Dynamic Covalent Star Poly(ethylene glycol) Model Hydrogels: A New

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Dynamic Covalent Star Poly(ethylene glycol) Model Hydrogels: A New Platform for Mechanically Robust, Multifunctional Materials Demetris E. Apostolides,† Takamasa Sakai,‡ and Costas S. Patrickios*,† †

Department of Chemistry University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan

‡

S Supporting Information *

ABSTRACT: We develop a new platform of dynamic covalent model polymer networks comprising two types of four-armed star poly(ethylene glycol)s (tetraPEG), one end-functionalized with benzaldehyde groups and the other with benzaacylhydrazides, resulting in hydrazone cross-links. These materials, henceforth to be called tetraPEG DYNAgels, display remarkable mechanical properties, much superior to those based on randomly cross-linked analogues. Fast aqueous gel formation takes place both at acidic and, unexpectedly, at alkaline conditions, with gel formation times covering 4 orders of magnitude in the pH range from 2.0 to 12.5 and a maximum gelation time appearing at pH 8.5. Frequency-dependent oscillatory rheology indicates a finite lifetime of the cross-links in tetraPEG DYNAgels at acidic conditions. Furthermore, these materials exhibit self-healing ability and reversibility under acidic and moderately acidic conditions; however, these properties can be canceled by chemical reduction of the cross-links. The system is highly modular, allowing the facile incorporation of other functionalities, e.g., hydrophobicity or amphiphilicity, introduced via polymers bearing terminal benzaldehyde groups.

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cleaved, and, more importantly, self-heal.12,13 This type of network recently emerged and complemented the also important areas of hydrogen-bonding,14 ion-pair-linked,15,16 thermogelling,17−19 supramolecular,20,21 and metal-linked22−24 gels. Common dynamic covalent bonds25 are found in boronic acid esters,26,27 Diels−Alder adducts, disulfides, oximes,28 and Schiff bases and hydrazones.29 Of particular interest are hydrazone groups, presenting high stability at neutral and alkaline pH conditions and exchange and reversibility at acidic conditions. These groups have recently been employed as cross-links in several dynamic covalent organogels,30−33 hydrogels,34,35 and hybrid organohydrogels.36 The aim in this work is to introduce dynamic covalent links in tetraPEG gels, so that well-defined structure and enhanced mechanical properties are combined with reversibility and selfhealing ability. Another important aim is to demonstrate the modularity of this highly hydrophilic system by readily introducing hydrophobic or amphiphilic components through appropriately functionalized polymers.

INTRODUCTION Model polymer networks represent an important class of polymeric materials, with precisely defined and known size of the constituting polymer chains and functionality of the core, allowing the derivation of accurate structure−property relationships and the validation of relevant thermodynamic and dynamic theories.1,2 Since the first appearance of these materials in the 1970s until 2008, their preparation involved the reaction between end-functionalized polymers with lowmolecular-weight linkers. In 2008, the development of “tetraPEG gels” was reported by us,3 resulting from the combination of two polymeric components, telechelic fourarmed star poly(ethylene glycol)s (“tetraPEG stars”), one endfunctionalized with primary amine groups and the other with the chemically complementary succinimide groups, leading to the formation of amide cross-links and gelation. The constitution of tetraPEG gels of both polymeric components minimizes loop formation,4,5 keeping the density of the elastic chains close to ideal. Moreover, the fact that the end-groups are reactive with the end-groups of the other type of star polymers but not with their own kind further reduces loop formation and also slows down the gelation reaction,6 reducing the occurrence of local heterogeneities and thus enhancing the mechanical properties. Since the first report in 2008, many studies have been published on the formation, structure, swelling, and mechanical properties of tetraPEG gels.7,8 Another timely area is that of polymer networks cross-linked with dynamic covalent bonds,9−11 which can be reversibly © XXXX American Chemical Society

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EXPERIMENTAL SECTION

For experimental details, see the Supporting Information. Received: February 2, 2017 Revised: February 20, 2017

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DOI: 10.1021/acs.macromol.7b00236 Macromolecules XXXX, XXX, XXX−XXX

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Scheme 1. Synthetic Route Followed for the Preparation of the TetraPEG DYNAgels, Starting from the Hydroxyl EndFunctionalized Four-Armed Star Poly(ethylene glycol)s

Figure 1. 1H NMR spectra in CDCl3 of (I) tetraPEG-OH, (II) TMPEG, and (III) TBPEG.

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RESULTS AND DISCUSSION Hydrazones based on aryl-substituted hydrazides and arylsubstituted aldehydes were chosen as the dynamic covalent groups. Scheme 1 illustrates the various synthetic steps followed for the preparation of the dynamic covalent tetraPEG gels, henceforth to be referred to as “tetraPEG DYNAgels”, using hydroxyl end-functionalized four-armed star poly-

(ethylene glycol)s (PEG) of number-average molecular weight of 10 000 g mol−1 as starting materials. The sufficient length of the PEG segments (2500 g mol−1 per arm) secured the water solubility of both end-functionalized star polymers, particularly the more hydrophobic benzaldehyde end-functionalized one. Thus, all reactions for gel formation can be performed in purely aqueous media. B


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Figure 2. 1H NMR spectra of (I) tetraPEG-OH in CDCl3, (II) TMPEG in CDCl3, (III) TBPAHPEG in d6-DMSO, and (IV) TBAHPEG in d6DMSO.

Figure 3. Temporal evolution of the storage modulus (G′) and loss modulus (G″) followed using rheology during the formation of the tetraPEG DYNAgels in aqueous buffer solutions of pH (a) 2.0, 4.5, and 12.5 and (b) 11.5.

Figure 4. Tube inversion experiments confirming the formation of tetraPEG DYNAgels across the whole pH range. (a) Before gel formation. (b) After gel formation. Sample coloration is due to the presence of small amounts of universal pH indicator.

C


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Macromolecules The synthesis first involved the activation of the hydroxyl end-groups of the PEG stars via mesylation,37 followed by displacement of the mesyl group either by an aldehydic phenol or by an aldehyde-protected acylhydrazide phenol;38 the latter derivative was converted to the benzaacylhydrazide derivative via hydrazinolysis. All end-functionalizations were driven to 100% using (large) excess of end-functionalization reagents; reported yields in the Supporting Information refer to recovery percentages, but purities were ∼100% in all cases. The 1H NMR spectra of tetrabenzaldehyde tetraPEG (TBPEG) and tetrabenzaacylhydrazide tetraPEG (TBAHPEG) (as well as those of their precursors) are given in Figures 1 and 2, respectively, whereas the reaction for the synthesis of the benzaldehyde-protected benzaacylhydrazide phenol and related 1 H NMR spectra are given in Figures S1 and S2, respectively, of the Supporting Information. The GPC traces and molecular weights for all tetraPEG stars are provided in Figure S3 and Table S1, respectively. Combination of stoichiometric amounts of the mutually reactive tetrabenzaacylhydrazide end-functional (TBAHPEG) and the tetrabenzaldehyde end-functional (TBPEG) tetraPEGs (15% w/v in water), catalyzed by acetic acid (final solution pH ∼ 3.5), led to gel formation within minutes, as concluded via tube inversion and rheology experiments. The effect of pH was systematically investigated within the range 2.0−12.5, using various aqueous buffers (phosphoric acid for pH ∼ 2, glacial acetic acid/sodium acetate for pH 4.5, sodium phosphate dibasic/sodium phosphate monobasic monohydrate for pH 7.0 and 8.5, sodium carbonate/sodium hydrogen carbonate for pH 10.0, boric acid/sodium hydroxide for pH 11.5, and potassium phosphate tribasic for pH ∼ 12.5) with buffering salt concentrations of 200 mM in all cases, an order of magnitude higher than the final concentration of each type of reactive star polymer end-group of 30 mM, using again the tube inversion test39 but also rheology for the pH values for which gelation times were 20 min or shorter. The temporal evolution of the elastic, G′, and viscous, G″, parts of the complex shear modulus during gel formation as followed by rheology at four different values of pH is shown in Figure 3, while the appearance of the samples before and after gel formation at all seven values of pH is illustrated in Figure 4; in these latter experiments, 2−3 drops of universal pH indicator were added to each pair of TBAHPEG-TBPEG sample solutions before mixing, so that the pH of each sample is also recognized from its color. Figure 5 plots the results of gel formation times determined by rheology and tube inversion against sample pH. Very fast gelation occurred at extreme pH values, 2.0 and 12.5, with the network forming within minutes. Gelation also occurred at intermediate pH values, but that required significantly longer

reaction periods, with the maximum observed at pH 8.5 where gel formation took 55 h. The low-pH branch was as expected from the literature, according to which hydrazone bond formation is catalyzed by the presence of acid.30−35,40 Surprisingly, the high-pH branch was almost symmetrical to the low-pH one, with gelation times minimized at highest pH. It is noteworthy that previous studies on aryl-substituted hydrazones went only up to pH 7.0 where the reaction rate was still very low.34 It is also noteworthy that the opposite trend with respect to pH was observed with aliphatic hydrazones where a maximum reaction rate was recorded at pH 7 (experiments performed within the pH range between 5 and 10).35 At alkaline conditions, the formation of hydrazone follows a mechanism41 different from the one operating at acidic conditions. The yield in the hydrazone bond formation reaction within the tetraPEG DYNAgels was estimated using FTIR spectroscopy on thin films of the gels swollen in D2O. Figure 6 displays

Figure 6. FTIR spectra of the tetraPEG DYNAgel (black) made in a buffer of pH 7.0, together with those of 10% solutions in D2O of its starting star polymers, TBAHPEG (red) and TBPEG (blue).

the infrared spectrum of the tetraPEG DYNAgel prepared in pH 7.0 buffer, together with those of the starting materials in D2O, after subtracting the solvent (D2O) contribution. Applying normalization with respect to the peak of PEG at 1450 cm−1, and comparing the relative intensities of the benzaldehyde peak at 1680 cm−1 of the tetrabenzaldehyde tetraPEG star polymer and the tetraPEG DYNAgel, benzaldehyde conversion was calculated to be 87% based on peak height. Thus, the yield in hydrazone bond formation was high. We also tried to access the extent of hydrazone bond formation using solution 1H NMR spectroscopy at both high polymer concentration, 15% w/v, and lower polymer concentration, 1.5% w/v. We could comfortably follow conversions up to ∼50% in the dense system, above which gelation caused peak broadening and made analysis difficult. However, we could follow conversions up to ∼75% in the dilute system (data provided as Figure S4), which may imply that at least similarly high conversions are also attainable in the dense system, supporting the FTIR data. Before their characterization described next, all tetraPEG DYNAgels were left 3 days after initial gel formation, so that hydrazone bond formation could reach a maximum. A key characteristic of dynamic covalent networks is their ability to repeatedly undergo sol−gel transitions. Figure 7 shows photographs illustrating this important property of tetraPEG DYNAgels. The different colors in the samples in this figure are again due to the addition of universal pH indicator.

Figure 5. pH dependence of gel formation time as determined using tube inversion and rheology experiments. D


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Figure 7. Highly reversible sol−gel transitions of a tetraPEG DYNAgel effected by the addition of acid and base. The various colors are due to the addition of universal pH indicator.

Figure 8. Adhesion between tetraPEG DYNAgels prepared at different pH values, without the need for added hydrazone bond exchange catalyst. The different colors are a direct result of the added universal pH indicator.

Figure 9. Equilibrium aqueous degrees of swelling (DS) of the tetraPEG DYNAgels (a) The tetraPEG DYNAgels were formed and equilibrated in the seven different aqueous buffer solutions at seven different pH values. The DSs are plotted against these equilibration pH values. (b) The tetraPEG DYNAgels were formed in the seven different aqueous buffer solutions at the seven different pH values but were subsequently all equilibrated in the aqueous buffer solution of pH 7.0. The DSs are plotted against the original gel formation pH values.

The photograph on the left presents a mixture of 15% w/v aqueous solutions of the TBPEG and TBAHPEG star polymers (167 μL from each solution, each containing 10 μmol of reactive end-groups) at pH 7.0, and at the stoichiometric molar ratio, before gel formation which would require a few hours at this pH (see Figure 5). Upon addition of glacial acetic acid, to a final acetic acid concentration of 0.5% v/v, which catalyzes the formation of hydrazone bonds (and also induces a change in the color of the system from yellow to orange), the solution is transformed to a gel within minutes. Next, 25 μL of HCl 5 M (containing 125 μmol of acid) is added onto the surface of the gel, causing its dissolution and a color change from orange to red. Afterward, the addition of 17.4 μL of triethylamine (containing 125 μmol of base) neutralizes the previously added HCl, changes the color from red back to orange, and re-forms

the tetraPEG DYNAgel. The system was successfully subjected to three gel-to-sol/sol-to-gel cycles. In all three cycles, the gelto-sol transition required around 20 min to complete, whereas the sol-to-gel transition took only around 1.5 min. Another important characteristic of dynamic covalent networks is their self-healing ability. This property was tested simply by cutting into two tetraPEG DYNAgel samples synthesized at the seven different buffers with pH values from 2.0 to 12.5 and then pressing together the two pieces for 48 h. It was observed that good healing occurred for tetraPEG DYNAgels made only in buffers of pH 2.0 and 4.5, without the need for the addition of acid catalyst, whereas tetraPEG DYNAgels made in buffers of pH 7.0 to 12.5 did not heal. Thus, healing could occur only under conditions where hydrazone bond exchange was sufficiently fast. Figure S5 E


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Figure 10. Dependence of the storage and loss moduli on the angular frequency at various pH values: (a) pH = 1.5, (b) pH = 2.0, (c) pH = 4.5, and (d) pH = 7.0.

To investigate the dynamic nature of the cross-links, we performed frequency-dependent oscillatory rheology (“frequency sweeps”) on tetraPEG DYNAgel samples prepared in buffers of acidic and neutral pH, and the results are presented in Figure 10. The value of the (amplitude of the) elastic shear modulus G′ over the whole frequency range for tetraPEG DYNAgels prepared at pH values 4.5 and 7.0 and over most of the (higher) frequency range for tetraPEG DYNAgels prepared at pH values 1.5 and 2.0 was constant at about 10 kPa, a value consistent with the value determined for metal-linked dynamic23 and amide-linked nondynamic43 gels made of tetraPEG star polymers of the same molecular weight and similar concentration and also in accord with the relevant theoretical models.43 Furthermore, the value of G′ was higher than that of G″ in most cases, indicating the presence of an elastic solid. However, in the lowest frequency range at pH 1.5 and 2.0, the G′ values are lower than this plateau value, increasing with frequency toward the plateau value. Importantly, at pH 1.5, in this lowest frequency range, G′ is lower than G″, with the two moduli crossing at 0.016 rad s−1. This indicates a finite lifetime of the cross-links in the tetraPEG DYNAgels at these acidic conditions, of order of tens of seconds, a result of hydrazone bond exchange, responsible for the reversibility and self-healing ability of these materials mentioned above. It can be estimated by extrapolation (principle of superposition) that this crossover frequency at pH 2.0 is higher than that at pH 1.5, located at 0.004 rad s−1, corresponding to a longer lifetime of the cross-links at this higher pH, of order of hundreds of seconds, and consistent with a slower exchange of hydrazone bonds at higher pH. Thus, the dynamic nature of the cross-links of tetraPEG DYNAgels at acidic pH can be captured by frequency-dependent oscillatory rheology. Another consequence of the dynamic nature of the crosslinks is creep. We performed a preliminary investigation on the creep properties of our materials using nanoindentation. In particular, we studied two tetraPEG DYNAgel samples (15% w/v): one prepared in a buffer of pH 7.0 and the other at pH

displays photographs with the self-healing tests at all pH values investigated. Gel adhesion could also take place between samples made at different pH buffers, provided that one of the samples possessed an acidic pH and the other was not far away from the acidic pH range. Figure 8 shows two such examples, in which a disklike tetraPEG DYNAgel sample made in a pH 4.5 buffer is successfully connected to two other samples of similar shape but different pH, one made in a pH 2.0 buffer and the other in pH 7.0. An important, and readily measurable, thermodynamic property of all hydrogels in general is their equilibrium aqueous swelling degree, studied next in two different ways. TetraPEG DYNAgels prepared in the seven different pH buffers were transferred and equilibrated either in (excess of) their own synthesis buffer or in (excess of) another nonacidic pH buffer (7.0 or 12.5). The results are presented in Figure 9 and Figure S6. It was observed from the former type of experiment that tetraPEG DYNAgels prepared and equilibrated in buffers of pH 2.0 and 4.5 completely dissolved within 56 h and 3 weeks, respectively. In contrast, those tetraPEG DYNAgels prepared and equilibrated in buffers of pH 7.0 to 12.5 only swelled but remained stable, without dissolving, all presenting aqueous swelling degrees of around 15 (within experimental error). These results are displayed in Figure 9a and indicate that the samples which could not self-heal (Figure S5) kept their integrity in the swelling test, while the self-healable ones underwent a gel-to-sol transition. These observations can again be understood considering the exchange rate of the hydrazone bonds, which is high at low pH but lower at neutral and high pH.42 The pH dependence of the hydrazone bond exchange rate can also be used to explain the latter type of swelling experiment in which tetraPEG DYNAgels possessing initial pH values from 2.0 to 12.5 were equilibrated in excess volumes of buffers of pH 7.0 (Figure 9b) and 12.5 (Figure S6). Because hydrazone bond exchange is slow at pH 7.0 and 12.5, all samples retained their gel-like character, exhibiting again aqueous swelling degrees of around 15. F


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Figure 11. Tensile stress−strain curves of (a) a tetraPEG DYNAgel formed in an aqueous buffer solution at pH 7.0 and (b) a classical tetraPEG hydrogel also formed in an aqueous buffer solution of pH 7.0.

covalent networks, in which we replaced HEGMA for N,Ndimethylacrylamide (DMAAm), with the polyDMAAm system not possessing the methacrylate structure of polyHEGMA known to convey brittleness and not having the (slight) comblike architecture of polyHEGMA which could influence the mechanical properties. In fact, the polyDMAAm system has a strong hydrogen-bonding capability (arising from the amide side groups) which may provide an advantage in the mechanical properties. Finally, again for comparison purposes, we also prepared another model dynamic covalent hydrogel but of lower cross-linking density than the tetraPEG DYNAgel. This dynamic hydrogel resulted from the combination of TBPEG with a stoichiometric amount of the α,ω-bis(benzaacylhydrazide)-PEG (“diPEG”) also used for the random crosslinking of the above-mentioned linear HEGMA-MAEBA and DMAAm-MAEBA statistical copolymers. All randomly cross-linked dynamic covalent hydrogels were mechanically very weak, which precluded their characterization using tensile measurements (gels would break upon their mounting on the holders of the instrument). Thus, we pursued compressive measurements, and the results, i.e., the stress and strain at break, σmax and εmax, respectively, and the low-strain Young’s modulus, E, along with those for the tetraPEG DYNAgel and the TBPEG-diPEG gel also prepared in pH 7.0 buffer, are listed in Table 1.

4.5. As expected, the sample prepared at pH 4.5 exhibited a higher creep (creep displacement = 1670 nm from a 30 s dwell time at maximum load of 0.5 mN) as compared to that at pH 7.0 (creep displacement = 1410 nm upon the same treatment). Subsequently, the present tetraPEG DYNAgels were converted to common tetraPEG gels via chemical reduction of the hydrazone bonds using sodium cyanoborohydride. The resulting gels became stable, not dissolving in aqueous buffers of any pH; however, they also lost their reversibility (ability for gel−sol transition) and self-healing ability (Figure S5i). The chemical reaction for the synthesis and reduction of a linear (soluble) model compound and relevant 1H NMR spectroscopic proof are presented in Figures S7 and S8, respectively. Next, the mechanical properties of a tetraPEG DYNAgel prepared in aqueous buffer of pH 7.0 were investigated in tension. Figure 11a displays the tensile stress−strain curves (three repetitions) for this tetraPEG DYNAgel, while Figure 11b presents the corresponding curves for an amide-linked, nondynamic, classical tetraPEG gel prepared in a buffer of the same pH. The tetraPEG DYNAgel exhibited a remarkable strain at break of 670 ± 110%the same, within experimental error, as that presented by the classical tetraPEG gel of 730 ± 110%. The stress at break and the low-strain elastic modulus were also comparable for the two systems, with the respective values for the tetraPEG DYNAgel being 340 ± 90 and 89 ± 7 kPa and those for the tetraPEG gel being 440 ± 140 and 95 ± 6 kPa. Afterward, we pursued the comparison of the mechanical properties of the tetraPEG DYNAgel with those of randomly cross-linked analogues. For this comparison, we would ideally need a linear PEG which could be cross-linked at random positions. However, because such a PEG structure is not readily accessible, we resorted to the following relatively close analogue: a linear statistical copolymer of hexa(ethylene glycol methacrylate) (HEGMA) (majority component) and a benzaldehyde-bearing monomer (minority component), p-(2methacryloxyethoxy)benzaldehyde (MAEBA),44,45 randomly cross-linked by reacting its 15% w/v solution in pH 7.0 buffer with a stoichiometric amount of α,ω-bis(benzaacylhydrazide)PEG (whose chemical structure and 1H NMR spectrum are shown in Figures S7 and S8) and having a molecular weight of 2300 g mol−1, similar to that of the arm of the tetraPEG star, of 2500 g mol−1. Such linear HEGMA-MAEBA statistical copolymers (Table S2) were prepared via conventional thermal radical polymerization (two compositions) and controlled radical (reversible addition−fragmentation chain transfer, RAFT) polymerization (one composition). Furthermore, we also prepared similar linear statistical copolymers (also Table S2) and the corresponding randomly cross-linked dynamic

Table 1. Mechanical Properties in Compression of Randomly Cross-Linked Dynamic Covalent Hydrogels Based on Statistical Hydrophilic Copolymers Bearing Benzaldehyde Groups Interconnected via the α,ωBis(benzaacylhydrazide)-PEG (“DiPEG”) and Comparison with the TetraPEG DYNAgel and the TBPEG-DiPEG Gel no.

polymer structure

1 2 3 4 4a

DMAAm98-co-MAEBA2 DMAAm95-co-MAEBA5 HEGMA95-co-MAEBA5 HEGMA90-co-MAEBA10 HEGMA90-coMAEBA10−RAFT tetraPEG DYNAgel TBPEG-diPEG

5 5a

σmax (kPa) 60 38 29 24 41

± ± ± ± ±

12 9 4 4 7

>12000 ± 1200 >2290 ± 520

εmax (%) 68 61 63 55 69

± ± ± ± ±

>95 >95

4 1 3 3 1

E (kPa) 12 21 6.5 11 9.2

± ± ± ± ±

5 7 0.3 1 0.8

31 ± 3 11 ± 3

Table 1 shows that as their cross-linking density (MAEBA content) increased, the randomly cross-linked dynamic covalent networks became stiffer (low-strain Young’s modulus, E, went up), but their ultimate mechanical properties, σmax and εmax, deteriorated. The randomly cross-linked dynamic covalent hydrogel prepared using the linear statistical copolymer G


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Macromolecules synthesized by RAFT polymerization exhibited the same E value as its counterpart whose linear precursor was synthesized by conventional radical polymerization; however, the ultimate mechanical properties, especially σmax, of the former were improved compared to those of the latter, indicating a beneficial effect of the structural control on the mechanical properties. Examining now the ultimate mechanical properties of the tetraPEG DYNAgel listed in Table 1, these were much better than those of all randomly cross-linked dynamic covalent hydrogels. Furthermore, it should be pointed out that the reported σmax and εmax values for the tetraPEG DYNAgel are lower bounds, as this material did not fail upon applying a compressive strain of 95%, inducing a compressive stress of 12.0 MPa, which is close to the maximum force allowed in the instrument for the particular load cell. The compressive stress at break for the tetraPEG DYNAgel was at least 200−500 times greater than those of the less well-defined analogues, whereas the compressive strain at break of the tetraPEG DYNAgel was at least between 38 and 73% better than those of the randomly cross-linked systems. Examining next the mechanical behavior of the TBPEG-diPEG dynamic gel, this did not fracture either when a 95% compressive strain was applied, although this hydrogel was expectedly less stiff than the tetraPEG DYNAgel due to its lower cross-linking density; nonetheless, it could withstand a compressive stress of 2.3 MPa without breaking. It apprears, therefore, that the model structure of the tetraPEG DYNAgel and the TBPEG-diPEG gel confer upon them remarkable mechanical properties, much higher than those of randomly cross-linked systems based on DMAAm or HEGMA. Regarding the latter system, the preparation and study of hydrazone randomly cross-linked dynamic covalent hydrogels based on statistical copolymers of oligo(ethylene glycol methacrylate) and an aliphatic aldehyde monomer have been pioneered by Hoare and co-workers, who also proposed for them several potential biomedical applications.46−48 Finally, we demonstrated the generality of our system as a platform for the synthesis of multifunctional networks by preparing dynamic covalent polymer networks, following modifications of our original recipe. To this end, we replaced, partially or totally, the TBPEG component of tetraPEG DYNAgels. First, we pursued the introduction of an α,ωbis(benzaldehyde)−poly(dimethylsiloxane) of molecular weight 10 000 g mol−1, using it to partially replace, by 10 and 50 mol %, TBPEG. Because of the insolubility of poly(dimethylsiloxane) (PDMS) in water or aqueous buffers, the synthesis was performed in 1,4-dioxane. As a control, a tetraPEG DYNAgel was also prepared in that solvent using only the TBPEG and TBAHPEG components in stoichiometric ratio. After gel formation (within 24 h), the three networks were transferred into pure water, where they were equilibrated. Because of the hydrophobic character of PDMS, the two networks bearing it swelled in water less than the control gel. Figure 12 shows a photograph of the three water-equilibrated gels: the pure tetraPEG DYNAgel, the one modified with 10 mol % with the PDMS derivative, and the other with 50 mol %, displaying aqueous degrees of swelling of 16, 10, and 8, respectively. More importantly, the amphiphilic49−54 character of the modified gels, together with the segmented nature of the PEG and PDMS components, is expected to lead to their aqueous phase separation on the nanoscale which is under investigation. Subsequently, we totally replaced TBPEG with a tetrabenzaldehyde-end-functionalized amphiphilic star block copolymer,

Figure 12. Photograph of the water-equilibrated PDMS-modified tetraPEG DYNAgels and the unmodified control.

Tetronic T904. Tetronics are commercially available amphiphilic four-armed star block copolymers of PEG and poly(propylene glycol) which have recently been employed to prepare covalent, nondynamic, amphiphilic polymer conetworks.55,56 The particular Tetronic used herein, T904, had a molecular weight of 6700 g mol−1 and a PEG content of 47 mol % and carried the PEG blocks at the periphery of the star. Because of the water solubility of the tetrabenzaldehydemodified Tetronic, its combination with a stoichiometric amount of TBAHPEG took place in pH 7.0 buffer, with both components used at concentrations of 15% w/v. Gel formation was observed within 24 h, and after equilibration in pure water, the tetraPEG/T904 hybrid DYNAgel exhibited a swelling degree of 9, lower than that of pure tetraPEG DYNAgels of ∼15, a result of the higher hydrophobicity of the amphiphilic T904 component relative to the hydrophilic tetraPEG stars.

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CONCLUSIONS In conclusion, the preparation and preliminary characterization of dynamic covalent tetraPEG hydrogels, tetraPEG DYNAgels, are reported. Preparation involved the appropriate endfunctionalization of tetra-armed star PEGs to yield tetrabenzaldehyde and tetrabenzaacylhydrazide telechelic star polymers. The rate of gel formation in water was highly pH-dependent, ranging from seconds to days and presenting a minimum at pH 8.5. Unexpectedly, fast gel formation was also observed at alkaline pH conditions. Self-healing ability and gel stability were similarly extremely sensitive to the pH value of the utilized buffer, with the former taking place at acidic pH values and the latter at neutral and alkaline pH values. The reduction of tetraPEG DYNAgels transformed them to common tetraPEG gels, incapable of self-healing but permanently protected from dissolution. The tensile properties of tetraPEG DYNAgels were remarkable, practically the same as those of standard (nondynamic) tetraPEG gels and much superior to those of randomly cross-linked dynamic covalent analogues also prepared for the purposes of the present investigation. Lastly, the developed dynamic covalent network system is highly modular, as other functionalities can be readily inserted, provided they bear benzaldehyde or benzaacylhydrazide moieties. The rather slow formation of tetraPEG DYNAgels at pH 7.0 (taking a few hours) precludes their use as injectable materials for biomedical applications. Moreover, the slow exchange of hydrazone bonds at that pH would not allow self-healing under physiological conditions. However, unlike counterparts crosslinked with aliphatic hydrazones, the present system crossH


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Macromolecules

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linked with aryl-substituted hydrazones would be very stable under physiological conditions. Thus, the developed system complements the toolbox of the biomaterials engineer. We envision that a hybrid system, bearing both aryl-substituted and aliphatic hydrazone cross-links, might provide an excellent design, in which the ratio of the two types of cross-links would be determined by the requirements of the application.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.7b00236. Experimental details on synthesis and characterization; chemical reactions and extra 1H NMR spectra; GPC traces; photographs of self-healing experiments; extra equilibrium aqueous swelling degree data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (C.S.P.). ORCID

Costas S. Patrickios: 0000-0001-8855-0370 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by the University of Cyprus Research Committee. The European Regional Development Fund and the Republic of Cyprus are gratefully acknowledged for cofunding, through the Cyprus Research Promotion Foundation, projects ANAVATHMISI/0609/12 and NEKYP/0308/ 02, which enabled the purchase of the rheometer and the NMR spectrometer, respectively, at the University of Cyprus used in this investigation. Furthermore, we thank our colleagues T. Matsushita of the University of Tokyo, Japan, for mechanical and spectroscopic measurements and Prof. E. Leontidis of the University of Cyprus for making available to us his rheometer. We also thank our colleague Prof. G. Constantinides of Cyprus University of Technology for the nanoindentation measurements. Finally, we thank BASF SE and our colleagues Dr. A. Blanazs (BASF SE, Ludwigshafen am Rhein, Germany) and Prof. Dr. M. Gradzielski (Technische Universität Berlin, Germany) for kindly donating to us Tetronic T904.

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REFERENCES

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Dynamic Covalent Star Poly(ethylene glycol) Model Hydrogels: A New

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