Programmed Degradation of Hydrogels with a Double-Locked Domain

Article abstract of DOI:10.1002/anie.201811848

The ability to control the degradation of a material is critical to various applications. The purpose of this study was to demonstrate a concept of controlling degradation by using a double-locked domain (DLD). DLDs are molecular structures with two functional units that work cooperatively under environmental stimulation. One unit is triggered to transform without cleavage in the presence of the first stimulus, but this transformation enables the activation of the other unit for cleavage in the presence of the second stimulus. A DLD is presented that is activated to transform through intramolecular reconfiguration when exposed to light. After this transformation, the light-triggered DLD can undergo rapid cleavage under acid treatment. When this DLD is used as the crosslinkers of hydrogels, hydrogels undergo rapid degradation after sequential exposure to light irradiation and acid treatment. Reversing the order of light irradiation and acid treatment or only using individual stimulation does not lead to comparable degradation. Thus, this study has successfully demonstrated the great potential of using DLDs to achieve programmable degradation of materials.

Full text of DOI:10.1002/anie.201811848

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Accepted Article
Title: Programmed Degradation of Hydrogels with a Double-Locked
Domain
Authors: Jinping Lai, Lidya Abune, Nan Zhao, and Yong Wang
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Angewandte Chemie International Edition
10.1002/anie.201811848
Programmed Degradation of Hydrogels with a Double-Locked Domain
Jinping Lai, Lidya Abune, Nan Zhao and Yong Wang*
Department of Biomedical Engineering, The Pennsylvania State University, Pennsylvania 16802, United
States.
*
yxw30@psu.edu
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ABSTRACT:
The ability to control the degradation of a material is critical to various applications. The purpose of this study
was to demonstrate a concept of controlling degradation by using a double-locked domain (DLD). DLD is a
molecular structure with two functional units that work cooperatively under environmental stimulation. One
unit is triggered to transform without cleavage in the presence of the first stimulus, but this transformation
enables the activation of the other unit for cleavage in the presence of the second stimulus. The results show
that DLD is activated to transform through intramolecular reconfiguration when exposed to light. After this
transformation, light-triggered DLD can undergo rapid cleavage under acid treatment. When DLD is used as
the crosslinkers of hydrogels, hydrogels undergo rapid degradation after sequentially exposed to light
irradiation and acid treatment. Reversing the order of light irradiation and acid treatment or only using
individual stimulation does not lead to comparable degradation. Thus, this study has successfully demonstrated
a great potential of using DLD to achieve programmable degradation of materials.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201811848
Control of degradation is an important mission in the field of materials science. It has been extensively
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studied for applications such as drug delivery, tissue engineering, surgery, coating and packaging. To
control degradation, it is necessary to integrate responsive molecules into materials as crosslinkers, structural
units or side groups. A variety of responsive molecules have been synthesized for molecular cleavage in
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response to environmental stimuli such as pH, light, temperature, redox potential and ions. Many of these
molecules have been successfully applied to the synthesis of degradable materials. Recent effort has been
further made in integrating different types of responsive molecules into one system to advance the ability to
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control the degradation of materials. However, these responsive molecules work independently rather than
cooperatively, providing no additional temporospatial specificity or accuracy in the control of degradation. To
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date no material with DLD has been developed. Materials with DLD would have the ability to undergo rapid
degradation after sequentially exposed to two stimuli whereas individual stimulation or reversing the order of
the two stimuli will not induce its rapid degradation. The development of materials of this kind is expected to
advance the diversity, flexibility and specificity of controlling the functions of materials temporospatially.
The purpose of this work was to develop a concept of controlling the degradation of materials by using
DLD. Figure 1 shows this concept and the comparison between it and traditional designs. With traditional
designs, a molecular bond undergoes cleavage after exposed to a specific stimulus. By contrast, when DLD is
exposed to a specific stimulus, one of its functional units undergoes molecular transformation but not cleavage.
This transformed unit enables the other unit to be activated for cleavage in the presence of another specific
stimulus. We used light- and pH- responsive chemical bonds as an example (Figure 1c) to synthesize DLDs
and hydrogels to prove the concept.
Figure 1. Schematic illustration of the principle of controlling molecular cleavage and degradation. (a)
Traditional design for triggered molecular cleavage in the presence of one specific stimulus (S). (b) DLD for
molecular transformation and cleavage after sequential treatment with two stimuli (S1 and S2). (c) An example
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of DLD as presented herein to show molecular transformation and cleavage after DLD is sequentially exposed
to light irradiation and acid treatment.
The synthetic route and molecular structures of three DLDs are shown in Figure 2a. We first examined
the molecular stability and responsiveness of DLD-1 to light and acid (Figure 2b) for its simplicity in
molecular structure. DLD-1 has two domains including o-nitrophenyl ethanol (ONPE) and acetal groups. On
one hand, it was hypothesized that acetal used as a substituted group of ONPE would not inhibit the photo
responsiveness of ONPE. On the other hand, the acetal group would be inert to low pH since ONPE has a p-
substituted nitro group to withdraw electrons strongly. Thus, DLD-1 would be responsive to light but not low
pH in its original state. However, when DLD-1 is exposed to light, it was expected that photoirradiation would
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lead to intramolecular photocyclization of OPNE. Accompanied with this intramolecular photocyclization,
it would lead to a reduction of the nitro group to form electron-abundant oxindole as a new substituted group
of acetal. As a result, the acetal group would become pH-sensitive and light-triggered DLD-1 would be
responsive to acid treatment for hydrolysis.
To test the hypothesis, the responsiveness of DLD-1 to environmental stimulation was first studied using
UV-vis spectroscopy. DLD-1 exhibited one characteristic UV-vis absorption peak at 272 nm. Without light
irradiation, this peak barely changed with time when the pH value of the DLD-1 solution was above 4 (Figure
S1). These results demonstrate that without exposure to light irradiation, DLD-1 is highly stable under the
acidic environment with the pH value above 4. However, the exposure of the DLD solution at pH7.4 to UV
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light (302 nm, 3 mW cm ) led to a decrease in absorption at 272 nm and a concomitant increase in absorption
at both 245 nm and 293 nm (Figure 2c). These changes occurred within one minute of light irradiation and
increased with time, clearly showing a fast responsiveness of DLD-1 to light irradiation. We also used HPLC
to analyze the solution of DLD-1. Consistent with the UV-vis spectra, the HPLC analysis shows one typical
peak of DLD-1 before light irradiation (Figure S2) but two peaks after light irradiation (Figure 2d). As
revealed by mass spectroscopy, the product of photolysis at the new peak has a molecular weight of 331.15
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g·mol , which exactly matches the molecular structure of the oxindole-acetal intermediate product (Figure
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b).
After demonstrating the photoresponsiveness of DLD-1, we studied its pH sensitivity after light
irradiation. The computation from the density functional theory suggested that the formation of oxindole is
accompanied with a significant rearrangement of the electron density (Figure S3) and this change is favorable
to the hydrolysis of the acetal group in response to an acidic environment. Indeed, light-triggered DLD-1 (i.e.,
the oxindole-acetal intermediate product) in the solution of pH 5.0 exhibited a fast change in the UV-vis
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absorption spectrum (Figure 2e). As time proceeded, the absorption at 259 nm decreased whereas the
absorption at 309 nm increased with a slight blue shift. This spectral change is consistent with the HPLC
analysis (Figure S4), showing the fast hydrolysis of the acetal group. In contrast with the fast change observed
at pH 5.0, the oxindole-acetal intermediate product exhibited a much smaller change at pH 7.4 during the same
time window (Figure 2e, bottom panel), suggesting that its hydrolysis in a neutral environment is slow. Taken
together, these results show that DLD-1 can undergo fast hydrolysis after sequentially exposed to light
irradiation and acid treatment.
Figure 2. Synthesis and characterization of DLDs. (a) Reaction scheme for the synthesis of DLDs. (b)
Structural transformation of DLD-1 during stimulation. (c) UV-vis absorption spectra of DLD-1 upon light
irradiation. The inset figure shows the time-dependent change of absorbance at 290 nm. (d) HPLC–MS analysis
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of DLD-1 before and after light irradiation. (e) Time-dependent UV-vis absorbance change of light-triggered
DLD-1 after incubated in the pH 5.0 (up) or pH 7.4 (bottom) solution. (f) Hydrolysis kinetics of light-triggered
DLDs at pH 5.0 or pH 7.4. (g) Half-lives of light-triggered DLDs at pH 5.0 or pH 7.4.
Next we studied the effect of molecular structure on the hydrolysis kinetics. In principle, there are two
general routes of changing the structure of DLD. One is to change R
c). When R is changed, it is possible to change the ability of intramolecular photocyclization and the
responsiveness of light irradiation. However, once the oxindole structure forms, it will favor the responsiveness
of R to an acidic environment for hydrolysis. There are a variety of pH-labile chemical bonds such as
acetal/ketal, hydrazone, imine and cis-acotinyl. Among them, acetals have attracted significant attention
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and the other is to change R (Figure
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recently for they are biocompatible and relatively easy to synthesize. Acetals also exhibit a wide spectrum of
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responsiveness to pH variation. Thus, in this proof-of-concept study, we changed the structure of R and
synthesized three acetals to understand the effect of molecular structure on the hydrolysis of DLD after light
irradiation (Figure 2a). This understanding would provide basic knowledge for the synthesis of a material with
desired degradation kinetics.
The three DLDs were synthesized with primary alcohols that have different lengths in the carbon chain
(
Figure 2a). We expected that the variation of the molecular structure of R
responsiveness of DLD as R is away from the conjugated system. Indeed DLD-2 and DLD-3 both exhibited
fast response to the light irradiation (Figures S5 and S6) similar to DLD-1 (Figure 2c). It confirms that the
structural variation at the R position does not affect the photoresponsiveness of DLD. We further examined
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may not affect the light
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the responsiveness of DLD-2 and DLD-3 to pH after light irradiation. These two molecules both exhibited a
rapid change in UV-vis absorbance at pH 5.0 (Figures S5 and S6). These results show that the two acetals
could undergo hydrolysis after DLD-2 and DLD-3 were sequentially exposed to light irradiation and acid
treatment.
While all of the three DLD molecules were responsive to light irradiation and acid treatment, their
hydrolysis profiles were significantly different (Figure 2f). By comparison, DLD-1 exhibited the fastest
hydrolysis kinetics with a half-life of 0.25 h and 33.1 h at pH 5.0 and pH 7.4, respectively (Figure 2g). DLD-
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exhibited the lowest hydrolysis kinetics with a half-life of 4.29 h and 163 h at 5.0 and pH 7.4, respectively
Figure 2g). DLD-2 fell in between DLD-1 and DLD-3. This difference is attributed to the structural variation
of R . In comparison to the R group of DLD-1, that of DLD-2 has an electron-withdrawing ester attached to
C3 of alcohol whereas that of DLD-3 has both the ester group and a shorter carbon chain that further enhances
the electron-withdrawing ability (Figure 2a). This observed effect of R on the hydrolysis of DLD is consistent
(
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with a previous report showing the pH sensitivity of acetals. Taken together, these results demonstrate the
feasibility of acquiring different hydrolysis kinetics through the molecular design of R
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.
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Hydrogels are crosslinked networks of hydrophilic polymers with a large amount of water. They are
viscoelastic with structural similarity to natural tissues. They can be developed in different forms such as
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particles, films, coatings and slabs. Thus, hydrogels are one of the most commonly studied materials for
various applications, particularly biomedical applications such as bioseparation, biosensing, drug delivery and
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regenerative medicine.
Great effort has been made in developing responsive hydrogels. After the
synthesis of the three DLD molecules and the demonstration of their responsiveness to light irradiation and
acid treatment, we used DLD-2 to synthesize a hydrogel to further test the hypothesis, i.e., the ability of using
DLD to control the programmable degradation of materials (Figure 3a). The hydrogel was exposed to four
different treatments including acid treatment (pH 5.0, 12 h), light irradiation (15 min, pH 7.4), acid treatment
(pH 5.0, 12 h) followed by light irradiation (15 min, pH 7.4), and light irradiation (15 min, pH 7.4) followed
by acid treatment (pH 5.0, 12 h). After these treatments, the morphology of hydrogels was examined with
SEM. In comparison to the fresh hydrogel without specific treatment, the hydrogels treated under the first three
conditions did not significantly exhibit large pore sizes (Figure 3b). By contrast, after sequentially exposed to
light irradiation and acid buffer, the entire hydrogel exhibited a macroporous structure (Figure 3b).
We further monitored the degradation of hydrogels using UV-vis and FT-IR spectroscopy. As shown in
Figure S7a, light irradiation led to an increase in the absorption at 335 nm that is a characteristic absorption
of the oxindole compound, and a concomitant change in the color of the hydrogel. It indicates the light-
activated formation of the acetal-oxindole intermediate. Figure S7b shows that the incubation of the light-
irradiated hydrogel in a solution of pH 5 led to a fast release of oxindole to the solution, demonstrating the
acid-catalyzed hydrolysis of the acetal unit. In contrast, the hydrogel without light activation did not show any
noticeable degradation in acidic solution (Figure S7b). The degradation of the hydrogel was further confirmed
by FT-IR spectroscopy (Figure S7c). We also prolonged the duration of stimulation and treated the hydrogel
sequentially with UV for 60 min and acid (pH 5) for 12 hours, finding that the whole hydrogel underwent
significant degradation and shape change (Figure S7d). Altogether, these data clearly demonstrate that
hydrogels with DLD can undergo fast degradation after sequentially exposed to light irradiation and acid
treatment whereas reversing the order of the two stimuli or only using individual stimulation does not lead to
fast degradation.
We further studied the feasibility of controlling degradation spatially. The hydrogels were covered with
photomasks, exposed to light irradiation, and immersed in a solution of pH 5.0. Depending on the patterns of
the photomasks, the hydrogels exhibited different patterns including dots, lines, grid and letters (Figure 3c).
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These results show that while the hydrogels were uniformly exposed to acid stimulation, their acid degradation
could be spatially and heterogeneously controlled.
As the permeability of a hydrogel is directly correlated to the pore size, the velocity of molecular transport
increases with the increase of pore size. Thus, to further confirm the SEM imaging analysis, we evaluated the
release of Cy3-labeled streptavidin from the hydrogels. Without light irradiation, the fluorescence intensity of
the hydrogel barely changed during the 24 h incubation in a solution of either pH 7.4 or pH 5.0 (Figure 3d).
After the hydrogel was exposed to light irradiation, its fluorescence intensity quickly decreased with time in
the solution of pH 5.0. After 60 h, the fluorescence intensity of the hydrogel at pH 5.0 decreased to 23%
whereas that at pH 7.4 decreased to 86% (Figure 3d). These results demonstrate that the transport of Cy3-
labeled streptavidin was significantly increased after the hydrogel was sequentially exposed to light irradiation
and acid treatment, confirming that the permeability and pore size of the hydrogel increased. These results also
demonstrate that the degradation of hydrogels with DLD can be temporally controlled.
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Figure 3. Evaluation of hydrogel degradation. (a) Schematic illustration of hydrogel synthesis and
degradation. (b) SEM images of hydrogels treated under different conditions. (c) Images of hydrogels after
sequentially exposed to patterned light irradiation and incubated in a buffer solution of pH 5.0. (d)
Representative fluorescence images of hydrogels (left) and intensity-time relationship (right). The hydrogels
were sequentially exposed to light irradiation and a buffer solution of pH 5.0 or 7.4.
Different from traditional designs with which each stimulus induces the cleavage of one bond for
degradation, the molecular design presented herein requires the cooperation of two stimuli for the control of
degradation. While this work is focused on the proof of the concept for programmable control of degradation,
this concept may find new applications that cannot be satisfied by traditional designs. For instance, a light-
pretreated hydrogel that initially possesses uniform integrity and properties can automatically acquire
heterogeneous structures when its microenvironment turns to be acidic. Such a transformation in response to
the environmental change may not be easily realized by using traditionally designed light- and/or pH-
responsive materials. Furthermore, quite a few organs and organelles naturally have an acidic environment,
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including skin, stomach, caecum, vagina, and endosome/lysosome. For instance, the pH of the skin surface
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is around 5. The skin is also directly exposed to the environment. There is a potential to design materials for
implantation and temporospatial control of drug delivery on the skin using the stimulation of light and acid.
However, it is important to note that UV penetration into deeper regions of a tissue is limited. This limitation
may be overcome by using near infrared (NIR) light that can penetrate tissues more deeply than UV light and
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upconversion nanoparticles that can convert NIR photons into UV light. These potential applications will be
explored in the future work.
In summary, we have successfully demonstrated the ability to control the degradation of hydrogels with
DLDs as the functional crosslinkers. These hydrogels undergo degradation after they are sequentially exposed
to two stimuli. They can maintain high integrity when the order of the two stimuli is reversed or only one
stimulus is applied. Notably, while we used light and pH as an example to demonstrate the design of hydrogels
with DLDs, it is possible to rationally design molecular structures that are responsive to other cooperative
stimuli such as light and enzymes. In addition to hydrogels, it is possible to extend this concept to synthesize
other types of DLD-bearing materials whose degradation can be temporospatially controlled.
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ACKNOWLEDGMENT
Research reported in this work was supported in part by the U.S. National Science Foundation (DMR-
322332) and the National Heart, Lung, and Blood Institute of the NIH (R01HL122311). We thank Mr. Letao
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Yang and the Husk Institute Microscopy Facility (University Park, PA) for technical support.
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TOC
Double-locked security: Programmable hydrogels with a double-locked domain are developed with the
ability to undergo rapid degradation after sequentially exposed to two stimuli. Reversing the order of the stimuli
or only using individual stimulation does not lead to comparable degradation.
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