cores of the micelles and the mobility of
the PS chains in the core are higher in THF or dioxane than
in DMF, which facilitates the micelle growth. Therefore, at
corresponding water contents between the CWC and the point
at which the morphology becomes frozen, Nagg and the core
dimensions of the resultant micelles are larger in THF or
dioxane than in DMF, leading to a higher degree of stretching
of the core blocks. Furthermore, the window of water
contents, in which the aggregates are still labile, is broader
in THF or dioxane than in DMF. These factors provide more
opportunities for morphological transitions, before the aggre-
gates are frozen.50
The strength of the repulsion among corona chains depends
on both the coil dimension and the charge density of the
chains. The coil dimensions of the corona-forming blocks as
well as their steric interactions depend on the interactions
(w-parameter) between the solvent and the hydrophilic blocks.50
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In a common solvent of high dielectric constant (e), such as DMF
(e = 38.2), the ionizable PAA blocks are partially
charged, the electrostatic repulsion among the corona chains is
relatively strong. By contrast, in a common solvent of lower
dielectric constant, such as dioxane (e = 2.2) or THF (e = 7.5),
the charge on the PAA blocks is negligible, and the repulsion
among the corona chains is weaker. The reduced repulsion
leads to a decrease in the effective volume per corona chain on
micelle surface. Thus, similar to the effect of decreasing the
PAA block length, the aggregates can change from spheres to
rods and to vesicles when the common solvent is changed from
DMF to dioxane or THF.
The solubility parameter and the dielectric constant of a
solvent mixture can be tuned by changing its composition.50,51
Therefore, solvent mixtures of different compositions may also be
employed as a versatile tool of controlling the aggregate
morphology, as mentioned at the beginning of this subsection.
3.3.5. Presence of additives
Added ions9,39. The morphology of BCP aggregates can also
be controlled via the addition of a small amount of acids,
bases, or salts, such as HCl, NaOH, or NaCl, etc. The effect of
added ions on the morphology is mainly due to a change in the
interactions among corona chains in the presence of ions. For
the PS-b-PAA copolymers, because the PAA blocks are
partially ionized during micellization at near-neutral pH or
above, the electrostatic interaction can be a major component
of the repulsions among the corona chains. The addition of
HCl protonates the ionized carboxylic acid units of the PAA
blocks, and thus decreases the degree of ionization. Accordingly,
the charge density of the PAA blocks decreases, leading to a
decrease in the interchain electrostatic repulsion, and consequently
a decrease in the effective volume per corona chain. Therefore,
similar to the effect of decreasing the PAA block length, as the
effective volume per corona chain decreases with increasing HCl
concentration, the aggregates change from spheres to rods and to
vesicles. The addition of a weak acid, e.g. acetic acid (HAc), has
only a weak effect, since changes in the degree of ionization of the
PAA blocks are very small. By contrast, the addition of a base,
e.g. NaOH, neutralizes the PAA segments, and thus the degree of
ionization and the strength of the interchain electrostatic repulsion,
both increase. Accordingly, with increasing NaOH concentration,
the morphology changes in the opposite direction, namely
from vesicles to spheres. The morphogenic effect of added
NaCl originates from a screening of charges of the partially
neutralized PAA by the NaCl, which results in a decrease of
the interchain repulsion, leading to a general morphological
change from spheres to vesicles.
Added homopolymer20. Under certain conditions, it has been
found that the addition of homopolystyrene can change the
morphologies. For example, vesicles are formed from a 2 wt%
DMF solution of PS410-b-PAA16, but spheres are obtained if
10 wt% of the copolymer is replaced by PS180 homopolymer.
The hydrophobic interaction induces the mixing of the homo-
polystyrene and the PS block of the copolymer. In order to
lower the overall free energy by increasing the entropy of the
chains in the aggregates, spheres are formed with the homo-
polymer aggregating preferentially near the core center, which
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reduces the degree of stretching of the PS blocks of the
copolymer because they need not extend as much as in the
absence of homopolymer. Therefore, the morphology can
change back from vesicles to spheres.
In addition to the major factors discussed in Section 3.3, other
factors that also affect the morphology of BCP aggre-
gates include temperature, polydispersity of block length,
added surfactants, etc.52 They are not discussed here because of
space limitations. Kinetic effects, such as the rate of water
addition,38 can have an influence on the kinetically controlled
morphologies (to be discussed in Section 3.4.3). To describe
quantitatively the effects of two or more factors on the morpho-
logies, morphological phase diagrams can be constructed.23,26,49,51
Two examples are given in Fig. 6. Phase diagrams are very useful
because they not only give a qualitative insight into the overall
thermodynamic features of importance in the self-assembly
process, but also allow the rapid preparation of aggregates of
specific morphologies.
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3.4. Thermodynamics and kinetics in aggregate formation
During self-assembly of amphiphilic BCPs, progressive addition of
the precipitant desolvates the hydrophobic blocks, leading to their
aggregation into the hydrophobic parts of the aggregates. The
aggregates are stabilized in solution by the hydrophilic segments.
The self-assembly process sacrifices the entropy of the single
chains, but prevents a larger enthalpy penalty resulting from
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energetically unfavourable hydrophobe–water inter- actions, and
therefore lowers the total free energy of the system (DG o 0).
Under thermodynamic control, the aggregate morphology is
governed by the composition and/or tempera- ture of the
system.20,23 Frequently, the morphological transitions can be
reversed through altering some parameters of the system, e.g.
copolymer concentration or temperature, provided that the
mobility of polymer chains remains sufficiently high.38 More
importantly, the structures are independent of the detailed
procedures of aggregate preparation, such as the period of water
addition.20,38 When the aggregate formation occurs under kinetic
control, the detailed morphological paths are relevant and may
involve such mechanisms as adhesive collisions among the
primary aggregates (spheres, rods, or vesicles) or between the
aggregates and polymer chains, along with subsequent processes of
fusion and structural rearrangement or the transformation of one
morphology to another.38,39 Clearly, the rate of kinetically
controlled aggregate formation depends on the hydrodynamic
interactions among the aggregates and/or polymer chains, as well
as the chain dynamic in the hydrophobic domain of the
aggregates. In practice, it depends on the details of aggregate
preparation. Even if the gross morphological trends are under
thermodynamic control, the achievement of a morphological
transition is influenced by kinetics under a wide range of
conditions. This subsection discusses several thermodynamic
and kinetic aspects of the formation of BCP aggregates of
various morphologies, with the focus on PS-b-PAA systems.
3.4.1. Mobility of copolymer chains in the hydrophobic
domains of the aggregates. In the early stages of aggregate
formation, the hydrophobic domains of the aggregates are
usually swollen by the common solvent. When the content of
common solvent is high, the mobility of the polymer chains is
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high and the aggregate structures are quite labile. The plasticizing
effect loses as the solvent is removed gradually from the hydro-
phobic domain during water addition. Therefore, at high water
contents at which the chain mobility is extremely slow, the
aggregates become frozen and retain their structural integrity during
further water addition and subsequent dialysis. This applies
especially to aggregates of PS-b-PAA and similar systems in which
the hydrophobic blocks have a high Tg.
3.4.2. Size hybridization among aggregates. The dynamics of
size hybridization among aggregates have been a subject of
many studies, one of which involved the mixing of two
separate solutions of different size micelles at elevated water
contents.48 Fig. 7 shows the size distributions of the spherical
micelles prepared from PS1140-b-PAA165 (Fig. 7a), PS170-b-PAA33
(Fig. 7b), and mixtures of these two micelle solutions with
increasing water contents in DMF–water (Fig. 7c–g).21,48 The
mixtures were stirred for one day for all runs, thus the studies were
isochronal. It is obvious that when the water content is less than
6 wt%, the mobility of polymer chains is high; size redistribution
occurs (Fig. 7c and d). Size hybridization can occur either
by polymer chain exchange or by a collisional mechanism
involving micelle coalescence and breakup of the larger
micelles, or possibly by both mechanisms. Above 7 wt%
water, bimodal distributions of the micelle sizes are seen
(Fig. 7e and f), indicating that chain mobility has slowed
down. At 11 wt% water content, the overall bimodal size
distribution (Fig. 7g) of the micelles is similar to the sum of the size
distributions of the two micelle solutions (Fig. 7a and b). This
similarity shows that whatever size hybridization mechanisms are
involved, they have become negligible on a time scale of one day,
and the micelle structures are frozen. The dynamics of size
hybridization decrease rapidly with increasing water content,
accompanying the decreases in both the CMC and the degree of
swelling of the micelle cores. Size hybridization among vesicles
will be discussed in Section 4.3.1.
3.4.3. Kinetics versus thermodynamics. When the content of
the common solvent and the mobility of polymer chains are
sufficiently high, the change of Nagg and the morphological
transitions can be faster than the changes of water content. Under
such circumstances, the morphologies and their transitions are
basically under thermodynamic control. The thermodynamically
controlled morphologies are kinetically frozen at high water contents
during sample preparations under most experimental conditions, e.g.
those involved in microscopy. On the other hand, if the
aggregates become kinetically frozen at high enough water
contents, thermodynamic equilibrium is unreachable over the
experimental time scale, the morphological characteristics of the
aggregates reflect the thermodynamics at the water content where
the structures become frozen.
Fig. 8 shows the relative importance of kinetics versus
thermodynamics in the formation of PS190-b-PAA20 aggregates in
DMF–water mixtures, as functions of water content and
experimental time.38 The slope of line A represents the rate of
water addition; the lower the rate, the smaller the slope. The water
content axis starts from 3.5 wt% because micellization starts
roughly at this point for the copolymer concentration range
(1.0–3.5 wt%) used in this example. Curve B represents
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Fig. 7 Size distribution of the spherical micelles made from PS1140-b-
PAA165 (a), PS170-b-PAA33 (b), and mixtures of the two separate micelle
solutions with different water contents in DMF–water (c–g). The numbers
near each peak are the average diameters with the standard deviations in
parentheses for each size distribution.21 Reproduced with permission from
ref. 21.
approximately the relationship between the water content and the
time needed for the system to reach thermodynamic equilibrium.
Below B5.5 wt% water content, the dynamics of aggregation
and/or structural rearrangement are faster than the rate of water
addition, so the formation of the aggregates occurs under
thermodynamic control. At B5.5 wt% water content, these two
rates become very close (intersection C); note that decreasing
the rate of water addition can raise the water content at the point
of intersection. If water addition is stopped at this point, the
system can establish a thermodynamic equilibrium rapidly. When
water addition resumes, the morpho- logies that reflect the
thermodynamics at 5.5 wt% water content can be easily frozen
because the overall kinetic processes become slower than the rate of
water addition. If the water addition is stopped at 6.5 wt%, although
the kinetics has slowed significantly, thermodynamic equilibrium is
still reachable after a certain waiting period (indicated by the
intersection of line D and curve B).
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Fig. 8 Schematic drawing of kinetics and thermodynamics of
morphological transitions vs. the water content.38 Reproduced with
permission from ref. 38.
Finally, if water addition is stopped at 7.5 wt% or more,
because the kinetics become extremely slow, thermodynamic
equilibrium becomes unachievable even over a time period of
weeks (line E in Fig. 8 does not intersect with curve B over that
time scale). Thus, one can understand why some morphologies
are under thermodynamic control while others are determined by
kinetics.
It should be mentioned that the window of water contents for
the dynamic equilibrium (5–9 wt% in Fig. 7) or the thermo-
dynamic equilibrium (3.5–7.5 wt% in Fig. 8) of PS-b-PAA
aggregates in DMF–water is narrow. The width of the window
depends on the copolymer composition, concentration, the nature of
the common solvent, temperature, and under conditions of kinetic
control, even the rate of water addition. For instance, if the common
solvent is changed from DMF to dioxane, the window can be
much broader.49 Besides, as the PS block length of the
copolymer increases, the window not only narrows, but also shifts to
a region of lower water contents.48,49
3.4.4. Other aspects related to thermodynamics and kinetics.
Intermediate structures can be kinetically trapped in the course of
the morphological transitions. For example, lamellae with rods
extending from the edge are a trapped intermediate structure,
probably formed during a rod-to-lamella transition.38
Intermediate structures can provide useful information on the
processes of self-assembly and the mechanisms of morphological
changes. For instance, open lamellae trapped in the process of the
rod-to-vesicle transition revealed that the process includes two
consecutive steps; the first is a rod-to-lamella transition, while
the second involves the closing of the open lamellae to closed
vesicles, which is slower than the first step.53 The closing of lamellae
to vesicles suggests that the rim-capping energy of lamellae is
larger than the curvature energy. Therefore, a closed vesicle is
more thermodynamically favorable than an open lamellar
structure.53 A similar mechanism applies to the formation of
hoops through the jointing of the two hemispherical ends of
cylindrical micelles.43
Coexistence of different morphologies is often observed in
BCP self-assembly in solution. Three possibilities can be considered.
First, the coexistence may be a true thermodynamic phenomenon,
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and different morphologies may coexist depending on the free
energy difference between them.49 Second, it is possible that during
water addition, stability boundaries for various morphologies are
crossed, or the aggregates of different morphologies are frozen
within a narrow but different range of water contents.38 Finally,
coexistence can also be ascribed to the effect of polydispersity in
block lengths of copolymers. Coexistence of blocks of different
lengths may generate different morphologies in the same
solution.54
3.5. ‘‘Permanent’’ morphologies
Independent of whether BCP aggregates are thermodynamically
stable or kinetically frozen, their morphologies may be deformed or
changed to other morphologies by changes in some external
factors, e.g. temperature or other relevant variables. Therefore, for
some applications that require robust and stabilized structures,
strategies were developed55 for the preparation of
‘‘permanent’’ aggregates. Two typical techniques have been
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frequently applied. One involves first the formation of aggre-
gates, and then the addition of crosslinking agents that can
crosslink specific regions of the aggregates. For example,
Wooley and co-workers prepared so-called shell-cross-linked
‘‘knedel’’-like (SCK) particles by crosslinking the PAA corona
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of PS-b-PAA spherical micelles with diamino linkers, e.g. diamino
oligo(ethylene glycol).56 Another method starts with preparation
of aggregates with BCPs containing self-crosslinkable groups, and
then induces crosslinking of these groups. For instance, Liu and
co-workers used polyisoprene-block-poly(2-cinnamoyloxyethyl
methacrylate)-block-poly(tert-butyl acrylate) (PI-b-PCEMA-b-
PtBA), to form nanofibers with a PCEMA layer between a PtBA
corona and a PI core; crosslinking of the double bonds in the
PCEMA blocks upon UV irradiation produced permanent
nanofibers with a crosslinked PCEMA layer.57 Du et al.
prepared vesicles with PEO-block-poly(3-(trimethoxysilyl)propyl
methacrylate) (PEO-b-PTMSPMA), in which the vesicle walls
consist of PTMSPMA while PEO forms the coronas; hydrolysis
of the –Si(OCH3)3 groups to –Si(OH3)3 and the subsequent
polycondensation of –Si(OH3)3 generates Si–O–Si networks
in the vesicle walls, which ‘‘lock’’ the morphology.58
3.6. Theoretical studies
Although a large number of experimental studies have been
conducted on BCP self-assembly in solution, only a few
theoretical studies have been published, probably because of
the complexity of the field. Some mechanisms of aggregate
formation or of morphological transitions in dilute solution were
treated theoretically. For example, Izzo and Marques published a
theoretical study dealing with aggregation of diblocks in a one-
component selective solvent as a function of the copolymer
composition. A mean-field approach was utilized, which showed that
a morphological transition from spheres to cylinders and to
lamellae may occur as the corona-forming block length
decreases.59 The factors that affect the aggregate morphology
are considered to arise mainly from the same three
contributions addressed in Section 3.3. Rubinstein and co-workers
performed theoretical studies on self-assembly of neutral (non-
ionic) diblock copolymers in selective solvents.60
They demonstrated that the sphere–cylinder–lamella transitions
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can occur for crew-cut aggregates, and the transitions are
governed by the same three contributions. This theoretical
study is supported by experiments on PS-block-polyisoprene (PS-
b-PI) copolymers in several selective organic solvents.61
4. Block copolymer vesicles
BCP vesicles, or polymersomes, are hollow spheres typically
with a hydrophobic wall and hydrophilic internal and external
coronas. Since 1995, BCP vesicles have attracted much attention
not only because of academic interest, but also in view of their
potential applications. Over 1800 papers, including many recent
reviews,42,62–66 have been published on this topic according to
statistics from the Web of Science. The remainder of this article
focuses on some introductory aspects of BCP vesicles, including
physicochemical properties, thermodynamic stabilization, morpho-
logical control, and several potential applications.
4.1. Physicochemical properties
BCPs can be considered as ‘‘super’’ amphiphiles because they
have molecular weights up to several orders of magnitude
higher than those of small-molecule amphiphiles, e.g. the
phospholipids. The hydrophobic polymer chains in vesicle
walls exhibit many properties typical of noncrystalline polymers in
bulk or thin films, and such behaviour as coil interpenetra- tion
and entanglement of the copolymer chains in vesicle walls
has been confirmed for vesicles formed from diblocks such
as PBO-b-PEO.67 BCP vesicles, therefore, are more robust,
more stable, and generally have improved mechanical
properties,40,68–70 compared to the lipid-based vesicles, namely
the liposomes. The higher molecular weight of BCPs leads to
increases in wall thickness69 and in coil interpenetration in the
wall, which, in turn, are accompanied by an increase in bending
rigidity of the vesicles.70 Some elastic properties of the
membrane of BCP vesicles have been shown to be independent of
molecular weight and similar to those of liposomes;40,69 however,
BCP vesicles can undergo higher tension and area strain before
rupture. Finally, compared to liposomes, the membrane fluidity
and permeability of BCP vesicles decrease as the molecular
weight increases.40,71 The diffusion coefficients of polymeric
membranes are at least one order of magnitude lower than those
of lipid membranes (D B 1 mm2 s—1).71
4.2. Thermodynamic stabilization
In liposomes, the closing of the vesicles (from open lamellae) is
subject to a bending modulus; however, in BCP vesicles, the
existence of a thermodynamic curvature stabilization mechanism has
been demonstrated. The study utilized PS-b-PAA vesicles. The
curvature stabilization is based on the polydispersity of the PAA
coronal chains. It was suggested that the longer PAA chains
were preferentially segregated to the outside of the vesicles and the
shorter ones to the inside. Thus, the repulsions of the PAA
chains on the outside are stronger than those on the inside,
which stabilizes the curvature. To prove this segrega- tion
hypothesis, Luo and Eisenberg attached pyrene molecules to the
junction points of several PS-b-PAA diblocks with different
PAA block lengths (Fig. 9).52,72 Subsequently, by co-
assembly of fluorescently labelled diblocks with shorter
PAA chains and unlabelled diblocks with longer PAA chains,
Chem. Soc. Rev., 2012, 41, 5969–5985
5979

they found that most of the shorter PAA chains were on the
inside of the vesicles because only a small fraction of pyrene
was quenched by Tl+, which was added to the solution after
vesicle formation.72 Fluorescence in similarly labelled copolymers
with long PAA segments was almost completely quenched
because the fluorescent labels were on the outside and thus
accessible to the quencher. The preferential segregation was shown
to be size-dependent: the larger the vesicles, the lower the degree
of segregation, and reversible in response to size changes.73
Preferential segregation also explains the decrease in vesicle sizes
with increasing polydispersity of the PAA blocks of PS-b-PAA
copolymers.54
4.3. Morphological control
This subsection discusses several aspects of morphological
control in vesicles, including size, wall thickness, deformation,
and surface topology.
Published on 09 July 2012 on http://pubs.rsc.org | doi:10.1039/C2CS35115C
4.3.1. Vesicle size. The average dimension of BCP vesicles
is affected greatly by the method of preparation. For instance, it
has been found that electroformation techniques usually lead
to micron-size vesicles, while film rehydration without or with
vigorous stirring, sonication, or extrusion leads to vesicles which
can be one to two order of magnitude smaller.42,74
Studies have shown that vesicle formation by film rehydration is
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dictated by the mutual diffusion between the selective
solvent (usually water) and the BCP film. The vesicle sizes
are inversely proportional to the concentration gradient
between the water front diffusing into copolymer and the
copolymer front advancing into the water; high and constant
concentration gradients result in vesicles on the order of
nanometers, while mild diffusion conditions yield vesicles of tens
of micrometers.74
The sizes of PS-b-PAA vesicles, prepared by the co-solvent
method, are in the range of tens of nanometers to several
micrometers, and can be controlled by changing the water
content.73 The increase in the water content causes an increase in
the interfacial energy between the wall and the solvent
outside the wall. In response to the increase in the interfacial
energy, there is an increase in the vesicle sizes to decrease the
total interfacial area. As the water content decreases, the
vesicle sizes also decrease. Fig. 10a illustrates the size changes
resulting from changes in the water content.40,73 Fusion and
fission mechanisms are involved in the increase and decrease of
vesicle sizes. The proposed mechanisms are shown in
Fig. 10b.40,73 The first fusion step involves the contact and
Fig. 9 Segregation in PS300-b-PAA44 vesicles. The quenched fraction
(F) of pyrene (Py) molecules increases with increasing the length of the
PAA blocks in the labeled PS-Py-b-PAA copolymers.52 Reproduced
with permission from ref. 52.
5980 Chem. Soc. Rev., 2012, 41, 5969–
5985
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adhesion of two vesicles. This is followed by coalescence and
the formation of a center wall between the two vesicles. The
wall is then destabilized and retracted into the outer wall. Finally,
there is a smoothing of the outer wall to form uniform vesicles.
The fission process involves the elongation of the vesicle,
followed by the formation of an internal waist and the narrowing
of the external waist. At this point, a connection between the two
compartments can still be seen. Eventually, complete separation
is achieved.
Vesicle sizes can be controlled not only by the water content
but also by several other factors, such as copolymer composi- tion,
common solvent composition, and presence of acids, bases,
or salts. For PS-b-PAA vesicles, the average size changes inversely
with the PAA block content in the copolymer.75,76
Increasing THF content in the THF–dioxane mixtures results in the
formation of smaller vesicles.75 Addition of HCl or NaCl yields
larger vesicles by reducing the electrostatic repulsion among
corona chains, while adding NaOH produces smaller vesicles by
increasing the electrostatic repulsion.75 These size control
mechanisms are governed by the three contributions addressed in
Section 3.3, and are not discussed again here. Finally, it is worth
noting that large vesicles generally have a relatively broad size
distribution, while small vesicles have a narrow one. This size
distribution behaviour arises because the interfacial area (and
thus also the total interfacial energy) of small vesicles is
strongly size-dependent, which induces
Fig. 10 (a) Reversibility of vesicle sizes in response to increasing or
decreasing the water content for PS300-b-PAA44 vesicles in a THF–
dioxane (44/56 w/w) mixture.40 (b) Fusion and fission of vesi- cles.40 In
the fusion process, Fu1: contact and adhesion; Fu2: coales- cence and
formation of center wall; Fu3: destabilization of center wall; Fu4:
asymmetric detachment of center wall; Fu5: retraction of center wall
into outer wall; Fu6: formation of uniform outer wall. In the fission
course, Fi1: spherical vesicle; Fi2: elongation; Fi3: internal waist
formation; Fi4: narrowing of external waist; Fi5: complete separation.
Pictures are reproduced with permission from ref. 40.
This journal is c The Royal Society of Chemistry
2012

a narrow size distribution; the interfacial area of large vesicles,
by contrast, is weakly size-dependent and therefore a wide size
distribution is observed.73,76
4.3.2. Wall thickness. The wall thickness of BCP vesicles is a
function of the molecular weight of the vesicle-forming
copolymers, especially the wall-forming blocks.76 Fig. 11a
shows that the average wall thickness of the vesicles made
from the PAA47-b-PSn series increases linearly with the square
root of the degree of polymerization (DP) of the PS block
PS ). When NPS itself is plotted against the average wall
thickness, a linear fit is also obtained (Fig. 11b). The linearity of
the two plots is due to the fact that only a narrow wall
1/2
(Nthickness range is considered. As mentioned in eqn (2) in
Section 3.3.1, the diameter of spherical micelles prepared from
PS-b-PAA copolymers can be correlated with N0.4N—0.15,
Published on 09 July 2012 on http://pubs.rsc.org | doi:10.1039/C2CS35115C
PS PAA
where NPAA is the DP of the PAA block. It was found
that the equation also applies to the average wall thickness
of PS-b-PAA vesicles, as shown in Fig. 11c. Clearly, the wall
thickness is a function of both block lengths. The higher slope
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obtained for the vesicles than that for the spherical0.4micelles
N—0.15
indicates that the wall thickness is more sensitive to N PS .
PAA
This relation is empirical, other scaling67,69
relationships have also
been found for vesicle wall thickness.
The relationship between wall thickness and vesicle size
is also noteworthy. Ma and Eisenberg found that the
wall thickness decreases as the size of PS-b-PAA vesicles
decreases.77 Two factors may contribute to the wall thickness
versus size behaviour. One is the segregation of shorter corona
chains to the interior of vesicles; the other is the decrease in
wall thickness to increase the area per corona chain, thus
relieving the interior corona repulsion.
Fig. 11 Average wall thickness of vesicles made from the PAA47-b-PSn
diblock series versus (a) N0.5
PS, and (b) N PS . (c) Average wall thickness of
vesicles (open circles) and the average diameter of micelles (filled circles)
versus N0.4N—0.15
PS PAA for different PS-b-PAA copolymers. NPS and NPAA
are the degrees of polymerization of PS and PAA, respectively.76
Reproduced with permission from ref. 76.
This journal is c The Royal Society of Chemistry
2012
View Online
4.3.3. Deformation of vesicles. BCP vesicles are frequently
observed as deformed 78hollow spheres; one often 79sees slight
indentations (Fig. 12a), stomatocytes (Fig. 12b), or even
fully collapsed ‘‘kippah’’ structures (Fig. 12c).78 The deforma-
tion is caused by pressure difference between the interior and
the exterior of vesicles during preparation. As described in
Section 3.2 for aggregate preparation using the co-solvent
method, vesicles can be formed above CWC during water
addition to the copolymer solution. At elevated water
contents, especially during quenching, the difference in water
concentration between the interior and the exterior of the
vesicles drives diffusion of the solvent to the exterior and that
of the water to the interior. Since the rate of diffusion of the
organic solvent through the hydrophobic wall is considerably
faster than that of water diffusion, a negative pressure is
generated inside the vesicles, which leads to indentation
or sometimes stomatocyte formation.78,79 By the time the
pressure has equalized, the Tg of the wall (e.g. PS) has risen
sufficiently, which ‘‘freezes’’ the deformed shapes. The specifics
of vesicle deformation can be influenced by, for example,
copolymer composition, common solvent, and water content.79
It is interesting to note that small vesicles are usually seen as
undeformed hollow spheres, since the volume of the wall in
small vesicles occupies a major portion of the
total vesicle volume, and the negative forces generated during
water addition are insufficient to deform the spherical shape of
the small vesicles.78
Kippah vesicles can be obtained by freeze-drying vesicle
solutions and subsequent rehydration in water, or by drying
the vesicle solutions under vacuum without freezing. When the
kippah vesicles are lying on a surface with their convex side up
or down, they appear to have no deformation under TEM
observation without tilting, but with an average wall thickness
twice as large as that of the ‘‘normal’’ vesicles prepared from
the same copolymer. The cause of the kippah vesicle formation is
postulated to be interplay of the relative flexibility of the vesicle
wall, interfacial tension, and pressure gradients.78
4.3.4. Vesicle surface topology. Vesicle surfaces can be
modified by introducing domains of different compositions. This
can be achieved through mixing different vesicle-forming
copolymers to induce vesicle-confined polymer–polymer phase
separation. Fig. 13 shows different surface topologies of
vesicles identified as a function of the PB-b-PAA/PB-b-PEO
ratio. Divalent cations, such as Ca2+, induce the phase separation
through crossbridging polyanionic amphiphiles, which thereby
Fig. 12 Deformation of vesicles. (a) Slight indentations.78 (b) Stomato-
79
cytes. (c) Fully collapsed ‘‘kippah’’ structure; kippah is a Hebrew word
for both dome and the traditional skullcap.78 Scale bar: 200 nm. Pictures
are reproduced with permission from ref. 78 and 79.
Chem. Soc. Rev., 2012, 41, 5969–5985
5981
 View Online

applications such as delivery and release of drugs or bioactive

agents, diagnostic imaging, nanoreactors, etc. Several examples
are given below.

4.4.1. Delivery and release of drugs or bioactive agents.

Fig. 13 Cation-induced phase segregation on vesicle surfaces induced by
mixing charged PB-b-PAA and neutral, fluorescently (red) labeled PB-b-
PEO copolymers at different ratios, and imaged by confocal microscopy
during micropipette aspiration.80 Scale bar: 2 mm. Pictures are reproduced
with permission from ref. 80.
Published on 09 July 2012 on http://pubs.rsc.org | doi:10.1039/C2CS35115C
Vesicles loaded with anticancer drugs have been used in
studies of tumour therapy in animals,24 and combination therapy,
using vesicles containing both hydrophilic and hydro- phobic
antitumor drugs, has been found to enhance the therapeutic
effects.86 Discher and colleagues used vesicles made from a
mixture of biocompatible PB-b-PEO and biodegradable PLA-b-
PEO for simultaneous delivery of two anticancer drugs:
hydrophilic doxorubicin (DOX) was encapsulated in the cavity,
while hydrophobic paclitaxel (TAX) was embedded in the
wall.86 In vivo studies with solid tumours in a mouse showed a
two-fold increase in tumour cell death after five days when DOX
and TAX were released from the vesicles upon PLA degradation,
leading to a more effective and sustainable tumour shrinkage,
compared to injections of the free drugs.

Nucleic acids (DNA or RNA) or proteins are usually too

demix from neutral amphiphiles and form spots or rafts on
the vesicle sufaces.80 Similar surface topologies were also
observed in other systems, such as in the polyisobutylene-
block-PEO (PIB-b-PEO)/1,2-dipalmitoyl-sn-glycero-3-phospho-
choline (DPPC lipid) system.81
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polar to enter cells directly and hence require some carriers
for cellular delivery.98 Vesicles show unique capabilities in
delivery of such bioactive agents, which are promising in
gene or protein therapies.98,99 DNA encapsulation has been

4.4. Potential applications of functional vesicles

Vesicles can be modified to include a range of desirable functions
which might make them useful in various technologies. Modifica-
tion of the coronas determines the surface characteristics of the
vesicles and hence their interactions with the environment. Vesicles
with PEO as coronas are biocompatible without interacting
with the immune system, due to the very limited interaction of
the hydrated and non-ionic PEO blocks with proteins. This so-
called ‘‘stealth’’ ability increases the circulation time of the
vesicles in biological environments.82 Furthermore, function-
alities can be incorporated into the vesicles by conjugating
specific ligands to the hydrophilic blocks in the coronas.83,84
Conjugating biotin to the coronas enables the decoration of
vesicle surfaces with avidinylated ligands or nanoparticles,
through the strong affinity between biotin and avidin.83
Attaching antibodies onto vesicle surfaces allows the targeted
delivery of the vesicles to specific cells.85 Modification of
vesicle walls permits the incorporation of hydrophobic mole-
cules,86,87 nanoparticles,88–91 or proteins,66,92,93 among others.
The wall incorporation can be accompanied by encapsulation of
hydrophilic compounds within the vesicle cavity to produce dual
purpose systems.66,86,91–93
Stimuli-responsiveness provides vesicles capabilities of
controlled release of cargo species in the cavity. The stimuli-
responsiveness can be introduced by incorporating stimuli-
sensitive blocks or groups into the vesicle-forming copolymers.
These blocks or groups can alter their water solubility
or molecular conformation in response to external stimuli,
thereby leading to disassembly, morphological transition, or
collapse of the vesicles. Based on the responsiveness of the
incorporated blocks or groups, the stimuli-responsive vesicles
mainly include pH-,94 thermo-,95 redox-,96 and photo-sensitive97
systems. The relevant studies are covered by several recent
reviews,62–64 and are not described in more detail here. Fig. 14 (a) Controlled localization of nanoparticles (NPs) in the
The above-mentioned types of functionalization and possibility to central portion of vesicle wall: TEM image (left) and the schematic
include stimuli-responsiveness, coupled with the intrinsic robust- ness diagram (right). The strategy involves stabilizing the NPs with diblocks
and the morphology control, make BCP vesicles promising in (e.g. PS-b-PEO) of a similar composition to that of the vesicle-forming diblocks
(e.g. PS-b-PEO or PS-b-PAA), followed by preparing the vesicles in the
presence of the copolymer-coated NPs in solution.89 (b) Near-infrared (NIR)-
emissive vesicles. (b1) Schematic representation of PB-b-PEO vesicle with
hydrophobic multiporphyrin-based fluorophores (PZn, red) in the wall;
(b2) chemical structures of PZn2–PZn5; (b3) scanning fluorescence confocal
microscope image of the NIR-emissive vesicles.87 Pictures are reproduced
with permission from ref. 87 and 89.

5982 Chem. Soc. Rev., 2012, 41, 5969– This journal is c The Royal Society of Chemistry
5985 2012

achieved within pH-responsive vesicles formed by poly(2-
(methacryloyloxy)ethyl phosphorylcholine)-block-poly(2-
(diisopropylamino)ethyl methacrylate) (PMPC-b-PDPA), as
well as its intracellular delivery in primary human dermal
fibroblast cells and Chinese hamster ovary cells.99 Compared to
other nucleic acid carriers, e.g. viruses and cationic lipids or
polymers, the PMPC-b-PDPA vesicles can encapsulate DNA
with a much higher transfection efficiency while affecting cell
viability only modestly. In addition, the biocompatible PMPC
coronas increase the in vivo circulation time of the vesicles.
4.4.2. Diagnostic imaging. Self-assembly techniques have
allowed the encapsulation of diagnostic probes, e.g. fluoro-
phores or nanoparticles,88–91 within vesicle walls, and even
87
the precise position-controlled incorporation has been
achieved (Fig. 14a).89 Embedding diagnostic probes in vesicle
walls can solve many problems encountered in the utilization of
probes in biological environments, such as increasing their water
Published on 09 July 2012 on http://pubs.rsc.org | doi:10.1039/C2CS35115C
solubility and detection sensitivity, while preventing their
toxicity. These features make vesicles a powerful tool for
diagnostic imaging. For example, near-infrared (NIR)-emissive
vesicles have been produced by incorporating multiporphyrin-
based fluorophores within the walls of PB-b-PEO vesicles
(Fig. 14b).87 It has been demonstrated that the total fluores- cence
emitted from these vesicles produces a localized optical signal of
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sufficient intensity to penetrate through the dense tumor tissue of
a live animal. Clustering of magnetic nano- particles (e.g. g-
Fe2O3) inside vesicle walls results in high particle loading
and a considerable increase in detection sensitivity in magnetic
resonance imaging (MRI).91 The drug- loaded vesicles
containing magnetic nanoparticles in the wall
Fig. 15 Illustrations of enzymatic nanoreactor in the processing of the external non-fluorescent substrate into an internalized fluorescent
substrate (a),92 of ‘‘proteopolymersome’’ generation of ATP from ADP (b),93 and of nanoreactor with a controllable permeability based on a
selective dissolution of sugar-responsive copolymers (c).100 Pictures are reproduced with permission from ref. 92, 93 and 100.
This journal is c The Royal Society of Chemistry
2012
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can be directed to appropriate locations by magnetic fields.
Drug release can be controlled through an oscillating magnetic
field which produces local hyperthermia in the wall.91
4.4.3. Nanoreactors. Nanoreactors can be produced from
BCP vesicles, taking advantage of the ability of vesicles to
compartmentalize different solution environments, coupled with
selective wall permeability, if required.42,66 In a study from
Meier, Hunziker and collaborators (Fig. 15a),92 a pH-
sensitive enzyme (acid phosphotase) was encapsulated within
vesicles containing active channel membrane proteins. This
enzyme proved to be catalytically active within the vesicle lumen,
converting a soluble non-fluorescent substrate into an insoluble
fluorescent product. These vesicles were only active at
low pH with incorporation of the protein channels, which
allowed diffusion of the soluble non-fluorescent substrate
through the protein channels to the enzyme within the cavities.
Montemagno and co-workers developed ‘‘proteo- polymersomes’’
by incorporation of two types of protein channels, namely
adenosine triphosphate (ATP) synthase (F0–F1) and
bacteriorhodopsin (BR), into the walls (Fig. 15b).93
Through coupled reactions involving both types of protein
channels upon light irradiation, adenosine diphosphate (ADP) was
converted successfully to ATP, a biological fuel. Another
example involves sugar-responsive vesicles developed by van Hest
and colleagues.100 As Fig. 15c shows, PEO-b-poly(styrene
boronic acid) (PEO-b-PSBA) copolymers become water-soluble
upon increasing solution pH and concentration of mono-
saccharides such as D-glucose, thus the PEO-b-PSBA domains in
the vesicles generated by co-assembly of PEO-b-PSBA and PEO-
b-PS dissolve in aqueous media, creating pores in the
Chem. Soc. Rev., 2012, 41, 5969–5985
5983

vesicle walls. Thereupon the encapsulated enzyme (CALB)
can catalyze the reaction for the substrates which penetrate
into the cavities through the pores. The wall permeability
can be controlled by adjusting the ratio of PEO-b-PSBA to PEO-
b-PS.
The development of polymer vesicles as biomimetic materials
has also been an active topic in vesicle research.42,66 Exciting
studies have reported the potential applications of vesicles as
artificial organelles with possibilities for the treatment of genetic
diseases.66 With advances of polymer vesicles towards new
biomimetic structures with complex functions, the generation of
polymer-based cells is a distinct possibility.
5. Summary
This paper reviews some fundamental principles of BCP self-
assembly in bulk and in solution. Experimental and theoretical
studies have demonstrated that BCPs in bulk can microphase
separate into a variety of morphologies, including spheres,
Published on 09 July 2012 on http://pubs.rsc.org | doi:10.1039/C2CS35115C
cylinders, bicontinuous structures, lamellae, etc. The morpho-
logies are determined by the copolymer composition, the
total degree of polymerization, and the w-parameters. BCP
self-assembly in solution shows a higher level of complexity than
in bulk, and can yield aggregates of various morpho- logies,
including some of those observed in bulk in addition to a number
of others. Based on three contributions to the free energy, i.e.
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the degree of stretching of the core-forming blocks, the
interfacial tension between the hydrophobic core and the
solvent outside the core, and the repulsive interactions among
corona-forming chains, the morphologies of thermo- dynamically
stable aggregates can be influenced by, among others, the
copolymer composition and concentration, the content of
precipitant (usually water), the nature of the common
solvent, and the presence of additives.
Vesicles represent a most interesting morphology obtained in
solution. The macromolecular nature imparts to BCP vesicles, or
polymersomes, an intrinsic stability and durability.
Technical advances in vesicle self-assembly have made it
possible to design a wide range of BCP vesicles, and have also
offered effective control of morphology, surface chemistry,
and wall incorporation, as well as opportunities for introduc-
tion of environmental responsiveness. These features make
vesicles promising candidates in applications including delivery
and release of drugs or bioactive agents, diagnostic imaging,
nanoreactors, biomimetic materials, and so forth.
The level of complexity of the present BCP assembly
systems is still much lower than that shown by nature,
e.g. the cell or virus systems. The need for increased complexity
of self-assembled structures to meet the requirements of
functional or biomimetic materials is advancing the field of BCP
self-assembly dramatically. The challenges involve exploration
of new controllable assembly strategies, deeper understanding of
structure-property relationships to allow prediction of the
performance of a given structure, formulation of more systematic
theories especially for ionic systems, and enhancement of
interdisciplinary collaboration. BCP self-assembly promises to
become a powerful tool for the fabrication of functional or
biomimetic materials with tailored structures, functionalities, and
applications.
5984 Chem. Soc. Rev., 2012, 41, 5969–
5985
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Acknowledgements
The authors thank the Natural Science and Engineering
Research Council of Canada (NSERC) for financial supports.
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