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Preparation and Timed Release Properties of Self-Rupturing Gels Udaka K. de Silva, and Yakov Lapitsky ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b09370 • Publication Date (Web): 03 Oct 2016 Downloaded from http://pubs.acs.org on October 13, 2016

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ACS Applied Materials & Interfaces

Preparation and Timed Release Properties of Self-Rupturing Gels Udaka K. de Silva1 and Yakov Lapitsky1,2,* 1

Department of Chemical and Environmental Engineering, University of Toledo, Toledo, Ohio 43606

2

School of Green Chemistry and Engineering, University of Toledo, Toledo, Ohio 43606 *Corresponding Author: [email protected]

ABSTRACT: Swelling of polymeric hydrogels is sensitive to their crosslink densities. Here, we exploit this principle to prepare self-rupturing gels, which are based on a commonly-used, non-toxic and inexpensive polyelectrolyte, poly(acrylic acid) (PAA) and are prepared through a simple and low-cost, polymerization-based technique. The self-rupture of these covalently crosslinked gels is achieved by preparing them to have highly non-uniform crosslink densities. This heterogeneity in crosslinking leads to highly non-uniform swelling, which generates stresses that are high enough to induce gel rupture. The time required for this rupture to occur depends on the difference in the crosslink densities between the adjoining gel regions, gel size, order in which the variably-crosslinked gel portions are synthesized, and on the ambient pH and ionic strength. Furthermore, when these selfrupturing gels are prepared to have liquid-filled (capsule-like) morphologies, they can act as timed/delayed release devices. The self-rupture of these capsules provides a burst payload release after a pre-programmed delay, which is on the timescale of days and can be easily tuned by varying the rupture time – i.e., by varying either the crosslink nonuniformity, or the pH and ionic strength of the release media. Keywords: Self-rupturing, self-destructing, hydrogels, timed release, polyelectrolytes

1 ACS Paragon Plus Environment


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1. Introduction Polymeric hydrogels are water-rich, solid polymer networks that are held together by either chemical (covalent) or physical (ionic, hydrophobic or hydrogen bonded) crosslinks.1-3 They are widely used in applications ranging from healthcare,4-5 to household products (e.g., hygienic products, foods and cosmetics),6 to industrial process technologies.7-8 This broad utility stems from their attractive characteristics such as tunable mechanical,9 solute transport10 and swelling11 properties and – depending on the base polymer used – ability to form, change their properties or dissolve in response to external stimuli.12-14 Polyelectrolyte-based hydrogels make up an important class of these stimulusresponsive materials.12-15 Due to the high osmotic pressures mediated by their dissociated counterions, these gels tend to swell more than their uncharged counterparts.16-17 They are also responsive to changes in ionic strength13, 18 and, when their electrolyte groups are weak, pH12, 15 and temperature.14, 19 These environmentally-triggered volumetric transitions find widespread use in applications ranging from drug delivery,3,

20

to liquid absorption in

personal hygiene products,21 to gating (where upon swelling the expanded gels can block fluid flow),22-24 to actuating device design, where non-uniform swelling is used to alter the gel shape.25-27 This non-uniform swelling can be generated by either creating gradients in polyelectrolyte-binding solute concentrations28 or preparing gels with differential swelling properties – i.e., by preparing gels with non-uniform crosslinking29-31 or hydrogel bilayers composed of two dissimilarly-swelling polymer types.26-27, 32-33 In the case of the bilayers, for instance, the hydrogel essentially behaves like a bimetallic strip thermometer, where the differential swelling causes the highly-swelling gel layer to bend or fold around the lessswollen gel layer.26-27, 33 Besides this work on tailoring the hydrogel shape, there has been one excellent report that showed that non-uniform swelling could also be used to rupture covalent bonds.34 This


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was achieved using thin bilayers composed of two dissimilarly-swelling gel types, which were used to seal weakly-swelling, poly(hydroxyethyl methacrylate) (pHEMA) hydrogel containers. Specifically, the pHEMA containers were sealed with pHEMA/poly(methacrylic acid) (PMAA) bilayer films.34 The PMAA layers, which were highly-swelling, were attached to the pHEMA containers (by contacting their surfaces before the covalently crosslinked PMAA and pHEMA networks were fully polymerized), while the weaklyswelling pHEMA sides of the bilayer films were on the exterior. When these devices were placed in swelling media, the differential swelling in the bilayer films caused them to bend and generated enough stress to break the covalent bonds between the PMMA layers and pHEMA containers. Once this happened, the bilayer films peeled themselves away and released the container contents (thus also demonstrating the use of self-rupturing gels in delayed/timed release applications).34 In addition to these PMAA/pHEMA devices, there has been a broader interest in self-destructing capsules.35-39 De Geest et al., for example, prepared polyelectrolyte complex (PEC) capsules via layer-by-layer (LbL) assembly, using hydrolytically degradable microgels as the core and multilayers of two oppositely charged polyelectrolyte species as the shell.35-37 As the solvent-swollen microgel cores degraded and became less-densely crosslinked, they underwent further osmotic swelling, ruptured the polyelectrolyte capsule shells, and rapidly released their contents.35 Similarly, such self-destructing capsules have been prepared using biodegradable polymers.38-40 These relied on the co-encapsulation of enzymes, which tuned the release properties by degrading the capsule shells at controlled rates.38-40 As a simpler alternative, here we show that self-rupturing gels can be prepared using a single polymer type and without any hydrolytic or enzymatic reactions. This effect is achieved by preparing gels with highly non-uniform crosslinking. Though this approach can



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likely be extended to a wide array of other polyelectrolytes, we demonstrate its proof of concept using polyacrylic acid (PAA) – a common commercial polyelectrolyte that is nontoxic41-44 and is already used in household,45 pharmaceutical46-47 and industrial process technologies.48-49 Furthermore, because this self-rupturing functionality might be useful in controlled release applications,34 we show how these self-rupturing gels can be utilized in the delayed/timed release of active payloads, where all of the payload is rapidly released after a tunable, predetermined delay.

2. Results and Discussion 2.1. Preparation of Self-Rupturing Gels. Self-rupturing gels were prepared from PAA crosslinked with N,N-methylenebisacrylamide (MBA), by copolymerizing the acrylic acid (AA) monomer with the MBA crosslinker (see Scheme 1).43, 50-51 In addition to observing these covalently crosslinked gels visually, their successful formation was confirmed by Fourier transform infrared (FTIR) spectroscopy and mechanical testing (both performed on samples with uniform crosslink densities). The FTIR analysis qualitatively verified the presence of both MBA and AA within the gels (see Supporting Information, Figure S1)52 while the mechanical tests established that the gel stiffness, fracture strength and crosslink density increased with the MBA:AA ratio (see Supporting Information, Figure S2). Thus, consistent with previous studies,53-54 these measurements confirmed that the crosslink density could be effectively tuned by varying the MBA:AA ratios used during polymerization.


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Scheme 1. Reaction scheme for the formation of MBA-crosslinked PAA hydrogels. This polymerization used ammonium persulfate (APS) as the thermal initiator.

The formation of gels with non-uniform crosslink densities was then (in all but one experiment) achieved through a LbL approach, where the crosslinking in each gel layer was controlled by the MBA:AA molar ratios used in its synthesis. A two-part gel, for instance, was prepared using a two-step process where a gel layer with one MBA:AA molar ratio was first formed through thermoinitiated free radical polymerization (at 65 °C), whereupon a second monomer solution with a different MBA:AA molar ratio was poured on top of the first layer to add a second layer with dissimilar swelling properties (see Scheme 2). During this second step, AA and MBA diffusion between the second monomer solution and the first (bottom) gel layer caused polymerization at the interface, which tightly connected the two gel layers and produced a single macroscopic gel with a non-uniform crosslink density. This simple approach also enabled preparation of more complicated multi-part gels where, by sequentially polymerizing more (e.g., three, four or five) layers of monomer solutions with different MBA:AA ratios, gels with any numbers or sequences of dissimilarly-crosslinked layers could be prepared (see Supporting Information, Figure S3).



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Scheme 2. Formation of multi-part gels with non-uniform crosslink densities.

When placed in water, the non-uniform crosslinking caused these multi-part gels to have disparate swelling properties. This is illustrated in Figure 1 which shows that, when single-block gels were prepared, the weight-based swelling ratio (Wt/W0, defined as the weight of the gel normalized to its initial weight) increased much more drastically for sparsely crosslinked gels than for densely crosslinked gels. The gels prepared using a 0.005:1 MBA:AA molar ratio, for instance, swelled to 200 times their initial weight. Conversely, gels prepared using the highest, 0.10:1 MBA:AA molar ratio swelled much less, with their weight only doubling at equilibrium (though equilibrium swelling for these lessswollen gels was achieved much quicker). These swelling trends agreed well with previous findings55 and reflected a change in the balance between the osmotic forces within the polymer matrix (which favored swelling) and elastic forces (which opposed swelling).56 When crosslinking was sparse, the elastic forces were relatively-weak and the gels absorbed lots of solvent before these osmotic and elastic forces became balanced. When crosslinking was more-dense, however, the elastic forces were stronger and the balance between the osmotic and elastic ratios was achieved at much lower swelling extents.56 This difference in swelling between the adjacent parts of multi-part gels generated stress near the interface of their dissimilarly-crosslinked parts and – when this stress was high enough to overcome the


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strength of the covalent bonds holding these networks together – caused the gels to rupture (Figure 2).

100 Wt /W0

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10

1

0

1

2 Time (d)

3

Figure 1. Swelling behavior of hydrogels with 6-mm initial diameters prepared using () 0.005:1, () 0.01:1, () 0.03:1, () 0.05:1 and () 0.1:1 and MBA:AA ratios. The error bars are standard deviations and the lines are guides to the eye.

Figure 2. Scheme and digital photographs of two-part gels that undergo self-rupture in pH 6.0 water. The photographed gel was prepared in a 6-mm test tube using MBA:AA molar ratios of 0.01:1 in the (clear) sparsely crosslinked layer and 0.1:1 in the (opaque) densely crosslinked layer. The images were obtained after (i) 0 d, (ii) 1.5 d and (iii) 2.7 d of swelling time.

The rupture of these gels occurred near the interface and (unless the densely crosslinked gel layer was much thinner than the sparsely crosslinked gel layer) always took place within the layer with the lower crosslinker concentration. This rupture pattern likely



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reflected the layer of intermediate crosslink density that formed on the sparsely crosslinked side due to some diffusion of the crosslinker from the densely crosslinked layer during the formation process. Moreover, the fact that the rupture always occurred within one of the layers (rather than at the interface between them) confirmed that it was caused by the differential swelling stress and not by a weak interface. Indeed, self-rupture could even be achieved in single-part gels (where no such interface existed), provided that the MBA crosslinker was not uniformly mixed with the AA solution before the polymerization (see Figure 3). Because this single-step approach made the spatial distribution of crosslinks more difficult to control, however, it was not the focus of this study.

Figure 3. Digital photographs of a single-part gel with a non-uniform MBA distribution undergoing self-rupture in pH 6.0 water (overall MBA:AA molar ratio = 0.03:1). The crosslinking within these gels was much denser at the (opaque) bottom than at the (clear) top and the images were obtained after (i) 0 d, (ii) 1.0 d and (iii) 3.0 d of swelling time.

2.2. Effect of Crosslinker Nonuniformity and Size on Rupture Kinetics. The rupture kinetics were probed by preparing two-part gels using MBA:AA ratios (which were varied independently for each gel layer) ranging between 0.005 to 0.10:1. At certain combinations of MBA:AA ratios, where the crosslink nonuniformity (defined as the quotient of MBA:AA ratios in the densely and sparsely crosslinked layers) was low, no rupture occurred. This was because the stress caused by the differential swelling was insufficient to rupture the gels. When the nonuniformity was large, however, the gels ruptured within roughly 1 to 7 d of immersion in the swelling media (see Tables 1 and 2). The time required for this rupture to


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occur increased with the initial gel diameter, which was varied by preparing the gels in either 6 or 12-mm diameter test tubes (cf. Tables 1 and 2, and circles and squares in Figures 4a and b). This change in rupture kinetics likely reflected the longer times required for solvent uptake, which were diffusion-controlled and increased with the gel diameter.57 Thus, varying the gel size provides a potential approach to tuning the rupture kinetics. Table 1. Days required for the self-rupture of 6-mm two-part gels in an excess of pH 6.0 water (mean ± standard deviation). Diameter = 6 mm

Top MBA:AA Ratio

0.005 0.01 0.03 0.05 0.10

0.005 No rupture No rupture 1.98 ± 0.15 3.08 ± 0.08 2.02 ± 0.16

Bottom MBA:AA Ratio 0.01 0.03 0.05 1.17 ± 0.12 1.83 ± 0.11 2.92 ± 0.06 No rupture 1.92 ± 0.12 3.13 ± 0.30 No rupture No rupture No rupture No rupture 3.35 ± 0.14 No rupture 2.63 ± 0.12 4.79 ± 0.30 No rupture

0.10 1.94 ± 0.15 2.56 ± 0.21 4.10 ± 0.15 No rupture No rupture

Table 2. Days required for the self-rupture of 12-mm two-part gels in an excess of pH 6.0 water (mean ± standard deviation). Diameter = 12 mm

Top MBA:AA Ratio

0.005 0.01 0.03 0.05 0.10

0.005 No rupture No rupture 4.21 ± 0.13 6.38 ± 0.12 4.69 ± 0.15

Bottom MBA:AA Ratio 0.01 0.03 0.05 2.60 ± 0.15 3.13 ± 0.16 6.10 ± 0.10 No rupture 4.02 ± 0.09 6.88 ± 0.06 No rupture No rupture No rupture 7.06 ± 0.09 No rupture No rupture 5.79 ± 0.12 7.40 ± 0.15 No rupture

(b)

(a) 7

7

2

5 No Rupture

Rupture TIme (d)

3

No Rupture

5 4

0.010 4.42 ± 0.12 5.54 ± 0.12 6.98 ± 0.15 No rupture No rupture

6

6 Rupture Time (d)

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0

0 0 5 10 15 20 [MBA in Dense Block]/[MBA in Sparce Block]

0

5

10

15

20

[MBA in Dense Block]/[MBA in Sparse Block]

Figure 4. Rupture times of () 6-mm and () 12-mm gels when: (a) the MBA:AA ratio in the sparsely crosslinked layer was varied with the MBA:AA ratio in the densely crosslinked layer fixed at 0.10:1; and (b) the MBA:AA ratio in the densely crosslinked layer was varied with the MBA:AA ratio in the sparsely crosslinked layer fixed at 0.005:1. The error bars are standard deviations and the lines are guides to the eye. 9 ACS Paragon Plus Environment


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The rupture times of these hydrogels also varied with their crosslink nonuniformity. This nonuniformity was tuned by two methods: (1) changing the MBA:AA ratio in the sparsely crosslinked layer while keeping the densely crosslinked layer constant; and (2) changing the MBA:AA ratio in the densely crosslinked layer while keeping the sparsely crossliked layer constant. In the first scenario, an increase in the nonuniformity led to an expected decrease in rupture time (from roughly 7 to 4.5 d for the 12-mm gels and from roughly 4 to 2 d for the 6-mm gels; see Figure 4a). This decrease reflected both an increase in the differential swelling and a reduction in the sparsely crosslinked gel layer strength, both of which stemmed from a decrease in crosslinking within the sparsely crosslinked gel layer and caused the stress required for gel rupture to be achieved earlier. Conversely, in the second scenario the nonuniformity was controlled by varying the MBA concentration in the densely crosslinked layer. This resulted in a maximum in the rupture times being reached at intermediate crosslink nonuniformities (of roughly 10; see Figure 4b). As the nonunifomities were raised from 2.5 to 10, the rupture times increased instead of decreasing, but decreased (just like in Figure 4a) as the nonuniformities were increased further to 20. Here, crosslink nonunifromity was increased by raising the MBA concentration in the densely crosslinked gel layer. Thus, during the formation of gels with higher crosslink nonuniformities, there was more MBA available to diffuse between the adjoining gel blocks. This rise in MBA diffusion likely resulted in the gels being stronger near the interface between its layers and increased the stress required for rupture to occur. In other words, the increase in non-uniform swelling (which accelerated rupture) was opposed by an amplification in the rupture stress. This might explain why the rupture times decreased with the nonuniformities only at nonuniformity values above 10 – i.e., at lower MBA:AA molar ratios in the densely crosslinked layers, the increase in the gel strength may have


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outweighed the amplification in differential swelling, and therefore delayed rupture despite the higher swelling nonuniformity. The rupture times were also affected by the order in which the gels were prepared. When the bottom layers (i.e., the layers that were formed first) were sparsely crosslinked, the rupture times were higher than when the densely crosslinked sections were at the bottom (see Tables 1 and 2). Indeed, for the two-part gels prepared using either 0.005 and 0.01:1 MBA:AA molar ratios or 0.01 and 0.03:1 MBA:AA ratios, rupture only occurred when the more-densely crosslinked layers were polymerized first. This change in rupture properties likely stemmed from the “order of addition effect” on the MBA diffussion between the adjacent gel sections. When the bottom gel layers were sparsely crosslinked, the introduction of crosslinker-rich solution as the top layer caused the MBA (and AA) to diffuse into the bottom (sparsely crosslinked) gel sections. This diffussion (and subsequent polymerization) likely reduced the crosslink nonuniformity near the interaface, thus making the two-part gels more-resistant to rupture. Conversely, when the densely crosslinked layer was polymerized first (and the crosslinker-lean MBA/AA solution was poured on the top) most (if not all) of the MBA in the bottom gel layer was already polymerized by the time the second (crosslinklean) monomer mixture was added. This inhibited the diffusion of MBA from the (bottom) MBA-rich gel layer to the (top) MBA-lean layer, resulted in greater crosslink nonuniformity near the interface, and caused gel rupture to occur more readily.

2.3. Self-Rupturing Devices for Timed/Delayed Release. Devices for timed release were prepared using coaxially aligned test tubes (first step in Scheme 3) to obtain hollow cores within the first gel layers. These cores were then filled with a colloidal payload mixed with an aqueous 1 wt% methylcellulose (MC) solution, where self-assembled chitosan/ poly(styrene sulfonate) (PSS) particles (average diameter ≈ 200 - 300 nm) were used as the



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model payload material (see Supporting Information, Section D). PSS-based particles were chosen here for their ability to absorb UV light, which facilitated their detection by UV-Vis spectroscopy. Conversely, MC was used because it is a nontoxic thermogelling polymer that gels when heated (in this case to 65 °C) and reverts to its solution state when returned to room temperature (RT).58-59 This gelation prevents the second precursor MBA/AA solution (for the top gel layer) from being advected into and gelling inside the payload-bearing liquid core. Importantly, to enable the encapsulation of biological payloads that degrade at elevated temperatures (e.g., cells or proteins), the sol-gel transition temperature of these MC mixtures can be easily lowered to 30 - 40 °C by varying the MC concentration and degree of methylation (i.e., its “degree of substitution”), and by raising the ionic strength to physiological levels.58-59 Heating the payload-bearing bottom gel layer gelled its MC-filled core, allowing the precursor solution for the second gel layer to be poured (and polymerized) on top of the payload compartment (see Scheme 3). Upon cooling to RT, the MC core of these two-part gels melted to produce the final, liquid-core timed release devices.

Scheme 3. Formation of payload-bearing self-rupturing devices for timed release.

To start testing their timed release properties, these devices were placed into 500 mL of stirred pH 6.0 water, while monitoring the UV-Vis absorbance (for the presence of chitosan/PSS particles) over time. Swelling of these devices resulted in their self-rupture 12 ACS Paragon Plus Environment

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near the interface, which occurred on the timescale of days and released the entire payload into the external solution. This is shown in the schematic and photographs in Figure 5a where, after swelling, the densely crosslinked top layer breaks off and releases the colloidal particles, whereupon the opaque (particle-filled) payload compartment becomes clear. The time of this delayed release was easily tuned by varying the crosslink nonuniformity within the two-part delayed release devices. As the MBA:AA ratio of the sparsely-crosslinked payload compartment was progressively increased from 0.005 to 0.03:1, the crosslinking became more uniform and the time for rupture and release increased from roughly 1 to 2.5 d (Figures 5b and c). Each of these release profiles had a step-function shape where, before rupture, no colloidal particles (which were too large to diffuse through the hydrogel network) were released, while after rupture the entire payload was released almost instantaneously (Figure 5b). Interestingly, the rupture times obtained using these devices were shorter than those of the two-part gels without internal cavities (cf. Table 2 and Figure 5c), despite both gels having the same initial diameters. This was likely because the cavity reduced the gel layer thickness near the interface between the two gel parts, which dropped the characteristic, diffusion-controlled swelling time and accelerated gel rupture. This (along with the “gel thickness effects” described in Section 2.2) suggests that, in addition to varying crosslink dissimilarity, delay times for the payload release can be tuned by adjusting the size and internal morphology of the timed/delayed release devices.



(a)

(b) 0.14 0.12 Absorbance

0.10 0.08 0.06 0.04 0.02 0.00 0.0

0.5

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2.0

2.5

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Time (d)

(c) 2.5 Delay Before Release (d)

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2.0 1.5 1.0 0.5 0.0 0.005 0.01 0.03 MBA:AA Ratio in Payload Compartment

Figure 5. (a) Scheme and digital photographs of the timed release device rupture (where the MBA:AA ratios in the two gel parts are 0.03 and 0.10:1). The images were obtained after (i) 0 d, (ii) 1.0 d and (iii) 2.5 d of swelling time in pH 6.0 water. (b) Absorbance evolution with time for devices with a 0.10:1 MBA:AA ratio in the densely crosslinked block and () 0.005:1, () 0.01:1 and () 0.03:1 MBA:AA ratios in the sparsely crosslinked payload compartment. (c) Average delay times obtained at each payload compartment MBA:AA ratio. The error bars are standard deviations and the lines are guides to the eye.


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2.4. Stimulus-Responsive Rupture and Release Properties. The fact that these gels were based on a weak polyelectrolyte (PAA) enabled them to also respond to external stimuli, such as changes in pH and ionic strength.20, 60-63 At higher pH-values, for instance, PAA gels (whose effective pKa was roughly 6.5)64-67 swelled more due to the deprotonation/ionization of their carboxylic acid groups.12, 60 Accordingly, the rupture and timed release properties of these gels were pH-dependent. When the pH of the swelling media was increased from 6.0 to 9.0, the rupture and payload release occurred much faster (cf. black squares and blue circles in Figure 5a). Conversely, when the pH was reduced to 3.0 (i.e., below the effective pKa of PAA), the carboxylate groups were largely neutralized and the gels shrunk slightly instead of swelling. Since this minimized the non-uniform swelling, rupture and payload release did not occur under these conditions, and absorbance outside the gels remained unchanged even after 14 d of equilibration (red triangles in Figure 6a). This pH-sensitivity was similar to that obtained with the two-gel PMMA/pHEMA devices (described in the Introduction) where, due to the pH-sensitivity of PMMA, the bond rupture could be turned off at low pH.34 (a)

(b)

0.14

0.14

0.12

0.12

0.10

0.10

Absorbance

Absorbance

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0.08 0.06 0.04 0.02 0.00

0.08 0.06 0.04 0.02 0.00

0

1

2 Time (d)

14

0

1

2 3 Time (d)

14

Figure 6. Change in absorbance with time for devices with a 0.10:1 MBA:AA ratio in the densely crosslinked top layer and a 0.01:1 MBA:AA ratio in the sparsely crosslinked payload compartment at: (a) pH-values of () 3.0, () 6.0 and () 9.0 (and no added NaCl); and (b) in the presence of () 0 mM, () 50 mM and () 150 mM NaCl (at pH 6.0). The lines are guides to the eye. 15 ACS Paragon Plus Environment


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Because polyelectrolyte gel swelling decreases with the ionic strength,60 the rupture/timed release properties were also ionic strength dependent. When 50 and 150 mM NaCl was added to pH 6.0 swelling media, the rupture and payload release was noticeably delayed at 50 mM NaCl (cf. black squares and blue circles in Figure 6b) and – at least for the MBA:AA ratios used in this experiment – was altogether prevented at 150 mM NaCl (red triangles in Figure 6b). The pH and ionic strength sensitivity of these self-rupturing gels suggests that, in addition to enabling delayed rupture and payload release, these gels can self-destruct or release their payload on demand in response to changes in their external environments – i.e., where the devices remain intact over extended times, but undergo triggered rupture when the ambient pH or ionic strength changes.

2.5. Further Discussion. We have shown that polyelectrolyte gels with non-uniform crosslinking can self-rupture when placed in swelling media and that this behavior can be used to achieve delayed/timed release of colloidal payloads. This simplifies the preparation of self-rupturing gels by enabling their formation from a single polymer, rather than by covalently attaching hydrogels prepared from two chemically-distinct polymer species (e.g., PMMA and pHEMA) as was done previously.34 It also demonstrates that self-rupture can be achieved with macroscopic gels, rather than just with thin microscale sheets, which were utilized in the earlier work.34 Moreover, though the present study only used PAA as the base polymer, its strategy can likely be extended to other polyelectrolyte types – e.g., weak polycations, which would rupture more-readily at lower (rather than at higher) pH-levels; strong polyelectrolytes, which would be insensitive to pH; or (to make these devices more attractive for biomedical and environmental applications) polyelectrolytes that would eventually undergo enzymatic or hydrolytic degradation. Given these possibilities, the


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present findings significantly expand the range of self-rupturing gels that can be prepared and may ultimately broaden the diversity of their applications. In terms of their delayed/timed release performance, the ability to achieve selfrupture with macroscopic gels rather than thin sheets extends the delay in the release to days rather than tens of minutes (which were the rupture/delay times reported previously34). Further, though the delayed release in this work was restricted to colloidal payloads (i.e., species that were too large to penetrate through the hydrogel matrix),68 this technology can likely be extended to smaller payloads (e.g., small molecules or proteins) by coating the payload-bearing cavity within the delayed release device with a deformable diffusion barrier (which would remain intact during swelling until the gel ruptures). Putty-like coacervates formed via ionotropic gelation of poly(allylamine) with either tripolyphosphate or polyphosphate, for instance, have recently been shown to combine plasticity with its ability to extend the release of small hydrophilic molecules to multiple months,69 and it could be attractive to explore such coatings in future studies. As an outlook for possible future applications, the self-rupturing functionality might be useful for preventing industrial or government espionage (i.e., by enabling the synthesis of soft devices that self-destruct before falling into hostile hands). Moreover, it provides a simple and tunable approach to achieving timed/delayed release in many potential industrial, environmental or household technologies; especially those requiring longer, multi-hour or multi-day delay times. These could be incredibly diverse, and could range from the delayed release of reactants/catalysts into chemical reactors, to timed release of coagulants, adsorbents or biocidal agents for water treatment, to consumer products (e.g., devices for the delayed release of fish food into aquariums when pet owners travel).



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3. Conclusions Highly non-uniform crosslinking within polyelectrolyte gels enables these materials to self-rupture. This occurs due to differential swelling, which generates stresses that are strong enough to break covalent bonds. The times required for the gels to rupture can be readily tuned by varying the gel size, internal morphology and crosslink nonuniformity, as well as the order in which the densely and sparsely crosslinked portions are synthesized. The self-rupturing properties are also ionic strength and (at least for weak polyelectrolytes) pHdependent. Thus, gel rupture can be delayed or suppressed by either adjusting the pH to reduce the polyelectrolyte charge or adding salt. Furthermore, by preparing self-rupturing gels with payload-bearing liquid cores, delayed/timed release of active payloads can be achieved where (when the payload cavity walls are impermeable to the payload) the entire payload is released in a single burst, and the delay time can be easily tailored by varying the rupture kinetics. These self-rupturing properties might be useful for preparing selfdestructing soft devices and for a wide array of delayed/timed release technologies.

4. Experimental Section 4.1. Materials. All experiments were conducted using Millipore Direct-Q deionized water with a 18.2 MΩ·cm resistivity. AA, MBA, ammonium persulfate (APS), chitosan (viscosityaverage molecular weight ≈ 154 kDa; degree of deacetylation ≈ 0.86) and sodium poly(styrene sulphonate) (PSS; nominal molecular weight ≈ 70 kDa) were all purchased from Sigma-Aldrich (St. Louis, MO). MC (nominal molecular weight ≈ 63 kDa; degree of substitution ≈ 1.7) was obtained from MP Biomedicals (Solon, OH). All materials were used as received.


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4.2. Preparation of Single-Part Gels. To prepare single-part gels with uniform crosslink densities (for testing crosslinking effects on swelling), 20-mL aliquots of 1 M aqueous AA solutions were prepared and charged with MBA crosslinker at variable (0.005 - 0.10:1) MBA:AA molar ratios. APS was then added as a thermal initiator at a 0.01:1 APS:AA molar ratio, whereupon 1 mL of each mixture was deposited into a test tube and sealed with a rubber septum. Each tube was then purged with nitrogen to remove all oxygen and placed into a 65 °C water bath for 30 min to copolymerize the AA and MBA into a crosslinked PAA hydrogel. Finally, the samples were cooled to RT before the glass test tubes were broken to obtain the gels. To prepare single-part gels with non-uniform crosslink densities (i.e., single-part gels that self-rupture), 0.15 mmol of solid MBA crosslinker was added into 12-mm test tubes containing 5 mL of 1 M aqueous AA and APS initiator at a 0.01:1 APS:AA molar ratio. The headspace of these mixtures was then purged with nitrogen, after which the mixtures were placed into a 65 °C water bath without mixing the solution to fully completely dissolve the solid MBA. This resulted in a highly non-uniform MBA distribution during the polymerization and, consequently, hydrogels with a highly non-uniform crosslinking.

4.3. Preparation of Multi-Part Gels. To prepare multi-part self-rupturing gels, either 50 or 800-µL aliquots of precursor MBA/AA solutions (prepared as described above) were deposited into test tubes that were either 6 mm or 12 mm in diameter (where the solution volumes were adjusted to preserve the L/D = 1 aspect ratio of each gel layer; see Scheme 2). These tubes were then sealed with septa and purged with nitrogen, whereupon they were placed into a 65 °C water bath for 30 min to form the first gel layer. Once the hydrogels formed, 50 or 800-µL aliquots of a second precursor solution (with the same volume but a different MBA:AA molar ratio) was poured on top of the newly formed gels. The tubes were



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then again purged with nitrogen, and placed in the water bath for 30 more min to polymerize the second layer (Scheme 1). This resulted in gels composed of two parts with dissimilar crosslink densities. Similarly, to form gels that were composed of more than two parts, this layer-by-layer polymerization procedure was repeated more times.

4.4.

Spectroscopic

and

Mechanical

Characterization.

To

confirm

successful

incorporation of both AA and MBA into the hydrogels, single-part gels were characterized by Fourier transform (FTIR) infrared spectroscopy. Here, freshly prepared gels were washed in pH 6.0 water for 24 h (to remove any unreacted monomer) and dried at 40 °C for 24 h prior to being characterized by FTIR in a micro-attenuated total reflectance (ATR) mode. These measurements were performed using a germanium crystal background and a Varian Excalibur Series FTS-4000 FTIR spectrometer (Palo Alto, CA) equipped with a Digilab® UMA-600 infrared microscope (Marlborough, MA). A control spectrum for pure (uncrosslinked) PAA was also obtained by preparing PAA in the same manner as described in Section 4.2 except without any MBA. The polymerized solution was dialyzed twice for 24 h against 4 L of deionized water (using a Spectra/Por™ regenerated cellulose membrane; MWCO = 1000 Da), whereupon it was freeze-dried to obtain the purified solid PAA for the FTIR analysis. To also confirm that the hydrogel crosslink densities were successfully tuned by varying the parent monomer solution MBA:AA molar ratios, effects of MBA:AA molar ratio on their mechanical properties were measured using an Instron® 5566 Universal Testing Machine (Norwood, MA). The gels used in these measurements were prepared as described in Section 4.2 and cut into cylinders (2 mm in height, 6 mm in diameter). These samples were then washed in pH 6.0 water (which was exchanged daily) until they reached their equilibrium swelling. Compression testing of the equilibrated gels was then performed


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using a 100-N load cell and a 2 mm/min crosshead speed to find the Young’s modulus and the fracture stress of the hydrogel network. The Young’s moduli were then used to estimate the crosslink concentrations, ρx, via the elasticity theory as:53, 70-71

ρx =

E

(1)

1 2(1 + υ )RT  v p,3s   

where E was the hydrogel Young’s modulus, υ was the Poisson’s ratio, R was the universal gas constant, T was the absolute temperature and νp,s was the volume fraction of polymer in the swollen state, obtained as:53, 72 ν p,s =

(2)

1  ρp  1 + Q p,s    ρw 

where Qp,s was the equilibrium swelling ratio (given by the equilibrium weight of each gel divided by its dry weight; see Supporting Information, Table S1), and ρp and ρw were the polymer and water densities. The υ-value, which for similar gels typically ranges between 0.40 and 0.47,73-74 was approximated as 0.43. Each mechanical measurement used for these analyses was replicated six times.

4.5. Swelling and Rupture Analysis. To characterize the effect of MBA:AA ratio on gel swelling, uniformly crosslinked single-part gels were prepared (as described in Section 4.2) in 6-mm test tubes at MBA:AA ratios ranging between 0.005 and 0.10:1. These gels were then placed in 1-L beakers filled with pH 6.0 water (which was agitated with 50 mm × 10 mm magnetic stir bars at 150 rpm) and washed for 24 h. The stir bars were kept from damaging the hydrogels by placing homemade horizontal aluminum foil partitions inside the beakers. These partitions (which divided the beakers in half) kept the hydrogels elevated above the stir bars but left gaps at the sides to allow mixing. The evolution in swelling was then measured gravimetrically over time and the swelling media was replaced every 24 h to 21 ACS Paragon Plus Environment


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ensure that its pH, ionic strength and solute composition remained constant throughout each experiment. Prior to the weight measurements, the gels were carefully wiped with a Kimwipe® tissue to remove all surface water. The swelling ratios were then determined as the quotients of their swollen weights at the measurement time, Wt, and their initial weights, W0. The self-rupture properties of two-part gels were systematically investigated using the same experimental setup as that used to examine the MBA:AA ratio effects on gel swelling. Immediately after their preparation, non-uniformly crosslinked gels (with variable sizes and MBA:AA ratios) were allowed to swell in pH 6.0 water. At regular time intervals, these gels were very carefully removed from the swelling media and visually inspected for rupture (whereupon the time when the gels broke into two fragments was recorded as the rupture time). Each swelling and self-rupture experiment was repeated three times.

4.5. Preparation of Delayed/Timed Release Devices. To prepare two-part gels with payload-bearing liquid compartments, homemade molds were constructed by placing 6-mm test tubes inside 12-mm test tubes (so that the two tubes were coaxially aligned). The gel layers with a lower MBA:AA ratio (of either 0.005, 0.01 or 0.03:1) were then formed within the annular spaces between the tubes (see Scheme 3). Once formed, these gel layers were cooled to RT and the 6-mm inner test tubes were carefully removed (without damaging the gels) to produce cavities within the hydrogels. These cavities were then filled to the brim with a payload-bearing 1 wt% MC solution (using 0.1 wt% of colloidal chitosan/PSS particles as the model payload; see Supporting Information, Section D for details on particle preparation and analysis). The test tubes were then sealed and placed into a 65 °C water bath for 15 min to gel the MC. Once the payload-bearing cavities within the PAA gels solidified, the precursor MBA/AA solutions with the higher MBA:AA ratio of 0.10:1 was poured on


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top, to prepare the second gel layer that would seal the payload compartments (Scheme 3). The test tubes were then once again sealed and heated for 30 min to polymerize the top portions of the two-part hydrogels. Finally, the test tubes were allowed to cool to RT (whereupon MC became a liquid again) and were broken to yield the final, liquid-core delayed release devices.

4.6. Release Experiments. The delayed/timed devices were allowed to swell in 500 mL of water at a pH of either 3.0, 6.0 or 9.0 and either 0, 50 or 150 mM NaCl (at pH 6.0). The apparent UV absorbance of the receiving medium was then measured at regular intervals using a Varian Cary 50 (Sparta, NJ) spectrophotometer (λ = 255 nm) to detect the released chitosan/PSS particles. The delay times before the payload release were determined as the times where the apparent absorbance suddenly jumped from their baseline values (of roughly 0.01) to above 0.10, which corresponded to the times where rupture of the payloadbearing gels was visually observed. Each release experiment was reproduced three times.

Supporting Information. Images of multi-part gels with alternating crosslink densities; preparation and dynamic light scattering (DLS) characterization of colloidal chitosan/PSS particles. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgement. The authors gratefully acknowledge the National Science Foundation (CBET-1150908) for supporting this work.



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References (1) Berger, J.; Reist, M.; Mayer, J. M.; Felt, O.; Peppas, N. A.; Gurny, R. Structure and Interactions in Covalently and Ionically Crosslinked Chitosan Hydrogels for Biomedical Applications. Eur. J. Pharm. Biopharm. 2004, 57, 19-34. (2) Hoare, T. R.; Kohane, D. S. Hydrogels in Drug Delivery: Progress and Challenges. Polymer 2008, 49, 1993-2007. (3) Gupta, P.; Vermani, K.; Garg, S. Hydrogels: From Controlled Release to pH-Responsive Drug Delivery. Drug Discovery Today 2002, 7, 569-579. (4) Peppas, N. A. Hydrogels and Drug Delivery. Curr. Opin. Colloid Interface Sci. 1997, 2, 531-537. (5) Drury, J. L.; Mooney, D. J. Hydrogels for Tissue Engineering: Scaffold Design Variables and Applications. Biomaterials 2003, 24, 4337-4351. (6) Darnell, M. C.; Sun, J.-Y.; Mehta, M.; Johnson, C.; Arany, P. R.; Suo, Z.; Mooney, D. J. Performance and Biocompatibility of Extremely Tough Alginate/Polyacrylamide Hydrogels. Biomaterials 2013, 34, 8042-8048. (7) Jing, G.; Wang, L.; Yu, H.; Amer, W. A.; Zhang, L. Recent Progress on Study of Hybrid Hydrogels for Water Treatment. Colloids Surf., A 2013, 416, 86-94. (8) Dzinomwa, G. P. T.; Wood, C. J.; Hill, D. J. T. Fine Coal Dewatering Using pH- and Temperature-Sensitive Superabsorbent Polymers. Polym. Adv. Technol. 1997, 8, 767-772. (9) Wang, L.-S.; Chung, J. E.; Pui-Yik Chan, P.; Kurisawa, M. Injectable Biodegradable Hydrogels with Tunable Mechanical Properties for the Stimulation of Neurogenesic Differentiation of Human Mesenchymal Stem Cells in 3D Culture. Biomaterials 2010, 31, 1148-1157. (10) Adrus, N.; Ulbricht, M. Novel Hydrogel Pore-Filled Composite Membranes with Tunable and Temperature-Responsive Size-Selectivity. J. Mater. Chem. 2012, 22, 30883098. (11) Gan, D.; Lyon, L. A. Tunable Swelling Kinetics in Core−Shell Hydrogel Nanoparticles. J. Am. Chem. Soc. 2001, 123, 7511-7517. (12) Jin, X.; Hsieh, Y.-L. pH-Responsive Swelling Behavior of Poly(vinyl alcohol)/Poly(acrylic acid) Bi-Component Fibrous Hydrogel Membranes. Polymer 2005, 46, 5149-5160. (13) Kozlovskaya, V.; Kharlampieva, E.; Mansfield, M. L.; Sukhishvili, S. A. Poly(methacrylic acid) Hydrogel Films and Capsules: Response to pH and Ionic Strength, and Encapsulation of Macromolecules. Chem. Mater. 2006, 18, 328-336. (14) Chen, H.; Fan, M. Novel Thermally Sensitive pH-Dependent Chitosan/ Carboxymethyl Cellulose Hydrogels. J. Bioact. Compat. Polym. 2008, 23, 38-48. (15) Khare, A. R.; Peppas, N. A. Swelling/Deswelling of Anionic Copolymer Gels. Biomaterials 1995, 16, 559-567.


Page 25 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(16) Flory, P. J. Principles of Polymer Chemistry. 1 ed.; Cornell University Press: Ithaca, NY, 1953. (17) Okay, O.; Durmaz, S. Charge Density Dependence of Elastic Modulus of Strong Polyelectrolyte Hydrogels. Polymer 2002, 43, 1215-1221. (18) Zhu, Y.; Shi, J.; Shen, W.; Dong, X.; Feng, J.; Ruan, M.; Li, Y. Stimuli-Responsive Controlled Drug Release from a Hollow Mesoporous Silica Sphere/Polyelectrolyte Multilayer Core–Shell Structure. Angew. Chem. 2005, 117, 5213-5217. (19) Lowe, T. L.; Tenhu, H. Interactions of Thermally Responsive Polyelectrolyte Latices with Low Molar Mass Organic Molecules Studied by Light Scattering. Macromolecules 1998, 31, 1590-1594. (20) Qiu, Y.; Park, K. Environment-Sensitive Hydrogels for Drug Delivery. Adv. Drug Delivery Rev. 2001, 53, 321-339. (21) Buchholz, F. L.; Pesce, S. R.; Powell, C. L. Deswelling Stresses and Reduced Swelling of Superabsorbent Polymer in Composites of Fiber and Superabsorbent Polymers. J. Appl. Polym. Sci. 2005, 98, 2493-2507. (22) Tokarev, I.; Minko, S. Stimuli-Responsive Porous Hydrogels at Interfaces for Molecular Filtration, Separation, Controlled Release, and Gating in Capsules and Membranes. Adv. Mater. 2010, 22, 3446-3462. (23) Park, Y. S.; Ito, Y.; Imanishi, Y. pH-Controlled Gating of a Porous Glass Filter by Surface Grafting of Polyelectrolyte Brushes. Chem. Mater. 1997, 9, 2755-2758. (24) Gargava, A.; Arya, C.; Raghavan, S. R. Smart Hydrogel-Based Valves Inspired by the Stomata in Plants. ACS Appl. Mater. Interfaces 2016, 8, 18430-18438. (25) Ionov, L. Biomimetic Hydrogel-Based Actuating Systems. Adv. Funct. Mater. 2013, 23, 4555-4570. (26) Guan, J.; He, H.; Hansford, D. J.; Lee, L. J. Self-Folding of Three-Dimensional Hydrogel Microstructures. J. Phys. Chem. B 2005, 109, 23134-23137. (27) Guan, J.; He, H.; Lee, L. J.; Hansford, D. J. Fabrication of Particulate ReservoirContaining, Capsulelike, and Self-Folding Polymer Microstructures for Drug Delivery. Small 2007, 3, 412-418. (28) Osada, Y.; Okuzaki, H.; Hori, H. A Polymer Gel with Electrically Driven Motility. Nature 1992, 355, 242-244. (29) Kim, J.; Hanna, J. A.; Byun, M.; Santangelo, C. D.; Hayward, R. C. Designing Responsive Buckled Surfaces by Halftone Gel Lithography. Science 2012, 335, 1201-1205. (30) Trujillo, V.; Kim, J.; Hayward, R. C. Creasing Instability of Surface-Attached Hydrogels. Soft Matter 2008, 4, 564-569. (31) Bae, J.; Na, J.-H.; Santangelo, C. D.; Hayward, R. C. Edge-Defined Metric Buckling of Temperature-Responsive Hydrogel Ribbons and Rings. Polymer 2014, 55, 5908-5914.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 29

(32) Wei, Z.; Jia, Z.; Athas, J.; Wang, C.; Raghavan, S. R.; Li, T.; Nie, Z. Hybrid Hydrogel Sheets that Undergo Pre-Programmed Shape Transformations. Soft Matter 2014, 10, 81578162. (33) Hu, Z.; Zhang, X.; Li, Y. Synthesis and Application of Modulated Polymer Gels. Science 1995, 269, 525-527. (34) He, H.; Cao, X.; Lee, L. J. Design of a Novel Hydrogel-Based Intelligent System for Controlled Drug Release. J. Controlled Release 2004, 95, 391-402. (35) De Geest, B. G.; Déjugnat, C.; Verhoeven, E.; Sukhorukov, G. B.; Jonas, A. M.; Plain, J.; Demeester, J.; De Smedt, S. C. Layer-By-Layer Coating of Degradable Microgels for Pulsed Drug Delivery. J. Controlled Release 2006, 116, 159-169. (36) De Geest, B. G.; Déjugnat, C.; Prevot, M.; Sukhorukov, G. B.; Demeester, J.; De Smedt, S. C. Self-Rupturing and Hollow Microcapsules Prepared from Bio-polyelectrolyte-Coated Microgels. Adv. Funct. Mater. 2007, 17, 531-537. (37) De Geest, B. G.; Déjugnat, C.; Sukhorukov, G. B.; Braeckmans, K.; De Smedt, S. C.; Demeester, J. Self-Rupturing Microcapsules. Adv. Mater. 2005, 17, 2357-2361. (38) Borodina, T.; Markvicheva, E.; Kunizhev, S.; Möhwald, H.; Sukhorukov, G. B.; Kreft, O. Controlled Release of DNA from Self-Degrading Microcapsules. Macromol. Rapid Commun. 2007, 28, 1894-1899. (39) Dowling, M. B.; Bagal, A. S.; Raghavan, S. R. Self-Destructing “Mothership” Capsules for Timed Release of Encapsulated Contents. Langmuir 2013, 29, 7993-7998. (40) Itoh, Y.; Matsusaki, M.; Kida, T.; Akashi, M. Enzyme-Responsive Release of Encapsulated Proteins from Biodegradable Hollow Capsules. Biomacromolecules 2006, 7, 2715-2718. (41) Xiong, L.; Yang, T.; Yang, Y.; Xu, C.; Li, F. Long-Term in Vivo Biodistribution Imaging and Toxicity of Polyacrylic Acid-Coated Upconversion Nanophosphors. Biomaterials 2010, 31, 7078-7085. (42) Dorkoosh, F. A.; Setyaningsih, D.; Borchard, G.; Rafiee-Tehrani, M.; Verhoef, J. C.; Junginger, H. E. Effects of Superporous Hydrogels on Paracellular Drug Permeability and Cytotoxicity Studies in Caco-2 Cell Monolayers. Int. J. Pharm. 2002, 241, 35-45. (43) Chen, Y.; Zheng, X.; Qian, H.; Mao, Z.; Ding, D.; Jiang, X. Hollow Core−Porous Shell Structure Poly(acrylic acid) Nanogels with a Superhigh Capacity of Drug Loading. ACS Appl. Mater. Interfaces 2010, 2, 3532-3538. (44) Argentiere, S.; Blasi, L.; Ciccarella, G.; Barbarella, G.; Cingolani, R.; Gigli, G. Nanogels of Poly(acrylic acid): Uptake and Release Behavior with Fluorescent Oligothiophene-Labeled Bovine Serum Albumin. J. Appl. Polym. Sci. 2010, 116, 2808-2815. (45) Sonneville-Aubrun, O.; Simonnet, J. T.; L'Alloret, F. Nanoemulsions: A New Vehicle for Skincare Products. Adv. Colloid Interface Sci. 2004, 108–109, 145-149. (46) Hu, Y.; Ding, Y.; Ding, D.; Sun, M.; Zhang, L.; Jiang, X.; Yang, C. Hollow Chitosan/Poly(acrylic acid) Nanospheres as Drug Carriers. Biomacromolecules 2007, 8, 1069-1076. 26 ACS Paragon Plus Environment

Page 27 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(47) Lehr, C.-M.; Bouwstra, J. A.; Tukker, J. J.; Junginger, H. E. Intestinal Transit of Bioadhesive Microspheres in an In-Situ Loop in the Rat—A Comparative Study with Copolymers and Blends Based on Poly(acrylic acid). J. Controlled Release 1990, 13, 51-62. (48) Hasson, D.; Shemer, H.; Sher, A. State of the Art of Friendly “Green” Scale Control Inhibitors: A Review Article. Ind. Eng. Chem. Res. 2011, 50, 7601-7607. (49) Amjad, Z. Effect of Precipitation Inhibitors on Calcium Phosphate Scale Formation. Can. J. Chem. 1989, 67, 850-856. (50) Yan, S.; Wu, Q.; Chang, A.; Lu, F.; Xu, H.-C.; Wu, W. Electrochemical Synthesis of Polymer Microgels. Polym. Chem. 2015, 6, 3979-3987. (51) Yu, Y.; Peng, R.; Yang, C.; Tang, Y. Eco-Friendly and Cost-Effective Superabsorbent Sodium Polyacrylate Composites for Environmental Remediation. J. Mater. Sci. 2015, 50, 5799-5808. (52) Dong, J.; Ozaki, Y.; Nakashima, K. Infrared, Raman, and Near-Infrared Spectroscopic Evidence for the Coexistence of Various Hydrogen-Bond Forms in Poly(acrylic acid). Macromolecules 1997, 30, 1111-1117. (53) Anseth, K. S.; Bowman, C. N.; Brannon-Peppas, L. Mechanical Properties of Hydrogels and their Experimental Determination. Biomaterials 1996, 17, 1647-1657. (54) Johnson, B. D.; Beebe, D. J.; Crone, W. C. Effects of Swelling on the Mechanical Properties of a pH-Sensitive Hydrogel for Use in Microfluidic Devices. Mater. Sci. Eng., C 2004, 24, 575-581. (55) Eichenbaum, G. M.; Kiser, P. F.; Dobrynin, A. V.; Simon, S. A.; Needham, D. Investigation of the Swelling Response and Loading of Ionic Microgels with Drugs and Proteins: The Dependence on Cross-Link Density. Macromolecules 1999, 32, 4867-4878. (56) Rubinstein, M.; Colby, R. H.; Dobrynin, A. V.; Joanny, J.-F. Elastic Modulus and Equilibrium Swelling of Polyelectrolyte Gels. Macromolecules 1996, 29, 398-406. (57) Tanaka, T.; Fillmore, D. J. Kinetics of Swelling of Gels. J. Chem. Phys. 1979, 70, 1214-1218. (58) Hirrien, M.; Chevillard, C.; Desbrières, J.; Axelos, M. A. V.; Rinaudo, M. Thermogelation of Methylcelluloses: New Evidence for Understanding the Gelation Mechanism. Polymer 1998, 39, 6251-6259. (59) Tate, M. C.; Shear, D. A.; Hoffman, S. W.; Stein, D. G.; LaPlaca, M. C. Biocompatibility of Methylcellulose-Based Constructs Designed for Intracerebral Gelation Following Experimental Traumatic Brain Injury. Biomaterials 2001, 22, 1113-1123. (60) Elliott, J. E.; Macdonald, M.; Nie, J.; Bowman, C. N. Structure and Swelling of Poly(acrylic acid) Hydrogels: Effect of pH, Ionic Strength, and Dilution on the Crosslinked Polymer Structure. Polymer 2004, 45, 1503-1510. (61) Philippova, O. E.; Hourdet, D.; Audebert, R.; Khokhlov, A. R. pH-Responsive Gels of Hydrophobically Modified Poly(acrylic acid). Macromolecules 1997, 30, 8278-8285.



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(62) Shibayama, M.; Ikkai, F.; Inamoto, S.; Nomura, S.; Han, C. C. pH and Salt Concentration Dependence of the Microstructure of Poly(N-isopropylacrylamide-co-acrylic acid) Gels. J. Chem. Phys. 1996, 105, 4358-4366. (63) Gudeman, L. F.; Peppas, N. A. Preparation and Characterization of pH-Sensitive, Interpenetrating Networks of Poly(vinyl alcohol) and Poly(acrylic acid). J. Appl. Polym. Sci. 1995, 55, 919-928. (64) Charman, W. N.; Christy, D. P.; Geunin, E. P.; Monkhouse, D. C. Interaction Between Calcium, a Model Divalent Cation, and a Range of Poly(acrylic acid) Resins as a Function of Solution pH. Drug Dev. Ind. Pharm. 1991, 17, 271-280. (65) Nekrasova, T. N.; Anufriyeva, Y. V.; Yel'yashevich, A. M.; Ptitsyn, O. B. Potentiometric Titration of Polyacrylic Acid, Polymethacrylic Acid and Poly-l-glutamic acid. Polym. Sci. U.S.S.R. 1965, 7, 1008-1018. (66) Katchalsky, A.; Spitnik, P. Potentiometric Titrations of Polymethacrylic Acid. J. Polym. Sci. 1947, 2, 432-446. (67) Petrov, A. I.; Antipov, A. A.; Sukhorukov, G. B. Base−Acid Equilibria in Polyelectrolyte Systems: From Weak Polyelectrolytes to Interpolyelectrolyte Complexes and Multilayered Polyelectrolyte Shells. Macromolecules 2003, 36, 10079-10086. (68) am Ende, M. T.; Peppas, N. A. Transport of Ionizable Drugs and Proteins in Crosslinked Poly(acrylic acid) and Poly(acrylic acid-co-2-hydroxyethyl methacrylate) Hydrogels. II. Diffusion and Release Studies. J. Controlled Release 1997, 48, 47-56. (69) Lawrence, P. G.; Patil, P. S.; Leipzig, N. D.; Lapitsky, Y. Ionically Cross-Linked Polymer Networks for the Multiple-Month Release of Small Molecules. ACS Appl. Mater. Interfaces 2016, 8, 4323-4335. (70) Metters, A. T.; Anseth, K. S.; Bowman, C. N. Fundamental Studies of a Novel, Biodegradable PEG-b-PLA Hydrogel. Polymer 2000, 41, 3993-4004. (71) Sperling, L. H. Introduction to Physical Polymer Science. 2 ed.; John Wiley and Sons Inc.: Hoboken, NJ, 1992. (72) Jabbari, E.; Nozari, S. Swelling Behavior of Acrylic Acid Hydrogels Prepared by γRadiation Crosslinking of Polyacrylic Acid in Aqueous Solution. Eur. Polym. J. 2000, 36, 2685-2692. (73) Urayama, K.; Takigawa, T.; Masuda, T. Poisson's Ratio of Poly(Vinyl Alcohol) Gels. Macromolecules 1993, 26, 3092-3096. (74) Takigawa, T.; Morino, Y.; Urayama, K.; Masuda, T. Poisson's Ratio of Polyacrylamide (PAAm) Gels. Polym. Gels Networks 1996, 4, 1-5.


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Preparation and Timed Release Properties of Self ... - ACS Publications

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