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Amino-yne Reaction for the Synthesis of Degradable Hydrogels: Study of the Cleavage of β-Aminoacrylate Cross-Links
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  • Sara Bescós-Ramo
    Sara Bescós-Ramo
    Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain
    Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain
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    Orcidhttps://orcid.org/0009-0008-6456-4856
  • Jesús del Barrio
    Jesús del Barrio
    Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain
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    Orcidhttps://orcid.org/0000-0002-5380-6863
  • Pilar Romero
    Pilar Romero
    Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain
    Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain
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    Orcidhttps://orcid.org/0000-0003-1378-0571
  • Laura Florentino-Madiedo
    Laura Florentino-Madiedo
    Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain
    Departamento de Ingeniería Química y Tecnologías del Medio Ambiente, Universidad de Zaragoza, C/María de Luna, 3, Zaragoza 50018, Spain
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  • Milagros Piñol*
    Milagros Piñol
    Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain
    Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain
    *Email: [email protected]
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  • Luis Oriol*
    Luis Oriol
    Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain
    Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-0922-5615
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Macromolecules

Cite this: Macromolecules 2024, 57, 23, 10926–10937
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https://doi.org/10.1021/acs.macromol.4c01403
Published November 28, 2024

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Abstract

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This work addresses a study of PEG-derived hydrogels based on β-aminoacrylate cross-links and obtained by amino-yne click chemistry, using a β-aminoacrylate-based model molecule as reference. The pH-triggered cleavage of the β-aminoacrylate bonds was monitored confirming not only the release of the conjugated amine but also the formation of a mixture of chemical species that depends on the acidity of the medium. Moreover, overall hydrogel degradation rates were able to be adjusted by modifying pH, temperature, polymer concentration, or the amine selected as linker of PEG chains. In particular, the labile nature of the β-aminoacrylate bond was confirmed even under physiological conditions (pH 7.4, 37 °C), leading to long-term material degradation. The release and recovery of the conjugated amine after the cleavage of the β-aminoacrylate bonds was demonstrated at both acidic and physiological pH, mimicking the results acquired through model molecule studies.

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Introduction

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Hydrogels are attractive candidates for a variety of biomedical applications such as tissue engineering, (1) wound dressing, (2,3) and drug delivery. (4) In this context, while natural polymers can effectively replicate certain properties of physiological environments, synthetic polymers offer the possibility of tuning their mechanical characteristics and chemical composition. Among them, poly(ethylene glycol) (PEG)-based materials have demonstrated excellent biocompatibility and low toxicity. (5) The gelation process can be achieved through numerous mechanisms using either noncovalent (electrostatic interactions, hydrogen bonds) or covalent cross-linking. (6) Comparatively, chemically cross-linked hydrogels have proven superior mechanical strength than noncovalently cross-linked ones. Various chemical approaches have been employed to synthesize chemically cross-linked hydrogels under physiological conditions, with radical polymerizations being one of the commonly used methods. Nevertheless, recent attention has been drawn to hydrogels synthesized using click-like chemistries, especially metal-free ones, due to their high efficiency, selectivity, and ease of implementation, as well as their improved biocompatibility. These methodologies encompass a range of reactions, including but not limited to, the strain or electron-withdrawing group-promoted azide–alkyne [3 + 2] cycloaddition (SPAAC), (7−13) radical mediated and Michael addition thiol-ene, (14−17) Diels–Alder, (18,19) oxime-forming, (20−23) and nucleophilic additions to activated alkynes such as thiol-yne (24−27) or hydroxyl-yne reactions. (28) However, covalent bonds are mostly stable, which limits their potential applications in the biological field when degradable materials are desirable. Alternatively, cleavable covalent bonds provide the opportunity to engineer materials that degrade over time or in response to specific stimuli in a controlled way. The incorporation of these labile bonds into the polymer network enables the degradability of the hydrogel system, which is essential to prevent long-term accumulation of polymer remnants. (29,30) Moreover, by including stimuli-responsive cleavable groups into the cross-linking points, hydrogels can not only degrade but also enable the conjugation of drugs through these labile groups and provoke their release upon applying the stimulus, rather than simply diffusing if the drug is physically retained within the hydrogel. (31−33) To date, among the various stimuli employed to induce breakage of a covalent bond, pH-responsive hydrogels have been commonly prepared using a wide variety of acid-labile cross-linking agents such as hydrazones, imines, and acetals or ketals. (34−36)
Among the different chemistries, the outstanding amino-yne click reaction has gained recent interest in polymer science since its initial report in 2017 by Tang’s group. (37) This reaction can occur under click-like conditions, i.e. it proceeds spontaneously at room temperature and in aqueous media, by simply mixing amines (amino-) and electron-withdrawing alkynes (-yne). Additionally, the resultant β-aminoacrylate bond has been found to be cleavable under acidic conditions (pH < 5.5), allowing for the recovery of the initial amine and generation of 3-oxopropanoates. (38,39) Besides, bond breakage can be induced by the presence of singlet oxygen species (1O2) resulting in the generation of alcohols and N-formyl derivatives, instead of affording the amine. (40) Despite being a versatile click reaction, amino-yne chemistry has been scarcely applied to the preparation of hydrogels. Langer et al. reported the first amino-yne-based hydrogels using PEG tetra-alkynoates and water-soluble primary, secondary, and tertiary amines. Their study demonstrated that the latter were unable to induce gelation. (41) Huang and Jiang prepared chitosan and dipropiolate PEG hydrogels showing their pH-responsiveness. (42) Furthermore, the applicability of this chemistry has also been demonstrated in various hydrogel fields, including the preparation of corneal substitutes, (43) enzyme immobilization, (44) wound healing, (45,46) 3D printing, (47) cell scaffolds, (48) or light-degradable hydrogels mediated by singlet oxygen using a photosensitizer molecule, (49,50) among others.
To engineer a degradable hydrogel, it is crucial to have a deep understanding of the chemistry of the cleavable groups, their byproducts, and the factors defining the degradation rates. (51) However, despite the confirmed recovery of the initial amine-based molecule at approximately pH < 5.5, (39,52,53) there is a lack of literature addressing the chemistry underlying the cleavage of the β-aminoacrylate and products generated by the breakage of this bond. Therefore, in this work, a β-aminoacrylate-based model molecule was synthesized through spontaneous amino-yne reaction to investigate (i) the feasibility of amine release in aqueous media at different pH, from physiological to strongly acidic, and different temperatures and (ii) the chemical nature of other products resulting from the β-aminoacrylate cleavage under different conditions. Next, PEG tetra-alkynoate-based hydrogels were synthesized using a variety of multifunctional primary and secondary amines and different polymer concentrations, in order to get further insights and precise control over their effect on the stability of the network. After hydrogel characterization, pH- and temperature-triggered degradations were studied, underscoring relatively fast β-aminoacrylate cleavage under acidic media. Such a process also occurs under physiological conditions, although at a slower pace. The feasibility of transferring the gained knowledge from the model molecule to the hydrogels was established by comparing the resultant byproducts of the hydrogel degradation with those identified in the low-molecular-weight model compound.

Results and Discussion

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Formation and Cleavage of β-Aminoacrylate Bond in a Model Molecule

With the aim of studying the amino-yne click reaction in aqueous media and the responsive properties of the resulting β-aminoacrylate bond, the model compound TEG2-A1 (Figure 1a) was prepared. First, water-soluble propiolate TEGalk was synthesized by reacting tri(ethylene glycol) monomethyl ether with propiolic acid according to a Fischer esterification protocol. (54) Then, TEG2-A1 was obtained by mixing TEGalk and N,N’-dimethyl-1,3-propanediamine (A1, Figure 1a) in a 2:1 molar ratio at pH 7.4, in a 0.1 M phosphate buffer (PB). Complete conversion was observed after approximately 10 min at room temperature in the absence of a catalyst. As previously reported for similar secondary amines, (37) the reaction demonstrated E-selectivity yielding exclusively the trans isomer as evidenced by the proton nuclear magnetic resonance (1H NMR) spectrum (Figure 1b, TEG2-A1 pH = 7.4).

Figure 1

Figure 1. (a) Scheme of amino-yne click reaction and β-aminoacrylate cleavage at pH = 2.0 and 25 °C; (b) from bottom to top: water-suppressed 1H NMR spectra of TEG2-A1 at pH = 7.4 (pH = 7.4, buffer/D2O 9:1, 300 MHz), after 10 min at pH = 2.0 (pH = 2.0, aqueous solution/D2O 9:1) and A1 at pH = 2.0, as reference.

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Based on previous references proposing the acid pH-triggered cleavage of β-aminoacrylate bond into amine and 3-oxopropanoate species, (39,42) strong acidic conditions were chosen for an initial study of a fast evolution of the bond, followed by exploring the differences with moderate acidic conditions. TEG2-A1 was dissolved in aqueous solutions of different pH values (2.0 and 5.0) at 25 °C, and changes were monitored by recording 1H NMR spectra at appropriate time intervals. Under pH 2.0, the enaminone protons disappeared completely in less than 10 min, accompanied by the emergence of the protonated amine signals, indicating the expected complete release of A1 (Figure 1b). However, the initially anticipated product 3-oxopropanoate (1 in Figure 1a) was not detected. Instead, two new signals at 5.40 and 2.65 ppm appeared that could be assigned to the resonances of the C═CH (i) and CH2 (j) groups, respectively, of the product resulting from an acid-catalyzed aldol condensation (2 in Figure 1a). This was confirmed by their correlation shown by the homonuclear correlation spectroscopy (COSY) experiment (Figure S7) and supported by the electrospray ionization (ESI) mass spectrometry experiment (Figure S8), which revealed a main peak (m/z = 474, (+Na)) that corresponds to the sodiated molecular species of the α,β-unsaturated aldehyde adduct.
When TEG2-A1 was dissolved in a moderately acidic buffer (pH = 5.0), a slowdown in the cleavage of the enamine bond was observed, and 24 h was required for almost complete disappearance of the corresponding 1H NMR signals (Figure 2b). Protons of the released A1 emerged concurrently with those of the species in which only one of the = C–N– bonds was broken (TEG-A1 in Figure 2a and protons labeled as c’ and d’). Additionally, different products arising from the cleavage of the β-aminoacrylate bond were also identified. Initially, a triplet at 5.40 ppm assigned to the aldehyde adduct 2 (labeled as i) appeared but, after 1 h, it turned into a new set of signals not detected when degradation was undertaken at pH = 2.0. Besides, two major singlets were observed downfield at 8.83 and 8.44 ppm. The former was associated with the ester of the benzene-1,3,5-tricarboxylic acid (3 in Figure 2a) according to the 1H–13C heteronuclear single-quantum correlation (HSQC) (correlation with 13C signal at δ = 137.3 ppm, Figures S12 and S13) and the main peak in the ESI-MS experiment (Figure S10, m/z = 671 (+Na)). The formation of this derivative (3) was fully confirmed by the 1H–13C heteronuclear multiple bond correlation (HMBC) spectrum (Figures S14 and S15). As previously described, this aromatic derivative results from the cyclotrimerization of enaminones in acidic conditions, (55,56) specifically using sodium acetate and acetic acid as catalyst and solvent, (57) respectively, which are components of the buffer used at pH = 5.0 in this study. However, this species was also observed when employing a pH 5.0 sodium citrate/citric acid buffer (Figure S17), suggesting that its formation could be considered a more generalized process rather than being solely a consequence of the buffer composition. The peak at δ = 8.44 ppm was assigned to an aldehyde-type species, according to its HSQC correlation with a 13C signal at δ = 173.6 ppm (Figures S12 and S13). The formation of oxopropanoate 1 was also observed, not as the isolated species but as a cyclic trimer resulting from its condensation equilibrium in this acidic medium. This resulting 1,3,5-trioxane derivative was identified by HSQC and HMBC correlations (Figures S12 and S14) as well as by ESI-MS (Figure S10, m/z = 725 (+Na)). Although the characterized species do not disclose the complete mixture of the overall degradation products, these results reveal that the β-aminoacrylate cleavage is a more complex process than previously reported in literature, involving the evolution of the initially resultant aldehyde, or even side reactions of β-aminoacrylates depending on the pH. Nonetheless, the release of the amine is complete and firmly established, with its release rate highly dependent on the pH of the medium.

Figure 2

Figure 2. β-Aminoacrylate cleavage at 25 °C: (a) scheme of TEG2-A1 degradation products at pH 5.0; (b) water-suppressed 1H NMR spectra at pH = 5.0 at different time intervals (pH = 5.0 buffer/D2O 9:1, 300 MHz); (c) water-suppressed 1H NMR spectra at pH = 7.4 at different time intervals (pH = 7.4 buffer/D2O 9:1, 300 MHz). Amine A1 appears as the protonated species in all cases.

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The evolution of TEG2-A1 at pH 7.4 and 25 °C was also investigated. Surprisingly, after 1 h, new signals appeared at the upfield part of the spectrum (labeled as c’ and d’ in Figure 2c). They seemed to correspond, again, to the species in which only one of the ═C–N– bonds was broken (TEG-A1). After 4 h, the amine A1 signals were also detected. Additionally, aldehyde and aromatic proton singlets appeared in the downfield as minor compounds. By recording a diffusion-ordered spectroscopy (DOSY) experiment after 24 h, at least three different species were identified according to their diffusion coefficients (Figure S18). The smallest diffusion coefficient corresponds to TEG2-A1, the highest to A1, and the intermediate one matches TEG-A1.
Finally, changes of TEG2-A1 at pH 7.4 and pH 5.0 were also monitored at 37 °C, to assess a possible acceleration of β-aminoacrylate cleavage at physiological temperature. In both cases, temperature accelerates the disappearance of the β-aminoacrylate bond, but its effect was far less pronounced than that of lowering the pH, at least within the first 48 h (Figure S19). Bond cleavage gave rise to the already described products, and no signals of ester hydrolysis were detected in the spectra. In conclusion, at physiological pH, the β-aminoacrylate bond has a much greater stability than in an acid medium, but a slow cleavage of the bond ultimately resulting in the release of the amine is still observed.

Synthesis and Characterization of Hydrogels

The synthesis of hydrogels was accomplished using a propiolate-functionalized four-armed poly(ethylene glycol) and different commercially available aliphatic amines. To this end, PEG tetra-alkynoate (PEGalk) with average molecular weight of 10,000 g mol–1 was first synthesized following a previously reported protocol (Figure S20). (41) Complete functionalization was corroborated by 1H NMR spectroscopy, and further characterization was accomplished by Fourier transform infrared spectroscopy (FTIR), matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectroscopy, and differential scanning calorimetry (DSC) (Figures S21–S24).
For the preparation of the hydrogels, PEGalk was weighted according to the desired polymer concentration (wt %) in the final hydrogel and dissolved in a pH = 7.4 buffer by orbital mixing overnight. Amine, which provokes macromolecular network formation, was separately dissolved in the same buffer. Both solutions were mixed, ensuring a 1:1 molar ratio of amine vs alkynoate groups and a final mass of 200 mg of the resulting hydrogel in all cases. After 10 s of vortex mixing, hydrogels were allowed to set at 25 °C (for a more detailed procedure, see Experimental Section and Table S1). Once gelation was completed, a self-standing yellowish material was obtained, as shown in Figure 3a, where difunctional amine A1 is used as an example to illustrate network formation.

Figure 3

Figure 3. (a) Depiction of hydrogel formation from PEGalk and A1 at pH 7.4 and 25 °C resulting in a self-standing transparent yellowish material (right); (b) chemical structure of the different amines investigated for the network formation and (c) gelation time by inverted vial test at 25 °C depending on the polymer concentration and cross-linker (data presented as mean ± SD (n = 3)). Crosses indicate no gelation was recorded after 24 h.

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The synthesis of hydrogels was studied by varying polymer concentration (5, 10, 20, and 30 wt %) and amine functionality. For the latter, five multifunctional primary and secondary amines were used: N,N’-dimethyl-1,3-propanediamine (A1), piperazine (A2), spermine (A3), diethylenetriamine (A4), and 1,4-diaminobutane (A5) (Figure 3b). Then, qualitative determination of gelation time was carried out by the inverted vial test. Various trends can be extracted from the results summarized in Figure 3c. First, gelation time could be tuned by varying the polymer weight percentage. As a result of increasing the concentration of reactive groups in the final mixture, higher polymer wt % led shorter gelation times for the same cross-linker. Second, taking into account cross-linkers with the same number of amine groups, A1, A2, and A5, gelation time decreased with increasing nucleophilicity of the amine. Whereas the cyclic secondary amines induced network formation faster than the linear ones (tgelA2 < tgelA1), gelation proceeded slower for primary amines (tgelA1 < tgelA5). Therefore, A5 only formed hydrogels overnight at 30 wt %, whereas all other gels were obtained at 10 wt % (A1 and A4) or even at 5 wt % (A2 and A3) polymer concentration. Finally, by increasing the number of cross-linking points, gelation was also accelerated. For instance, A4, which has two primary and one secondary amine groups, formed hydrogels faster and at a lower polymer concentration than A5, with only two primary amines. The biobased spermine, A3, which has the highest number of cross-linking points, induced the fastest gelation among all linear amines, and only A2 cross-linked faster at 5 wt % polymer concentration.
Preliminary rheological studies were performed to follow the kinetics of network formation at pH 7.4, using PEGalk-A1 hydrogel as example (see Experimental Section, Rheological measurements). For that purpose, the evolution of the storage (G′) and loss (G″) moduli of the hydrogel (10 wt % polymer concentration) with time was monitored at 25 °C (Figure 4a). The material was left to gel for 24 h to ensure the maximum possible cross-link density, observing two different regions in our time sweeps. Initially, G′ exhibited a sharp increase, where G′ surpassed G″ only 6 min after lowering the upper plate, to then steadily grow until it reached a maximum at approximately 7 h. Subsequently, the storage modulus began to decrease, presumably due to some kind of network degradation over time (vide infra). Experiments were replicated at 37 and 15 °C, revealing a temperature-dependent degradation boosted at the physiological temperature (Figures S26 and S27). It was observed that the decline of G′ at a higher temperature (37 °C) initiated at earlier times and also dropped to a larger extent in comparison to samples evaluated at 15 °C. Indeed, G′ remained stable when the time sweep was recorded at a temperature below rt. In these time sweep experiments, the maximum G′ value for the 30 wt % hydrogel was higher than that for the 10 wt % hydrogel (ca. 8.9 and 0.7 kPa for 30 and 10 wt %, respectively). However, as previously discussed, G′ decreases after reaching its maximum, with this decline being more pronounced in the 30 wt % hydrogel compared to the 10 wt % hydrogel (Figure S28). This decay in G′ might be associated with polymer network degradations.

Figure 4

Figure 4. (a) Evolution of storage (G′) and loss (G″) moduli as a function of time at 25 °C for 10 wt % PEGalk-A1 hydrogel. Gelation time is pointed out by the crossover point between G′ and G″. (b) 1H-HR-MAS NMR spectrum of 10 wt % PEGalk-A1 hydrogel 24 h after mixing both PEGalk and A1 at pH = 7.4 (a drop of D2O was added before starting the experiment, 400 MHz, up) and water-suppressed 1H NMR of TEG2-A1 model molecule after 24 h at pH = 7.4 (pH = 7.4 buffer/D2O 9:1, 300 MHz, down as reference). (c) Swelling behavior of PEGalk-A1 hydrogels varying polymer concentration (data was presented as mean ± SD (n = 3)) and (d) SEM image of the cross-sectional morphology of PEGalk-A1 swollen hydrogels 10 wt % (left) and 30 wt % (right).

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Encouraged by the apparent loss of network integrity over time even at 25 °C, the structural characterization of 10 wt % hydrogel was performed 24 h after mixing the precursor solutions by high-resolution magic angle spinning (HR-MAS) NMR spectroscopy. As seen in Figure 4b, a mixture of β-aminoacrylate (signals labeled as a, b, and c), partially broken species (signals labeled d, e), and free amine (signals labeled f, g) were clearly observed in the hydrogel matrix. Hence, the emergence of these signals and the decrease in G′ over time at pH 7.4 could be elucidated by the partial cleavage of β-aminoacrylate (as proposed with the model molecule) prior to or just after the complete formation of the hydrogel, with both processes likely occurring simultaneously after a certain time.
We then moved to the macroscopic characterization of hydrogels in order to quantify their water permeability. Accordingly, their swelling ratio, i.e., the relative weight increase of the hydrogel due to water absorption, (58) and equilibrium water content (EWC), which indicates the water content of the hydrogel in a steady state, were calculated at pH = 7.4 and a fixed temperature (25 °C). As shown in Figure 4c, PEGalk-A1 hydrogels at 10, 20, and 30 wt % were able to rapidly absorb water, reaching their equilibrium state after 24 h with high EWC percentages (>94%). When comparing the swelling ratios of 10, 20, and 30 wt % hydrogels (approximately 2100, 1650, and 1350, respectively), it was highlighted that the increase in polymer concentration led to a decrease in water uptake. These findings also matched with the high porosity of the materials, as well as with the trend in porous size, exposed while observing the cross-section of swelled and freeze-dried hydrogels by scanning electron microscopy (SEM, Figure 4d) and the results of mercury intrusion porosimetry (MIP, Figures S29–S31). Their morphology characterization revealed a highly porous structure, for which the porous size decreased as polymer concentration increased (Figure 4d). MIP allowed us to evaluate the macroporosity (>50 nm) and mesoporosity (50–2 nm) of PEGalk-A1 swollen hydrogels of 10, 20, and 30 wt % in detail. The results clearly indicate that the hydrogels were predominantly macroporous (97–99% of total pore volume, Table S2). 10 and 20 wt % hydrogels presented quite a bit of variability in their replicas, resulting in the same average pore volume value (2.1 mL/g). However, when using 30 wt %, the replicates exhibited very similar porosity, and the difference compared to the lower percentages was clear, with the volume being reduced by half (1.0 mL/g). Therefore, an increase in the polymer concentration resulted in a smaller pore size and, consequently, lower swelling. This might be a consequence of an increase in the number of physical chain entanglements formed when polymer concentration increased, as previously reported. (59) Since disentanglement of polymeric chains does not occur completely with swelling experiments, swelling ratio includes the effect of both chemical cross-linking and physical entanglements. (59−61) Furthermore, the contribution of the degradation over time observed during rheological experiments cannot be dismissed.

Hydrogel Degradation

Concerning the pH-responsiveness of the hydrogel, network degradation rate was studied by immersing freshly prepared 10 wt % PEGalk-A1 hydrogels (total mass of hydrogel approximately 200 mg) into 2 mL of the aqueous solutions at different pH (2.0, 5.0, and 7.4) at 25 °C and weighting them over time (see details in Experimental Section). Their relative weight was monitored as an indirect measure of their degradation associated with mass loss and the formation of soluble species in the media. In Figure 5a, it is observed that pH = 2.0 led to fast erosion of the material and its solubilization after 1 h, which can be mainly attributed to the breakage of β-aminoacrylate cross-links of the network. With model molecule studies, it was demonstrated that strong acidic conditions induce rapid β-aminoacrylate cleavage, whereas pH 5.0 led to a more gradual cleavage with emergence of free amines. In the case of the hydrogels, a moderately acidic medium, pH = 5.0, appeared to facilitate network degradation leading to soluble species after 3 h, while at pH = 7.4, relative weight only started to decrease after the 8th day, and complete solubilization was not detected before the 14th day. Macroscopically, the acidic pH resulted in progressive erosion of the hydrogel, which decreased in weight and size over time and more rapidly as the pH became more acidic (Figure 5b).

Figure 5

Figure 5. pH-induced degradation behavior at 25 °C. (a) Relative weight over time of 10 wt % PEGalk-A1 hydrogels immersed at pH = 7.4, 5.0, and 2.0 at 25 °C; (b) images of 10 wt % PEGalk-A1 hydrogels (with same initial shape and weight) after 30 min immersed at different pH (all three images were taken in the same scale; see Figure S34); (c) relative weight over time of 10 wt % PEGalk-A1/2/3/4 hydrogels at pH = 5.0.

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In order to check the influence of the cross-linker on the network degradation rate, experiments were replicated with 10 wt % PEGalk-A2/3/4, using the other three different amines that proved to gel at the selected polymer concentration (10 wt%). When comparing degradation rates of the hydrogels at 25 °C, the same trend was observed independently of the pH (Figure S32 for pH = 2.0 and 7.4, Figure 5c for pH = 5.0). Whereas PEGalk-A1 and PEGalk-A2 behaved similarly, hydrogels prepared with A3 and A4 exhibited a retarded decrease in their relative weight, likely attributed to their higher number of theoretical cross-link points, which creates more dense networks that are less prone to degradation. PEGalk-A3 had significantly longer lifetime under acidic conditions, since weight loss was not registered before 8 h and the 4th day at pH = 2.0 and 5.0, respectively. 1 and 14 days were needed for their complete solubilization, compared to the hours-scale degradation of both PEGalk-A1 and PEGalk-A2. For a more concentrated hydrogel, 30 wt % PEGalk-A1, similar results were obtained when compared with that of 10 wt % (Figure S33), so that polymer concentration does not seem to induce a big change on pH-responsive properties.
Recovery of the amine used as cross-linker after the hydrogel network degradation at acidic pH was also studied in aqueous solution. In order to do that, a small piece of 10 wt % PEGalk-A1 hydrogel was introduced in an NMR tube and immersed in 9:1 (v/v) solution of pH = 5.0 buffer and D2O. 1H NMR spectra, which correspond to degradation products solubilized in aqueous media, were collected over time. Clear signals of amine A1 were observed, as highlighted in Figure 6. The integration of amine protons gradually increased, revealing its progressive release, until signals seem to maintain their intensity approximately after 3 h. Additionally, the downfield part of the spectra revealed the apparition of the signals assigned to the β-aminoacrylate cleavage species already characterized on the model molecule studies (Figure S35).

Figure 6

Figure 6. Water-suppressed 1H NMR spectra over time of 10 wt % PEGalk-A1’s solubilized degradation products (pH = 5.0 buffer/D2O 9:1, 500 MHz). The spectrum of A1 is included as a reference.

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The effect of temperature on β-aminoacrylate hydrogel stability was studied by comparing their swelling and degradation at pH 7.4 at two different temperatures: 25 and 37 °C. Therefore, 10 wt % PEGalk-A1 hydrogels were immersed in the buffer at the selected temperature and, again, weighted over time. As observed in Figure 7a, the material initially underwent a weight increase as a result of water uptake at both temperatures. However, after 2–3 days, clear signs of hydrogel erosion such as rounded edges were shown for those at 37 °C. The material suffered a continuous decrease in weight that led to complete solubilization after 6 days, whereas for those immersed at 25 °C, collapse did not occur until the 14th day. With the aim to know the structural changes behind the degradation of the hydrogel at 37 °C, 1H NMR spectrum of the fully solubilized hydrogel was recorded after freeze-drying the final resulting aqueous solution (Figure S36). First, signals of the protonated amine were observed, confirming that although β-aminoacrylate cleavage is significantly slowed down, it occurs even at physiological pH as previously demonstrated on the model molecule studies and HR-MAS NMR spectroscopy of the hydrogel. Furthermore, alpha protons of the ester group were not detected in the spectrum, suggesting that complete solubilization is also accompanied by ester hydrolysis at long degradation times. β-Aminoester-based molecules resulting from Michael addition of amines to acrylates have been proved to be hydrolytically labile at neutral or basic-like pH, even within hour scale. (62) However, ester hydrolysis seems not to be as favored in our case, probably because of the higher electron density on the acyl carbon of the ester bond provided by the double bond. Since ester hydrolysis was not detected in the degradation studies of the model molecule for up to 48 h, it is suggested that it occurs preferentially over extended periods of time, possibly spanning several days according to the results on the hydrogels.

Figure 7

Figure 7. (a) Temperature-induced degradation behavior over time of 10 wt % PEGalk-A1 hydrogels at 25 and 37 °C and (b) 10 wt % PEGalk-A1/2/3/4 hydrogels at 37 °C.

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Swelling/degradation experiments were also undertaken for 10 wt % PEGalk-A2/A3/A4 at pH = 7.4 and 37 °C (Figure 7b). As expected, they reproduced the trend observed at 25 °C, so a higher cross-linking density seems to favor a stronger stability (A3 > A4 > A2/1). Therefore, hydrogels that were robust toward pH-triggered cleavage were also more resistant against the action of temperature. Regarding the effect of using a cyclic amine as piperazine (PEGalk-A2), it was noticed that the water uptake was lower than for PEGalk-A1, probably due to the higher rigidity of the network, which retards aminoacrylate cleavage and hydrolysis. In the case of PEGalk-A3, being the most stable hydrogel, relative weight started to decrease after the 9th day and complete breaking down of the material occurred beyond the 16th day. For PEGalk-A1, A2, and A4, complete solubilization of the hydrogel was detected at the 6th, 8th, and 10th days, respectively.

Conclusions

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This work provides a deep insight into the degradation of hydrogels based on β-aminoacrylate cross-links. Studies have been conducted on a model bis(β-aminoacrylate) molecule to improve our understanding of the chemistry underlying the recovery of the initial amine after the cleavage of the bond. It should be underscored that contrary to previous assumptions, the pH-triggered cleavage of β-aminoacrylate not only yields 3-oxopropanoates but also different species are detected depending on the pH. Furthermore, it has been demonstrated that the β-aminoacrylate bond is also cleavable at physiological pH. Even though dissociation of the bond is slower compared to more acidic environments, it still results in a slow release of the amine. Regarding the hydrogels, they have shown a high-water-uptake capacity that makes them attractive candidates for biomedical applications such as wound dressing. Rheological measurements combined with HR-MAS NMR spectroscopy have revealed the dynamic nature of the β-aminoacrylate bond within the hydrogels even at physiological pH, as well as the significant differences in the final properties of the material induced by small changes in temperature (25 to 37 °C). The tunability of their degradation rates once the hydrogel is prepared has been proven to strongly depend on the cross-link density, as well as external changes on pH and temperature of the media. Finally, release of the conjugated amine after the pH-induced cleavage of the β-aminoacrylate bonds was demonstrated, mimicking results acquired through model molecule studies. This proof of concept paves the way to the use of amino-yne click reaction for conjugation and release of amino-based drugs, mediated by cleavage of β-aminoacrylate links inside of our hydrogel’s network with a tunable degradability.

Experimental Section

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Materials

Triethylene glycol monomethyl eter, propiolic acid, N,N’-dimethyl-1,3-propanediamine, piperazine, spermine, diethylenetriamine, 1,4-diaminobutane, and 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt (TMSP) were purchased from Sigma-Aldrich and used without purification. 4-arm poly(ethylene glycol) (pentaerythritol as core) with a molar mass of 10,000 g mol–1 was purchased from JenKem Technology (Tianjin). Phosphate buffer (PB, 0.1 M, pH 7.4) was prepared by mixing 50 vol % of sodium phosphate dibasic heptahydrate solution (72 mM) and 50 vol % sodium phosphate monobasic monohydrate solution (28 mM) in Milli-Q water. Acetate buffer (0.1 M, pH 5) was prepared by mixing 50 vol % of 70 mM sodium acetate solution and 50 vol % of 30 mM acetic acid solution in Milli-Q water. An aqueous solution at pH 2.0 (0.1 M) was prepared by mixing appropriate amounts of potassium chloride (0.1 M) and hydrochloric acid (0.02 M) in Milli-Q water.

Characterization

1H NMR and 13C NMR spectra were acquired on a Bruker Avance NEO 400 spectrometer if not detailed in the specific method. The experiments were performed at room temperature in different deuterated solvents (CDCl3 or D2O). FTIR spectra were recorded on a Bruker Vertex 70 FTIR spectrometer. The samples were prepared on KBr pellets with a concentration of the product of 1–2% (w/w). MALDI-TOF mass spectrometry was performed on an Autoflex Bruker mass spectrometer with a dithranol matrix. Positive and negative ion electrospray ionization high resolution (ESI HRMS) was performed on a Bruker Q-TOF-MS instrument in positive or negative ESI mode. Thermal analysis was performed by differential scanning calorimetry with DSC TA Instruments Q2000 at 10 °C min–1 scan rate. The sample was sealed in aluminum hermetic pans.

Synthesis

Synthesis of TEGalk

Triethylene glycol monomethyl ether (3.22 g, 19.39 mmol) was dissolved in toluene (50 mL). To this solution were added both propiolic acid (2.70 g, 38.58 mmol) and para-toluenesulfonic acid (184 mg, 0.97 mmol), and the mixture was allowed to reflux for 18 h using a Dean–Stark apparatus to remove water and drive the reaction to completion. The reaction was cooled to room temperature and then evaporated to dryness. The residue was purified by flash column chromatography on silica gel, initially eluting with hexane/ethyl acetate (8:2), gradually increasing the polarity to finish with a (1:1) mixture. The target compound was obtained as a yellow oil. Yield: 78%. 1H NMR (CDCl3, 400 MHz) δ (ppm): 4.33 (2H, t, J = 4.8 Hz), 3.74–3.54 (10H, m), 3.38 (3H, s), 2.90 (1H, s). 13C NMR (CDCl3, 100 MHz) δ (ppm): 152.8, 75.3, 72.1, 70.9, 70.8, 70.7, 68.8, 65.4, 59.2. FTIR (KBr) υ (cm–1): 3340–3120 (Csp-H), 3020–2740 (Csp3-H), 2115 (C≡C), 1717 (C═O).

Syntheis of TEG2-A1

A solution of N,N’-dimethyl-1,3-propanediamine (244 mg, 2.32 mmol) in PB (2.5 mL) was added dropwise to the TEGalk (1 g, 4.64 mmol) solution in PB (2.5 mL). After stirring for 10 min, the aqueous solution was extracted with ethyl acetate (3 × 15 mL) and the organic fraction was dried over MgSO4 and evaporated to dryness. The compound was obtained as a yellow oil. Yield: 82%. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.57 (2H, d, J = 12.8 Hz), 4.56 (2H, d, J = 12.8 Hz), 4.19 (4H, t, J = 4.8 Hz), 3.77–3.59 (20H, m), 3.37, (6H, s), 3.30 (4H, t, J = 7.2 Hz), 2.86 (6H, s), 1.91 (2H, quint, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz,) δ (ppm): 169.3, 152.1, 84.9, 71.9, 70.6, 70.5, 70.5, 69.8, 62.3, 59.1. FTIR (KBr) υ (cm–1): 3708–3217 (Csp2-H), 3072–3760 (Csp3-H), 1687 (C═O), 1614 (C═C).

Synthesis of PEGalk

4-arm poly(ethylene glycol) (HO-ended) (1.50 g, 0.15 mmol) was dissolved in toluene (25 mL). Propiolic acid (422 mg, 6.00 mmol) and para-toluenesulfonic acid (37.1 mg, 0.20 mmol) were added, and the mixture was allowed to reflux for 48 h using a Dean–Stark apparatus to remove water and drive the reaction to completion. After cooling down the reaction to room temperature, the mixture was evaporated to dryness. The resultant residue was dissolved in dichloromethane and precipitated in ice-cold diethyl ether three times (3 × 200 mL), isolating the product by filtration. The final compound was dried under vacuum overnight, obtaining a white powder. It was observed that after storing the product at room temperature for several weeks, it eventually became insoluble in water as well as in other common organic solvents. Therefore, it should be stored in the refrigerator under argon. Under these storing conditions, the final compound can be safely handled at room temperature during a few days before observing any side reaction. Yield: 90%. 1H NMR (CDCl3, 400 MHz) δ (ppm): 4.34 (8H, t, J = 4.8 Hz), 3.75–3.52 (896H, m), 3.40 (8H, s), 2.96 (4H, s). FTIR (KBr) υmax, (cm–1): 3220 (Csp-H), 2889 (Csp3–H), 2112 (Csp-Csp), 1715 (C═O).

Model Molecule NMR Study of the pH-Induced β-Aminoacrylate Cleavage

TEG2-A1 was dissolved in an aqueous solution of the appropriate pH (7.4, 5.0 or 2.0) in a concentration of 0.06 M. Aliquots of 450 μL were diluted with 50 μL of D2O (TMSP was used as internal standard in the deuterated solvent at 1 mg mL–1 concentration) and transferred into an NMR tube. 1H NMR spectra were collected over time. pH was adjusted when needed with 1 M HCl. Monodimensional NMR spectra were recorded at room temperature in a Bruker Avance III 300 MHz spectrometer equipped with a BBOF probe and applying a NOE water suppression experiment. Bidimensional experiments were acquired on a Bruker Avance NEO 400 spectrometer. Chemical shifts are given in parts per million relative to the TMSP internal standard.

Hydrogel Preparation

Hydrogels were prepared in 1.5 mL glass vials (8 × 35 mm) with a final mass of 200 mg (PEGalk + solvent), assuming the pH 7.4 buffer density is approximately 1 g/mL and dismissing the amine’s mass. First, an appropriate amount of PEGalk was weighted in the glass vial to achieve polymer concentrations of 5, 10, 20, or 30 wt % in the final mass. Then, it was dissolved in 75% of final volume of pH 7.4 buffer used by orbital mixing overnight. PEGalk 1H NMR spectrum was collected after 24 h of being dissolved in pH = 7.4 buffer in order to verify that no side reactions occur before hydrogel preparation (Figure S25). The amine solution in the pH 7.4 buffer was prepared so that a 1:1 stoichiometric ratio of amine group:alkynoate is reached after adding the cross-linker in 25% of the final volume of the buffer. After 10 s of vortex mixing, hydrogels were allowed to set at a controlled temperature of 25 °C for 24 h. Table S1 exemplifies the mass, volume, and concentrations used for PEGalk-A1 hydrogel preparation for each polymer concentration (see Supporting Information, Table S1).

Inverted Vial Test

Hydrogels were prepared as stated above. The timer was started immediately after the addition of the amine solution and vortex mixing. Gelation time was determined when no flow was observed after inverting the vial. The experiments were carried out in triplicate, so gelation times were presented as an average.

Rheological Analysis

Rheological measurements were performed on a HAAKE MARS 40 rheometer with a parallel plate measuring system and a gap of 0.5 mm. The lower plate was heated to the desired temperature. Then, the precursor solutions of hydrogels were prepared separately so that they were pipetted onto the plate, mixed in situ, and the measurement started immediately after.

EWC

The EWC index was studied to characterize the water content of the hydrogel in a steady state. In order to be measured, free hydrogels were removed from the reaction vials, frozen in liquid nitrogen, and lyophilized for 24 h. Freeze-dried hydrogels were weighted (dried mass, Wd) and immersed in pH = 7.4 buffer. Swelling was monitored by a weighting method, where the hydrogels were allowed to swell and their weight was recorded over time (Wt), calculating their swelling ratio at each time as follows:
SwellingRatio=Wt−WdWd×100%
All measurements were repeated in triplicate. Swelling equilibrium is considered to be reached once Wt stays constant over time (Wf), so that EWC is calculated as follows:
EWC=Wf−WdWf×100%

Hydrogel Morphology

The microstructure of the gel was visualized by SEM. The hydrogel was prepared as stated above, in a 4 mL vial at 10, 20, or 30 wt % polymer concentration in a final mass of 200 mg. Then, the recovered hydrogel was immersed in pH 7.4 buffer for 1 h, frozen in liquid nitrogen, and subsequently snapped to expose the cross-section. After being lyophilized, the xerogel was coated with Pt for observation under SEM.

MIP

MIP was performed using a Micromeritics AutoPore IV 9500 porosimeter to determine macro- and mesoporosity and pore size distribution. Between 2 and 3 replicas were evaluated to ensure accurate results. The pore diameter distribution curves were calculated using the Washburn equation:
pd=−4ϒcosϑ
where p is the pressure required to force mercury into the pores, d is the diameter of the pores, ϒ is the mercury surface tension (485 dyn cm–1), and ϑ is the contact angle between mercury and the sample.

1H-HR-MAS NMR Spectroscopy

All HR-MAS NMR spectra were acquired at room temperature on a Bruker Avance NEO 400 spectrometer operating at a proton Larmor frequency of 400.13 MHz and equipped with a 4 mm double-resonance (1H, 13C) gradient HR-MAS probe. Samples were prepared in a pH 7.4 buffer and swollen with a drop of deuterium oxide in the probe. Chemical shifts were referenced to the TMSP (as an internal reference). The gels were mechanically stable at the moderate MAS rate of 4 kHz used in all the HR-MAS experiments, and no sample instabilities resulting from centrifugation-related phenomena were detected.

Hydrogel pH-Induced Degradation

Free hydrogels were removed from the reaction vials, so the material was able to be weighted (W0) and immersed in 2 mL of aqueous solution of the appropriate pH (7.4, 5.0 or 2.0) at 25 °C. Swelling/degradation was monitored by a weighting method, where the hydrogels were allowed to swell, and their weight was recorded at appropriate time points (Wt). The aqueous solution of the appropriate pH was renewed every 24 h. All measurements were repeated in triplicate. Results are represented as a function of the relative weight at each time (mean ± SD (n = 3)):
RelativeWeight=WtW0

Hydrogel Temperature-Induced Degradation

Process is performed identically as stated above, immersing hydrogels in 2 mL of pH 7.4 buffer at the desired temperature (25 or 37 °C).

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.macromol.4c01403.

  • Additional characterization data including NMR, FTIR, ESI HRMS, MALDI-ToF MS, DSC, rheology, and MIP results (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Authors
    • Milagros Piñol - Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain;  Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain;  Email: [email protected]
    • Luis Oriol - Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain;  Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain;  Orcidhttps://orcid.org/0000-0002-0922-5615;  Email: [email protected]
  • Authors
    • Sara Bescós-Ramo - Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain;  Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain;  Orcidhttps://orcid.org/0009-0008-6456-4856
    • Jesús del Barrio - Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain;  Orcidhttps://orcid.org/0000-0002-5380-6863
    • Pilar Romero - Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain;  Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain;  Orcidhttps://orcid.org/0000-0003-1378-0571
    • Laura Florentino-Madiedo - Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain;  Departamento de Ingeniería Química y Tecnologías del Medio Ambiente, Universidad de Zaragoza, C/María de Luna, 3, Zaragoza 50018, Spain
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was financially supported by Ministerio de Ciencia e Innovación (PID2021-126132NB-I00), the Grant CEX2023-001286-S funded by MICIU/AEI/10.13039/501100011033, and Gobierno de Aragón-FSE (E47_23R research group). S.B-R. acknowledges Gobierno de Aragón for her Ph.D. grant. The authors would like to acknowledge the use of Laboratorio de Microscopias Avanzadas-LMA (Instituto de Nanociencia y Materiales de Aragón-Universidad de Zaragoza), Servicio General de Apoyo a la Investigación-SAI (Universidad de Zaragoza), and Servicios Científico-Técnicos of CEQMA (CSIC-Universidad de Zaragoza) and Conexión Nanomedicina (CSIC).

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    A water-sol. azide-functionalized chitosan was crosslinked with propiolic acid ester-functional poly(ethylene glycol) using copper-free click chem. The resultant hydrogel materials were formed within 5-60 min at 37 °C and resulted in mech. robust materials with tuneable properties such as swelling, mech. strength and degrdn. Importantly, the hydrogels supported mesenchymal stem cell attachment and proliferation and were also non-toxic to encapsulated cells. As such these studies indicate that the hydrogels have potential to be used as injectable biomaterials for tissue engineering.
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  11. 11
    Ono, R. J.; Lee, A. L. Z.; Voo, Z. X.; Venkataraman, S.; Koh, B. W.; Yang, Y. Y.; Hedrick, J. L. Biodegradable Strain-Promoted Click Hydrogels for Encapsulation of Drug-Loaded Nanoparticles and Sustained Release of Therapeutics. Biomacromolecules 2017, 18 (8), 2277– 2285,  DOI: 10.1021/acs.biomac.7b00377
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    11
    Biodegradable Strain-Promoted Click Hydrogels for Encapsulation of Drug-Loaded Nanoparticles and Sustained Release of Therapeutics
    Ono, Robert J.; Lee, Ashlynn L. Z.; Voo, Zhi Xiang; Venkataraman, Shrinivas; Koh, Bei Wei; Yang, Yi Yan; Hedrick, James L.
    Biomacromolecules (2017), 18 (8), 2277-2285CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Biodegradable polycarbonate-based ABA triblock copolymers were synthesized via organocatalyzed ring-opening polymn. and successfully formulated into chem. crosslinked hydrogels by strain-promoted alkyne-azide cycloaddn. (SPAAC). The synthesis and crosslinking of these polymers are copper-free, thereby eliminating the concern over metallic contaminants for biomedical applications. Gelation occurs rapidly within a span of 60 s by simple mixing of the azide- and cyclooctyne-functionalized polymer solns. The resultant hydrogels exhibited pronounced shear-thinning behavior and could be easily dispensed through a 22G hypodermic needle. To demonstrate the usefulness of these gels as a drug delivery matrix, doxorubicin (DOX)-loaded micelles prepd. using catechol-functionalized polycarbonate copolymers were incorporated into the polymer solns. to eventually form micelle/hydrogel composites. Notably, the drug release rate from the hydrogels was significantly more gradual compared to the soln. formulation. DOX release from the micelle/hydrogel composites could be sustained for 1 wk, while the release from the micelle soln. was completed rapidly within 6 h of incubation. Cellular uptake of the released DOX from the micelle/hydrogel composites was obsd. at 3 h of incubation of human breast cancer MDA-MB-231 cells. A blank hydrogel contg. PEG-(Cat)12 micelles showed almost negligible toxicity on MDA-MB-231cells where cell viability remained high at >80% after treatment. When the cells were treated with the DOX-loaded micelle/hydrogel composites, there was a drastic redn. in cell viability with only 25% of cells surviving the treatment. In all, this study introduces a simple method of formulating hydrogel materials with incorporated micelles for drug delivery applications.
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  12. 12
    Fu, S.; Dong, H.; Deng, X.; Zhuo, R.; Zhong, Z. Injectable Hyaluronic Acid/Poly(Ethylene Glycol) Hydrogels Crosslinked via Strain-Promoted Azide-Alkyne Cycloaddition Click Reaction. Carbohydr. Polym. 2017, 169, 332– 340,  DOI: 10.1016/j.carbpol.2017.04.028
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    12
    Injectable hyaluronic acid/poly(ethylene glycol) hydrogels crosslinked via strain-promoted azide-alkyne cycloaddition click reaction
    Fu, Shuangli; Dong, Hui; Deng, Xueyi; Zhuo, Renxi; Zhong, Zhenlin
    Carbohydrate Polymers (2017), 169 (), 332-340CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)
    This paper reports injectable hyaluronic acid (HA)-based hydrogels crosslinked with azide-modified poly(ethylene glycol) (PEG) via the strain-promoted azide-alkyne cycloaddn. (SPAAC) between cyclooctyne and azide groups. Cyclooctyne-modified HA (Cyclooctyne-HA) is prepd. by the reaction of HA with 2-(aminoethoxy)cyclooctyne. To crosslink the modified HA, quadruply azide-terminated poly(ethylene glycol) (Azide-PEG) is designed and prepd. The mixt. of Cyclooctyne-HA and Azide-PEG gelates in a few minutes to form a strong HA-PEG hydrogel. The hydrogel has fast gelation time, good strength, and slow degrdn. rate, because of the high reactivity of SPAAC, high crosslinking d. originated from the quadruply-substituted Azide-PEG, and the good stability of the crosslinking amide bonds. In vitro cell culturing within the hydrogel demonstrated an excellent cell-compatibility. The bioorthogonality of SPAAC makes the hydrogel injectable. With good mech. properties and biocompatibility, the hydrogel would be useful in a wide range of applications such as injection filling materials for plastic surgery.
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  13. 13
    Lagneau, N.; Tournier, P.; Halgand, B.; Loll, F.; Maugars, Y.; Guicheux, J.; Le Visage, C.; Delplace, V. Click and Bioorthogonal Hyaluronic Acid Hydrogels as an Ultra-Tunable Platform for the Investigation of Cell-Material Interactions. Bioact. Mater. 2023, 24, 438– 449,  DOI: 10.1016/j.bioactmat.2022.12.022
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    There is no corresponding record for this reference.
  14. 14
    van de Wetering, P.; Metters, A. T.; Schoenmakers, R. G.; Hubbell, J. A. Poly(Ethylene Glycol) Hydrogels Formed by Conjugate Addition with Controllable Swelling, Degradation, and Release of Pharmaceutically Active Proteins. J. Controlled Release 2005, 102 (3), 619– 627,  DOI: 10.1016/j.jconrel.2004.10.029
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    14
    Poly(ethylene glycol) hydrogels formed by conjugate addition with controllable swelling, degradation, and release of pharmaceutically active proteins
    van de Wetering, Petra; Metters, Andrew T.; Schoenmakers, Ronald G.; Hubbell, Jeffrey A.
    Journal of Controlled Release (2005), 102 (3), 619-627CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    Hydrogels were formed by conjugate addn. of polyethylene glycol (PEG) multiacrylates and dithiothreitol (DTT) for encapsulation and sustained release of protein drugs; human growth hormone (hGH) was considered as an example. Prior to encapsulation, the hGH was pptd. either by Zn2+ ions or by linear PEG, to protect the hGH from reaction with the gel precursors during gelation. Pptn. by Zn2+ ions yielded ppts. that dissolved slowly and delayed release from even highly permeable gels, whereas linear PEG yielded rapidly dissolving ppts. To independently protect the protein and delay its release, linear PEG pptn. was adopted, and release control via modulation of the PEG gel mesh size was sought. By varying the mol. wt. of the multiarm PEG acrylates, control over gel swelling and hGH release, from a few hours to a few months, could be obtained. Protein release from the swollen and degrading PEG-based gel networks was modeled as a diffusion process with a time-dependent diffusion coeff., calcd. from swelling measurements and theor. mesh sizes. Release following zero-order kinetics was obtained by the counter influences of decreasing protein concn. and increasing protein diffusion coeff. over time.
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  15. 15
    Rydholm, A. E.; Reddy, S. K.; Anseth, K. S.; Bowman, C. N. Development and Characterization of Degradable Thiol-Allyl Ether Photopolymers. Polymer 2007, 48 (15), 4589– 4600,  DOI: 10.1016/j.polymer.2007.05.063
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    There is no corresponding record for this reference.
  16. 16
    Kharkar, P. M.; Kloxin, A. M.; Kiick, K. L. Dually Degradable Click Hydrogels for Controlled Degradation and Protein Release. J. Mater. Chem. B 2014, 2 (34), 5511– 5521,  DOI: 10.1039/C4TB00496E
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    16
    Dually degradable click hydrogels for controlled degradation and protein release
    Kharkar, Prathamesh M.; Kloxin, April M.; Kiick, Kristi L.
    Journal of Materials Chemistry B: Materials for Biology and Medicine (2014), 2 (34), 5511-5521CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
    Click reactions have emerged as one of the most powerful paradigms in materials chem. owing to their high regioselectivity and efficient reaction yields under mild conditions. While stability of the bonds formed by these reactions often is highly valued, their controlled cleavage is promising as an elegant approach to engineer material degrdn. for a no. of applications, including drug delivery and tissue engineering. However, cleavage of click linkages under physiol. conditions remains a major challenge in the design of degradable biomaterials. Here, we demonstrate the use of cleavable click linkages formed by Michael-type addn. reactions in conjunction with hydrolytically cleavable functionalities for the degrdn. of injectable hydrogels by dual mechanisms for controlled protein release. Specifically, the reaction between maleimides and thiols was utilized for hydrogel formation, where thiol selection dictates the degradability of the resulting linkage under thiol-rich reducing conditions. Relevant microenvironments would include those rich in glutathione (GSH), a tripeptide that is found at elevated concns. in carcinoma tissues. Degrdn. of the hydrogels was monitored with rheometry and volumetric swelling measurements. Arylthiol-based thioether succinimide linkages underwent degrdn. via click cleavage and thiol exchange reaction in the presence of GSH as well as ester hydrolysis, whereas alkylthiol-based thioether succinimide linkages only undergo ester hydrolysis. The resulting control over the degrdn. rate within a reducing microenvironment resulted in ∼2.5 fold differences in the release profile of cargo mols. (fluorescently labeled bovine serum albumin as a model protein) from dually degradable hydrogels compared to non-degradable hydrogels. These unique degradable chemistries are promising for controlling the rate of degrdn. and local release of therapeutic cargo mols. in cancer tissue microenvironments.
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  17. 17
    Kharkar, P. M.; Rehmann, M. S.; Skeens, K. M.; Maverakis, E.; Kloxin, A. M. Thiol–Ene Click Hydrogels for Therapeutic Delivery. ACS Biomater. Sci. Eng. 2016, 2 (2), 165– 179,  DOI: 10.1021/acsbiomaterials.5b00420
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    17
    Thiol-ene Click Hydrogels for Therapeutic Delivery
    Kharkar, Prathamesh M.; Rehmann, Matthew S.; Skeens, Kelsi M.; Maverakis, Emanual; Kloxin, April M.
    ACS Biomaterials Science & Engineering (2016), 2 (2), 165-179CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)
    A review. Hydrogels are of growing interest for the delivery of therapeutics to specific sites in the body. For use as a delivery vehicle, hydrophilic precursors are usually laden with bioactive moieties and then directly injected to the site of interest for in situ gel formation and controlled release dictated by precursor design. Hydrogels formed by thiol-ene click reactions are attractive for local controlled release of therapeutics owing to their rapid reaction rate and efficiency under mild aq. conditions, enabling in situ formation of gels with tunable properties often responsive to environmental cues. Herein, we will review the wide range of applications for thiol-ene hydrogels, from the prolonged release of anti-inflammatory drugs in the spine to the release of protein-based therapeutics in response to cell-secreted enzymes, with a focus on their clin. relevance. We will also provide a brief overview of thiol-ene click chem. and discuss the available alkene chemistries pertinent to macromol. functionalization and hydrogel formation. These chemistries include functional groups susceptible to Michael type reactions relevant for injection and radically mediated reactions for greater temporal control of formation at sites of interest using light. Addnl., mechanisms for the encapsulation and controlled release of therapeutic cargoes are reviewed, including (i) tuning the mesh size of the hydrogel initially and temporally for cargo entrapment and release and (ii) covalent tethering of the cargo with degradable linkers or affinity binding sequences to mediate release. Finally, myriad thiol-ene hydrogels and their specific applications also are discussed to give a sampling of the current and future utilization of this chem. for delivery of therapeutics, such as small mol. drugs, peptides, and biologics.
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  18. 18
    Alge, D. L.; Azagarsamy, M. A.; Donohue, D. F.; Anseth, K. S. Synthetically Tractable Click Hydrogels for Three-Dimensional Cell Culture Formed Using Tetrazine–Norbornene Chemistry. Biomacromolecules 2013, 14 (4), 949– 953,  DOI: 10.1021/bm4000508
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    18
    Synthetically Tractable Click Hydrogels for Three-Dimensional Cell Culture Formed Using Tetrazine-Norbornene Chemistry
    Alge, Daniel L.; Azagarsamy, Malar A.; Donohue, Dillon F.; Anseth, Kristi S.
    Biomacromolecules (2013), 14 (4), 949-953CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    The implementation of bio-orthogonal click chemistries is a topic of growing importance in the field of biomaterials, as it is enabling the development of increasingly complex hydrogel materials capable of providing dynamic, cell-instructive microenvironments. Here, we introduce the tetrazine-norbornene inverse electron demand Diels-Alder reaction as a new crosslinking chem. for the formation of cell laden hydrogels. The fast reaction rate and irreversible nature of this click reaction allowed for hydrogel formation within minutes when a multifunctional PEG-tetrazine macromer was reacted with a dinorbornene peptide. In addn., the cytocompatibility of the polymn. led to high postencapsulation viability of human mesenchymal stem cells, and the specificity of the tetrazine-norbornene reaction was exploited for sequential modification of the network via thiol-ene photochem. These advantages, combined with the synthetic accessibility of the tetrazine mol. compared to other bio-orthogonal click reagents, make this crosslinking chem. an interesting and powerful new tool for the development of cell-instructive hydrogels for tissue engineering applications.
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  19. 19
    Guaresti, O.; García–Astrain, C.; Aguirresarobe, R. H.; Eceiza, A.; Gabilondo, N. Synthesis of Stimuli–Responsive Chitosan–Based Hydrogels by Diels–Alder Cross–Linking ̀click′ Reaction as Potential Carriers for Drug Administration. Carbohydr. Polym. 2018, 183, 278– 286,  DOI: 10.1016/j.carbpol.2017.12.034
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    There is no corresponding record for this reference.
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    Zander, Z. K.; Hua, G.; Wiener, C. G.; Vogt, B. D.; Becker, M. L. Control of Mesh Size and Modulus by Kinetically Dependent Cross-Linking in Hydrogels. Adv. Mater. 2015, 27 (40), 6283– 6288,  DOI: 10.1002/adma.201501822
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    20
    Control of Mesh Size and Modulus by Kinetically Dependent Cross-Linking in Hydrogels
    Zander, Zachary K.; Hua, Geng; Wiener, Clinton G.; Vogt, Bryan D.; Becker, Matthew L.
    Advanced Materials (Weinheim, Germany) (2015), 27 (40), 6283-6288CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    It was shown that small changes in the structural features, resulting from variations in the kinetics of crosslinking, are capable of producing mech. distinguishable hydrogels from chem. identical precursors. For an oxime crosslinking reaction, the kinetics of network formation are influenced by pH and buffer strength, and may be utilized to intrinsically control the degree of heterogeneity within the scaffold microstructure. The significance of this study, in comparison to existing hydrogel systems, is the use of kinetics for tuning the microstructure and modulus. This method provides tunability, yet maintains the chem. identity, concn. and stoichiometry of the hydrogel. Further, developing and understanding this and other kinetically driven systems should enable a facile route for precise control over the mech. properties of hydrogels. Overall, these PEG-based hydrogels could provide definitive insight into the effect of substrate elasticity on hMSC differentiation because the scaffolds employ the same precursor chem., yet exhibit a range of mech. properties.
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  21. 21
    Grover, G. N.; Lam, J.; Nguyen, T. H.; Segura, T.; Maynard, H. D. Biocompatible Hydrogels by Oxime Click Chemistry. Biomacromolecules 2012, 13 (10), 3013– 3017,  DOI: 10.1021/bm301346e
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    21
    Biocompatible Hydrogels by Oxime Click Chemistry
    Grover, Gregory N.; Lam, Jonathan; Nguyen, Thi H.; Segura, Tatiana; Maynard, Heather D.
    Biomacromolecules (2012), 13 (10), 3013-3017CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Oxime Click chem. was used to form hydrogels that support cell adhesion. Eight-armed aminooxy poly(ethylene glycol) (PEG) was mixed with glutaraldehyde to form oxime-linked hydrogels. The mech. properties, gelation kinetics, and water swelling ratios were studied and found to be tunable. It was also shown that gels contg. the integrin ligand arginine-glycine-aspartic acid (RGD) supported mesenchymal stem cell (MSC) incorporation. High cell viability and proliferation of the encapsulated cells demonstrated biocompatibility of the material.
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  22. 22
    Grover, G. N.; Braden, R. L.; Christman, K. L. Oxime Cross-Linked Injectable Hydrogels for Catheter Delivery. Adv. Mater. 2013, 25 (21), 2937– 2942,  DOI: 10.1002/adma.201205234
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    22
    Oxime Cross-Linked Injectable Hydrogels for Catheter Delivery
    Grover, Gregory N.; Braden, Rebecca L.; Christman, Karen L.
    Advanced Materials (Weinheim, Germany) (2013), 25 (21), 2937-2942CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    We have demonstrated a new approach for gelation of injectable materials utilizing oxime crosslinking. Tunable in vitro gelation was achieved by altering the pH with a bioinert-PEG system, as well as with oxidized hyaluronic acid and alginate. Oxime chem. allowed these materials to be injected multiple times through a catheter in vitro over the course of hours while at 37 degrees C, mimicking the in vivo situation. PEG and polysaccharide systems form gels within 20 min upon injection into the s.c. space. The PEG-oxime system was capable of rapid gelation upon injection into myocardial tissue.
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  23. 23
    Lin, F.; Yu, J.; Tang, W.; Zheng, J.; Defante, A.; Guo, K.; Wesdemiotis, C.; Becker, M. L. Peptide-Functionalized Oxime Hydrogels with Tunable Mechanical Properties and Gelation Behavior. Biomacromolecules 2013, 14 (10), 3749– 3758,  DOI: 10.1021/bm401133r
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    23
    Peptide-Functionalized Oxime Hydrogels with Tunable Mechanical Properties and Gelation Behavior
    Lin, Fei; Yu, Jiayi; Tang, Wen; Zheng, Jukuan; Defante, Adrian; Guo, Kai; Wesdemiotis, Chrys; Becker, Matthew L.
    Biomacromolecules (2013), 14 (10), 3749-3758CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    We demonstrate the formation of polyethylene glycol (PEG) based hydrogels via oxime ligation and the photoinitiated thiol-ene 3D patterning of peptides within the hydrogel matrix postgelation. The gelation process and final mech. strength of the hydrogels can be tuned using pH and the catalyst concn. The time scale to reach the gel point and complete gelation can be shortened from hours to seconds using both pH and aniline catalyst, which facilitates the tuning of the storage modulus from 0.3 to over 15 kPa. Azide- and alkene-functionalized hydrogels were also synthesized, and we have shown the post gelation "click"-type Huisgen 1,3 cycloaddn. and thiolene-based radical reactions for spatially defined peptide incorporation. These materials are the initial demonstration for translationally relevant hydrogel materials that possess tunable mech. regimes attractive to soft tissue engineering and possess atom neutral chemistries attractive for post gelation patterning in the presence or absence of cells.
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  24. 24
    Truong, V. X.; Ablett, M. P.; Richardson, S. M.; Hoyland, J. A.; Dove, A. P. Simultaneous Orthogonal Dual-Click Approach to Tough, in-Situ-Forming Hydrogels for Cell Encapsulation. J. Am. Chem. Soc. 2015, 137 (4), 1618– 1622,  DOI: 10.1021/ja511681s
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    24
    Simultaneous Orthogonal Dual-Click Approach to Tough, in-Situ-Forming Hydrogels for Cell Encapsulation
    Truong, Vinh X.; Ablett, Matthew P.; Richardson, Stephen M.; Hoyland, Judith A.; Dove, Andrew P.
    Journal of the American Chemical Society (2015), 137 (4), 1618-1622CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The use of tough hydrogels as biomaterials is limited as a consequence of time-consuming fabrication techniques, toxic starting materials, and large strain hysteresis under deformation. Herein, we report the simultaneous application of nucleophilic thiol-yne and inverse electron-demand Diels-Alder addns. to independently create two interpenetrating networks in a simple one-step procedure. The resultant hydrogels display compressive stresses of 14-15 MPa at 98% compression without fracture or hysteresis upon repeated load. The hydrogel networks can be spatially and temporally postfunctionalized via radical thiylation and/or inverse electron-demand Diels-Alder addn. to residual functional groups within the network. Furthermore, gelation occurs rapidly under physiol. conditions, enabling encapsulation of human cells.
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  25. 25
    Cai, X. Y.; Li, J. Z.; Li, N. N.; Chen, J. C.; Kang, E.-T.; Xu, L. Q. PEG-Based Hydrogels Prepared by Catalyst-Free Thiol–Yne Addition and Their Post-Antibacterial Modification. Biomater. Sci. 2016, 4 (11), 1663– 1672,  DOI: 10.1039/C6BM00395H
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    There is no corresponding record for this reference.
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    Macdougall, L. J.; Truong, V. X.; Dove, A. P. Efficient In Situ Nucleophilic Thiol-Yne Click Chemistry for the Synthesis of Strong Hydrogel Materials with Tunable Properties. ACS Macro Lett. 2017, 6 (2), 93– 97,  DOI: 10.1021/acsmacrolett.6b00857
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    26
    Efficient In Situ Nucleophilic Thiol-yne Click Chemistry for the Synthesis of Strong Hydrogel Materials with Tunable Properties
    MacDougall, Laura J.; Truong, Vinh X.; Dove, Andrew P.
    ACS Macro Letters (2017), 6 (2), 93-97CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
    Synthetic hydrogel materials offer the ability to tune the mech. properties of the resultant networks by controlling the mol. structure of the polymer precursors. Herein, we demonstrate that the nucleophilic thiol-yne click reaction presents a highly efficient chem. for forming robust high water content (ca. 90%) hydrogel materials with tunable stiffness and mech. properties. Remarkably, optimization of the mol. wt. and geometry of the poly(ethylene glycol) (PEG) precursors allows access to materials with compressive strength up to 2.4 MPa which, can be repeatedly compressed to >90% stress. Beyond this, we demonstrate the ability to access hydrogels with storage moduli ranging from 0.2 to 7 kPa. Moreover, we also demonstrate that by a simple precursor blending process, we can access intermediate stiffness across this range with minimal changes to the hydrogel structure. These characteristics present the nucleophilic thiol-yne addn. as an excellent method for the prepn. of hydrogels for use as versatile synthetic biomaterials.
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  27. 27
    Fan, B.; Zhang, K.; Liu, Q.; Eelkema, R. Self-Healing Injectable Polymer Hydrogel via Dynamic Thiol-Alkynone Double Addition Cross-Links. ACS Macro Lett. 2020, 9 (6), 776– 780,  DOI: 10.1021/acsmacrolett.0c00241
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    27
    Self-Healing Injectable Polymer Hydrogel via Dynamic Thiol-Alkynone Double Addition Cross-Links
    Fan, Bowen; Zhang, Kai; Liu, Qian; Eelkema, Rienk
    ACS Macro Letters (2020), 9 (6), 776-780CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
    Introduction of dynamic thiol-alkynone double addn. crosslinks in a polymer network enable the formation of a self-healing injectable polymer hydrogel. A four-arm polyethylene glycol (PEG) tetra-thiol star polymer is crosslinked by a small mol. alkynone via the thiol-alkynone double adduct to generate a hydrogel network under ambient aq. conditions (buffer pH = 7.4 or 8.2, room temp.). The mech. properties of these hydrogels can be easily tuned by varying the concn. of polymer precursors. Through the dynamic thiol-alkynone double addn. crosslink, these hydrogels are self-healing and shear thinning, as demonstrated by rheol. measurements, macroscopic self-healing, and injection tests. These hydrogels can be injected through a 20G syringe needle and recover after extrusion. In addn., good cytocompatibility of these hydrogels is confirmed by cytotoxicity test. This work shows the application of the thiol-alkynone double addn. dynamic covalent chem. in the straightforward prepn. of self-healing injectable hydrogels, which may find future biomedical applications such as tissue engineering and drug delivery.
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  28. 28
    Worch, J. C.; Stubbs, C. J.; Price, M. J.; Dove, A. P. Click Nucleophilic Conjugate Additions to Activated Alkynes: Exploring Thiol-Yne, Amino-Yne, and Hydroxyl-Yne Reactions from (Bio)Organic to Polymer Chemistry. Chem. Rev. 2021, 121 (12), 6744– 6776,  DOI: 10.1021/acs.chemrev.0c01076
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    28
    Click Nucleophilic Conjugate Additions to Activated Alkynes: Exploring Thiol-yne, Amino-yne, and Hydroxyl-yne Reactions from (Bio)Organic to Polymer Chemistry
    Worch, Joshua C.; Stubbs, Connor J.; Price, Matthew J.; Dove, Andrew P.
    Chemical Reviews (Washington, DC, United States) (2021), 121 (12), 6744-6776CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. The 1,4-conjugate addn. reaction between activated alkynes or acetylenic Michael acceptors and nucleophiles (i.e., the nucleophilic Michael reaction) is a historically useful org. transformation. Despite its general utility, the efficiency and outcomes can vary widely and are often closely dependent on specific reaction conditions. Nevertheless, with improvements in reaction design, including catalyst development and expansion of the substrate scope to feature more electrophilic alkynes, many examples now present with features that are congruent with Click chem. Although several nucleophilic species can participate in these conjugate addns., ubiquitous nucleophiles such as thiols, amines and alcs. are commonly employed and, consequently, among the most well developed. For many years, these conjugate addns. were largely relegated to org. chem. but in the last few decades their use has expanded into other spheres such as bioorg. chem. and polymer chem. Within these fields, they have been particularly resourceful for bioconjugation reactions and step-growth polymns., resp., due to their excellent efficiency, orthogonality and ambient reactivity. The reaction is expected to feature in increasingly divergent application settings as it continues to emerge as a Click reaction. Thus, this review examines click nucleophilic addns. to activated alkynes from (bio)org. to polymer chem.
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    Yang, R.; Zhang, X.; Chen, B.; Yan, Q.; Yin, J.; Luan, S. Tunable Backbone-Degradable Robust Tissue Adhesives via in Situ Radical Ring-Opening Polymerization. Nat. Commun. 2023, 14 (1), 6063,  DOI: 10.1038/s41467-023-41610-1
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    Burek, M.; Waśkiewicz, S.; Lalik, A.; Wandzik, I. Hydrogels with Novel Hydrolytically Labile Trehalose-Based Crosslinks: Small Changes – Big Differences in Degradation Behavior. Polym. Chem. 2018, 9 (27), 3721– 3726,  DOI: 10.1039/C8PY00488A
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    Feng, X.; Du, M.; Wei, H.; Ruan, X.; Fu, T.; Zhang, J.; Sun, X. Chemically Triggered Life Control of “Smart” Hydrogels through Click and Declick Reactions. Front. Chem. Sci. Eng. 2022, 16 (9), 1399– 1406,  DOI: 10.1007/s11705-022-2149-z
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    Schneider, E. L.; Henise, J.; Reid, R.; Ashley, G. W.; Santi, D. V. Hydrogel Drug Delivery System Using Self-Cleaving Covalent Linkers for Once-a-Week Administration of Exenatide. Bioconjugate Chem. 2016, 27 (5), 1210– 1215,  DOI: 10.1021/acs.bioconjchem.5b00690
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    Hydrogel Drug Delivery System Using Self-Cleaving Covalent Linkers for Once-a-Week Administration of Exenatide
    Schneider, Eric L.; Henise, Jeff; Reid, Ralph; Ashley, Gary W.; Santi, Daniel V.
    Bioconjugate Chemistry (2016), 27 (5), 1210-1215CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    We have developed a unique long-acting drug-delivery system for the GLP-1 agonist exenatide. The peptide was covalently attached to Tetra-PEG hydrogel microspheres by a cleavable β-eliminative linker; upon s.c. injection, the exenatide is slowly released at a rate dictated by the linker. A second β-eliminative linker with a slower cleavage rate was incorporated in polymer cross-links to trigger gel degrdn. after drug release. The uniform 40 μm microspheres were fabricated using a flow-focusing microfluidic device and in situ polymn. within droplets. The exenatide-laden microspheres were injected s.c. into the rat, and serum exenatide measured over a one-month period. Pharmacokinetic anal. showed a t1/2,β of released exenatide of about 7 days which represents over a 300-fold half-life extension in the rat and exceeds the half-life of any currently approved long-acting GLP-1 agonist. Hydrogel-exenatide conjugates gave an excellent Level A in vitro-in vivo correlation of release rates of the peptide from the gel, and indicated that eventide release was 3-fold faster in vivo than in vitro. Pharmacokinetic simulations indicate that the hydrogel-exenatide microspheres should support weekly or biweekly s.c. dosing in humans. The rare ability to modify in vivo pharmacokinetics by the chem. nature of the linker indicates that an even longer acting exenatide is feasible.
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    Du, M.; Jin, J.; Zhou, F.; Chen, J.; Jiang, W. Dual Drug-Loaded Hydrogels with pH-Responsive and Antibacterial Activity for Skin Wound Dressing. Colloids Surf. B Biointerfaces 2023, 222, 113063  DOI: 10.1016/j.colsurfb.2022.113063
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    Zhu, C.; Zhao, J.; Kempe, K.; Wilson, P.; Wang, J.; Velkov, T.; Li, J.; Davis, T. P.; Whittaker, M. R.; Haddleton, D. M. A Hydrogel-Based Localized Release of Colistin for Antimicrobial Treatment of Burn Wound Infection. Macromol. Biosci. 2017, 17 (2), 1600320,  DOI: 10.1002/mabi.201600320
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    Yang, H.; Fustin, C.-A. Design and Applications of Dynamic Hydrogels Based on Reversible C═N Bonds. Macromol. Chem. Phys. 2023, 224 (20), 2300211,  DOI: 10.1002/macp.202300211
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    Zhang, X.; Malhotra, S.; Molina, M.; Haag, R. Micro- and Nanogels with Labile Crosslinks – from Synthesis to Biomedical Applications. Chem. Soc. Rev. 2015, 44 (7), 1948– 1973,  DOI: 10.1039/C4CS00341A
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    Micro- and nanogels with labile crosslinks - from synthesis to biomedical applications
    Zhang, Xuejiao; Malhotra, Shashwat; Molina, Maria; Haag, Rainer
    Chemical Society Reviews (2015), 44 (7), 1948-1973CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    Micro- or nanosized three-dimensional crosslinked polymeric networks have been designed and described for various biomedical applications, including living cell encapsulation, tissue engineering, and stimuli responsive controlled delivery of bioactive mols. For most of these applications, it is necessary to disintegrate the artificial scaffold into nontoxic residues with smaller dimensions to ensure renal clearance for better biocompatibility of the functional materials. This can be achieved by introducing stimuli-cleavable linkages into the scaffold structures. pH, enzyme, and redox potential are the most frequently used biol. stimuli. Moreover, some external stimuli, for example light and additives, are also used to trigger the disintegration of the carriers or their assembly. In this review, we highlight the recent progress in various chem. and phys. methods for synthesizing and crosslinking micro- and nanogels, as well as their development for incorporation of cleavable linkages into the network of micro- and nanogels.
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    He, B.; Su, H.; Bai, T.; Wu, Y.; Li, S.; Gao, M.; Hu, R.; Zhao, Z.; Qin, A.; Ling, J.; Tang, B. Z. Spontaneous Amino-Yne Click Polymerization: A Powerful Tool toward Regio- and Stereospecific Poly(β-Aminoacrylate)s. J. Am. Chem. Soc. 2017, 139 (15), 5437– 5443,  DOI: 10.1021/jacs.7b00929
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    Spontaneous Amino-yne Click Polymerization: A Powerful Tool toward Regio- and Stereospecific Poly(β-aminoacrylate)s
    He, Benzhao; Su, Huifang; Bai, Tianwen; Wu, Yongwei; Li, Shiwu; Gao, Meng; Hu, Rongrong; Zhao, Zujin; Qin, Anjun; Ling, Jun; Tang, Ben Zhong
    Journal of the American Chemical Society (2017), 139 (15), 5437-5443CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Efficient synthesis of poly(enamine)s has been a great challenge because of their poor stability, poor soly., and low mol. wts. In this work, a spontaneous amino-yne click polymn. for the efficient prepn. of poly(enamine)s was established, which could proceed with 100% atom efficiency under very mild conditions without any external catalyst. Through systematic optimization of the reaction conditions, several sol. and thermally stable poly(β-aminoacrylate)s with high mol. wts. (Mw up to 64400) and well-defined structures were obtained in excellent yields (up to 99%). Moreover, the polymn. can perform in a regio- and stereospecific fashion. NMR spectra anal. revealed that solely anti-Markovnikov additive products with 100% E-isomer were obtained. The reaction mechanism was well demonstrated with the assistance of d. functional theory calcns. In addn., by introducing the tetraphenylethene moiety, the resulting polymers exhibit unique aggregation-induced emission characteristics and could be applied in explosives detection and bioimaging. This polyhydroamination is a new type of click polymn. and opens up enormous opportunities for prepg. functional polymeric materials.
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    Zhang, J.; Zhang, Z.; Wang, J.; Zang, Q.; Sun, J. Z.; Tang, B. Z. Recent Progress in the Applications of Amino–Yne Click Chemistry. Polym. Chem. 2021, 12 (20), 2978– 2986,  DOI: 10.1039/D1PY00113B
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    Recent progress in the applications of amino-yne click chemistry
    Zhang, Jie; Zhang, Zhiming; Wang, Jia; Zang, Qiguang; Sun, Jing zhi; Tang, Ben Zhong
    Polymer Chemistry (2021), 12 (20), 2978-2986CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    Click chem. has been rapidly developed in recent years. Among various established click reaction systems, the spontaneous amino-yne click reaction stands out. In addn. to the general advantages assocd. with click reactions, amino-yne click reaction possesses extra merits, such as spontaneity of reactions, ubiquity of amines and cleavability of products with specific stimuli. Therefore, the amino-yne click reaction has become a useful tool and provided convenience for scientists in various fields since its first report in 2017. In this review, we capture the recent progress in the applications of amino-yne click reaction, which are briefly classified and reviewed in the fields of surface immobilization, drug delivery carrier design, hydrogel materials prepn. and synthesis of polymers with unique structures.
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    Li, D.; Song, Y.; He, J.; Zhang, M.; Ni, P. Polymer–Doxorubicin Prodrug with Biocompatibility, pH Response, and Main Chain Breakability Prepared by Catalyst-Free Click Reaction. ACS Biomater. Sci. Eng. 2019, 5 (5), 2307– 2315,  DOI: 10.1021/acsbiomaterials.9b00301
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    Chi, T.; Sang, T.; Wang, Y.; Ye, Z. Cleavage and Noncleavage Chemistry in Reactive Oxygen Species (ROS)-Responsive Materials for Smart Drug Delivery. Bioconjugate Chem. 2024, 35 (1), 1– 21,  DOI: 10.1021/acs.bioconjchem.3c00476
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    Fenton, O. S.; Andresen, J. L.; Paolini, M.; Langer, R. β-Aminoacrylate Synthetic Hydrogels: Easily Accessible and Operationally Simple Biomaterials Networks. Angew. Chem., Int. Ed. 2018, 57 (49), 16026– 16029,  DOI: 10.1002/anie.201808452
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    Huang, J.; Jiang, X. Injectable and Degradable pH-Responsive Hydrogels via Spontaneous Amino–Yne Click Reaction. ACS Appl. Mater. Interfaces 2018, 10 (1), 361– 370,  DOI: 10.1021/acsami.7b18141
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    Li, H.-C.; Sun, X.-M.; Huang, Y.-R.; Peng, Y.-H.; Liu, J.; Ren, L. Synthetic Crosslinker Based on Amino–Yne Click to Enhance the Suture Tension of Collagen-Based Corneal Repair Materials. ACS Appl. Polym. Mater. 2022, 4 (6), 4495– 4507,  DOI: 10.1021/acsapm.2c00472
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    Oktay, B.; Demir, S.; Kayaman-Apohan, N. Immobilization of Pectinase on Polyethyleneimine Based Support via Spontaneous Amino-Yne Click Reaction. Food Bioprod. Process. 2020, 122, 159– 168,  DOI: 10.1016/j.fbp.2020.04.010
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    Immobilization of pectinase on polyethyleneimine based support via spontaneous amino-yne click reaction
    Oktay, Burcu; Demir, Serap; Kayaman-Apohan, Nilhan
    Food and Bioproducts Processing (2020), 122 (), 159-168CODEN: FBPREO; ISSN:0960-3085. (Elsevier B.V.)
    The immobilization of an enzyme can improve catalytic activity, stability, and reusability of its. In this study, we investigated a new method for enzyme immobilization. Alkyne-pectinase was first immobilized on the polyethyleneimine-based cryogel via a spontaneous amino-yne click reaction under very mild conditions and then the apple juice was clarified. Amino-yne click reactions do not need any photoinitiator or catalyst, unlike other click reactions. The immobilization efficiency of the alkyne pectinase was 90%. The immobilized enzyme continued to retain 70% of its initial activity after 60 days. An improvement obsd. in the pH tolerance in the range of 6.5-8.0. The higher thermal tolerance of the immobilized pectinase was increased above 50°C. Immobilized pectinase showed 100% activity at 55°C and pH 6.5. The clarification rate of apple juice was achieved about 50% by the pectinase immobilized support.
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    Zhang, R.; Tian, Y.; Pang, L.; Xu, T.; Yu, B.; Cong, H.; Shen, Y. Wound Microenvironment-Responsive Protein Hydrogel Drug-Loaded System with Accelerating Healing and Antibacterial Property. ACS Appl. Mater. Interfaces 2022, 14 (8), 10187– 10199,  DOI: 10.1021/acsami.2c00373
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    Wound Microenvironment-Responsive Protein Hydrogel Drug-Loaded System with Accelerating Healing and Antibacterial Property
    Zhang, Rong; Tian, Yongchang; Pang, Long; Xu, Taimin; Yu, Bing; Cong, Hailin; Shen, Youqing
    ACS Applied Materials & Interfaces (2022), 14 (8), 10187-10199CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Growth factors play a vital role in wound healing, and novel hydrogel carriers suitable for growth factors have always been a research hotspot in the wound healthcare field. In this work, a wound microenvironment-responsive hydrogel drug-loading system was constructed by crosslinking of the internal electron-deficient polyester and bovine serum albumin (BSA) via catalyst-free amino-yne bioconjugation. The slightly acidic microenvironment of wound tissues induces the charge removal of BSA chains, thus releasing the basic fibroblast growth factor (bFGF) loaded through electrostatic action. Besides, the BSA chains in the gel network further endow their excellent biocompatibility and biodegradability, also making them more suitable for bFGF loading. The wound caring evaluation of the hydrogel in the full-thickness skin wound indicated that the protein-based hydrogel significantly promotes the proliferation and differentiation of fibroblasts, collagen accumulation, and epidermal layer stacking, thus significantly shortening the healing process. This strategy paved the way for broadening the application of the growth factors in the wound care field.
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    Deng, M.; Wu, Y.; Ren, Y.; Song, H.; Zheng, L.; Lin, G.; Wen, X.; Tao, Y.; Kong, Q.; Wang, Y. Clickable and Smart Drug Delivery Vehicles Accelerate the Healing of Infected Diabetic Wounds. J. Controlled Release 2022, 350, 613– 629,  DOI: 10.1016/j.jconrel.2022.08.053
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    Clickable and smart drug delivery vehicles accelerate the healing of infected diabetic wounds
    Deng, Mingyan; Wu, Ye; Ren, Yan; Song, Haoyang; Zheng, Li; Lin, Guangzhi; Wen, Xin; Tao, Yiran; Kong, Qingquan; Wang, Yu
    Journal of Controlled Release (2022), 350 (), 613-629CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    In this study, an adipic acid dihydrazide (ADH)/ tannic acid (TA)-grafted hyaluronic acid (HA)-based multifunctional hydrogel was synthesized through a spontaneous amino-yne click reaction and used to promote the improved healing of infected diabetic wounds. This hydrogel exhibited a range of beneficial properties such as tunable gelation time, adjustable mech. properties, pH-sensitive response characteristics, excellent injectability, the ability to readily adhere to tissue, and ultra-intimate contact capabilities. Following the encapsulation of ultrasmall Ag nanoclusters (AgNCs) and deferoxamine loaded polydopamine/ hollow mesoporous manganese dioxide (PHMD, PDA/H-mMnO2@DFO) nanoparticles, the prepd. hydrogel presented with robust antibacterial, anti-inflammatory, and pro-angiogenic properties and a desirable smart drug release profile. In this fabricated platform, PHMD was able to effectively alleviate localized oxidative stress and prolonged oxygen deprivation via the decompn. of endogenous H2O2 to produce O2. Further in vivo assays revealed that this hydrogel was capable of facilitating the healing of infected wounds through the sequential engagement of antibacterial, anti-inflammatory, and pro-angiogenic activities. Together, this synthesized clickable environmentally-responsive hydrogel offers great promise as a tool that can be applied to aid in the healing of chronically infected diabetic wounds and other inflammatory conditions.
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    Li, Q.; Hu, Z.; Ji, X. Hydrogel-Based Macroscopic Click Chemistry. Angew. Chem., Int. Ed. 2023, 62 (52), e202315086  DOI: 10.1002/anie.202315086
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    Nguyen, C. T. V.; Chow, S. K. K.; Nguyen, H. N.; Liu, T.; Walls, A.; Withey, S.; Liebig, P.; Mueller, M.; Thierry, B.; Yang, C.-T.; Huang, C.-J. Formation of Zwitterionic and Self-Healable Hydrogels via Amino-Yne Click Chemistry for Development of Cellular Scaffold and Tumor Spheroid Phantom for MRI. ACS Appl. Mater. Interfaces 2024, 16 (28), 36157– 36167,  DOI: 10.1021/acsami.4c06917
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    Paula, C. T. B.; Pereira, P.; Coelho, J. F. J.; Fonseca, A. C.; Serra, A. C. Development of Light-Degradable Poly(Urethane-Urea) Hydrogel Films. Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 131, 112520  DOI: 10.1016/j.msec.2021.112520
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    Paula, C. T. B.; Leandro, A.; Pereira, P.; Coelho, J. F. J.; Fonseca, A. C.; Serra, A. C. Fast-Gelling Polyethylene Glycol/Polyethyleneimine Hydrogels Degradable by Visible-Light. Macromol. Biosci. 2024, 24 (2), 2300289,  DOI: 10.1002/mabi.202300289
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    Kharkar, P. M.; Kiick, K. L.; Kloxin, A. M. Designing Degradable Hydrogels for Orthogonal Control of Cell Microenvironments. Chem. Soc. Rev. 2013, 42 (17), 7335– 7372,  DOI: 10.1039/C3CS60040H
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    Designing degradable hydrogels for orthogonal control of cell microenvironments
    Kharkar, Prathamesh M.; Kiick, Kristi L.; Kloxin, April M.
    Chemical Society Reviews (2013), 42 (17), 7335-7372CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Degradable and cell-compatible hydrogels can be designed to mimic the phys. and biochem. characteristics of native extracellular matrixes and provide tunability of degrdn. rates and related properties under physiol. conditions. Hence, such hydrogels are finding widespread application in many bioengineering fields, including controlled bioactive mol. delivery, cell encapsulation for controlled three-dimensional culture, and tissue engineering. Cellular processes, such as adhesion, proliferation, spreading, migration, and differentiation, can be controlled within degradable, cell-compatible hydrogels with temporal tuning of biochem. or biophys. cues, such as growth factor presentation or hydrogel stiffness. However, thoughtful selection of hydrogel base materials, formation chemistries, and degradable moieties is necessary to achieve the appropriate level of property control and desired cellular response. In this review, hydrogel design considerations and materials for hydrogel prepn., ranging from natural polymers to synthetic polymers, are overviewed. Recent advances in chem. and phys. methods to crosslink hydrogels are highlighted, as well as recent developments in controlling hydrogel degrdn. rates and modes of degrdn. Special attention is given to spatial or temporal presentation of various biochem. and biophys. cues to modulate cell response in static (i.e., non-degradable) or dynamic (i.e., degradable) microenvironments. This review provides insight into the design of new cell-compatible, degradable hydrogels to understand and modulate cellular processes for various biomedical applications.
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    He, B.; Zhang, J.; Wang, J.; Wu, Y.; Qin, A.; Tang, B. Z. Preparation of Multifunctional Hyperbranched Poly(β-Aminoacrylate)s by Spontaneous Amino-Yne Click Polymerization. Macromolecules 2020, 53 (13), 5248– 5254,  DOI: 10.1021/acs.macromol.0c00813
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    Preparation of multifunctional hyperbranched poly(β-aminoacrylate)s by spontaneous amino-yne click polymerization
    He, Benzhao; Zhang, Jing; Wang, Jia; Wu, Yongwei; Qin, Anjun; Tang, Ben Zhong
    Macromolecules (Washington, DC, United States) (2020), 53 (13), 5248-5254CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    A series of multifunctional hyperbranched poly(β-aminoacrylate)s (hb-PAAs) were synthesized using spontaneous amino-yne click polymn for the first time. Using the optimized polymn. conditions, sol. and thermally stable hb-PAAs with high wt.-av. mol. wts. (Mw up to 18,290) were obtained in excellent yields (up to 99%). This click polymn. also can proceed in stereo- and regiospecific and anti-Markovnikov addn. fashion, and 100% E-isomers were obtained. Moreover, introducing the aggregation-induced emission (AIE)-active tetraphenylethene moiety into polymer backbones endows the resultant polymers with unique AIE properties, and their nanoaggregates can be used for sensitive detection of explosives. This work not only enriches the family of hyperbranched polymers but also confirms the universality of the spontaneous amino-yne click polymn.
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    Wang, D.; Zhang, N.; Yang, T.; Jing, X.; Meng, L. Construction Polyprodrugs by Click-Reactions and Metal-Coordination: pH-Responsive Release for Magnetic Resonance Imaging Guided Chemotherapy. Chem. Eng. J. 2021, 422, 130108  DOI: 10.1016/j.cej.2021.130108
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    Elghamry, I. Cyclotrimerization of Enaminones: An Efficient Method for the Synthesis of 1,3,5-Triaroylbenzenes. Synthesis 2003, 35 (15), 2301,  DOI: 10.1055/s-2003-41056
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    Park, H.; Guo, X.; Temenoff, J. S.; Tabata, Y.; Caplan, A. I.; Kasper, F. K.; Mikos, A. G. Effect of Swelling Ratio of Injectable Hydrogel Composites on Chondrogenic Differentiation of Encapsulated Rabbit Marrow Mesenchymal Stem Cells In Vitro. Biomacromolecules 2009, 10 (3), 541– 546,  DOI: 10.1021/bm801197m
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    Effect of Swelling Ratio of Injectable Hydrogel Composites on Chondrogenic Differentiation of Encapsulated Rabbit Marrow Mesenchymal Stem Cells In Vitro
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  • Abstract

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    Figure 1

    Figure 1. (a) Scheme of amino-yne click reaction and β-aminoacrylate cleavage at pH = 2.0 and 25 °C; (b) from bottom to top: water-suppressed 1H NMR spectra of TEG2-A1 at pH = 7.4 (pH = 7.4, buffer/D2O 9:1, 300 MHz), after 10 min at pH = 2.0 (pH = 2.0, aqueous solution/D2O 9:1) and A1 at pH = 2.0, as reference.

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    Figure 2

    Figure 2. β-Aminoacrylate cleavage at 25 °C: (a) scheme of TEG2-A1 degradation products at pH 5.0; (b) water-suppressed 1H NMR spectra at pH = 5.0 at different time intervals (pH = 5.0 buffer/D2O 9:1, 300 MHz); (c) water-suppressed 1H NMR spectra at pH = 7.4 at different time intervals (pH = 7.4 buffer/D2O 9:1, 300 MHz). Amine A1 appears as the protonated species in all cases.

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    Figure 3

    Figure 3. (a) Depiction of hydrogel formation from PEGalk and A1 at pH 7.4 and 25 °C resulting in a self-standing transparent yellowish material (right); (b) chemical structure of the different amines investigated for the network formation and (c) gelation time by inverted vial test at 25 °C depending on the polymer concentration and cross-linker (data presented as mean ± SD (n = 3)). Crosses indicate no gelation was recorded after 24 h.

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    Figure 4

    Figure 4. (a) Evolution of storage (G′) and loss (G″) moduli as a function of time at 25 °C for 10 wt % PEGalk-A1 hydrogel. Gelation time is pointed out by the crossover point between G′ and G″. (b) 1H-HR-MAS NMR spectrum of 10 wt % PEGalk-A1 hydrogel 24 h after mixing both PEGalk and A1 at pH = 7.4 (a drop of D2O was added before starting the experiment, 400 MHz, up) and water-suppressed 1H NMR of TEG2-A1 model molecule after 24 h at pH = 7.4 (pH = 7.4 buffer/D2O 9:1, 300 MHz, down as reference). (c) Swelling behavior of PEGalk-A1 hydrogels varying polymer concentration (data was presented as mean ± SD (n = 3)) and (d) SEM image of the cross-sectional morphology of PEGalk-A1 swollen hydrogels 10 wt % (left) and 30 wt % (right).

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    Figure 5

    Figure 5. pH-induced degradation behavior at 25 °C. (a) Relative weight over time of 10 wt % PEGalk-A1 hydrogels immersed at pH = 7.4, 5.0, and 2.0 at 25 °C; (b) images of 10 wt % PEGalk-A1 hydrogels (with same initial shape and weight) after 30 min immersed at different pH (all three images were taken in the same scale; see Figure S34); (c) relative weight over time of 10 wt % PEGalk-A1/2/3/4 hydrogels at pH = 5.0.

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    Figure 6

    Figure 6. Water-suppressed 1H NMR spectra over time of 10 wt % PEGalk-A1’s solubilized degradation products (pH = 5.0 buffer/D2O 9:1, 500 MHz). The spectrum of A1 is included as a reference.

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    Figure 7

    Figure 7. (a) Temperature-induced degradation behavior over time of 10 wt % PEGalk-A1 hydrogels at 25 and 37 °C and (b) 10 wt % PEGalk-A1/2/3/4 hydrogels at 37 °C.

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      Biodegradable polycarbonate-based ABA triblock copolymers were synthesized via organocatalyzed ring-opening polymn. and successfully formulated into chem. crosslinked hydrogels by strain-promoted alkyne-azide cycloaddn. (SPAAC). The synthesis and crosslinking of these polymers are copper-free, thereby eliminating the concern over metallic contaminants for biomedical applications. Gelation occurs rapidly within a span of 60 s by simple mixing of the azide- and cyclooctyne-functionalized polymer solns. The resultant hydrogels exhibited pronounced shear-thinning behavior and could be easily dispensed through a 22G hypodermic needle. To demonstrate the usefulness of these gels as a drug delivery matrix, doxorubicin (DOX)-loaded micelles prepd. using catechol-functionalized polycarbonate copolymers were incorporated into the polymer solns. to eventually form micelle/hydrogel composites. Notably, the drug release rate from the hydrogels was significantly more gradual compared to the soln. formulation. DOX release from the micelle/hydrogel composites could be sustained for 1 wk, while the release from the micelle soln. was completed rapidly within 6 h of incubation. Cellular uptake of the released DOX from the micelle/hydrogel composites was obsd. at 3 h of incubation of human breast cancer MDA-MB-231 cells. A blank hydrogel contg. PEG-(Cat)12 micelles showed almost negligible toxicity on MDA-MB-231cells where cell viability remained high at >80% after treatment. When the cells were treated with the DOX-loaded micelle/hydrogel composites, there was a drastic redn. in cell viability with only 25% of cells surviving the treatment. In all, this study introduces a simple method of formulating hydrogel materials with incorporated micelles for drug delivery applications.
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    12. 12
      Fu, S.; Dong, H.; Deng, X.; Zhuo, R.; Zhong, Z. Injectable Hyaluronic Acid/Poly(Ethylene Glycol) Hydrogels Crosslinked via Strain-Promoted Azide-Alkyne Cycloaddition Click Reaction. Carbohydr. Polym. 2017, 169, 332– 340,  DOI: 10.1016/j.carbpol.2017.04.028
      12
      Injectable hyaluronic acid/poly(ethylene glycol) hydrogels crosslinked via strain-promoted azide-alkyne cycloaddition click reaction
      Fu, Shuangli; Dong, Hui; Deng, Xueyi; Zhuo, Renxi; Zhong, Zhenlin
      Carbohydrate Polymers (2017), 169 (), 332-340CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)
      This paper reports injectable hyaluronic acid (HA)-based hydrogels crosslinked with azide-modified poly(ethylene glycol) (PEG) via the strain-promoted azide-alkyne cycloaddn. (SPAAC) between cyclooctyne and azide groups. Cyclooctyne-modified HA (Cyclooctyne-HA) is prepd. by the reaction of HA with 2-(aminoethoxy)cyclooctyne. To crosslink the modified HA, quadruply azide-terminated poly(ethylene glycol) (Azide-PEG) is designed and prepd. The mixt. of Cyclooctyne-HA and Azide-PEG gelates in a few minutes to form a strong HA-PEG hydrogel. The hydrogel has fast gelation time, good strength, and slow degrdn. rate, because of the high reactivity of SPAAC, high crosslinking d. originated from the quadruply-substituted Azide-PEG, and the good stability of the crosslinking amide bonds. In vitro cell culturing within the hydrogel demonstrated an excellent cell-compatibility. The bioorthogonality of SPAAC makes the hydrogel injectable. With good mech. properties and biocompatibility, the hydrogel would be useful in a wide range of applications such as injection filling materials for plastic surgery.
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    13. 13
      Lagneau, N.; Tournier, P.; Halgand, B.; Loll, F.; Maugars, Y.; Guicheux, J.; Le Visage, C.; Delplace, V. Click and Bioorthogonal Hyaluronic Acid Hydrogels as an Ultra-Tunable Platform for the Investigation of Cell-Material Interactions. Bioact. Mater. 2023, 24, 438– 449,  DOI: 10.1016/j.bioactmat.2022.12.022
      There is no corresponding record for this reference.
    14. 14
      van de Wetering, P.; Metters, A. T.; Schoenmakers, R. G.; Hubbell, J. A. Poly(Ethylene Glycol) Hydrogels Formed by Conjugate Addition with Controllable Swelling, Degradation, and Release of Pharmaceutically Active Proteins. J. Controlled Release 2005, 102 (3), 619– 627,  DOI: 10.1016/j.jconrel.2004.10.029
      14
      Poly(ethylene glycol) hydrogels formed by conjugate addition with controllable swelling, degradation, and release of pharmaceutically active proteins
      van de Wetering, Petra; Metters, Andrew T.; Schoenmakers, Ronald G.; Hubbell, Jeffrey A.
      Journal of Controlled Release (2005), 102 (3), 619-627CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      Hydrogels were formed by conjugate addn. of polyethylene glycol (PEG) multiacrylates and dithiothreitol (DTT) for encapsulation and sustained release of protein drugs; human growth hormone (hGH) was considered as an example. Prior to encapsulation, the hGH was pptd. either by Zn2+ ions or by linear PEG, to protect the hGH from reaction with the gel precursors during gelation. Pptn. by Zn2+ ions yielded ppts. that dissolved slowly and delayed release from even highly permeable gels, whereas linear PEG yielded rapidly dissolving ppts. To independently protect the protein and delay its release, linear PEG pptn. was adopted, and release control via modulation of the PEG gel mesh size was sought. By varying the mol. wt. of the multiarm PEG acrylates, control over gel swelling and hGH release, from a few hours to a few months, could be obtained. Protein release from the swollen and degrading PEG-based gel networks was modeled as a diffusion process with a time-dependent diffusion coeff., calcd. from swelling measurements and theor. mesh sizes. Release following zero-order kinetics was obtained by the counter influences of decreasing protein concn. and increasing protein diffusion coeff. over time.
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    15. 15
      Rydholm, A. E.; Reddy, S. K.; Anseth, K. S.; Bowman, C. N. Development and Characterization of Degradable Thiol-Allyl Ether Photopolymers. Polymer 2007, 48 (15), 4589– 4600,  DOI: 10.1016/j.polymer.2007.05.063
      There is no corresponding record for this reference.
    16. 16
      Kharkar, P. M.; Kloxin, A. M.; Kiick, K. L. Dually Degradable Click Hydrogels for Controlled Degradation and Protein Release. J. Mater. Chem. B 2014, 2 (34), 5511– 5521,  DOI: 10.1039/C4TB00496E
      16
      Dually degradable click hydrogels for controlled degradation and protein release
      Kharkar, Prathamesh M.; Kloxin, April M.; Kiick, Kristi L.
      Journal of Materials Chemistry B: Materials for Biology and Medicine (2014), 2 (34), 5511-5521CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
      Click reactions have emerged as one of the most powerful paradigms in materials chem. owing to their high regioselectivity and efficient reaction yields under mild conditions. While stability of the bonds formed by these reactions often is highly valued, their controlled cleavage is promising as an elegant approach to engineer material degrdn. for a no. of applications, including drug delivery and tissue engineering. However, cleavage of click linkages under physiol. conditions remains a major challenge in the design of degradable biomaterials. Here, we demonstrate the use of cleavable click linkages formed by Michael-type addn. reactions in conjunction with hydrolytically cleavable functionalities for the degrdn. of injectable hydrogels by dual mechanisms for controlled protein release. Specifically, the reaction between maleimides and thiols was utilized for hydrogel formation, where thiol selection dictates the degradability of the resulting linkage under thiol-rich reducing conditions. Relevant microenvironments would include those rich in glutathione (GSH), a tripeptide that is found at elevated concns. in carcinoma tissues. Degrdn. of the hydrogels was monitored with rheometry and volumetric swelling measurements. Arylthiol-based thioether succinimide linkages underwent degrdn. via click cleavage and thiol exchange reaction in the presence of GSH as well as ester hydrolysis, whereas alkylthiol-based thioether succinimide linkages only undergo ester hydrolysis. The resulting control over the degrdn. rate within a reducing microenvironment resulted in ∼2.5 fold differences in the release profile of cargo mols. (fluorescently labeled bovine serum albumin as a model protein) from dually degradable hydrogels compared to non-degradable hydrogels. These unique degradable chemistries are promising for controlling the rate of degrdn. and local release of therapeutic cargo mols. in cancer tissue microenvironments.
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    17. 17
      Kharkar, P. M.; Rehmann, M. S.; Skeens, K. M.; Maverakis, E.; Kloxin, A. M. Thiol–Ene Click Hydrogels for Therapeutic Delivery. ACS Biomater. Sci. Eng. 2016, 2 (2), 165– 179,  DOI: 10.1021/acsbiomaterials.5b00420
      17
      Thiol-ene Click Hydrogels for Therapeutic Delivery
      Kharkar, Prathamesh M.; Rehmann, Matthew S.; Skeens, Kelsi M.; Maverakis, Emanual; Kloxin, April M.
      ACS Biomaterials Science & Engineering (2016), 2 (2), 165-179CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)
      A review. Hydrogels are of growing interest for the delivery of therapeutics to specific sites in the body. For use as a delivery vehicle, hydrophilic precursors are usually laden with bioactive moieties and then directly injected to the site of interest for in situ gel formation and controlled release dictated by precursor design. Hydrogels formed by thiol-ene click reactions are attractive for local controlled release of therapeutics owing to their rapid reaction rate and efficiency under mild aq. conditions, enabling in situ formation of gels with tunable properties often responsive to environmental cues. Herein, we will review the wide range of applications for thiol-ene hydrogels, from the prolonged release of anti-inflammatory drugs in the spine to the release of protein-based therapeutics in response to cell-secreted enzymes, with a focus on their clin. relevance. We will also provide a brief overview of thiol-ene click chem. and discuss the available alkene chemistries pertinent to macromol. functionalization and hydrogel formation. These chemistries include functional groups susceptible to Michael type reactions relevant for injection and radically mediated reactions for greater temporal control of formation at sites of interest using light. Addnl., mechanisms for the encapsulation and controlled release of therapeutic cargoes are reviewed, including (i) tuning the mesh size of the hydrogel initially and temporally for cargo entrapment and release and (ii) covalent tethering of the cargo with degradable linkers or affinity binding sequences to mediate release. Finally, myriad thiol-ene hydrogels and their specific applications also are discussed to give a sampling of the current and future utilization of this chem. for delivery of therapeutics, such as small mol. drugs, peptides, and biologics.
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    18. 18
      Alge, D. L.; Azagarsamy, M. A.; Donohue, D. F.; Anseth, K. S. Synthetically Tractable Click Hydrogels for Three-Dimensional Cell Culture Formed Using Tetrazine–Norbornene Chemistry. Biomacromolecules 2013, 14 (4), 949– 953,  DOI: 10.1021/bm4000508
      18
      Synthetically Tractable Click Hydrogels for Three-Dimensional Cell Culture Formed Using Tetrazine-Norbornene Chemistry
      Alge, Daniel L.; Azagarsamy, Malar A.; Donohue, Dillon F.; Anseth, Kristi S.
      Biomacromolecules (2013), 14 (4), 949-953CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      The implementation of bio-orthogonal click chemistries is a topic of growing importance in the field of biomaterials, as it is enabling the development of increasingly complex hydrogel materials capable of providing dynamic, cell-instructive microenvironments. Here, we introduce the tetrazine-norbornene inverse electron demand Diels-Alder reaction as a new crosslinking chem. for the formation of cell laden hydrogels. The fast reaction rate and irreversible nature of this click reaction allowed for hydrogel formation within minutes when a multifunctional PEG-tetrazine macromer was reacted with a dinorbornene peptide. In addn., the cytocompatibility of the polymn. led to high postencapsulation viability of human mesenchymal stem cells, and the specificity of the tetrazine-norbornene reaction was exploited for sequential modification of the network via thiol-ene photochem. These advantages, combined with the synthetic accessibility of the tetrazine mol. compared to other bio-orthogonal click reagents, make this crosslinking chem. an interesting and powerful new tool for the development of cell-instructive hydrogels for tissue engineering applications.
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    19. 19
      Guaresti, O.; García–Astrain, C.; Aguirresarobe, R. H.; Eceiza, A.; Gabilondo, N. Synthesis of Stimuli–Responsive Chitosan–Based Hydrogels by Diels–Alder Cross–Linking ̀click′ Reaction as Potential Carriers for Drug Administration. Carbohydr. Polym. 2018, 183, 278– 286,  DOI: 10.1016/j.carbpol.2017.12.034
      There is no corresponding record for this reference.
    20. 20
      Zander, Z. K.; Hua, G.; Wiener, C. G.; Vogt, B. D.; Becker, M. L. Control of Mesh Size and Modulus by Kinetically Dependent Cross-Linking in Hydrogels. Adv. Mater. 2015, 27 (40), 6283– 6288,  DOI: 10.1002/adma.201501822
      20
      Control of Mesh Size and Modulus by Kinetically Dependent Cross-Linking in Hydrogels
      Zander, Zachary K.; Hua, Geng; Wiener, Clinton G.; Vogt, Bryan D.; Becker, Matthew L.
      Advanced Materials (Weinheim, Germany) (2015), 27 (40), 6283-6288CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      It was shown that small changes in the structural features, resulting from variations in the kinetics of crosslinking, are capable of producing mech. distinguishable hydrogels from chem. identical precursors. For an oxime crosslinking reaction, the kinetics of network formation are influenced by pH and buffer strength, and may be utilized to intrinsically control the degree of heterogeneity within the scaffold microstructure. The significance of this study, in comparison to existing hydrogel systems, is the use of kinetics for tuning the microstructure and modulus. This method provides tunability, yet maintains the chem. identity, concn. and stoichiometry of the hydrogel. Further, developing and understanding this and other kinetically driven systems should enable a facile route for precise control over the mech. properties of hydrogels. Overall, these PEG-based hydrogels could provide definitive insight into the effect of substrate elasticity on hMSC differentiation because the scaffolds employ the same precursor chem., yet exhibit a range of mech. properties.
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    21. 21
      Grover, G. N.; Lam, J.; Nguyen, T. H.; Segura, T.; Maynard, H. D. Biocompatible Hydrogels by Oxime Click Chemistry. Biomacromolecules 2012, 13 (10), 3013– 3017,  DOI: 10.1021/bm301346e
      21
      Biocompatible Hydrogels by Oxime Click Chemistry
      Grover, Gregory N.; Lam, Jonathan; Nguyen, Thi H.; Segura, Tatiana; Maynard, Heather D.
      Biomacromolecules (2012), 13 (10), 3013-3017CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Oxime Click chem. was used to form hydrogels that support cell adhesion. Eight-armed aminooxy poly(ethylene glycol) (PEG) was mixed with glutaraldehyde to form oxime-linked hydrogels. The mech. properties, gelation kinetics, and water swelling ratios were studied and found to be tunable. It was also shown that gels contg. the integrin ligand arginine-glycine-aspartic acid (RGD) supported mesenchymal stem cell (MSC) incorporation. High cell viability and proliferation of the encapsulated cells demonstrated biocompatibility of the material.
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    22. 22
      Grover, G. N.; Braden, R. L.; Christman, K. L. Oxime Cross-Linked Injectable Hydrogels for Catheter Delivery. Adv. Mater. 2013, 25 (21), 2937– 2942,  DOI: 10.1002/adma.201205234
      22
      Oxime Cross-Linked Injectable Hydrogels for Catheter Delivery
      Grover, Gregory N.; Braden, Rebecca L.; Christman, Karen L.
      Advanced Materials (Weinheim, Germany) (2013), 25 (21), 2937-2942CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We have demonstrated a new approach for gelation of injectable materials utilizing oxime crosslinking. Tunable in vitro gelation was achieved by altering the pH with a bioinert-PEG system, as well as with oxidized hyaluronic acid and alginate. Oxime chem. allowed these materials to be injected multiple times through a catheter in vitro over the course of hours while at 37 degrees C, mimicking the in vivo situation. PEG and polysaccharide systems form gels within 20 min upon injection into the s.c. space. The PEG-oxime system was capable of rapid gelation upon injection into myocardial tissue.
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    23. 23
      Lin, F.; Yu, J.; Tang, W.; Zheng, J.; Defante, A.; Guo, K.; Wesdemiotis, C.; Becker, M. L. Peptide-Functionalized Oxime Hydrogels with Tunable Mechanical Properties and Gelation Behavior. Biomacromolecules 2013, 14 (10), 3749– 3758,  DOI: 10.1021/bm401133r
      23
      Peptide-Functionalized Oxime Hydrogels with Tunable Mechanical Properties and Gelation Behavior
      Lin, Fei; Yu, Jiayi; Tang, Wen; Zheng, Jukuan; Defante, Adrian; Guo, Kai; Wesdemiotis, Chrys; Becker, Matthew L.
      Biomacromolecules (2013), 14 (10), 3749-3758CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      We demonstrate the formation of polyethylene glycol (PEG) based hydrogels via oxime ligation and the photoinitiated thiol-ene 3D patterning of peptides within the hydrogel matrix postgelation. The gelation process and final mech. strength of the hydrogels can be tuned using pH and the catalyst concn. The time scale to reach the gel point and complete gelation can be shortened from hours to seconds using both pH and aniline catalyst, which facilitates the tuning of the storage modulus from 0.3 to over 15 kPa. Azide- and alkene-functionalized hydrogels were also synthesized, and we have shown the post gelation "click"-type Huisgen 1,3 cycloaddn. and thiolene-based radical reactions for spatially defined peptide incorporation. These materials are the initial demonstration for translationally relevant hydrogel materials that possess tunable mech. regimes attractive to soft tissue engineering and possess atom neutral chemistries attractive for post gelation patterning in the presence or absence of cells.
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    24. 24
      Truong, V. X.; Ablett, M. P.; Richardson, S. M.; Hoyland, J. A.; Dove, A. P. Simultaneous Orthogonal Dual-Click Approach to Tough, in-Situ-Forming Hydrogels for Cell Encapsulation. J. Am. Chem. Soc. 2015, 137 (4), 1618– 1622,  DOI: 10.1021/ja511681s
      24
      Simultaneous Orthogonal Dual-Click Approach to Tough, in-Situ-Forming Hydrogels for Cell Encapsulation
      Truong, Vinh X.; Ablett, Matthew P.; Richardson, Stephen M.; Hoyland, Judith A.; Dove, Andrew P.
      Journal of the American Chemical Society (2015), 137 (4), 1618-1622CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The use of tough hydrogels as biomaterials is limited as a consequence of time-consuming fabrication techniques, toxic starting materials, and large strain hysteresis under deformation. Herein, we report the simultaneous application of nucleophilic thiol-yne and inverse electron-demand Diels-Alder addns. to independently create two interpenetrating networks in a simple one-step procedure. The resultant hydrogels display compressive stresses of 14-15 MPa at 98% compression without fracture or hysteresis upon repeated load. The hydrogel networks can be spatially and temporally postfunctionalized via radical thiylation and/or inverse electron-demand Diels-Alder addn. to residual functional groups within the network. Furthermore, gelation occurs rapidly under physiol. conditions, enabling encapsulation of human cells.
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    25. 25
      Cai, X. Y.; Li, J. Z.; Li, N. N.; Chen, J. C.; Kang, E.-T.; Xu, L. Q. PEG-Based Hydrogels Prepared by Catalyst-Free Thiol–Yne Addition and Their Post-Antibacterial Modification. Biomater. Sci. 2016, 4 (11), 1663– 1672,  DOI: 10.1039/C6BM00395H
      There is no corresponding record for this reference.
    26. 26
      Macdougall, L. J.; Truong, V. X.; Dove, A. P. Efficient In Situ Nucleophilic Thiol-Yne Click Chemistry for the Synthesis of Strong Hydrogel Materials with Tunable Properties. ACS Macro Lett. 2017, 6 (2), 93– 97,  DOI: 10.1021/acsmacrolett.6b00857
      26
      Efficient In Situ Nucleophilic Thiol-yne Click Chemistry for the Synthesis of Strong Hydrogel Materials with Tunable Properties
      MacDougall, Laura J.; Truong, Vinh X.; Dove, Andrew P.
      ACS Macro Letters (2017), 6 (2), 93-97CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
      Synthetic hydrogel materials offer the ability to tune the mech. properties of the resultant networks by controlling the mol. structure of the polymer precursors. Herein, we demonstrate that the nucleophilic thiol-yne click reaction presents a highly efficient chem. for forming robust high water content (ca. 90%) hydrogel materials with tunable stiffness and mech. properties. Remarkably, optimization of the mol. wt. and geometry of the poly(ethylene glycol) (PEG) precursors allows access to materials with compressive strength up to 2.4 MPa which, can be repeatedly compressed to >90% stress. Beyond this, we demonstrate the ability to access hydrogels with storage moduli ranging from 0.2 to 7 kPa. Moreover, we also demonstrate that by a simple precursor blending process, we can access intermediate stiffness across this range with minimal changes to the hydrogel structure. These characteristics present the nucleophilic thiol-yne addn. as an excellent method for the prepn. of hydrogels for use as versatile synthetic biomaterials.
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    27. 27
      Fan, B.; Zhang, K.; Liu, Q.; Eelkema, R. Self-Healing Injectable Polymer Hydrogel via Dynamic Thiol-Alkynone Double Addition Cross-Links. ACS Macro Lett. 2020, 9 (6), 776– 780,  DOI: 10.1021/acsmacrolett.0c00241
      27
      Self-Healing Injectable Polymer Hydrogel via Dynamic Thiol-Alkynone Double Addition Cross-Links
      Fan, Bowen; Zhang, Kai; Liu, Qian; Eelkema, Rienk
      ACS Macro Letters (2020), 9 (6), 776-780CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
      Introduction of dynamic thiol-alkynone double addn. crosslinks in a polymer network enable the formation of a self-healing injectable polymer hydrogel. A four-arm polyethylene glycol (PEG) tetra-thiol star polymer is crosslinked by a small mol. alkynone via the thiol-alkynone double adduct to generate a hydrogel network under ambient aq. conditions (buffer pH = 7.4 or 8.2, room temp.). The mech. properties of these hydrogels can be easily tuned by varying the concn. of polymer precursors. Through the dynamic thiol-alkynone double addn. crosslink, these hydrogels are self-healing and shear thinning, as demonstrated by rheol. measurements, macroscopic self-healing, and injection tests. These hydrogels can be injected through a 20G syringe needle and recover after extrusion. In addn., good cytocompatibility of these hydrogels is confirmed by cytotoxicity test. This work shows the application of the thiol-alkynone double addn. dynamic covalent chem. in the straightforward prepn. of self-healing injectable hydrogels, which may find future biomedical applications such as tissue engineering and drug delivery.
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    28. 28
      Worch, J. C.; Stubbs, C. J.; Price, M. J.; Dove, A. P. Click Nucleophilic Conjugate Additions to Activated Alkynes: Exploring Thiol-Yne, Amino-Yne, and Hydroxyl-Yne Reactions from (Bio)Organic to Polymer Chemistry. Chem. Rev. 2021, 121 (12), 6744– 6776,  DOI: 10.1021/acs.chemrev.0c01076
      28
      Click Nucleophilic Conjugate Additions to Activated Alkynes: Exploring Thiol-yne, Amino-yne, and Hydroxyl-yne Reactions from (Bio)Organic to Polymer Chemistry
      Worch, Joshua C.; Stubbs, Connor J.; Price, Matthew J.; Dove, Andrew P.
      Chemical Reviews (Washington, DC, United States) (2021), 121 (12), 6744-6776CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. The 1,4-conjugate addn. reaction between activated alkynes or acetylenic Michael acceptors and nucleophiles (i.e., the nucleophilic Michael reaction) is a historically useful org. transformation. Despite its general utility, the efficiency and outcomes can vary widely and are often closely dependent on specific reaction conditions. Nevertheless, with improvements in reaction design, including catalyst development and expansion of the substrate scope to feature more electrophilic alkynes, many examples now present with features that are congruent with Click chem. Although several nucleophilic species can participate in these conjugate addns., ubiquitous nucleophiles such as thiols, amines and alcs. are commonly employed and, consequently, among the most well developed. For many years, these conjugate addns. were largely relegated to org. chem. but in the last few decades their use has expanded into other spheres such as bioorg. chem. and polymer chem. Within these fields, they have been particularly resourceful for bioconjugation reactions and step-growth polymns., resp., due to their excellent efficiency, orthogonality and ambient reactivity. The reaction is expected to feature in increasingly divergent application settings as it continues to emerge as a Click reaction. Thus, this review examines click nucleophilic addns. to activated alkynes from (bio)org. to polymer chem.
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    29. 29
      Yang, R.; Zhang, X.; Chen, B.; Yan, Q.; Yin, J.; Luan, S. Tunable Backbone-Degradable Robust Tissue Adhesives via in Situ Radical Ring-Opening Polymerization. Nat. Commun. 2023, 14 (1), 6063,  DOI: 10.1038/s41467-023-41610-1
      There is no corresponding record for this reference.
    30. 30
      Burek, M.; Waśkiewicz, S.; Lalik, A.; Wandzik, I. Hydrogels with Novel Hydrolytically Labile Trehalose-Based Crosslinks: Small Changes – Big Differences in Degradation Behavior. Polym. Chem. 2018, 9 (27), 3721– 3726,  DOI: 10.1039/C8PY00488A
      There is no corresponding record for this reference.
    31. 31
      Feng, X.; Du, M.; Wei, H.; Ruan, X.; Fu, T.; Zhang, J.; Sun, X. Chemically Triggered Life Control of “Smart” Hydrogels through Click and Declick Reactions. Front. Chem. Sci. Eng. 2022, 16 (9), 1399– 1406,  DOI: 10.1007/s11705-022-2149-z
      There is no corresponding record for this reference.
    32. 32
      Schneider, E. L.; Henise, J.; Reid, R.; Ashley, G. W.; Santi, D. V. Hydrogel Drug Delivery System Using Self-Cleaving Covalent Linkers for Once-a-Week Administration of Exenatide. Bioconjugate Chem. 2016, 27 (5), 1210– 1215,  DOI: 10.1021/acs.bioconjchem.5b00690
      32
      Hydrogel Drug Delivery System Using Self-Cleaving Covalent Linkers for Once-a-Week Administration of Exenatide
      Schneider, Eric L.; Henise, Jeff; Reid, Ralph; Ashley, Gary W.; Santi, Daniel V.
      Bioconjugate Chemistry (2016), 27 (5), 1210-1215CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      We have developed a unique long-acting drug-delivery system for the GLP-1 agonist exenatide. The peptide was covalently attached to Tetra-PEG hydrogel microspheres by a cleavable β-eliminative linker; upon s.c. injection, the exenatide is slowly released at a rate dictated by the linker. A second β-eliminative linker with a slower cleavage rate was incorporated in polymer cross-links to trigger gel degrdn. after drug release. The uniform 40 μm microspheres were fabricated using a flow-focusing microfluidic device and in situ polymn. within droplets. The exenatide-laden microspheres were injected s.c. into the rat, and serum exenatide measured over a one-month period. Pharmacokinetic anal. showed a t1/2,β of released exenatide of about 7 days which represents over a 300-fold half-life extension in the rat and exceeds the half-life of any currently approved long-acting GLP-1 agonist. Hydrogel-exenatide conjugates gave an excellent Level A in vitro-in vivo correlation of release rates of the peptide from the gel, and indicated that eventide release was 3-fold faster in vivo than in vitro. Pharmacokinetic simulations indicate that the hydrogel-exenatide microspheres should support weekly or biweekly s.c. dosing in humans. The rare ability to modify in vivo pharmacokinetics by the chem. nature of the linker indicates that an even longer acting exenatide is feasible.
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    33. 33
      Du, M.; Jin, J.; Zhou, F.; Chen, J.; Jiang, W. Dual Drug-Loaded Hydrogels with pH-Responsive and Antibacterial Activity for Skin Wound Dressing. Colloids Surf. B Biointerfaces 2023, 222, 113063  DOI: 10.1016/j.colsurfb.2022.113063
      There is no corresponding record for this reference.
    34. 34
      Zhu, C.; Zhao, J.; Kempe, K.; Wilson, P.; Wang, J.; Velkov, T.; Li, J.; Davis, T. P.; Whittaker, M. R.; Haddleton, D. M. A Hydrogel-Based Localized Release of Colistin for Antimicrobial Treatment of Burn Wound Infection. Macromol. Biosci. 2017, 17 (2), 1600320,  DOI: 10.1002/mabi.201600320
      There is no corresponding record for this reference.
    35. 35
      Yang, H.; Fustin, C.-A. Design and Applications of Dynamic Hydrogels Based on Reversible C═N Bonds. Macromol. Chem. Phys. 2023, 224 (20), 2300211,  DOI: 10.1002/macp.202300211
      There is no corresponding record for this reference.
    36. 36
      Zhang, X.; Malhotra, S.; Molina, M.; Haag, R. Micro- and Nanogels with Labile Crosslinks – from Synthesis to Biomedical Applications. Chem. Soc. Rev. 2015, 44 (7), 1948– 1973,  DOI: 10.1039/C4CS00341A
      36
      Micro- and nanogels with labile crosslinks - from synthesis to biomedical applications
      Zhang, Xuejiao; Malhotra, Shashwat; Molina, Maria; Haag, Rainer
      Chemical Society Reviews (2015), 44 (7), 1948-1973CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      Micro- or nanosized three-dimensional crosslinked polymeric networks have been designed and described for various biomedical applications, including living cell encapsulation, tissue engineering, and stimuli responsive controlled delivery of bioactive mols. For most of these applications, it is necessary to disintegrate the artificial scaffold into nontoxic residues with smaller dimensions to ensure renal clearance for better biocompatibility of the functional materials. This can be achieved by introducing stimuli-cleavable linkages into the scaffold structures. pH, enzyme, and redox potential are the most frequently used biol. stimuli. Moreover, some external stimuli, for example light and additives, are also used to trigger the disintegration of the carriers or their assembly. In this review, we highlight the recent progress in various chem. and phys. methods for synthesizing and crosslinking micro- and nanogels, as well as their development for incorporation of cleavable linkages into the network of micro- and nanogels.
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    37. 37
      He, B.; Su, H.; Bai, T.; Wu, Y.; Li, S.; Gao, M.; Hu, R.; Zhao, Z.; Qin, A.; Ling, J.; Tang, B. Z. Spontaneous Amino-Yne Click Polymerization: A Powerful Tool toward Regio- and Stereospecific Poly(β-Aminoacrylate)s. J. Am. Chem. Soc. 2017, 139 (15), 5437– 5443,  DOI: 10.1021/jacs.7b00929
      37
      Spontaneous Amino-yne Click Polymerization: A Powerful Tool toward Regio- and Stereospecific Poly(β-aminoacrylate)s
      He, Benzhao; Su, Huifang; Bai, Tianwen; Wu, Yongwei; Li, Shiwu; Gao, Meng; Hu, Rongrong; Zhao, Zujin; Qin, Anjun; Ling, Jun; Tang, Ben Zhong
      Journal of the American Chemical Society (2017), 139 (15), 5437-5443CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Efficient synthesis of poly(enamine)s has been a great challenge because of their poor stability, poor soly., and low mol. wts. In this work, a spontaneous amino-yne click polymn. for the efficient prepn. of poly(enamine)s was established, which could proceed with 100% atom efficiency under very mild conditions without any external catalyst. Through systematic optimization of the reaction conditions, several sol. and thermally stable poly(β-aminoacrylate)s with high mol. wts. (Mw up to 64400) and well-defined structures were obtained in excellent yields (up to 99%). Moreover, the polymn. can perform in a regio- and stereospecific fashion. NMR spectra anal. revealed that solely anti-Markovnikov additive products with 100% E-isomer were obtained. The reaction mechanism was well demonstrated with the assistance of d. functional theory calcns. In addn., by introducing the tetraphenylethene moiety, the resulting polymers exhibit unique aggregation-induced emission characteristics and could be applied in explosives detection and bioimaging. This polyhydroamination is a new type of click polymn. and opens up enormous opportunities for prepg. functional polymeric materials.
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    38. 38
      Zhang, J.; Zhang, Z.; Wang, J.; Zang, Q.; Sun, J. Z.; Tang, B. Z. Recent Progress in the Applications of Amino–Yne Click Chemistry. Polym. Chem. 2021, 12 (20), 2978– 2986,  DOI: 10.1039/D1PY00113B
      38
      Recent progress in the applications of amino-yne click chemistry
      Zhang, Jie; Zhang, Zhiming; Wang, Jia; Zang, Qiguang; Sun, Jing zhi; Tang, Ben Zhong
      Polymer Chemistry (2021), 12 (20), 2978-2986CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      Click chem. has been rapidly developed in recent years. Among various established click reaction systems, the spontaneous amino-yne click reaction stands out. In addn. to the general advantages assocd. with click reactions, amino-yne click reaction possesses extra merits, such as spontaneity of reactions, ubiquity of amines and cleavability of products with specific stimuli. Therefore, the amino-yne click reaction has become a useful tool and provided convenience for scientists in various fields since its first report in 2017. In this review, we capture the recent progress in the applications of amino-yne click reaction, which are briefly classified and reviewed in the fields of surface immobilization, drug delivery carrier design, hydrogel materials prepn. and synthesis of polymers with unique structures.
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    39. 39
      Li, D.; Song, Y.; He, J.; Zhang, M.; Ni, P. Polymer–Doxorubicin Prodrug with Biocompatibility, pH Response, and Main Chain Breakability Prepared by Catalyst-Free Click Reaction. ACS Biomater. Sci. Eng. 2019, 5 (5), 2307– 2315,  DOI: 10.1021/acsbiomaterials.9b00301
      There is no corresponding record for this reference.
    40. 40
      Chi, T.; Sang, T.; Wang, Y.; Ye, Z. Cleavage and Noncleavage Chemistry in Reactive Oxygen Species (ROS)-Responsive Materials for Smart Drug Delivery. Bioconjugate Chem. 2024, 35 (1), 1– 21,  DOI: 10.1021/acs.bioconjchem.3c00476
      There is no corresponding record for this reference.
    41. 41
      Fenton, O. S.; Andresen, J. L.; Paolini, M.; Langer, R. β-Aminoacrylate Synthetic Hydrogels: Easily Accessible and Operationally Simple Biomaterials Networks. Angew. Chem., Int. Ed. 2018, 57 (49), 16026– 16029,  DOI: 10.1002/anie.201808452
      There is no corresponding record for this reference.
    42. 42
      Huang, J.; Jiang, X. Injectable and Degradable pH-Responsive Hydrogels via Spontaneous Amino–Yne Click Reaction. ACS Appl. Mater. Interfaces 2018, 10 (1), 361– 370,  DOI: 10.1021/acsami.7b18141
      There is no corresponding record for this reference.
    43. 43
      Li, H.-C.; Sun, X.-M.; Huang, Y.-R.; Peng, Y.-H.; Liu, J.; Ren, L. Synthetic Crosslinker Based on Amino–Yne Click to Enhance the Suture Tension of Collagen-Based Corneal Repair Materials. ACS Appl. Polym. Mater. 2022, 4 (6), 4495– 4507,  DOI: 10.1021/acsapm.2c00472
      There is no corresponding record for this reference.
    44. 44
      Oktay, B.; Demir, S.; Kayaman-Apohan, N. Immobilization of Pectinase on Polyethyleneimine Based Support via Spontaneous Amino-Yne Click Reaction. Food Bioprod. Process. 2020, 122, 159– 168,  DOI: 10.1016/j.fbp.2020.04.010
      44
      Immobilization of pectinase on polyethyleneimine based support via spontaneous amino-yne click reaction
      Oktay, Burcu; Demir, Serap; Kayaman-Apohan, Nilhan
      Food and Bioproducts Processing (2020), 122 (), 159-168CODEN: FBPREO; ISSN:0960-3085. (Elsevier B.V.)
      The immobilization of an enzyme can improve catalytic activity, stability, and reusability of its. In this study, we investigated a new method for enzyme immobilization. Alkyne-pectinase was first immobilized on the polyethyleneimine-based cryogel via a spontaneous amino-yne click reaction under very mild conditions and then the apple juice was clarified. Amino-yne click reactions do not need any photoinitiator or catalyst, unlike other click reactions. The immobilization efficiency of the alkyne pectinase was 90%. The immobilized enzyme continued to retain 70% of its initial activity after 60 days. An improvement obsd. in the pH tolerance in the range of 6.5-8.0. The higher thermal tolerance of the immobilized pectinase was increased above 50°C. Immobilized pectinase showed 100% activity at 55°C and pH 6.5. The clarification rate of apple juice was achieved about 50% by the pectinase immobilized support.
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    45. 45
      Zhang, R.; Tian, Y.; Pang, L.; Xu, T.; Yu, B.; Cong, H.; Shen, Y. Wound Microenvironment-Responsive Protein Hydrogel Drug-Loaded System with Accelerating Healing and Antibacterial Property. ACS Appl. Mater. Interfaces 2022, 14 (8), 10187– 10199,  DOI: 10.1021/acsami.2c00373
      45
      Wound Microenvironment-Responsive Protein Hydrogel Drug-Loaded System with Accelerating Healing and Antibacterial Property
      Zhang, Rong; Tian, Yongchang; Pang, Long; Xu, Taimin; Yu, Bing; Cong, Hailin; Shen, Youqing
      ACS Applied Materials & Interfaces (2022), 14 (8), 10187-10199CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Growth factors play a vital role in wound healing, and novel hydrogel carriers suitable for growth factors have always been a research hotspot in the wound healthcare field. In this work, a wound microenvironment-responsive hydrogel drug-loading system was constructed by crosslinking of the internal electron-deficient polyester and bovine serum albumin (BSA) via catalyst-free amino-yne bioconjugation. The slightly acidic microenvironment of wound tissues induces the charge removal of BSA chains, thus releasing the basic fibroblast growth factor (bFGF) loaded through electrostatic action. Besides, the BSA chains in the gel network further endow their excellent biocompatibility and biodegradability, also making them more suitable for bFGF loading. The wound caring evaluation of the hydrogel in the full-thickness skin wound indicated that the protein-based hydrogel significantly promotes the proliferation and differentiation of fibroblasts, collagen accumulation, and epidermal layer stacking, thus significantly shortening the healing process. This strategy paved the way for broadening the application of the growth factors in the wound care field.
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    46. 46
      Deng, M.; Wu, Y.; Ren, Y.; Song, H.; Zheng, L.; Lin, G.; Wen, X.; Tao, Y.; Kong, Q.; Wang, Y. Clickable and Smart Drug Delivery Vehicles Accelerate the Healing of Infected Diabetic Wounds. J. Controlled Release 2022, 350, 613– 629,  DOI: 10.1016/j.jconrel.2022.08.053
      46
      Clickable and smart drug delivery vehicles accelerate the healing of infected diabetic wounds
      Deng, Mingyan; Wu, Ye; Ren, Yan; Song, Haoyang; Zheng, Li; Lin, Guangzhi; Wen, Xin; Tao, Yiran; Kong, Qingquan; Wang, Yu
      Journal of Controlled Release (2022), 350 (), 613-629CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      In this study, an adipic acid dihydrazide (ADH)/ tannic acid (TA)-grafted hyaluronic acid (HA)-based multifunctional hydrogel was synthesized through a spontaneous amino-yne click reaction and used to promote the improved healing of infected diabetic wounds. This hydrogel exhibited a range of beneficial properties such as tunable gelation time, adjustable mech. properties, pH-sensitive response characteristics, excellent injectability, the ability to readily adhere to tissue, and ultra-intimate contact capabilities. Following the encapsulation of ultrasmall Ag nanoclusters (AgNCs) and deferoxamine loaded polydopamine/ hollow mesoporous manganese dioxide (PHMD, PDA/H-mMnO2@DFO) nanoparticles, the prepd. hydrogel presented with robust antibacterial, anti-inflammatory, and pro-angiogenic properties and a desirable smart drug release profile. In this fabricated platform, PHMD was able to effectively alleviate localized oxidative stress and prolonged oxygen deprivation via the decompn. of endogenous H2O2 to produce O2. Further in vivo assays revealed that this hydrogel was capable of facilitating the healing of infected wounds through the sequential engagement of antibacterial, anti-inflammatory, and pro-angiogenic activities. Together, this synthesized clickable environmentally-responsive hydrogel offers great promise as a tool that can be applied to aid in the healing of chronically infected diabetic wounds and other inflammatory conditions.
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    47. 47
      Li, Q.; Hu, Z.; Ji, X. Hydrogel-Based Macroscopic Click Chemistry. Angew. Chem., Int. Ed. 2023, 62 (52), e202315086  DOI: 10.1002/anie.202315086
      There is no corresponding record for this reference.
    48. 48
      Nguyen, C. T. V.; Chow, S. K. K.; Nguyen, H. N.; Liu, T.; Walls, A.; Withey, S.; Liebig, P.; Mueller, M.; Thierry, B.; Yang, C.-T.; Huang, C.-J. Formation of Zwitterionic and Self-Healable Hydrogels via Amino-Yne Click Chemistry for Development of Cellular Scaffold and Tumor Spheroid Phantom for MRI. ACS Appl. Mater. Interfaces 2024, 16 (28), 36157– 36167,  DOI: 10.1021/acsami.4c06917
      There is no corresponding record for this reference.
    49. 49
      Paula, C. T. B.; Pereira, P.; Coelho, J. F. J.; Fonseca, A. C.; Serra, A. C. Development of Light-Degradable Poly(Urethane-Urea) Hydrogel Films. Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 131, 112520  DOI: 10.1016/j.msec.2021.112520
      There is no corresponding record for this reference.
    50. 50
      Paula, C. T. B.; Leandro, A.; Pereira, P.; Coelho, J. F. J.; Fonseca, A. C.; Serra, A. C. Fast-Gelling Polyethylene Glycol/Polyethyleneimine Hydrogels Degradable by Visible-Light. Macromol. Biosci. 2024, 24 (2), 2300289,  DOI: 10.1002/mabi.202300289
      There is no corresponding record for this reference.
    51. 51
      Kharkar, P. M.; Kiick, K. L.; Kloxin, A. M. Designing Degradable Hydrogels for Orthogonal Control of Cell Microenvironments. Chem. Soc. Rev. 2013, 42 (17), 7335– 7372,  DOI: 10.1039/C3CS60040H
      51
      Designing degradable hydrogels for orthogonal control of cell microenvironments
      Kharkar, Prathamesh M.; Kiick, Kristi L.; Kloxin, April M.
      Chemical Society Reviews (2013), 42 (17), 7335-7372CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Degradable and cell-compatible hydrogels can be designed to mimic the phys. and biochem. characteristics of native extracellular matrixes and provide tunability of degrdn. rates and related properties under physiol. conditions. Hence, such hydrogels are finding widespread application in many bioengineering fields, including controlled bioactive mol. delivery, cell encapsulation for controlled three-dimensional culture, and tissue engineering. Cellular processes, such as adhesion, proliferation, spreading, migration, and differentiation, can be controlled within degradable, cell-compatible hydrogels with temporal tuning of biochem. or biophys. cues, such as growth factor presentation or hydrogel stiffness. However, thoughtful selection of hydrogel base materials, formation chemistries, and degradable moieties is necessary to achieve the appropriate level of property control and desired cellular response. In this review, hydrogel design considerations and materials for hydrogel prepn., ranging from natural polymers to synthetic polymers, are overviewed. Recent advances in chem. and phys. methods to crosslink hydrogels are highlighted, as well as recent developments in controlling hydrogel degrdn. rates and modes of degrdn. Special attention is given to spatial or temporal presentation of various biochem. and biophys. cues to modulate cell response in static (i.e., non-degradable) or dynamic (i.e., degradable) microenvironments. This review provides insight into the design of new cell-compatible, degradable hydrogels to understand and modulate cellular processes for various biomedical applications.
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    52. 52
      He, B.; Zhang, J.; Wang, J.; Wu, Y.; Qin, A.; Tang, B. Z. Preparation of Multifunctional Hyperbranched Poly(β-Aminoacrylate)s by Spontaneous Amino-Yne Click Polymerization. Macromolecules 2020, 53 (13), 5248– 5254,  DOI: 10.1021/acs.macromol.0c00813
      52
      Preparation of multifunctional hyperbranched poly(β-aminoacrylate)s by spontaneous amino-yne click polymerization
      He, Benzhao; Zhang, Jing; Wang, Jia; Wu, Yongwei; Qin, Anjun; Tang, Ben Zhong
      Macromolecules (Washington, DC, United States) (2020), 53 (13), 5248-5254CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      A series of multifunctional hyperbranched poly(β-aminoacrylate)s (hb-PAAs) were synthesized using spontaneous amino-yne click polymn for the first time. Using the optimized polymn. conditions, sol. and thermally stable hb-PAAs with high wt.-av. mol. wts. (Mw up to 18,290) were obtained in excellent yields (up to 99%). This click polymn. also can proceed in stereo- and regiospecific and anti-Markovnikov addn. fashion, and 100% E-isomers were obtained. Moreover, introducing the aggregation-induced emission (AIE)-active tetraphenylethene moiety into polymer backbones endows the resultant polymers with unique AIE properties, and their nanoaggregates can be used for sensitive detection of explosives. This work not only enriches the family of hyperbranched polymers but also confirms the universality of the spontaneous amino-yne click polymn.
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    53. 53
      Wang, D.; Zhang, N.; Yang, T.; Jing, X.; Meng, L. Construction Polyprodrugs by Click-Reactions and Metal-Coordination: pH-Responsive Release for Magnetic Resonance Imaging Guided Chemotherapy. Chem. Eng. J. 2021, 422, 130108  DOI: 10.1016/j.cej.2021.130108
      There is no corresponding record for this reference.
    54. 54
      Gonzaga, F.; Grande, J. B.; Brook, M. A. Morphology-Controlled Synthesis of Poly(Oxyethylene)Silicone or Alkylsilicone Surfactants with Explicit, Atomically Defined, Branched, Hydrophobic Tails. Chem. - Eur. J. 2012, 18 (5), 1536– 1541,  DOI: 10.1002/chem.201103093
      There is no corresponding record for this reference.
    55. 55
      Abdel-Khalik, M. M.; Elnagdi, M. H. Enaminones in Organic Synthesis: A Novel Synthesis of 1,3,5-Trisubstituted Benzene Derivatives and of 2-Substituted-5-Aroylpyridines. Synth. Commun. 2002, 32 (2), 159– 164,  DOI: 10.1081/SCC-120001996
      There is no corresponding record for this reference.
    56. 56
      Wan, J.-P.; Lin, Y.; Hu, K.; Liu, Y. Metal-Free Synthesis of 1,3,5-Trisubstituted Benzenes by the Cyclotrimerization of Enaminones or Alkynes in Water. RSC Adv. 2014, 4 (39), 20499– 20505,  DOI: 10.1039/C4RA00475B
      There is no corresponding record for this reference.
    57. 57
      Elghamry, I. Cyclotrimerization of Enaminones: An Efficient Method for the Synthesis of 1,3,5-Triaroylbenzenes. Synthesis 2003, 35 (15), 2301,  DOI: 10.1055/s-2003-41056
      There is no corresponding record for this reference.
    58. 58
      Park, H.; Guo, X.; Temenoff, J. S.; Tabata, Y.; Caplan, A. I.; Kasper, F. K.; Mikos, A. G. Effect of Swelling Ratio of Injectable Hydrogel Composites on Chondrogenic Differentiation of Encapsulated Rabbit Marrow Mesenchymal Stem Cells In Vitro. Biomacromolecules 2009, 10 (3), 541– 546,  DOI: 10.1021/bm801197m
      58
      Effect of Swelling Ratio of Injectable Hydrogel Composites on Chondrogenic Differentiation of Encapsulated Rabbit Marrow Mesenchymal Stem Cells In Vitro
      Park, Hansoo; Guo, Xuan; Temenoff, Johnna S.; Tabata, Yasuhiko; Caplan, Arnold I.; Kasper, F. Kurtis; Mikos, Antonios G.
      Biomacromolecules (2009), 10 (3), 541-546CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      An injectable, biodegradable hydrogel composite of oligo(poly(ethylene glycol) fumarate) (OPF) and gelatin microparticles (MPs) has been investigated as a cell and growth factor carrier for cartilage tissue engineering applications. In this study, hydrogel composites with different swelling ratios were prepd. by crosslinking OPF macromers with poly(ethylene glycol) (PEG) repeating units of varying mol. wts. from 1000∼35000. Rabbit marrow mesenchymal stem cells (MSCs) and MPs loaded with transforming growth factor-β1 (TGF-β1) were encapsulated in the hydrogel composites to examine the effect of the swelling ratio of the hydrogel composites on the chondrogenic differentiation of encapsulated rabbit marrow MSCs both in the presence and in the absence of TGF-β1. The swelling ratio of the hydrogel composites increased as the PEG mol. wt. in the OPF macromers increased. Chondrocyte-specific genes were expressed at higher levels in groups contg. TGF-β1-loaded MPs and varied with the swelling ratio of the hydrogel composites. OPF hydrogel composites with PEG repeating units of mol. wt. 35000 and 10000 with TGF-β1-loaded MPs exhibited a 159 ± 95- and a 89 ± 31-fold increase in type II collagen gene expression at day 28, resp., while OPF hydrogel composites with PEG repeating units of mol. wt. 3000 and 1000 with TGF-β1-loaded MPs showed a 27 ± 10- and a 17 ± 7-fold increase in type II collagen gene expression, resp., as compared to the composites with blank MPs at day 0. The results indicate that chondrogenic differentiation of encapsulated rabbit marrow MSCs within OPF hydrogel composites could be affected by their swelling ratio, thus suggesting the potential of OPF composite hydrogels as part of a novel strategy for controlling the differentiation of stem cells.
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    59. 59
      Ferreira, L.; Gil, M. H.; Dordick, J. S. Enzymatic Synthesis of Dextran-Containing Hydrogels. Biomaterials 2002, 23 (19), 3957– 3967,  DOI: 10.1016/S0142-9612(02)00132-1
      There is no corresponding record for this reference.
    60. 60
      Camci-Unal, G.; Cuttica, D.; Annabi, N.; Demarchi, D.; Khademhosseini, A. Synthesis and Characterization of Hybrid Hyaluronic Acid-Gelatin Hydrogels. Biomacromolecules 2013, 14 (4), 1085– 1092,  DOI: 10.1021/bm3019856
      60
      Synthesis and Characterization of Hybrid Hyaluronic Acid-Gelatin Hydrogels
      Camci-Unal, Gulden; Cuttica, Davide; Annabi, Nasim; Demarchi, Danilo; Khademhosseini, Ali
      Biomacromolecules (2013), 14 (4), 1085-1092CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Biomimetic hybrid hydrogels have generated broad interest in tissue engineering and regenerative medicine. Hyaluronic acid (HA) and gelatin (hydrolyzed collagen) are naturally derived polymers and biodegradable under physiol. conditions. Moreover, collagen and HA are major components of the extracellular matrix (ECM) in most of the tissues (e.g., cardiovascular, cartilage, neural). When used as a hybrid material, HA-gelatin hydrogels may enable mimicking the ECM of native tissues. Although HA-gelatin hybrid hydrogels are promising biomimetic substrates, their material properties have not been thoroughly characterized in the literature. Herein, we generated hybrid hydrogels with tunable phys. and biol. properties by using different concns. of HA and gelatin. The phys. properties of the fabricated hydrogels including swelling ratio, degrdn., and mech. properties were investigated. In addn., in vitro cellular responses in both two and three-dimensional culture conditions were assessed. It was found that the addn. of gelatin methacrylate (GelMA) into HA methacrylate (HAMA) promoted cell spreading in the hybrid hydrogels. Moreover, the hybrid hydrogels showed significantly improved mech. properties compared to their single component analogs. The HAMA-GelMA hydrogels exhibited remarkable tunability behavior and may be useful for cardiovascular tissue engineering applications.
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    61. 61
      Peppas, N. A.; Moynihan, H. J.; Lucht, L. M. The structure of highly crosslinked poly(2-hydroxyethyl methacrylate) hydrogels. J. Biomed. Mater. Res. 1985, 19 (4), 397– 411,  DOI: 10.1002/jbm.820190405
      61
      The structure of highly crosslinked poly(2-hydroxyethyl methacrylate) hydrogels
      Peppas, Nikolaos A.; Moynihan, Humphrey J.; Lucht, Lucy M.
      Journal of Biomedical Materials Research (1985), 19 (4), 397-411CODEN: JBMRBG; ISSN:0021-9304.
      Films were prepd. by reaction of 2-hydroxyethyl methacrylate (HEMA) monomer with the crosslinking agent ethylene glycol dimethacrylate (EGDMA) [97-90-5] at crosslinking ratios, X, of 0.005, 0.01, 0.0128, 0.025, and 0.050 mol EGDMA/mol HEMA in the presence of 40 wt.% water at 60° for 12 h. These membranes were subsequently swollen in water at 37° and their structure analyzed using a modified Gaussian distribution equation of equil. swelling. The calcd. values of mol. wt. between crosslinks (‾Mc) varied between 800 and 3700 daltons, which corresponded to a correlation length of the mesh size ξ of 16.2 to 35.6 Å. The structural anal. and diffusive studies of poly(2-hydroxyethyl methacrylate) (PHEMA) [25249-16-5] membranes indicate that the recent detns. of ‾Mc for PHEMA by Migliaresi et al. (1981) and others are not accurate. The methods presented can also be used for anal. of any highly crosslinked polymer network produced by simultaneous polymn. and crosslinking reactions.
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    62. 62
      Muralidharan, A.; McLeod, R. R.; Bryant, S. J. Hydrolytically Degradable Poly(β-Amino Ester) Resins with Tunable Degradation for 3D Printing by Projection Micro-Stereolithography. Adv. Funct. Mater. 2022, 32 (6), 2106509,  DOI: 10.1002/adfm.202106509
      62
      Hydrolytically Degradable Poly(β-amino ester) Resins with Tunable Degradation for 3D Printing by Projection Micro-Stereolithography
      Muralidharan, Archish; McLeod, Robert R.; Bryant, Stephanie J.
      Advanced Functional Materials (2022), 32 (6), 2106509CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Applications of 3D printing that range from temporary medical devices to environmentally responsible manufg. will benefit from printable resins that yield polymers with controllable architecture, material properties, and degrdn. behavior. Towards this goal, poly(β-amino ester) (PBAE)-diacrylate resins are investigated due to the wide range of available chemistries and tunable material properties. PBAE-diacrylate resins are synthesized from hydrophilic and hydrophobic chemistries and with varying electron densities on the ester bond to provide control over degrdn. Hydrophilic PBAE-diacrylates led to degrdn. behaviors characteristic of bulk degrdn., while hydrophobic PBAE-diacrylates led to degrdn. behaviors dominated initially by surface degrdn. and then transitioned to bulk degrdn. Depending on the chem., the crosslinked PBAE-polymers exhibited a range of degrdn. times under accelerated conditions, from complete mass loss in 90 min to minimal mass loss at 45 days. Patterned features with 55μm resoln. are achieved across all resins, but their fidelity is dependent on PBAE-diacrylate mol. wt., reactivity, and printing parameters. In summary, simple chem. modifications in the PBAE-diacrylate resins coupled with projection microstereolithog. enable high-resoln. 3D printed parts with similar architectures and initial properties but widely different degrdn. rates and behaviors.
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