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Synergism among Polydispersed Amphiphilic Block Copolymers

Leading to Spontaneous Physical Hydrogelation upon Heating
Shuquan Cui, Liang Chen, Lin Yu, and Jiandong Ding*
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ABSTRACT: Molecular weight distribution (MWD) is an

intrinsic character of synthetic polymers and influences many
properties of polymeric materials. In this work, the effects of MWD
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on thermogelation of an amphiphilic block copolymer in water

were studied mainly by a dynamic Monte Carlo simulation. Molar
mass dispersity D̵ M, defined as weight-average molecular weight
Mw over number-average molecular weight Mn, was found to be a
key molecular parameter to influence the existence of sol−gel
transition or the phase transition temperature if gellable. We also
demonstrated that such a D̵ M effect in a selective solvent was
closely related to the formation of micelles, particularly to the
thickness of micellar corona. We revealed that the thermogelation of the polydispersed macromolecules resulted from the synergism
among chains of different lengths leading to a percolated network of semibald micelles. The effect of D̵ M of hydrophobic blocks and
that of hydrophilic blocks on thermogelation were compared and analyzed. By combining the simulation results with the previous
experimental results about triblock copolymer PLGA−PEG−PLGA in water [PEG: poly(ethylene glycol); PLGA: poly(lactide-co-
glycolide)], we proposed a D̵ M−Mw diagram for design of the thermogellable copolymers. This mechanism study deepens the
understanding of thermogels and is helpful for guiding the molecular engineering of such a kind of soft matter in biomedical fields as
an injectable hydrogel.

■ INTRODUCTION
Most synthetic polymers and some natural macromolecules are
composed of a series of molecular species covering a broad
range of sizes. Polymers are molecular mixtures instead of
chemical individuals in the customary sense.1 The chains in a
polymer system are of molecular weight distribution (MWD).
The most common molecular parameter to describe MWD is
molar mass dispersity (D̵ M), which is defined as the ratio of the
weight-average molecular weight (Mw) to the number-average
molecular weight (Mn), namely, D̵ M = Mw/Mn. MWD is an
intrinsic character of synthetic polymers and is almost
inevitable in practice. It plays an important role in many
aspects of polymeric materials, from mechanical properties to
nearly all aspects of phase behaviors.2−5
Compared to homopolymers, copolymers in selective
solvents exhibit more complicated effects of MWD owing to
self-assembly and a multiscale supermolecular structure. Jiang’s
group found that D̵ M could change the assembly structure of
copolymers under various confined conditions, such as two-
parallel-wall, circle boundary, spherical space, or cylindrical
space.6 After combining the experimental results with the self-
consistent field theory calculations, Hillmyer and Bates et al.
proposed that D̵ M could be used to stabilize the core−shell
gyroid morphology.7 Eisenberg’s group studied the effects of
the block length distribution of polystyrene-b-poly(acrylic
acid) on vesicles in a selective solvent and elucidated that the
vesicle size decreased with the increase of the poly(acrylic
acid) block dispersity.8 Some other groups also examined well
the D̵ M effects on the micelle formation of amphiphilic
copolymers.9,10
Previously, our group reported the effects of D̵ M on
thermogelation of an amphiphilic block copolymer composed
of a polyether such as poly(ethylene glycol) (PEG) and an
aliphatic polyester such as poly(D,L-lactide-co-glycolide)
(PLGA), in particular, poly(D,L-lactide-co-glycolide)-b-poly-
(ethylene glycol)-b-poly(D,L-lactide-co-glycolide) (PLGA−
PEG−PLGA) in water.11 In our experiments, the copolymer
with a very small D̵ M under the examined average molecular
weight (MW) and block ratio was poorly soluble and even
insoluble in water. With increasing D̵ M, the solubility became
better and the copolymers self-assembled into micelles at low
temperatures; then upon heating, this copolymer aqueous
solution underwent a sol−gel transition and transformed into a
macroscopic hydrogel.
Received: June 18, 2020
Revised: August 7, 2020

© XXXX American Chemical Society https://dx.doi.org/10.1021/acs.macromol.0c01430

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Figure 1. Schematic of the thermogelling process of PLGA−PEG−PLGA under the effect of D̵ M. The path to modulate the change of D̵ M in this
scheme is by introducing the dispersity of hydrophobic blocks.

Figure 2. Simulation process and parameters. (A) Schematic of the multichain simulated system. Here, for clarity, the lattice number is shown
much less than that in the real modeling; (B) relationship between energy parameters and temperature set in simulations; (C) paths to modulate
the change of D̵ M in this work.

The findings of the MWD effects enrich the understanding
of the PEG/polyester copolymer thermogela promising
material in medical fields.12−18 Some PEG/polyester copoly-
mers exhibit a sol−gel transition upon heating in water. The
material system with a gelation temperature (Tgel) a bit lower
than body temperature affords an ideal injectable thermogel
potentially used in clinics. At low temperatures, this copolymer
aqueous system is a flowing sol and can be easily mixed with
drugs or cells; once injected into the body, the system can,
under the stimulus of body temperature, spontaneously
transform to a semisolid hydrogel as a carrier for the
encapsulated objects. Combined with other excellent proper-
ties, such as adjustable biodegradability, good biocompatibility,
controllable thermogellability, and in vivo maintenance time,
this kind of new materials is promising in many aspects, such as
delivery carriers,19−21 tissue engineering,22,23 prevention of
postoperative adhesion,24,25 and so on.26 Thermogelling
behaviors of PEG/polyester copolymers are influenced by
several factors, from molecular weight (MW) or block
length,27−29 end groups30 to some additive agents.31,32 Our
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previous experimental research revealed that the D̵ M could also
affect the thermogelling behaviors significantly.11
While we have found the D̵ M effects on thermogelation in
experiments, the internal mechanism is still unknown. In this
work, a dynamic Monte Carlo simulation was employed to
investigate the mechanism of the D̵ M effects on thermogela-
tion. Based on the experiments, the D̵ M of a PEG/polyester
copolymer is mainly determined by the synthesized polyester
block because the PEG block is usually generated by the PEG
initiator with a given D̵ M (PEG), namely, molar mass dispersity
of this block.14,33 If we use the same batch of PEG as the
synthetic initiator, the D̵ M contributed from the PEG block
remains a constant. Thus, in the present simulations, we mainly
investigated the effects of D̵ M from the polyester (or
hydrophobic block) on thermogelation, whereas the effects
of D̵ M from PEG (or relatively hydrophilic block) were also
simply examined. In order to compare with our previous
experimental studies, we employed ABA-type triblock copoly-
mers as model chains in our simulations. Here, A and B
represent the hydrophobic block (corresponding to the
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polyester block) and the hydrophilic block (corresponding to
the PEG block), respectively.
Our previous Monte Carlo simulations of monodispersed
block copolymers in a selective solvent have revealed that the
thermogel has a supermolecular structure of a percolated
micelle network with semibald micelles linked mainly by
hydrophobic channels34 and for ABA-type triblock copolymers
also auxiliary by hydrophilic bridges.35 The present paper is
focused on the examination of the MWD effects on the
thermogelation of amphiphilic block copolymers, as schemati-
cally presented in Figure 1. The introduction of appropriate
polydispersity can even enable an otherwise nongellable
copolymer (insoluble or always flowing in water upon heating)
exhibit a sol−gel transition upon heating; the parameter D̵ M
can also be used to modulate Tgel in the gellable systems.
This mechanism study is helpful for guiding the design of
thermogellable copolymers and thus for promoting the
application of this novel material class. Furthermore,
polydispersity is a universal character of synthetic polymers,
and thus, this fundamental investigation might be stimulating
to other systems containing polydispersed chains.
■
SIMULATION METHODS
Thermogelling behaviors of the polydispersed amphiphilic block
copolymers were investigated by a dynamic Monte Carlo simulation
for its high simulation efficiency and wide use in soft matter
fields.36−41 In our simulations, copolymer chains were coarse-grained
to model chains connected by a series of beads, as schematically
shown in Figure 2A. The mass of every bead was set to 1. Similar to a
Kuhn segment in polymer physics, one bead corresponds to a few
repeating units in a real copolymer chain. The modeled coarse-
grained chain is represented as AxByAx, where A and B refer to
hydrophobic and hydrophilic beads, respectively, and the subscripts
indicate the numbers of beads in the corresponding blocks. A coarse-
grained solvent was treated as a vacancy and represented by V.
Multiple self-avoiding chains were simulated in two-dimensional (2D)
square lattices, where a site was occupied by either a bead or a
vacancy (solvent).
In order to eliminate the finite size effect, the periodic boundary
condition was applied in both directions of the 2D lattice system. The
volume fraction φ of model chains in the lattice system was calculated
by
Nbead
φ=
L2 (1)
where Nbead represents the total number of the beads in the lattice
system and L2 is the lattice number. In this work, L = 128.
Microrelaxation in our simulations obeyed the Larson bond
fluctuation mode42 with a permitted bond length of 1 or 2 (in
the unit of the lattice size). The partial-reptation algorithm43,44 was
employed to promote the simulation efficiency (Figure S1). Besides,
Metropolis importance sampling45 was used to endow the simulation
process with a linear relation to the real physical process.46 In a
dynamic Monte Carlo simulation, time t is measured in the unit of the
Monte Carlo step (MCS). One MCS means the trial in which every
bead in the system has been randomly selected once on average.
Similar to the interactions between species in the real world, energy
parameters between different beads were set in simulations. Nearest-
neighbor and next-nearest-neighbor pairwise interactions between
beads were considered. Reduced energy εij*, where the subscripts i and
j represent the bead types, was input in the simulations. The
relationship between εij* and energy εij is
εij
εij* =
kBT (2)
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where kB is the Boltzmann constant and T is the Kelvin temperature.
In simulations, ε*ij < 0 means an attractive interaction between i and j
beads, whereas εij* > 0 means a repulsive interaction.
Hydrophobicity of the A bead required that the ε*AV in simulations
was set positive. Considering that miscibility between PEG and some
polyester was observed based on some reports,47,48 we set the ε*AB
negative. To simplify the simulation, both εAV * and εAB * were set
constants. In addition, ε*ij between the same species was set at zero.
The driving force for the evolution of the system with temperature
T was introduced by the relationship between ε*BV and T based on the
experimental phenomenon that the hydrophilicity of the PEG block
depends on temperature.49,50 The quantitative relationship between
εBV
* and T is derived as follows.
From the physical essence of the εBV * and its corresponding
Huggins parameter χ, the relation between these two parameters can
be written as
* ∼ χ − 0.5
εBV (3)
If ignoring the concentration effect, the χ is related to T as
b′
χ = a′ +
T (4)
Here, a′ and b′ are constants corresponding to the contributions of
the entropy and the enthalpy, respectively. Based on eqs 3 and 4, the
relation between ε*BV and T can be derived as
* ∼a+ b
εBV
T (5)
Here, a and b are constants dependent on the simulated system. In
water, PEG exhibits a property of lower critical solution temper-
ature;49 hence, the εBV
* should evolve from negative to positive. From
this point, a > 0 and b < 0. A quantitative relationship between εBV
*
and T after trial-and-error computer experiments was finally set as
* = 2.1 − 671
εBV
T (6)
The values of the energy parameters input in our simulations are
shown in Figure 2B.
In our simulations, two paths were employed to modulate D̵ M. Path
1 was by changing Mw but fixing Mn, and path 2 was by changing Mn
but fixing Mw. When D̵ M increases, path 1 is accompanied with the
increase of Mw under a given Mn, while path 2 is accompanied with
the decrease of Mn under a given Mw. In other words, the change
trend of D̵ M is not necessarily the same as that of MW in a path. Both
paths were examined in our simulations, as schematically shown in
Figure 2C. For convenience, the D̵ M achieved by path 1 was named
D̵ M (fixed Mn) and the D̵ M achieved by path 2 was named D̵ M (fixed
Mw).
To mimic a polydispersed system, model chains with different bead
numbers were placed into the lattices. Compared with the real
polydispersed systems, the consecutive distribution of the MW cannot
be achieved in such simulations because of the much less chain
number in simulated systems. Similar to some reports,6,51 here, the
D̵ M was modulated by changing the relative numbers of three types of
chains with different bead numbers. The default three model chains
were A2B8A2, A28B8A28, and A54B8A54, where A28B8A28 was the
standard starting point for changing D̵ M.
For convenience, we usually used P1, P2, and P3 to represent the
short (low MW) chain (A2B8A2), the medium (moderate MW) chain
(A28B8A28), and the long (high MW) chain (A54B8A54). In each
system modulated by path 1, we set N(P1) = N(P3), while in each
system modulated by path 2, we set M(P1) = M(P3). Here, N and M
are the total chain number and the total chain weight (bead number)
of the indicated species. Therefore, according to the lengths of the
three model chains, the predetermined D̵ M, and the volume fraction φ
(or the total beads in the 128 × 128 lattice system), the number of
each model chain could be determined. For systems with different
D̵ M, the chain parameters are presented in Figure S2.
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Figure 3. Effects of D̵ M (fixed Mw) on thermogelation. The path to modulate the change of D̵ M here is by introducing the dispersity of hydrophobic
blocks. (A) Snapshots of different states of the system with D̵ M = 2.2 (fixed Mw) and φ = 0.25. The temperatures corresponding to the states from
left to right are 5, 30, and 55 °C. The orange, red, and pink beads correspond to the hydrophobic beads of the P1 (short), P2 (medium), and P3
(long) model chains, and the light blue, dark blue, and blue beads correspond to the hydrophilic beads of these chains, respectively; (B) criteria of
the Tgel‑1 (or Tgel, transition temperature from sol to gel) and Tgel‑2 (transition temperature from gel-1 to gel-2). Gel-1 and gel-2 are two thermogel
substrates with different extents of the main cross-linking points (hydrophilic bridge or hydrophobic channel). The typical system is the same as the
system in (A); (C) criterion of the Tprecipitate. The typical system is the same as the system in (A); (D) T−φ state diagrams of indicated systems.
The red circle represents the Tgel and the gray circle represents the Tprecipitate; (E) transition temperatures of systems (φ = 0.25) with different D̵ M
(fixed Mw).

The relaxation process of the model chain is described in the

Supporting Information Methods. The general simulation process is
briefly introduced as follows: initially, a certain number of model
chains were put into the 2D lattice system according to the chain
models, preset D̵ M and φ; after sufficiently relaxed for 106 MCS at the
athermal state, where all reduced energies were set to zero, the
multiple self-avoiding chains were further relaxed at a predetermined
temperature based on eq 6; at each temperature, after relaxing for 5 ×
106 MCS to reach equilibrium, the statistics for thermodynamic
parameters were operated during the following 5 × 106 MCS. The
sampling interval was 103 MCS; thus, total 5000 time points were
sampled for the time average in a run. For the ensemble average, 10
independent runs were generally conducted.
The simulation code was written by the authors using Fortran and
run on a computer with a 3.0 GHz CPU.
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■ RESULTS
Simulated Thermogelling Behaviors of Polydispersed
Systems with Varied D̵ M under Fixed Mw. After model
chains being generated into the lattices and then randomized
for 106 MCS at the athermal state, the equilibrium state was
achieved with the corresponding parameters tending to be
stable. Then, the system was further relaxed at a predetermined
temperature with energy parameters as shown in Figure 2B.
The statistics of thermodynamic parameters were carried out
after 5 × 106 MCS to guarantee the state equilibrium. The
evolution of the typical parameters and the typical snapshots
with time t are shown in Figures S3 and S4.
Thermogelling behaviors were first investigated in a series of
polydispersed systems with various D̵ M (fixed Mw). Here, the
polydispersity was achieved by introducing dispersity of
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hydrophobic A blocks. For a system with D̵ M (fixed Mw) = 2.2
and φ = 0.25, the typical snapshots at different temperatures
are presented in Figure 3A. At low temperatures, model chains
assembled to form some relatively small aggregates dispersed
in the system; then, further aggregation among aggregates
occurred and a network-like structure formed at higher
temperatures; at very high temperatures, most of the beads
aggregated together and were significantly separated from the
solvent.
The hydrogel network was one of our main focuses in this
work. In order to observe the network more clearly, an
enlarged snapshot of the network is presented in Figure S5 as
well as a snapshot only showing the hydrophobic beads. These
snapshots illustrated that the aggregation of the hydrophobic
beads was the key to the formation of the network.
In order to analyze the system quantitatively, we defined
some terms for statistics. If any hydrophobic bead of a block A
contacted with any bead of another block A, these two blocks
belonged to the same micellar core. In simulations, the contact
between two beads meant that these two beads were nearest-
neighbor or next-nearest-neighbor. Besides, as a characteristic
structure of the ABA copolymer, the hydrophilic bridge was
defined as the middle B block of the ABA chain with two A
blocks inserted into two different micellar cores. Once two
hydrophobic A beads from two micellar cores contacted, these
two cores merged into one and the hydrophobic channel
formed at the core-to-core location; meanwhile, the hydro-
philic bridge between the previous two cores disappeared.
Aggregate-core and aggregate-total are two important
aggregate terms in simulations. As schematically presented in
Figure 3B, the aggregate-total was linked by either the
hydrophobic channel or the hydrophilic bridge, while the
aggregate-core was linked only by the hydrophobic channel.
Based on these definitions, at low temperatures before
thermogelation, the aggregate-core referred to the micelle
but the aggregated-total referred to the aggregate of micelles
linked by the hydrophilic bridge; then, at high temperatures
after thermogelation, the aggregate-core referred to the
network with hydrophobic channels as the cross-linking points,
while the aggregate-total referred to the network with either
hydrophobic channels or hydrophilic bridges as the cross-
linking points.
The size of an aggregate-core was defined as the total beads
of the AB semichains belonging to it (e.g., an A28B8A28 chain
corresponded to two A28B4 semichains). For aggregate-total, its
size corresponded to the total beads of ABA model chains it
contained. Size distributions of aggregates at different temper-
atures are shown in Figure S6; an aggregation tendency with an
increase of temperature was observed both from the aggregate-
core distribution and the aggregate-total distribution. The
shape of a micelle at low temperatures was near circle in our
statistics as shown in Figure S7; then, with the increase of
temperature, the homogeneous network-like structure formed.
The average size of the aggregates in a simulated system was
characterized by the weight-average molecular weight of
aggregates as
∑ Mi 2
M w (aggregate) =
∑ Mi (7)
Here, Mi denotes the number of beads in the i-th aggregate.
For aggregate-total and aggregate-core, this parameter was
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termed Mw (aggregate-total) and Mw (aggregate-core),
respectively.
The Mw (aggregate-total)−T and Mw (aggregate-core)−T
curves of a typical system with D̵ M (fixed Mw) = 2.2 and φ =
0.25 are shown in Figure 3B. Both Mw (aggregate-total) and
Mw (aggregate-core) were relatively small at low temperatures,
corresponding to a flowing sol state with micelles in a real
system. Then, the increase of these two parameters indicated
further aggregation. According to some previous work,35,52 the
divergent point of the Mw (aggregate)−T curve could be
defined as the gelation temperature. In simulations, the
gelation temperatures obtained from Mw (aggregate-total)−T
and Mw (aggregate-core)−T curves were termed Tgel‑1 and
Tgel‑2, respectively.
Both the hydrophobic channel and the hydrophilic bridge
can act as the physical cross-linking point in the network.
However, from the analysis of the corresponding parameters
(Figure S8), the number of hydrophobic channels increased
with an increase of temperature while the number of the
hydrophilic bridges decreased, which indicated that the
aggregation was caused eventually by the formation of the
hydrophobic channel. The essential reasons for the abrupt
increases of Mw (aggregate-total) and Mw (aggregate-core)
around transition points are the same, namely, the driving
forces in both phase transitions come from the formation of
the hydrophobic channel. As Tgel‑1 < Tgel‑2, it is Tgel‑1 that
identifies Tgel, namely, the sol−gel transition temperature upon
heating.
In experiments, a precipitate state was observed in the
amphiphilic block copolymer aqueous system at very high
temperatures. In order to mimic the real system, a criterion for
the precipitate state in simulations should be built. In our
simulations, we employed the inflection point of the S−T
curve as the precipitate temperature (Tprecipitate), as shown in
Figure 3C. Here, S represents the area of an equivalent ellipse
corresponding to all beads in the system and can be calculated
by the position matrix of all beads.53
Based on the criteria of Tgel and Tprecipitate, the state diagram
of a system from computer simulations can be obtained, with
results presented in Figure 3D. When the φ increased to a
critical value (critical gel concentration, CGC), the system
underwent a sol−gel transition; a gel-precipitate transition
took place with the further increase of temperature. As the φ
further increased, the Tgel decreased while the Tprecipitate
increased, leading to the enlargement of the thermogel
window.
Comparison of the state diagrams of different systems
revealed that CGC, Tgel, and Tprecipitate were much higher in the
system with a higher D̵ M (fixed Mw). The effect of the D̵ M
(fixed Mw) on Tgel was more obvious than that on Tprecipitate;
thus, the thermogel window became narrow as the D̵ M (fixed
Mw) increased. This phenomenon was reflected more directly
from Figure 3E, where the φ of all systems was the same (φ =
0.25) and the molar mass dispersity was changed. As the D̵ M
(fixed Mw) increased, the Tgel and Tprecipitate got closer. These
two transition temperatures were even almost equal when the
D̵ M (fixed Mw) = 2.8, indicating only a sol-precipitate transition
in this case. Besides, the Tgel was not obtained when D̵ M (fixed
Mw) = 1 as the divergent point in the Mw (aggregate-total)−T
curve was nonobvious. This might correspond to an insoluble
system. Thermogelling behaviors under the effect of the D̵ M
(fixed Mw) obtained from simulations are consistent with the
experimental results well.11
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Figure 4. Effects of D̵ M (fixed Mw) and D̵ M (fixed Mn) on thermogelation. The path to modulate the change of D̵ M here is by introducing the
dispersity of hydrophobic blocks. (A) Evolution of Mw (aggregate-total) against temperature of the indicated systems; (B) evolution of Tgel against
D̵ M or MW of the indicated systems. For all systems, φ = 0.25.
Effects of D̵ M (fixed Mw) and D̵ M (fixed Mn) on
Thermogelation. As mentioned in the section Simulation
Methods, the change of D̵ M can be modulated by fixing Mw but
changing Mn [corresponding to D̵ M (fixed Mw)] or by fixing Mn
but changing Mw [corresponding to D̵ M (fixed Mn)]. Here,
both the effects of D̵ M (fixed Mw) and D̵ M (fixed Mn) on
thermogelation were examined.
From the Mw (aggregate-total)−T curves in Figure 4A, a
similar tendency of the effects of D̵ M (fixed Mw) and D̵ M (fixed
Mn) on thermogelation was observed. With the increase of D̵ M,
the abrupt change of the Mw (aggregate-total) occurred at
higher temperatures. The more visual results are represented
by the Tgel−D̵ M curve, as shown in Figure 4B. An increase of
either D̵ M (fixed Mw) or D̵ M (fixed Mw) led to an increase of
Tgel.
According to previous reports54,55 and our present
simulations (Figure 4A), MW also influences the thermogelling
behavior significantly. Modulating of D̵ M was achieved by
changing Mw or Mn. The increase of D̵ M (fixed Mn) is
accompanied with the increase of Mw, while the increase of D̵ M
(fixed Mw) is accompanied with the decrease of Mn. It is
interesting that Tgel did not change monotonously with MW
for polydispersed systems but changed monotonously with
both D̵ M (fixed Mw) and D̵ M (fixed Mn) (Figure 4B). On the
contrary, the Tgel changed monotonously with MW in
monodispersed systems. These results indicate that D̵ M is,
independent of MW, a regulator of thermogelation. This
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conclusion is, according to our further Monte Carlo
simulations, strengthened in other simulated systems, as
shown in Figure S9.
Mechanism of the D̵ M Effect on Thermogelation.
Thermogelation is a macroscopic reflection of the formation of
a network. As analyzed in the Supporting Information (Figure
S8) and schematically shown in Figure 5A, the general
thermogelling mechanism of the amphiphilic copolymer in
water can be described as follows: at low temperatures, the
copolymers self-assemble to micelles with the core−corona
structure; the reversed thermosensitive micellar corona
collapses upon heating; when the corona becomes sufficiently
thin, the collapsed corona might not totally wrap the
hydrophobic core, forming a semibald micelle with partially
exposed core area; because of the hydrophobicity of the
exposed core area, the semibald micelles are unstable and
aggregate together, leading to the formation of a percolated
network. According to this mechanism, the corona plays a
tricky role in thermogelation. For a star-like micelle with a very
thick corona, the partially collapsed corona is still sufficiently
thick and tightly wraps the micellar core, which hinders the
formation of the semibald micelle and the following micellar
aggregation.
We speculated that the corona of the micelle might be
affected by the D̵ M. In simulations, the definition of the corona
thickness dcorona was
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Figure 5. Microscopic understanding of the D̵ M effect on thermogelation. The path to modulate D̵ M here is by introducing the dispersity of
hydrophobic blocks. (A) General mechanism of thermogelation. The corona change plays an essential role in the formation of the network; (B)
corona thickness in unit of lattice size at different temperatures in the indicated systems with φ = 0.25. The symbol ⟨⟩ means average by the
aggregate-core mass in this work; (C) Tgel−dcorona curves. Here, the dcorona was calculated using the data from the system at 5 °C. The dashed line is
used only for guidance of eyes.

dcorona = R g (aggregate‐core) − R g (core)
where the Rg (aggregate-core) and Rg (core) are the radii of
gyration of the aggregate-core (with both blocks A and B) and
the core in this aggregate-core (with only block A joining in
statistics), respectively. The results of dcorona of different
systems are shown in Figure 5B. In addition, a series of other
parameters were defined and calculated to characterize the
micellar morphology, as shown in Figures S10−S14.
Comparison of these figures with the Tgel−D̵ M curve in Figure
4B illustrated that the tendency of corona thickness dcorona with
D̵ M was much similar to that of Tgel with D̵ M. Besides, for all
simulated systems, dcorona decreased upon heating, indicating
the collapse of the corona. Figure 5C reflects the relation
between Tgel and dcorona. Similar results could be obtained from
other polydispersed systems and monodispersed systems, as
presented in Figure S15. These results confirmed the direct
(8) relation between corona thickness and thermogelation and
thus revealed that the D̵ M effects on thermogelation worked via
affecting the micellar corona.
Synergism among Chains on Thermogelation. In a
polydispersed copolymer system, the different chain lengths
lead to different amphiphilic extents of macromolecules. On
this basis, we speculated that the chains of different lengths
might play different roles in thermogelation. While it is hard to
distinguish the roles of different chains in experiments, it is
available in simulations.
As mentioned in Simulation Methods, the continuous
distribution of the MW cannot be achieved in such a kind of
modeling, and P1, P2, and P3 were used to represent the low
MW chain, medium MW chain, and high MW chain,
respectively. The path to modulate the change of D̵ M here is
by changing the length of hydrophobic blocks, and thus the
hydrophobicity from P1, P2 to P3 is from weak to strong.
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Micelles serve as the precursor of the hydrogel network in
this study. Therefore, the assembly structures of micelles at low
temperatures before thermogelation were first analyzed. We
found that the spatial distribution of different chains in a
micelle was heterogeneous: the P1, P2, and P3 chains preferred
to distribute from outside to inside along the micellar radius, as
shown in Figure S16. Quantitative statistics reflected that the
P1 distributed relatively outside of the core−corona interface,
while the P3 distributed relatively inside of the core−corona
interface (Figure S17). This intramicelle heterogeneity was
maintained even after thermogelation and insignificant only at
the precipitate state (Figure S18).
The length contribution of each component to the corona
thickness dcorona(Pi) was also calculated. The results are shown
in Figure S19. Although the relative hydrophilic B blocks are of
the same length, the “brush height” of the component Pi in a
micelle corona dcorona(Pi) would be influenced by some factors,
such as the relative position of the component in the micelle.
The more restrictive condition inside the micelle might lead to
a low dcorona(Pi), while the less restrictive condition outside the
micelle might lead to a high dcorona(Pi). From the relative
position of P1, P2, and P3 in the micelle, the relative values of
dcorona(Pi) in a polydispersed system read dcorona(P1) >
dcorona(P2) > dcorona(P3). The tendency of the dcorona(P1)
with D̵ M (Figure S19) was similar to the tendency of the dcorona
with D̵ M (Figure 5B), indicating that the relatively more
hydrophilic P1 component made a larger contribution to the
corona thickness.
Then, the aggregation of every two components Pi and Pj
was examined by the corresponding analysis of the Mw(PiPj)−
T curve. The parameter Mw(PiPj) was defined as weight
average MW of the aggregate-core only considering the two
components (Pi and Pj) in the system with actually three
components (P1, P2, and P3). From Figure S20, compared
with the nongellable system, the Mw(P2P3) was larger than the
Mw(P1P2) and Mw(P1P3) at the thermogel state in the
gellable system, indicating that the skeleton of the network was
mainly composed by P2 and P3. Next, we employed Mw(Pi),
weight-average MW of the aggregate-core only considering the
component Pi to evaluate the self-aggregation of Pi in the
system containing three components. The Mw(Pi) was
normalized by the Mw(Pi) at 0 °C to reflect the further self-
aggregation tendency with the increase of temperature. In
gellable systems, the normalized Mw(P2) obviously increased
around Tgel and became larger than the normalized Mw(P1)
and Mw(P3) after thermogelation. Further considering the P2
and P3 distributions in the micelle (Figures S16−S18), we
speculated that in the network skeleton P2 acted as the
network adhesive, while P3 acted as the network unit. The
network units were stuck together by the network adhesive,
and then the whole network formed.
We also designed a series of “knock-out” computer
experiments. Thermogelation of the system lacking one
component Pi (called system 2 with only two components)
was studied to compare with the corresponding polydispersed
system (called system 1 with three components, P1, P2, and
P3) in order to illustrate the role of Pi on thermogelation. The
“knock-out” system lacked the Pi component, but the other
two components in the system were the same as those in the
corresponding polydispersed system. As shown in Figure S21,
the Mw (aggregate-core) of the system 2 lacking P1 increased
at lower temperatures compared with that of the system 1.
This interesting phenomenon indicated that the P1 might
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Article
hinder the further aggregation of the system. Compared with
the system 1, the aggregation of system 2 lacking P2 or P3
occurred at higher temperatures, confirming that P2 and P3
made up the skeleton of the network.
The roles of different components in thermogelation were
further studied by the analysis of aggregate structures. At low
temperatures, according to the distribution of each component
in different aggregates (Figure S22), P1 with low MW of ABA-
type copolymer under a given chain length of the central
hydrophilic block B and thus relatively higher hydrophilicity
inclined to be isolated chains or enter into small micelles.
Therefore, in more polydispersed systems with more P1
chains, more isolated chains or small micelles existed (Figure
S23), which led to lower volume fraction of aggregates (Figure
S24).
With the increase of temperature, the fraction of the isolated
P1 chains decreased and the fraction of P1 in larger micelles
increased (Figures S22 and S25). This phenomenon resulted
from the much thinner coronae of larger micelles (Figure S26).
As temperature increased, the corona collapse might lead to
the larger micelles unstable. The isolated chains (mainly P1)
had to fuse to the larger micelles to stabilize them.
Effects of D̵ M of Hydrophilic Blocks on Thermogela-
tion. In experiments, D̵ M (PEG) can be determined before
synthesis of the triblock copolymer PLGA−PEG−PLGA; and
the D̵ M from hydrophilic blocks is stable if we use the same
batch of PEG with two end hydroxyl groups as the initiator to
trigger the ring-opening polymerization of lactide and
glycolide. To alter the initiator’s D̵ M can thus be used to
regulate the property of the resultant block copolymer of
polyether and polyester in experiments, and some results have
been reported in our previous publication.56 In the present
study, the effects of D̵ M from hydrophilic blocks on
thermogelation were also considered in simulations. Compared
with the D̵ M from hydrophobic blocks, the value range of the
D̵ M from hydrophilic blocks was much narrower because of the
short B block in the default model chain. Therefore, we
employed another set of model chains, A20B4A20, A20B24A20,
and A20B44A20, to investigate the effects of D̵ M from hydrophilic
blocks on thermogelation. As shown in Figure 6A, when either
D̵ M (fixed Mw) or D̵ M (fixed Mn) increased, the Mw (aggregate-
total) increased at higher temperatures.
The thermogelling behaviors of systems with different D̵ M
from hydrophilic blocks were compared with those of systems
with different D̵ M from hydrophobic blocks (Figure 6B). To
improve comparability, the chain lengths of the corresponding
components were set the same between the systems with
various hydrophilic blocks and the systems with various
hydrophobic blocks. Therefore, for changing hydrophobic
blocks to modulate D̵ M, A10B24A10, A20B24A20, and A30B24A30
were used as models. Interestingly, although the Tgel increased
with the D̵ M in both types of systems, the working extents of
the effects of D̵ M (fixed Mn) and D̵ M (fixed Mw) on
thermogelation were quite different. In systems with D̵ M
from hydrophilic blocks, the effect of D̵ M (fixed Mn) on
thermogelation was more obvious than that of D̵ M (fixed Mw),
while systems with D̵ M from hydrophobic blocks exhibited the
opposite trend. If we employed the D̵ M (block), the molar
mass dispersity of the corresponding block, instead of the D̵ M
of the whole copolymer as the independent variable, similar
results could also be obtained (Figure 6B).
From Figure S27, the different working extents of the effects
of D̵ M (fixed Mn) and D̵ M (fixed Mw) between these two types
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Figure 6. Effects of D̵ M from hydrophilic blocks of the ABA triblock copolymer on thermogelation in water and comparison with the effects of D̵ M
from hydrophobic blocks. (A) Evolution of Mw (aggregate-total) with temperature of the indicated systems. The path to modulate the change of
D̵ M here is by introducing the dispersity of hydrophilic blocks. The three components in polydispersed systems were A20B4A20, A20B24A20, and
A20B44A20, where A20B24A20 was the starting point for changing D̵ M; (B) evolution of Tgel with D̵ M of the indicated systems. In the right, the D̵ M
(block) represents the molar mass dispersity of the block instead of the whole copolymer. For changing hydrophobic blocks to modulate D̵ M,
A10B24A10, A20B24A20, and A30B24A30 were used as models. For changing hydrophilic blocks to modulate D̵ M, the models were the same as in (A).

of systems were also reflected from the statistics of the dcorona,
further confirming that the mechanism of the D̵ M effect on
thermogelation was by affecting the micellar corona.
In Figure 6A, there was a temperature range before
thermogelation where the Mw (aggregate-total) of a higher
D̵ M system with either D̵ M (fixed Mn) or D̵ M (fixed Mw) was
larger than that of a lower D̵ M system. This could be ascribed
to the larger micelles in the higher D̵ M system, as shown in
Figure S28. These simulated results might interpret why a
higher viscosity was observed before thermogelation in systems
with higher D̵ M (PEG) in our experiments.56
different lengths led to the final thermogelation with the
formation of a percolated network of semibald micelles. In
addition, the effects of D̵ M from hydrophilic blocks and
hydrophobic blocks on thermogelation were compared (Figure
6). In the following contents, some further discussion based on
our above results will be conducted.
D̵ M−Mw Diagram. If we choose Mw as the abscissa and D̵ M
as the ordinate, a copolymer with known Mw and D̵ M (yet not
necessarily thermogellable) can be treated as a point in this
coordinate system. According to the definition of molar mass
dispersity, the Mn of this copolymer can be obtained from the

■
DISCUSSION
Compared with small molecules, one of the characters of
macromolecules is of MWD, which has great effects on the
properties of polymeric materials. Usually, MWD was
described by molar mass dispersity D̵ M. In the present study,
the effects of this parameter on thermogelling behaviors of an
amphiphilic block copolymer in water were investigated by
dynamic Monte Carlo simulations (Figure 2). The effects were
significant (Figure 3), and the D̵ M served as a macromolecular
parameter independent of MW to regulate the thermogelation
(Figure 4). We further found that the D̵ M effects on
thermogelation originated from its effects on micellar corona
(Figure 5). We revealed that the synergism among chains with
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slope of the slash through the origin and this copolymer point.
We further labeled the values characterizing the aggregation of
the copolymer aqueous system (e.g., Tgel) in Figure 7A. Then,
the effects of the molecular parameters (Mw, D̵ M, and Mn) on
aggregation including thermogelation can be well reflected.
This representing diagram is suggested and called D̵ M−Mw
diagram by us.
The copolymer parameters can be adjusted via changing
hydrophobic blocks and hydrophilic blocks. Considering the
probability in experiments of thermogels, we mainly discuss the
cases of fixing hydrophilic blocks but changing hydrophobic
blocks here. The D̵ M−Mw diagram obtained from simulations
of our default models and some corresponding monodispersed
systems is shown in Figure 7A, according to which the
aggregation becomes weaker (better solubility, increased Tgel,
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Figure 7. D̵ M−Mw diagrams with data summarized from simulations and experiments. Here, the path to modulate the change of D̵ M is by
introducing dispersity of hydrophobic blocks. (A) Map of Tgel with D̵ M and Mw as independent coordination axes in simulations and experiments.
The oblique line represents a series of samples with fixed Mn. The arrow direction means the increase of the Tgel or the weakening of the
aggregation. In simulations, φ = 0.25. In experiments, the concentration was 20 wt %. The solid red squares represent systems with sol−gel
transition upon heating, and the numbers near the squares indicate the Tgel values of the corresponding systems in units of Celsius degree. For
clarity, some Tgel values are not shown. The blue hollow squares and the blue solid squares represent the systems always flowing upon heating and
the insoluble systems, respectively. In simulations, the system state was judged by the Mw (aggregate-total)−T and S−T curves, while in
experiments, the state was judged by the test-tube inversion method;11 (B) schematic form of the D̵ M−Mw diagram based on our simulations and
experiments. The different areas in the D̵ M−Mw diagram predict the aggregation-in-water tendency of copolymers of D̵ M and Mw different from the
reference sample, which can be any sample with any molecular parameter in practice. In other words, the reference sample can be either
thermogellable or nonthermogellabe (insoluble or always flowing) in water.

or even nongellable) with the decrease of Mw as well as with
the increase of D̵ M (fixed Mw) or D̵ M (fixed Mn). These
phenomena were also observed in other model systems (Figure
S29).
Some experimental data from ref 11 and some unpublished
data at that time in our group are employed to compare with
the simulation results. The copolymer parameters in experi-
ments are listed in Table S1 and presented in the D̵ M−Mw
diagram in Figure 7A. Our experimental results are consistent
with our simulation outputs.
Based on the above data, the schematic D̵ M−Mw diagram is
summarized and presented in Figure 7B. The lines relative to a
point indicating a known reference copolymer divide the plane
into a few areas. It should be noted that the reference sample
can be any sample with any molecular parameter and not
necessarily thermogellable. Different areas in the D̵ M−Mw
diagram can tell us the aggregate tendency of other copolymers
relative to the reference sample.
This is much important in practice. If one synthesizes a
copolymer and obtains its molecular parameters (Mw, D̵ M, and
Mn) and aggregation ability, the D̵ M−Mw diagram can be
J https://dx.doi.org/10.1021/acs.macromol.0c01430
employed to design other copolymers with required
aggregation ability. Or, if one synthesizes a copolymer and
obtains its molecular parameters, its aggregation ability can be
predicted based on a copolymer with the known molecular
parameters and aggregation ability and the corresponding D̵ M−
Mw diagram.
Mechanism of the Thermogelation of a Polydis-
persed System. Mechanism studies can enrich our knowl-
edge and guide one to design new materials.57−59 Based on our
simulations (Figure S8) and our previous works,34 the key to
the thermogelation is the formation of the semibald micelle,
whose prerequisite structure is the crew-cut micelle with a very
thin corona. While the concept of crew-cut micelle was
originally suggested by the Eisenberg group,60,61 that of the
semibald micelle was put forward by the Ding group.34,35 From
our present findings, either D̵ M (fixed Mw) or D̵ M (fixed Mn)
has an obvious effect on the micellar corona thickness (Figure
5). According to Figure 8A, if the D̵ M is very small, the micellar
corona is too thin to stabilize the micelle even at a very low
temperature; thus the micelles tend to aggregate; and in an
extreme case, the copolymer with a given average MW and
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Figure 8. Self-assembly mechanism of amphiphilic copolymer systems in a selective solvent with the effect of D̵ M. Here, the path to modulate D̵ M is
by introducing dispersity of hydrophobic blocks. (A) With the increase of D̵ M, the corona of the micelle gets thicker, which stabilizes the micelle
and prohibits the further aggregation; (B) schematic of the synergistic action of chains of different lengths in the thermogelling process.

block ratio might be insoluble in water at all. Thermogelation
takes place in systems with a moderate D̵ M: at low
temperatures, the copolymers self-assemble to crew-cut
micelles with thin coronae; then, the micellar corona
composed of the reversed thermosensitive PEG blocks
collapses upon heating; at a high temperature, the collapsed
thin corona cannot totally wrap the hydrophobic core, and the
semibald micelle with partial exposed core areas forms; the
semibald micelles are unstable and thus aggregate together,
leading to the hydrogel network. In another extreme case of
very large D̵ M, the micellar corona is very thick in a star-like
micelle, and even the collapsed corona can still wrap the
micellar core, which hinders the formation of semibald micelles
and the following micellar network. At very high temperatures,
the excessive hydrophobicity makes the system precipitate
straightforwardly.
In experiments, the micellar corona thickness can be
theoretically measured by the small-angle neutron scattering
or small-angle X-ray scattering.62,63 Our simulation results
might be verified by these experimental methods in the future.
As Flory wrote in his classic book Principles of Polymer
Chemistry, “Ideally, perhaps, interpretation of a given property
of a polymer should proceed from consideration of the
contribution of each molecular species to that property, the
final result being obtained by summing the contributions from
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all species present”.1 The contribution of each species is too
difficult to consider in experiments, but it is available in
simulations. In this study, we attempt to distinguish the roles
of different chains on thermogelation (Figures S16−S26), and
the synergism among different chains has been revealed
(Figure 8B).
The path to modulate D̵ M here is first by changing the length
of the hydrophobic block, thus the working extent of
hydrophobicity from low MW chains, medium MW chains
to high MW chains is from weak to strong. At low
temperatures, many micelles are dispersed in the system. In
a micelle, the chains of low MW, medium MW, and high MW
tend to distribute from outside to inside along the micellar
radius. The micellar corona is mainly contributed by the
hydrophilic blocks of low MW chains; thus, more P1 chains in
a highly polydispersed system lead to thicker coronae. Besides,
the low MW chains prefer to be isolated chains or enter into
small micelles. With an increase of temperature, the micellar
corona collapses. The larger micelles with the thinner corona
get to be unstable; and the isolated chains or small micelles
with mainly low MW chains fuse to the larger micelles to
stabilize them and hinder their aggregation. Considering the
spatial distribution of low MW chains in an aggregate, the
corona contribution of low MW chains in aggregates and the
fusion of isolated low MW chains to larger micelles, the low
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Macromolecules pubs.acs.org/Macromolecules
MW chains act as a micelle stabilizer. At higher temperatures,
the number of isolated chains is too small to stabilize the larger
micelles, and the aggregation among larger micelles occurs.
The larger micelle is mainly composed of the chains of
medium MW and high MW, constituting the main
components of the network skeleton. Based on our findings,
the medium MW chains act as a skeleton adhesive, which
sticks the high MW chains together; the high MW chains act as
the skeleton unit, and the much hydrophobicity of this chain
promotes the self-aggregation even at very low temperatures.
The synergism among different chains can be used to better
understand the mechanism of the D̵ M effects on thermogela-
tion. As either D̵ M (fixed Mw) or D̵ M (fixed Mn) increases, the
numbers of polymer chains of low MW and high MW increase
but the number of medium MW chains decreases (Figure S2).
Because the low MW chains act as the micelle stabilizer, the
aggregation becomes weaker with the increase of D̵ M.
Furthermore, less medium MW chains (skeleton adhesive) in
systems with high D̵ M are disadvantageous for the formation of
the micellar network. Thus, the thermogel window becomes
narrow as D̵ M increases. In systems with very high D̵ M (with
thus only a few medium MW chains), once the low MW chains
cannot stabilize the larger micelles mainly composed of high
MW chains, the precipitate forms. In this case, the system only
exhibits a sol-precipitate transition upon heating. We believe
that the corresponding synergism mechanism can be
generalized to other systems containing chains with different
amphiphilicities.
Comparison of Effects of D̵ M from Hydrophobic
Blocks and Hydrophilic Blocks on Thermogelation.
Herein, we compare the effects of D̵ M of hydrophilic blocks
and D̵ M of hydrophobic blocks on thermogelation. According
to Figure 6, the aggregation ability becomes weaker with the
increase of D̵ M for both systems. This can be ascribed to the
increase of the relatively more hydrophilic chains as D̵ M
increased.
Specifically, the effects of D̵ M (fixed Mn) and D̵ M (fixed Mw)
on thermogelation exhibited different extents between these
two system types. In systems with D̵ M from hydrophilic blocks,
the effect of D̵ M (fixed Mn) on thermogelation was more
obvious than that of D̵ M (fixed Mw), while in systems with D̵ M
from hydrophobic blocks, the opposite was observed. This
phenomenon can be understood from the D̵ M−Mw diagrams.
In the D̵ M−Mw diagram of fixing hydrophobic blocks but
changing hydrophilic blocks (Figure 7B), the D̵ M (fixed Mn)
line is located at a position where the effects of Mw and D̵ M
(fixed Mw) on thermogelation is antagonistic; in contrast, in
the D̵ M−Mw diagram of fixing hydrophobic blocks but
changing hydrophilic blocks (Figure S30), the D̵ M (fixed Mn)
line is at a position where the effects of Mw and D̵ M (fixed Mw)
on thermogelation is cooperative.
■
CONCLUSIONS
In this work, thermogelling behaviors of the polydispersed
ABA-type amphiphilic copolymer systems were investigated by
dynamic Monte Carlo simulations of multiple self-avoiding
lattice chains. We found that D̵ M is a macromolecular
parameter independent of MW to significantly regulate the
thermogelation of block copolymers in water. The D̵ M affects
the formation of polymer micelles, in particular, the micellar
corona, and then the formation of a percolated network of
semibald micelles linked by hydrophobic channels. The
synergism among different chains in thermogelation was
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Article
revealed. By comparing the simulation results with the previous
experimental results, we proposed the D̵ M−Mw diagram to
design the thermogellable copolymers. The findings might be
helpful for promoting the material applications in biomedicine
and other fields and for understanding the hierarchical self-
assembly behaviors in the polydispersed systems. Considering
that the polydispersity is an intrinsic character of synthetic
polymers, this fundamental research might have a general
impact in Polymer Science and Engineering.
■
ASSOCIATED CONTENT
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.macromol.0c01430.
Microrelaxation model and sampling method in
simulations, default chain parameters in simulations,
evolutions of some typical parameters with time,
evolution process of typical simulated systems, network
structure of the thermogel, aggregate size distribution,
structure of aggregate-cores, roles of hydrophobic
channels and hydrophilic bridges on thermogelation,
further confirmation of the D̵ M effects on thermogela-
tion, micellar structure characterization at 5 °C, Tgel−
dcorona curves of some systems, heterogeneous spatial
distribution of polymer components of different chain
lengths in aggregates at 5 °C, position of different chains
in aggregate-cores at 5 °C, evolution of heterogeneous
distribution of different chains in aggregates with
temperature, contributions of different chains to corona
thickness, roles of medium MW and high MW chains on
thermogelation, role of the low MW component on
thermogelation, evolution of component distribution in
aggregates as temperature increased, number of small
micelles in different systems at 5 °C, volume fraction of
micelles in different systems at 5 °C, fractions of
different components in aggregates, structures of
micelles with different sizes at 5 °C, corona thickness
of some systems at different temperatures, micelle size
and bridge fraction of some systems, map of Tgel of some
systems with D̵ M and Mw as independent coordination
axes, molecular parameters of copolymers in experi-
ments, and schematic D̵ M−Mw diagram of fixing
hydrophobic blocks but changing hydrophilic blocks
(PDF)
■ AUTHOR INFORMATION
Corresponding Author
Jiandong Ding − State Key Laboratory of Molecular Engineering
of Polymers, Department of Macromolecular Science, Fudan
University, Shanghai 200438, China; Zhuhai Fudan
Innovation Institute, Zhuhai, Guangdong 519000, China;
orcid.org/0000-0001-7527-5760; Email: jdding1@
fudan.edu.cn
Authors
Shuquan Cui − State Key Laboratory of Molecular Engineering
of Polymers, Department of Macromolecular Science, Fudan
University, Shanghai 200438, China
Liang Chen − State Key Laboratory of Molecular Engineering of
Polymers, Department of Macromolecular Science, Fudan
University, Shanghai 200438, China
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Macromolecules pubs.acs.org/Macromolecules
Lin Yu − State Key Laboratory of Molecular Engineering of
Polymers, Department of Macromolecular Science, Fudan
University, Shanghai 200438, China; Zhuhai Fudan
Innovation Institute, Zhuhai, Guangdong 519000, China;
orcid.org/0000-0001-7660-3367
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.macromol.0c01430
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This research was supported by NSF of China (grants nos.
21774024 and 51533002), National Key R&D Program of
China (grant no. 2016YFC1100300), Science and Technology
Commission of Shanghai Municipality (grant no.
17JC1400200), and Zhuhai Fudan Innovation Institute
(grant no. ZFCY-technology-2019-007).
■
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