Chinese Journal of

POLYMER SCIENCE FEATURE ARTICLE

https://doi.org/10.1007/s10118-018-2061-7
Chinese J. Polym. Sci. 2018, 36, 8−17

Controlled Cross-linking Strategy for Formation of Hydrogels, Microgels

and Nanogels
Qing-Chen Caoa, b, Xing Wanga*, and De-Cheng Wua, b*
a
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics & Chemistry, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China
b
University of Chinese Academy of Sciences, Beijing 100049, China

Abstract Hydrogels are a kind of unique cross-linking polymeric materials with three-dimensional networks. Various efforts have been
devoted to manipulate the formation of functional hydrogels in situ and enrich the production of hydrogels, microgels and nanogels with
improved modulation capacity. However, these methods always fail to tune the gel properties because of the difficulty in achieving the
precise control of cross-linking extents once the gel formation is initiated. Therefore, the preparation of tailor-made hydrogels remains a
great challenge. Herein, we summarize a controlled cross-linking strategy towards not only fabrication of hydrogels at nano-, micro- and
macro-scales, but also achievement of controlled assembly of nanoparticles into multifunctional materials in macroscopic and microscopic
scales. The strategy is conducted by controllably activating and terminating the disulfide reshuffling reactions of disulfide-linked core/shell
materials with selective core/shell separation using system pH or UV triggers. So it provides a facile approach to producing hydrogels,
hydrogel particles and nanoparticle aggregates with tunable structures and properties, opening up the design possibility, flexibility and
complexity of hydrogels, microgels/nanogels and nanoparticle aggregates from nanoscopic components to macroscopic objects.

Keywords Thiol-disulfide exchange; Controlled cross-linking; Hybrid hydrogels; Hydrogel particles; Biodegradation

Citation: Cao, Q. C.; Wang, X.; Wu, D. C. Controlled Cross-linking Strategy for Formation of Hydrogels, Microgels and Nanogels. Chinese J. Polym. Sci.
2018, 36(1), 8−17.

INTRODUCTION system with the explicit criteria that the gelation should have
capacities to be activated, controllably terminated and
Hydrogels are three-dimensional and water-swollen networks interrupted, and reinitiated by the external stimuli whenever
of hydrophilic polymers with physical or chemical crosslinks. needed.
Due to the soft consistency and good biocompatibility, The authors’ research group has recently proposed a
hydrogels are extremely suitable in applications of drug controlled cross-linking strategy to dynamically optimize
delivery[1, 2], bioimaging[3, 4], chemical separation[5] and hydrogel properties[20]: from the solution to loose hydrogels
catalysis[6, 7]. To produce hydrogels with tunable properties, with low crosslinking degree to compact hydrogels with high
stimuli-responsive hydrogels have been greatly developed for crosslinking degree (Fig. 1). The strategy can in situ tune the
handily and readily manipulating their properties under gelation process with the selective core/shell separation:
various external stimuli, such as pH[8, 9], temperature[10, 11], dissociation of the shells and cross-linking of the cores. The
electricity[12], redox[13, 14], light[15, 16], etc. In most common fulfillment of controlled gelation is based on the precise
method, chemically cross-linked hydrogels are prepared from manipulation of thiol-disulfide exchange reaction in aqueous
the solution of monomers together with a small and pre- solutions. As shown in the Fig. 2, the thiol-disulfide exchange
calculated amount of cross-linkers. However, the reaction can be reversibly activated or terminated by
conventional gelation methods fail to tune the gel structures deprotonating the free thiols or protonating the thiolates under
and properties in situ as a result of the difficulty in achieving different pH conditions with a rapid response; the dynamic
the precise control on the pre-set amount of multifunctional disulfide bonds show redox responsiveness under the
cross-linkers and degree of cross-linking once the gel presence of glutathione (GSH) or dithiothreitol (DTT)[21]. By
formation is initiated[17−19]. To circumvent this problem, it is means of this congenital advantage, we report a facile method
greatly desirable to design a ‘living’ controlled in situ gelling to create the ‘living’ in situ gelling system for the controlled
hydrogels from a disulfide-linked core/shell structure. The
*
Corresponding authors: E-mail wangxing@iccas.ac.cn (X.W.) gelation process can be triggered, dynamically interrupted and
E-mail dcwu@iccas.ac.cn (D.C.W.) reinitiated by manipulating the pH-responsive gelling system,
Invited Feature Article
allowing the facile fabrication of hydrogels with the tailor-
Received September 29, 2017; Accepted October 11, 2017; Published online
October 30, 2017 made structures and properties and opening up the novel

© Chinese Chemical Society

Institute of Chemistry, CAS www.cjps.org
Springer-Verlag GmbH Germany 2018 link.springer.com
 Q.C. Cao et al. / Chinese J. Polym. Sci. 2018, 36, 8−17 9

Fig. 1 Schematic illustration of controlled cross-linking strategy with core/shell separation process

was the hydrophobic core[22, 23] and the poly(ethylene glycol)

(PEG) acted as the easy-leaving shell. In this system, BAP
aqueous solution had good stability under low pH but could
be cross-linked to form the ‘living’ gel due to the trigger of
thiol-disulfide exchange reaction under alkaline conditions.
When the cross-linking time was prolonged, the ‘living’ gel
network evolved from the loose to compact (Fig. 3A),
generating a smaller pore size and denser network in
Fig. 3(B). Notably, the cross-linking process could be
interrupted at any time by neutralizing the pH of ‘living’ gel
Fig. 2 Schematic illustration of pH and redox responsiveness system. At this point, the ‘living’ gel was converted to ‘stable’
in regard to the thiol-disulfide exchange reaction gel that could be inert for a long period of time in a neutral
solution. Once the system was re-basified, the ‘stable’ gel
design possibilities for the in situ hydrogels under mild could quickly revert to the ‘living’ gel state as well as the
reaction conditions. restart of size-shrinkage evolution. Therefore, hydrogels with
To the best of our knowledge, there is no review that customized structures and properties are easily fabricated
summarizes the development of thiol-disulfide exchange through controlling the pH value at a predetermined time.
reaction for the controlled gelling system. Herein, we intend Biodegradable hydrogels are widely used in biomedical
to introduce a controlled cross-linking strategy for fabricating applications of drug delivery and tissue engineering[24−26]. The
various kinds of macro-, micro- and nano-scale hydrogels by disulfide bonds, as dynamic covalent linkages, can be easily
two stimuli-triggered cross-linking methods in detail. cleaved in response to the redox stimuli from GSH or DTT.
Conclusions and perspectives are also presented and So the controlled cross-linking strategy is used to develop the
discussed. redox-responsive biodegradable hydrogels. These disulfide-
containing hydrogels had a good long-term stability and
THE CONCEPT OF CONTROLLED CROSS- basically maintained their shapes and sizes in phosphate
LINKING STRATEGY buffer saline (PBS) solutions. However, these hydrogels were
quickly disintegrated after addition of 10 mmol/L DTT,
Controlled Gelling Process and Mechanism presenting a redox-responsive degradation behavior in
For a conventional hydrogel preparation, the compactness of Fig. 3(C). Since the hydrogels were formed through disulfide
cross-linked networks mainly relies on the pre-set amount of shuffling of the polymer cores, the resulting neutralized
cross-linking agents in the initial system[18, 19] . But once the hydrogels, possessing the low cytotoxicity, were
cross-linking reaction is activated, the crosslinking degree and biocompatible as shown in Fig. 3(D). So these hydrogels were
network structure are usually difficult to be further adjusted. suitable for in situ encapsulation of active molecular drugs
To overcome this difficulty, we performed the controlled that can tolerate a relatively high pH environment. For
cross-linking strategy to tailor the gelling process, which is example, two model drugs, hydrophilic doxorubicin (DOX)
enabled to be dynamically terminated and re-opened via and hydrophobic paclitaxel (PTX), were used to yield the
controlling the thiol-disulfide exchange reaction under mild drug-loaded hydrogels. These results illustrated that tailor-
conditions. The gelling product, namely the ‘controlled gel’, made hydrogels allowed the fine modulation of drug delivery
can be fabricated with customized crosslinking degree and system to facilitate the preparation of smart drug vectors that
performance from rational design of the disulfide-containing were stable in an extracellular medium and decomposable in
gel precursors[20]. an intracellular environment to trigger the drug release.
The unique chemical structure of gel precursors plays an The thiolate-mediated thiol-disulfide exchange mechanism
important role in the controlled cross-linking process. We can interpret the formation of loose and compact hydrogels
first synthesized a class of hyperbranched polymers and demonstrate this ‘living’ controlled process in Fig. 4. In
(poly(N,N'-bis(acryloyl)cystamine-1-(2-aminoethy)piperazine- detail, BAP system had a small number of thiols that could
poly(ethylene glycol), BAP) with a disulfide-linked core-shell initially generate thiolates in the presence of alkali solution.
structure as a gel precursor, wherein the poly(amido amine) The active thiolates could immediately attack the disulfide

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Fig. 3 (A) Graphical representation of basification of BAP solution and derived methodology for producing loose and compact
hydrogels: (a) 10 wt% BAP solution, (b) loose hydrogel after basification for 1 h, (b*) inert neutralized loose hydrogel after 1 h of cross-
linking, and (c) compact hydrogel after basification for 24 h; (B) SEM images of the hydrogels obtained after basification for various
time; (C) Remained amounts of the hydrogels with different gelling time in 1 × PBS containing 10 mmol/L of DTT, at 37 °C as a function
of time (n = 3); (D) Cytotoxicity of the loose hydrogel after 4 h of cross-linking in L929 cells after incubation for 1 day and 3 days
(n = 4) (Reproduced with permission from Ref. [20]; Copyright (2010) American Chemical Society) (The online version is colorful.)

Fig. 4 Schematic illustration of gelation mechanism of cross-linked cores and release of shells

linkages between the core and shell of BAP, resulting in the quickly transform into a white hydrogel with the loosely
newly-formed disulfides linkages between the hydrophobic cross-linked network within a short time, and then the
cores and released PEG shells because of the shifting of continuous thiol-disulfide exchange reactions further
equilibrium toward the stable cross-linked products. Based on increased the crosslinking degree of hydrogel networks along
the above-mentioned process, the initially clear solution could with the shape transformation from the loose to compact

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structures. After removal of the alkali stimulus, the thiol loose hydrogel particles with the similar diameter of initial
groups could be regenerated in order that the termination of droplets. When gelling time was extended, the dissociation of
thiol-disulfide exchange reaction immobilized the shape and hydrophilic shells resulted in the shrinkage from the loose to
size of hydrogels for a long time under mild environments. small and compact hydrogel particles. Therefore, adjusting
However, once the gelling system rebasified again, the the initial diameters of droplets from nano- to micro-scales
reactive thiolates restarted a new round of cross-linking and tailoring the gelation time, the controlled formation of
reaction and the stable hydrogel network further evolved into macro/nanogels was facilely achieved in the confined space.
the dense and tight structures. Meanwhile, after neutralization of gelation system to trap the
intermediate particles at a predetermined time, various stable
Controlled Formation of Micro- and Nano-gels in a hydrogel particles could be produced with customized
Confined Space chemical structure, particle size and stability, because the
The controlled cross-linking strategy, as a versatile platform, transition process from loose to compact hydrogel particles
also provides a new approach towards the well-defined tailor- was arbitrarily terminated and immobilized.
made hydrogel particles[27]. Combined with an inverse Multilayered hydrogel particles, originating from their
emulsion technique, the strategy is further developed to fascinating multilayer structures that can offer the attractive
produce various micro- and nano-gels in a confined space as integration of core-based carrier properties and shell-
depicted in Fig. 5(A). By manipulating gelation of mediated biological interactions, receive the steady interest
micro/nanosized droplets of aqueous BAP solutions, the and widespread attention. Unfortunately, the reported
controlled formation of micro/nanogels is in situ facilely preparation methods are basically cumbersome for
fabricated with flexibly designable structures and properties. independently tailoring the architectures and properties of the
In detail, the BAP solution was firstly well-dispersed into the
respective layer[28−30]. To address the challenge, we fabricate
micro- or nano-droplets using the inverse emulsion method,
a multilayered hydrogel particle using the controlled in situ
then the initial diameter of droplets was adjusted via
gelation method in association with the seed emulsion
controlling the emulsion conditions, including the organic
technology[27]. By freestanding tailor of each on-demand
continuous phase, surfactant, stirring rate and so on. Upon
layer, the multilayered hydrogel particles were easily gained
basification of the droplets, gelation caused the formation of

Fig. 5 (A) Schematic illustration of the core/shell separation process: dissociation of the shells and cross-linking of the cores and
depiction of the synthetic approach to controlled formation of (multilayered) hydrogel particles; (B) TEM images of the mono-
/double-/triple-layered nanogels obtained by cross-linking for various time (Reproduced with permission from Ref. [27]; Copyright
(2012) American Chemical Society) (The online version is colorful.)

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with adjustable structural performance for every layer. Multilayered Composite Nanoparticles from a
Specifically, the pre-prepared hydrogel particles were utilized Controlled Nanogel Template for Bone Generation
as the seed cores for the heterogeneous growth of subsequent Multilayered composite nanoparticles (MC-NPs) receive
deposition and cross-linking of the shell layer, generating the significant attention in the pharmaceutical applications of
double-layered core/shell hydrogel particles. After an controlled drug delivery and diagnostic bioimaging[31, 32].
appointed time, the other fresh BAP solution was added into Typically, the fabrication process involves layer-by-layer
the core/shell hydrogel particles for the continuously deposition of biologically functional surfaces onto the silica
heterogeneous growth of subsequent deposition and cross- (Si), gold (Au) or polystyrene (PS) templates, but the
liking of the secondary shell layer, producing the smart triple- traditional fabrication methods, including chemical coating,
layered (core/double shells) hydrogel particles as clearly condensation from vapor and solid-state process, offer little
observed in Fig. 5(B). Notably, the structures and properties control over the morphology, elasticity, particle size and
of multilayered hydrogels can be selectively designed and property of individual layers.
simultaneously tailored by optimizing the suitable Inspired from the design flexibility and complexity of
crosslinking time and/or adopting various functional materials customized multilayered nanogels, we applied the general
with similar disulfide-linked core/shell structures, e.g., controlled in situ method towards the production of multi-
inorganic nanoparticle or stimulus-responsive polymer cores responsive MC-NPs with fine-tunable functional layers[33] as
and hydrophilic polymer shells. The formation of hydrogel shown in Fig. 6. With the facile control on the tailor-made
particles was ascribed to the cross-linking of polymer cores structures and biodegradable properties, a smart disulfide-
linked by a number of built-up disulfide bonds; as a result, the linked nanogel, possessing the varying size, was utilized as an
hydrogel particles were biodegradable since disulfide ideal template for fabricating the MC-NPs, which exhibited
linkages can be effectively cleaved by GSH or DTT agents. excellent advantages on the biofunctional surfaces, tunable
Therefore, this general method can be utilized to build up the drug release kinetics and multi-responsive functions for
high performance and intelligent layers of drug carriers, targeted drug/growth factor releases towards the bone tissue
paving a facile approach toward customized multilayered formation in vivo. Therefore, this layer-by-layer technique is
hydrogel particles in applications of drug diagnostics and scalable and highly controllable, providing a powerful tool for
therapeutic delivery system. considerable therapeutic potential in clinical fields of
oncology and orthopedics[34].

Fig. 6 (A) Controlled formation of the nanogel core, silica shell-nanogel core NPs (GS), pH-responsive poly(acrylic acid) (PAA)-
silica-nanogel NPs (GSP), hydroxyapatite (HA) coated PAA-silica-nanogel NPs (GSPH) and doped biomimic films; (B) TEM images
of various multilayered composite nanoparticles; (C) In vivo translation of multilayered composite nanoparticles toward periosteum-
mimetic biomaterials for bone repair; (D) X-ray, micro-CT, photograph, and H&E characterizations of ectopic bone formation in the
mouse gastrocnemius pocket model after 4 weeks of film implantation (Reproduced with permisison from from Ref. [33]; Copyright
(2017) Elsevier) (The online version is colorful.)

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THE DEVELOPMENT OF CONTROLLED (Fig. 7Ac), which ultimately converted into a glass-like
CROSS-LINKING STRATEGY aggregate after standing for another 9 days (Fig. 7Ad). The
transition from the polymeric solutions to the hybrid
Controlled Gels Functionalized by Functional Cores hydrogels then to the irregular aggregates can be facilely
The controlled cross-linking strategy is a general method interrupted and reinitiated by neutralization and rebasification
because it can be also suitable for other materials with at any time. Besides, these neutralized hybrid hydrogels
functional disulfide-linked core/shell structures, e.g., silica exhibited high stability during the long-term storage
(Si), metal, metal oxide, polyhedral oligomeric silsesquioxane (Fig. 7Ab*). Therefore, rational pH control of gelling system
(POSS), polyester-, dendritic-, comb-, capsule- and can facilely obtain the customized hybrid hydrogels and
polysaccharide-like cores[35−41]. To validate this proposal, we nanoparticle aggregates.
produced an organic-inorganic hybrid hydrogel from a hybrid Similarly, the ‘living’ controlled cross-linking mechanism
precursor of POSS-(SS-PEG)8 polymer. On account of its is also based on the reversibly deprotonating thiols and
well-defined cage structure (~0.53 nm) with an inorganic protonating thiolates through the tailor of pH values in
silica-like core[42−45], this star-shaped polymer was adopted to aqueous solutions, and thus switching on/off the exchange
yield a kind of hybrid hydrogels and nanoparticle aggregates reaction can obtain the hybrid hydrogels and macroscopic
with the customized structures and properties on the basis of nanoparticle aggregates with tunable structures and properties.
a pH-responsive ‘on/off’ reaction. Specially, the polymeric Distinct from the existence of many sharp peaks for the
solution (10 wt%) could keep unchanged after basification at POSS-(SS-PEG)8 polymer in Fig. 7(B), XRD patterns
the initial stage (Fig. 7Aa) but turned into a loose hydrogel displayed that the aggregates only had a broad glass-like peak,
after addition of cysteamine for 1 h (Fig. 7Ab). Then the loose indicating the successful transitions from hybrid hydrogels to
hydrogel started to shrink into a compact hydrogel in 24 h macroscopic aggregates. The rheological measurement gave

Fig. 7 (A) Schematic representation of the production of loose, compact hybrid hydrogels and the aggregate: 10 wt% POSS-(SS-
PEG)8 solution after basification for (a) 1 h without addition of cysteamine, (b) 1 h, (c) 24 h and (d) 240 h with addition of cysteamine,
(b*) an inert neutralized loose hydrogel after 1 h of cross-linking; (B) XRD patterns of (a) POSS-(SH)8, (b) POSS-(SS-PEG)8 and the
resulted hydrogels or aggregate after basification of solution for (c) 1 h, (d) 8 h, (e) 24 h and (f) 240 h with addition of cysteamine;
(C) Storage modulus G′ of POSS-(SS-PEG)8 solution after basification to pH 12 as a function of time (Oscillatory frequency: 1 rad/s.)
(Reproduced from Ref. [42] with permission from The Royal Society of Chemistry) (The online version is colorful.)

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another intuitional evidence to observe this transformation environment to modulate the thiol-disulfide exchange
process. Figure 7(C) showed a multistage abrupt increase of reaction, UV switcher has unique advantages of remote
the storage modulus G′ during the gelation process; in manipulation, tunable intensity, spatiotemporal precision and
particular, the G′ of hybrid hydrogel was more than 0.08 MPa “turn-off” effect, which enables to realize real-time control
after cross-linking for 8 h, manifesting the formation of stable over the photochemical process. So we developed a
hydrogel with high mechanical strength. photochemical method to prepare the controlled cross-linking
Currently, we are also utilizing another two kinds of hydrogels using a comb-like P(EMA-SS-PEG) polymer
functional cores, multi-site drugs and fluorescent agents[46, 47], (poly(ethyl methacrylate)-dithio-poly(ethylene glycol)) based
to customize the functionalized hybrid hydrogels in on the UV-triggered thiol-disulfide exchange reaction, which
applications of drug delivery and bioimaging. Therefore, the could not only avoid the strong alkali environments but also
‘living’ controlled strategy is not only beneficial for provide the precise spatiotemporal control on the structures
preparation of functionalized hydrogels but also applicable and properties of hydrogels[49]. By varying the irradiation
for assembling individualized nanoparticles into cluster time, the crosslinking degrees and morphology of the
aggregates with tailored features and customized hydrogels were also easily adjusted, exhibiting the
functionalities, expanding a new pathway for the controlled concomitant transitions in the conformation, mechanical and
assembly of nanoparticles. swelling properties in Fig. 8(A).
For the thiolates-mediated exchange reaction, the driving
Controlled Gelation Triggered by Ultraviolet Light
force is determined by the shifting of equilibrium toward the
In contrast to the anion-mediated disulfide exchange
stable disulfide-linked materials through release of PEG
mechanism, the dynamic disulfide bond can also undergo the
shells by the selective core/shell separations. In contrast, UV
thiol-disulfide exchange reactions with sulfhydryl radical via
irradiation can break one disulfide into two freely thiyl
a radical-mediated mechanism under the photo-irradiation
radicals in the presence of photoinitiator (2-hydroxy-4′-(2-
condition[48]. In consideration of the requirement of alkali
hydroxyethoxy)-2-methylpropiophenone, IR2959) and
environment to induce the controlled gelling process, many
catalyst (mercaptoethylamine, MCA), which induced the
functional and intelligent hydrogel materials are not stable in
random radical-centered disulfide exchange reaction to
the strong alkali conditions and thus not conducive to
prepare the hydrogels in an aqueous solution. By attacking
biomedical applications. Compared with the harsh pH
disulfide bonds of the nearby polymeric chains, the thiyl

Fig. 8 (A) Schematic representation of the hydrogel formation under various UV irradiation time; (B) The
mechanism of forming hydrogels via a UV-triggered thiol-disulfide exchange reaction (Reproduced from Ref. [49]
with permission from The Royal Society of Chemistry) (The online version is colorful.)

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radicals could effectively trigger thiol-disulfide exchange inverse emulsion technique, the cross-linking strategy can be
reaction using two different ways, both of which resulted in utilized to produce various micro/nanogels in microscopic
the formation of thiyl radicals on the polymeric backbones scales and fabricate the multilayered hydrogel particles in the
(Fig. 8B). So that the extramolecular disulfide exchange or confined space with flexibly designable structures and
radical combination reaction could link the two isolated properties. It is worth noting that this controlled cross-linking
polymers together by detachment of PEG side chains. strategy is a general method because it can be also suitable for
Prolongation of irradiation time further caused the continuous other materials with functional disulfide-linked core/shell
disulfide exchange reactions, thus leading to the crosslinking structures, by which the various multifunctional hybrid
of more polymer backbones and rupturing of PEG chains to hydrogels are yielded with tunable networks and high-
the solutions. In other words, rational control of UV performance features. Meanwhile, UV-triggered thiol-
irradiation time can easily tailor the hydrophobic/hydrophilic disulfide exchange reaction has been developed to prepare the
ratio and topological structures, which are two key factors for hydrogels with a radical-centered disulfide exchange
manipulating the self-assembly behaviors in aqueous mechanism, opening up another cross-linking method for the
solutions[50−54]. As the hydrophilic/hydrophobic ratio was precise spatiotemporal control on the photochemical gelation
decreased to a critical value, the hydrophobic polymer process. More importantly, these hydrogel materials,
sections were aggregated together along with the hydrophilic possessing a large number of the disulfide linkers among the
PEG side chains extending into the water layer to reduce the cross-linking cores, are biocompatible and biodegradable in
free energy of system, ultimately resulting in the formation of medical applications. So this controlled cross-linking strategy
self-assembled aggregates. Further reducing the has great potentials to be developed as a powerful tool for the
hydrophilicity, the aggregates transferred into the micelle-like design, synthesis and self-assembly of novel intelligent
structures in aqueous solutions, in which the hydrophobic biomaterials and drug delivery systems.
polymer areas acted as the core while the hydrophilic PEG Although remarkable advantages on the preparation of
chains modeled as the shell. Notably, the UV-triggered thiol- tailor-made hydrogels have been represented by this
disulfide exchange reaction was simultaneously conducted controlled cross-linking strategy, the wide application fields
inside and/or outside the micelle-like nanoaggregates; thereby of controllable hydrogels materials remain a grand challenge.
the loose hydrogels were finally formed by a mass of On one hand, the currently investigated hydrogels are mainly
disulfide-crosslinked nanoaggregates. If the irradiation time based on the hydrophobic cores; other hydrophilic or
was further extended, the sustained disulfide shuffling and multifunctional cores have rarely been reported. On the other
hydrophobic interactions drove the integration of micelle-like hand, although the crosslinking degree of hydrogel network
nanoaggregates to form the large hydrophobic ones as well as can be well-fabricated by termination of the disulfide
more reassemble PEG chains releasing into the aqueous exchange reactions, the networks themselves are
solutions; in this case, these resultant hydrophobic cores heterogeneous crosslinking during the gelation or transition
expelled out more encapsulated water, thus inducing the loose process in order that the single chemically-cross-linked
hydrogel to further shrink to the compact and dense network networks make these highly swollen hydrogels notoriously
structure. Based on this UV-triggered hydrogel preparation, brittle, which greatly limits their applications in the
we recently produce another visible light-triggered controlled antifouling materials, drug delivery, biological imaging and
formation of hydrogels with a rapid self-healing behavior, tissue engineering. To overcome this challenge, we currently
which will be discussed in details in our future work. manage to fabricate the controlled double-network (DN)
UV-triggered thiol-disulfide exchange method is also an hydrogel by merging the cross-linking strategy into the DN
efficient and universal strategy to prepare the bioreducible gel systems[55] or other robust hydrogel systems[56, 57]. Our
hydrogels with good temporal and spatial control, paving a groups are committed to design and develop a series of DN
promising way for the precise spatiotemporal control on the hydrogels with remarkable mechanical strengths[58−60].
photochemical gelation process in applications of macro- Therefore, combining controlled cross-linked strategy with
/micro-patterned hydrogels, photolithography and controlled excellent properties of DN hydrogels, we aim to elaborately
drug delivery. design a type of controlled DN hydrogels by precisely
adjusting the network topologies and mechanical properties,
CONCLUSIONS AND PERSPECTIVES hoping to elucidate the underlying mechanisms for further
enhancement of gel properties.
In summary, we have mainly demonstrated a controlled cross-
linking strategy for the formation of hydrogels and hybrid ACKNOWLEDGMENTS
hydrogels at macro-, micro- and nanoscales based on the
precise manipulation of thiol-disulfide exchange reaction. This work was financially supported by the National Natural Science
The reversibly activated or terminated by deprotonating the Foundation of China (Nos. 21674120, 21504096, 21474115 and
free thiols or protonating the thiolates under different pH 21174147) and the ‘Young Thousand Talents Program’.
conditions furnished the disulfide-linked core/shell polymers
with a rapid response, resulting in the dissociation of shells REFERENCES
and cross-linking of cores and thus dynamically optimizing
hydrogel structures: from the solution to loose and to compact 1 Murthy, N.; Thng, Y. X.; Schuck, S.; Xu, M. C.; Fréchet, J. M.
hydrogels in macroscopic dimensions. Combined with the A novel strategy for encapsulation and release of proteins:
hydrogels and microgels with acid-labile acetal cross-linkers. J.

https://doi.org/10.1007/s10118-018-2061-7
16 Q.C. Cao et al. / Chinese J. Polym. Sci. 2018, 36, 8−17

Am. Chem. Soc. 2002, 124(42), 12398−12399. method toward tailor-made biodegradable hydrogels. J. Am.
2 Murthy, N.; Xu, M. C.; Schuck, S.; Kunisawa, J.; Shastri, N.; Chem. Soc. 2010, 132(43), 15140−15143.
Fréchet, J. M. A macromolecular delivery vehicle for protein- 21 Fernandes, P. A.; Ramos, M. J. Theoretical insights into the
based vaccines: acid-degradable protein-loaded microgels. J. mechanism for thiol/disulfide exchange. Chem-Eur. J. 2004,
Proc. Matl. Acad. Sci. 2003, 100(9), 4995−5000. 10(1), 257−266.
3 Wang, J. Z.; Loh, K. P.; Wang, Z.; Yan, Y. L.; Zhong, Y. L.; 22 You, Y. Z.; Yu, Z. Q.; Cui, M. M.; Hong, C. Y. Preparation of
Xu, Q. H.; Ho, P. C. Fluorescent nanogel of arsenic sulfide photoluminescent nanorings with controllable bioreducibility
nanoclusters. Angew. Chem. Int. Ed. 2009, 48(34), 6282−6285. and stimuli-responsiveness. Angew. Chem. Int. Ed. 2010, 49(6),
4 Gota, C.; Okabe, K.; Funatsu, T.; Harada, Y.; Uchiyama, S. 1099−1102.
Hydrophilic fluorescent nanogel thermometer for intracellular 23 Cheng, W. R.; Wu, D. C.; Liu, Y. Michael addition
thermometry. J. Am. Chem. Soc. 2009, 131(8), 2766−2767. polymerization of trifunctional amine and acrylic monomer: a
5 Nayak, S.; Lyon, L. A. Ligand-functionalized core/shell versatile platform for development of biomaterials.
microgels with permselective shells. Angew. Chem. Int. Ed. Biomacromolecules 2016, 17(10), 3115−3126.
2004, 43(48), 6706−6709. 24 Drury, J. L.; Mooney, D. J. Hydrogels for tissue engineering:
6 Terashima, T.; Nomura, A.; Ito, M.; Ouchi, M.; Sawamoto, M. scaffold design variables and applications. Biomaterials 2003,
Star-polymer-catalyzed living radical polymerization: microgel- 24(24), 4337−4351.
core reaction vessel by tandem catalyst interchange. Angew. 25 Meng, F. H.; Hennink, W. E.; Zhong, Z. Y. Reduction-sensitive
Chem. Int. Ed. 2011, 50(34), 7892−7895. polymers and bioconjugates for biomedical applications.
7 Lu, Y.; Mei, Y.; Drechsler, M.; Ballauff, M. Thermosensitive Biomaterials 2009, 30(12), 2180−2198.
core-shell particles as carriers for Ag nanoparticles: modulating 26 Li, D. W.; Bu, Y. Z.; Zhang, L. N.; Wang, X.; Yang, Y. Y.;
the catalytic activity by a phase transition in networks. Angew. Zhuang, Y. P.; Yang, F.; Shen, H.; Wu, D. C. Facile construction
Chem. Int. Ed. 2006, 45(5), 813−816. of pH- and redox-responsive micelles from a biodegradable
8 Ladet, S.; David, L.; Domard, A. Multi-membrane hydrogels. poly(beta-hydroxyl amine) for drug delivery.
Nature 2008, 452(7183), 76−79. Biomacromolecules 2016, 17(1), 291−300.
9 Cheng, E. J.; Xing, Y. Z.; Chen, P.; Yang, Y.; Sun, Y. W.; 27 Zhang, J.; Yang, F.; Shen, H.; Wu, D. C. Controlled formation
Zhou, D. J.; Xu, L. J.; Fan, Q. H.; Liu, D. S. A pH-triggered, fast- of microgels/nanogels from a disulfide-linked core/shell
responding DNA hydrogel. Angew. Chem. Int. Ed. 2009, hyperbranched polymer. ACS Macro Lett. 2012, 1(11),
121(41), 7796−7799. 1295−1299.
10 Nowak, A. P.; Breedveld, V.; Pakstis, L. M.; Ozbas, B.; 28 Hu, X. B.; Tong, Z.; Lyon, L. A. Multicompartment core/shell
Pine, D. J.; Pochan, D.; Deming, T. J. Rapidly recovering microgels. J. Am. Chem. Soc. 2010, 132(33), 11470−11472.
hydrogel scaffolds from self-assembling diblock copolypeptide 29 Lu, Y.; Ballauff, M. Thermosensitive core-shell microgels: from
amphiphiles. Nature 2002, 417(6887), 424−428. colloidal model systems to nanoreactors. Prog. Polym. Sci. 2011,
11 Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Biodegradable 36(6), 767−792.
block copolymers as injectable drug-delivery systems. Nature 30 Xiong, M. H.; Bao, Y.; Yang, X.; Wang, Y. Z.; Sun, B. L.; Wang,
1997, 388(6645), 860−862. J. Lipase-sensitive polymeric triple-layered nanogel for “on-
12 Murdan, S. Electro-responsive drug delivery from hydrogels. J. demand” drug delivery. J. Am. Chem. Soc. 2012, 134(9),
Control. Release 2003, 92(12), 1−17. 4355−4362.
13 Moriyama, K.; Minamihata, K.; Wakabayashi, R.; Goto, M.; 31 Chen, Y.; Chen, H. R.; Zeng, D. P.; Tian, Y. B.; Chen, F.; Feng, J. W.;
Kamiya, N. Enzymatic preparation of a redox-responsive Shi, J. L. Core/shell structured hollow mesoporous
hydrogel for encapsulating and releasing living cells. Chem. nanocapsules: a potential platform for simultaneous cell imaging
Commun. 2014, 50(44), 5895−5898. and anticancer drug delivery. ACS Nano 2010, 4(10),
14 Nakahata, M.; Takashima, Y.; Harada, A. Redox-responsive 6001−6013.
macroscopic gel assembly based on discrete dual interactions. 32 Mitragotri, S.; Anderson, D. G.; Chen, X. Y.; Chow, E. K.;
Angew. Chem. Int. Ed. 2014, 53(14), 3617−3621. Ho, D.; Kabanov, A. V.; Karp, J. M.; Kataoka, K.; Mirkin, C. A.;
15 Collier, J. H.; Hu, B. H.; Ruberti, J. W.; Zhang, J.; Shum, P.; Petrosko, S. H. Accelerating the translation of nanomaterials in
Thompson, D. H.; Messersmith, P. B. Thermally and biomedicine. ACS Nano 2015, 9(7), 6644−6654.
photochemically triggered self-assembly of peptide hydrogels. J. 33 Zhang, J.; Jia, J. P.; Kim, J. P.; Yang, F.; Wang, X.; Shen, H.;
Am. Chem. Soc. 2001, 123(38), 9463−9464. Xu, S. J.; Yang, J.; Wu, D. C. Construction of versatile
16 Haines, L. A.; Rajagopal, K.; Ozbas, B.; Salick, D. A.; multilayered composite nanoparticles from a customized
Pochan, D. J.; Schneider, J. P. Light-activated hydrogel nanogel template. Bioactive Materials 2017, DOI:
formation via the triggered folding and self-assembly of a 10.1016/j.bioactmat.2017.06.003
designed peptide. J. Am. Chem. Soc. 2005, 127(48), 34 Zhang, J.; Jia, J. P.; Kim, J. P.; Shen, H.; Yang, F.; Zhang, Q.;
17025−17029. Xu, M.; Bi, W. Z.; Wang, X.; Yang, J.; Wu, D. C. Ionic colloidal
17 Naficy, S.; Brown, H. R.; Razal, J. M.; Spinks, G. M.; Whitten, P. G. molding as a biomimetic scaffolding strategy for uniform bone
Progress toward robust polymer hydrogels. Aust. J. Chem. 2011, tissue regeneration. Adv. Mater. 2017, 29(17), 1605546.
64(8), 1007−1025. 35 Xu, S. J.; Liu, J. H.; Zhang, L. C.; Yang, F.; Tang, P. F.; Wu, D.
18 Cohen, Y.; Ramon, O.; Kopelman, I. J.; Mizrahi, S. C. Effects of HAp and TCP in constructing tissue engineering
Characterization of inhomogeneous polyacrylamide hydrogels. scaffolds for bone repair. J. Mater. Chem. B 2017, 5(30),
J. Polym. Sci., Part B: Polym. Phys. 1992, 30(9), 1055−1067. 6110−6118.
19 Hsu, T. P.; Ma, D. S.; Cohen, C. Effects of inhomogeneities in 36 Zhuang, Y. P.; Shen, H.; Yang, F.; Wang, X.; Wu, D. C.
polyacrylamide gels on thermodynamic and transport properties. Synthesis and characterization of PLGA nanoparticle/4-arm-
Polymer 1983, 24(10), 1273−1278. PEG hybrid hydrogels with controlled porous structures. RSC
20 Wu, D. C.; Loh, X. J.; Wu, Y. L.; Lay, C. L.; Liu, Y. 'Living' Adv. 2016, 6(59), 53804−53812.
controlled in situ gelling systems: thiol-disulfide exchange

https://doi.org/10.1007/s10118-018-2061-7
 Q.C. Cao et al. / Chinese J. Polym. Sci. 2018, 36, 8−17 17

37 Huang, D.; Yang, F.; Wang, X.; Shen, H.; You, Y. Z.; Wu, D. C. Li, Z. C.; Wu, D. C. UV-triggered thiol-disulfide exchange
Facile synthesis and self-assembly behaviour of pH-responsive reaction towards tailored biodegradable hydrogels. Polym.
degradable polyacetal dendrimers. Polym. Chem. 2016, 7(40), Chem. 2016, 7(7), 1429−1438.
6154−6158. 50 Wang, J.; Wang, X.; Yang, F.; Shen, H.; You, Y. Z.; Wu, D. C.
38 Wang, L. H.; Wu, D. C.; Xu, H. X.; You, Y. Z. High DNA- Effect of topological structures on the self-assembly behavior of
binding affinity and gene-transfection efficacy of bioreducible supramolecular amphiphiles. Langmuir 2015, 31(51),
cationic nanomicelles with a fluorinated core. Angew. Chem. 13834−13841.
Int. Ed. 2016, 55(2), 755−759. 51 Wang, J.; Wang, X.; Yang, F.; Shen, H.; You, Y. Z.; Wu, D. C.
39 Liu, B. X.; Zhou, X.; Yang, F.; Shen, H.; Wang, S. G.; Zhang, B.; Self-assembly behavior of a linear-star supramolecular
Zhi, G.; Wu, D. C. Fabrication of uniform sized polylactone amphiphile based on host-guest complexation. Langmuir 2014,
microcapsules by premix membrane emulsification for 30(43), 13014−13020.
ultrasound imaging. Polym. Chem. 2014, 5(5), 1693−1701. 52 Wang, J.; Li, B. X.; Wang, X.; Yang, F.; Shen, H.; Wu, D. C.
40 Wang, X.; Wang, J.; Yang, Y. Y.; Yang, F.; Wu, D. C. Morphological evolution of self-assembled structures induced
Fabrication of multi-stimuli responsive supramolecular by the molecular architecture of supra-amphiphiles. Langmuir
hydrogels based on host-guest inclusion complexation of a 2016, 32(51), 13706−13715.
tadpole-shaped cyclodextrin derivative with the azobenzene 53 Wang, X.; Yang, Y. Y.; Yang, F.; Shen, H.; Wu, D. C. pH-
dimer. Polym. Chem. 2017, 8(26), 3901−3909. triggered decomposition of polymeric fluorescent vesicles to
41 Li, D. W.; Niu, Y. G.; Yang, Y. Y.; Wang, X.; Yang, F.; Shen, H.; induce growth of tetraphenylethylene nanoparticles for long-
Wu, D. C. Synthesis and self-assembly behavior of POSS- term live cell imaging. Polymer 2017, 118(2), 75−84.
embedded hyperbranched polymers. Chem. Commun. 2015, 54 Wang, X.; Yang, Y. Y.; Gao, P. Y.; Yang, F.; Shen, H.; Guo, H.
51(39), 8296−8299. X.; Wu, D. C. Synthesis, self-assembly, and photoresponsive
42 Wang, X.; Li, D.; Yang, F.; Shen, H.; Li, Z. B.; Wu, D. C. behavior of tadpole-shaped azobenzene polymers. ACS Macro
Controlled cross-linking strategy: from hybrid hydrogels to Lett. 2015, 4(12), 1321−1326.
nanoparticle macroscopic aggregates. Polym. Chem. 2013, 55 Gong, J. P.; Katsuyama, Y.; Kurokawa, T.; Osada, Y. Double-
4(17), 4596−4600. network hydrogels with extremely high mechanical strength.
43 Yang, Y. Y.; Wang, X.; Hu, Y.; Hu, H.; Wu, D. C.; Xu, F. J. Adv. Mater. 2003, 15(14), 1155−1158.
Bioreducible POSS-cored star-shaped polycation for efficient 56 Liu, X. Y.; Zhong, M.; Shi, F. K.; Xu, H.; Xie, X. M. Multi-bond
gene delivery. ACS Appl. Mater. Interfaces 2014, 6(2), network hydrogels with robust mechanical and self-healable
1044−1052. properties. Chinese J. Polym. Sci. 2017, 35(10), 1253−1267.
44 Wang, X.; Yang, Y. Y.; Gao, P. Y.; Li, D.; Yang, F.; Shen, H.; 57 Shi, F. K.; Zhong, M.; Zhang, L. Q.; Liu, X. Y.; Xie, X. M.
Guo, H. X.; Xu, F. J.; Wu, D. C. POSS dendrimers constructed Toughening mechanism of nanocomposite physical hydrogels
from a 1 → 7 branching monomer. Chem. Commun. 2014, fabricated by a single gel network with dual crosslinking—the
50(46), 6126−6129. roles of the dual crosslinking points. Chinese J. Polym. Sci.
45 Bu, Y. Z.; Sun, G. F.; Zhang, L. C.; Liu, J. H.; Yang, F.; Tang, P. F.; 2017, 35(1), 25−35.
Wu, D. C. POSS-modified PEG adhesives for wound closure. 58 Yang, Y. Y.; Wang, X.; Yang, F.; Shen, H.; Wu, D. C.
Chinese J. Polym. Sci. 2017, 35(10), 1231−1242. A universal soaking strategy to convert composite hydrogels into
46 Wang, X.; Yang, Y. Y.; Zhuang, Y. P.; Gao, P. Y.; Yang, F.; extremely tough and rapidly recoverable double-network
Shen, H.; Guo, H. X.; Wu, D. C. Fabrication of pH-responsive hydrogels. Adv. Mater. 2016, 28(33), 7178−7184.
nanoparticles with an AIE feature for imaging intracellular drug 59 Bu, Y. Z.; Shen, H.; Yang, F.; Yang, Y. Y.; Wang, X.; Wu, D.
delivery. Biomacromolecules 2016, 17(9), 2920−2929. C. Construction of tough, in situ forming double-network
47 Wang, X.; Yang, Y. Y.; Zuo, Y. F.; Yang, F.; Shen, H.; Wu, D. C. hydrogels with good biocompatibility. ACS Appl. Mater.
Facile creation of FRET systems from a pH-responsive AIE Interfaces 2017, 9(3), 2205−2212.
fluorescent vesicle. Chem. Commun. 2016, 52(30), 5320−5323. 60 Bu, Y. Z.; Zhang, L. C.; Liu, J. H.; Zhang, L. H.; Li, T. T.;
48 Li, L. Y.; Song, C. F.; Jennings, M.; Thayumanavan, S. Shen, H.; Wang, X.; Yang, F.; Tang, P. F.; Wu, D. C. Synthesis
Photoinduced heterodisulfide metathesis for reagent-free and properties of hemostatic and bacteria-responsive in situ
synthesis of polymer nanoparticles. Chem. Commun. 2015, hydrogels for emergency treatment in critical situations. ACS
51(8), 1425−1428. Appl. Mater. Interfaces 2016, 8(20), 12674−12683.
49 Wang, L. L.; Li, L.; Wang, X.; Huang, D.; Yang, F.; Shen, H.;

https://doi.org/10.1007/s10118-018-2061-7