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Multiresponsive 4D Printable Hydrogels with Anti-Inflammatory Properties
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Multiresponsive 4D Printable Hydrogels with Anti-Inflammatory Properties
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  • Maria Regato-Herbella
    Maria Regato-Herbella
    POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018, Donostia-San Sebastián, Spain
    Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA). Paseo de Miramón 194, 20014, Donostia-San Sebastián, Spain
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  • Daniele Mantione
    Daniele Mantione
    POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018, Donostia-San Sebastián, Spain
    Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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  • Agustín Blachman
    Agustín Blachman
    Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Junín 956, 1113 Ciudad Autónoma de Buenos Aires, Buenos Aires C1053ABH, Argentina
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  • Antonela Gallastegui
    Antonela Gallastegui
    POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018, Donostia-San Sebastián, Spain
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  • Graciela C. Calabrese
    Graciela C. Calabrese
    Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Junín 956, 1113 Ciudad Autónoma de Buenos Aires, Buenos Aires C1053ABH, Argentina
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    Orcidhttps://orcid.org/0000-0001-5835-423X
  • Sergio E. Moya*
    Sergio E. Moya
    Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA). Paseo de Miramón 194, 20014, Donostia-San Sebastián, Spain
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-7174-1960
  • David Mecerreyes*
    David Mecerreyes
    POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018, Donostia-San Sebastián, Spain
    Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-0788-7156
  • Miryam Criado-Gonzalez*
    Miryam Criado-Gonzalez
    POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018, Donostia-San Sebastián, Spain
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-5502-892X
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ACS Macro Letters

Cite this: ACS Macro Lett. 2024, 13, 9, 1119–1126
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https://doi.org/10.1021/acsmacrolett.4c00404
Published August 14, 2024

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Multiresponsive hydrogels are valuable as biomaterials due to their ability to respond to multiple biologically relevant stimuli, i.e., temperature, pH, or reactive oxygen species (ROS), which can be present simultaneously in the body. In this work, we synthesize triple-responsive hydrogels through UV light photopolymerization of selected monomer compositions that encompass thermoresponsive N-isopropylacrylamide (NIPAM), pH-responsive methacrylic acid (MAA), and a tailor-made ROS-responsive diacrylate thioether monomer (EG3SA). As a result, smart P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels capable of being manufactured by digital light processing (DLP) 4D printing are obtained. The thermo-, pH-, and ROS-response of the hydrogels are studied by swelling tests and rheological measurements at different temperatures (25 and 37 °C), pHs (3, 5, 7.4, and 11), and in the absence or presence of ROS (H2O2). The hydrogels are employed as matrixes for the encapsulation of ketoprofen (KET), an anti-inflammatory drug that shows a tunable release, depending on the hydrogel composition and stimuli applied. The cytotoxicity properties of the hydrogels are tested in vitro with mouse embryonic fibroblasts (NIH 3T3) and RAW 264.7 murine macrophage (RAW) cells. Finally, the anti-inflammatory properties are assessed, and the results exhibit a ≈70% nitric oxide reduction up to base values of pro-inflammatory RAW cells, which highlights the anti-inflammatory capacity of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels, per se, without being necessary to encapsulate an anti-inflammatory drug within their network. It opens the route for the fabrication of customizable 4D printable scaffolds for the effective treatment of inflammatory pathologies.

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Copyright © 2024 The Authors. Published by American Chemical Society

Multiresponsive hydrogels, also known as intelligent or smart hydrogels, can undergo controlled shape changes in response to more than one stimulus, which has attracted great attention in the biomedical field for drug delivery, (1) tissue engineering, (2,3) cancer therapy, (4) or biosensing. (5,6) Their ability to change their properties upon response to biological (i.e., temperature, pH, enzyme activity, reactive oxygen species), and/or external stimuli, (i.e., light, electrical or magnetic field), (7−9) make them ideal candidates for 4D printing, a cutting-edge technology for manufacturing customizable dynamic materials combining 3D printing and stimuli-responsiveness. (10,11)

The design of tailor-made stimuli-responsive polymers allows to provide specific and simultaneous responses to different stimuli, a common scenario in biology. (12−16) Poly(N-isopropylacrylamide) (PNIPAM) is the most studied polymer to develop thermoresponsive hydrogels. PNIPAM displays a reversible volume phase transition through swelling at temperatures below the so-called lower critical solution temperature (LCST ∼ 32 °C) and shrinking above it. (3) This swelling/shrinking process has been modulated through copolymerization with other monomers, which in turn confer responsiveness to other environmental stimuli such as pH. (12) For example, copolymers of PNIPAM and methacrylic acid (MAA) or acrylic acid (AA) can be deprotonated at high pHs, above their pKa, endowing hydrogels with pH-response in addition to temperature sensitivity. (17) PMAA and PAA hydrogels have also been exploited for targeted drug release as they acted as drug protectors at acidic conditions in the stomach to be later released at higher pH ∼ 8 in the gastrointestinal tract. (18) The dual response of P[NIPAM-co-MAA] and P[NIPAM-co-PAA] copolymers to temperature and pH changes has also been studied by many authors for controlled drug release. (19−21) More recently, the use of reactive oxygen species (ROS), oxidant species present in the human body, has drawn attention as possible stimuli for responsive hydrogels. ROS effect can vary from beneficial cell survival to nondesirable oxidative stress when they are overproduced, thus causing inflammation, cancer, and age-related diseases. (22,23) Among different types of ROS-responsive polymers (i.e., sulfides, diselenides, thioketals, aryl boronic esters, etc.), those bearing thioether groups present interesting hydrophobic to hydrophilic transitions when oxidized by ROS without requiring cleavage. (24−27) Very recently, we developed ROS-responsive photopolymerizable thioether-based hydrogels through the synthesis of aqueous soluble redox monomers from oligomers of ethylene glycol sulfur diacrylate (EG3SA). The resulting hydrogels were used as 5-Fluorouracil carriers to inhibit the growth of melanoma cancer cells. (28)

Considering that overproduction of ROS in tumor/inflamed areas is generally linked to pH changes becoming slightly acidic (pH 5.4–7.1), (29,30) the development of intelligent hydrogels that respond simultaneously to ROS, acidic pH, and body temperature is an interesting approach to modulate the simultaneous multistimulation in complex biological environments. Here, we have synthesized multiresponsive hydrogels through UV-light photopolymerization of a selected monomers mixture consisting of thermoresponsive NIPAM, pH-responsive MAA, and a tailor-made ROS-responsive EG3SA monomer. P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels’ response to external stimuli (temperature, pH, and ROS) and controlled-release properties are investigated. Their additive manufacturing through digital light processing (DLP) 4D printing is also performed to obtain customizable hydrogels. Finally, we show that the hydrogels display anti-inflammatory properties.

P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels were synthesized by copolymerization of three different responsive monomers, thermoresponsive NIPAM (x = 80, 70 or 40%mol), pH-responsive MAA (y = 15, 15 or 20%mol), and ROS-responsive EG3SA (z = 5, 15 or 40%mol). Then, the hydrogels were obtained by UV-light photopolymerization (λ = 365 nm) using Darocur 1173 (2-hydroxy-2-methylpropiophenone) as a photoinitiator and 30 wt % CHCl3 as a sacrificial solvent (Figure 1). In all cases, transparent hydrogels were formed.

Figure 1

Figure 1. (a) Chemical route employed for the synthesis of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels by UV light at 365 nm for 3–5 min and using Darocur as a photoinitiator. (b) Pictures of the synthesized hydrogels with different monomer ratios.

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The chemical characterization of the hydrogels was performed by infrared spectroscopy (Figure S1). The peak at 1720 cm–1 is attributed to C═O vibrations of the acid carbonyl groups of MAA and the acrylate groups of EG3SA. The peaks at 1650, 1540, and 1130 cm–1 are assigned to C═O, N─H, and C─N stretching of amide groups present in NIPAM. The peak at around 1455 cm–1 is attributed to C─H bending in the −(CH3)2 and −CH2 groups of NIPAM and MAA, (31) and the peaks at 690 and 715 cm–1 are the signatures of symmetric and asymmetric dimethyl sulfide bonds, respectively. After H2O2 treatment, thioether groups of EG3SA are oxidized into sulfoxides and/or sulfones, as corroborated by the appearance of two peaks at 1020 and 1320 cm–1 corresponding to the stretching of the double bond S═O in sulfoxides and O═S═O in sulfones, respectively. (28)

The response of the hydrogels to different stimuli, ROS, temperature, and pH, was tested (Figure 2a). Four different scenarios can be considered. (i) Single pH-response: under nonoxidative conditions (PBS) at room temperature (25 °C < LCST of PNIPAM) and different pHs, swelling is controlled by the protonation state of MAA (Figure 2b). P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels exhibited a ≈140 wt % swelling at pH 7.4. Increasing the EG3SA percentage resulted in cross-linking points and more reticulated hydrogels with less water-holding capacity decreasing the swelling of P[NIPAM40-co-MAA20-co-(EG3SA)40] up to ≈10%wt. At acidic pHs (<pKa ≈ 5.5 of PMAA), carboxylic groups of PMAA are protonated (COOH) and hydrogels shrank, decreasing the swelling. For P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels, a decrease of up to ≈47 wt % at pH 3 was observed, while swelling was almost negligible for P[NIPAM40-co-MAA20-co-(EG3SA)40]. At alkaline pH 11, COO– deprotonates, promoting the swelling of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels up to ≈215%wt. (ii) Dual thermo- and pH-response under nonoxidative conditions (PBS) at 37 °C (>LCST of PNIPAM) and different pHs (Figure 2c): At this temperature, hydrogels contract due to the presence of PNIPAM. The swelling of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels decreased up to ≈93 wt % at pH 7.4 and ≈17 wt % at pH 3, whereas for P[NIPAM70-co-MAA15-co-(EG3SA)15] and P[NIPAM40-co-MAA20-co-(EG3SA)40] hydrogels with a larger content of EG3SA, the high cross-linking degree induced similar swelling values to those observed at 25 °C. The same tendency was observed at pH 11 (>pKa of PMAA). (iii) Dual ROS- and pH-response under oxidative conditions (9 mM H2O2) at 25 °C and different pHs (Figure 2d): P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels experienced a huge swelling of ≈465 wt % at pH 7.4 due to the oxidation of the thioether groups present in the EG3SA domains, which led to more hydrophilic hydrogels. This effect was less pronounced in hydrogels with a larger content of EG3SA due to their higher cross-linking density. All hydrogels exhibited the highest swelling properties in H2O2 at pH 11, as all copolymer components are in the most hydrophilic state, holding the largest quantity of water, ≈1320 wt % for P[NIPAM80-co-MAA15-co-(EG3SA)5], ≈615 wt % for P[NIPAM70-co-MAA15-co-(EG3SA)15], and ≈265 wt % for P[NIPAM40-co-MAA20-co-(EG3SA)40]. (iv) Triple ROS-, thermo-, and pH-response under oxidative conditions (9 mM H2O2) at 37 °C and different pHs, where all monomers are involved in the stimuli-responsive properties (Figure 2e): The least cross-linked P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels presented the highest swelling at all pHs (Figures 1f,g and S2). At pH 7.4, P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels showed the lowest swelling (≈93 wt %), as they contained the highest percentage of PNIPAM. The swelling decreased with the pH up to ≈8 wt % at pH 3 due to the combination of the shrinking behavior of PNIPAM and PMAA that camouflaged the hydrophilic oxidation properties of PEG3SA. At alkaline pH 11, the swelling increased exponentially due to the deprotonation of COO– groups of PMAA together with the more hydrophilic oxidized PEG3SA, which led to the hydrogel’s breaking, probably due to the high pressure produced by the water, which broke their network and made them difficult to handle.

Figure 2

Figure 2. (a) Schematic representation of the swelling/shrinking behavior of each monomer within the P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels in response to external stimuli, temperature, pH, and/or ROS. (b) Swelling of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels at different pHs immersed in (b) PBS at 25 °C, (c) PBS at 37 °C, (d) 9 mM H2O2 at 25 °C, and (e) 9 mM H2O2 at 37 °C, for 24 h. Diagrams (b)–(e) include the mean and standard deviation (n = 3) and the ANOVA results. Different letters indicate statistically significant differences at a significance level of p < 0.05 using Tukey’s test. Bars with no common letters are significantly different (p < 0.05). (f) Representative pictures of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels after 24 h at different temperatures, pHs, and under nonoxidant (PBS) or oxidant (H2O2) conditions. Scale bars = 5 mm. (g) Swelling comparison of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels at different temperatures (25 and 37 °C) and pHs (3, 5, 7.4 and 11), in Phosphate Buffer Solution (PBS) or H2O2.

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P[NIPAMn-co-MAAm-co-(EG3SA)x] hydrogels were tested as scaffolds to encapsulate an anti-inflammatory drug, ketoprofen (KET). The KET release under different stimuli (temperature, pH, ROS; Figure 3a,b) was correlated with the hydrogels’ swelling behavior (Figure 2). P[NIPAM80-co-MAA15-co-(EG3SA)5] and P[NIPAM70-co-MAA15-co-(EG3SA)15] hydrogels showed a much higher capability of releasing KET than P[NIPAM40-co-MAA20-co-(EG3SA)40], in agreement with swelling tests. P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels released 0.26 mg/mL of KET after 24 h in PBS at pH 7.4 and 25 °C. The release decreased up to 0.21 mg/mL at 37 °C due to the NIPAM-induced shrinking trapping a higher part of KET molecules inside. The decrease of pH to 5, at 37 °C, induced a slight reduction of the KET released up to 0.19 mg/mL because of the MAA-induced shrinking, while the pH increase to 11 increased the release (0.33 mg/mL). In the presence of H2O2 at pH 7.4 and 37 °C, the release of KET increased (0.27 mg/mL) due to the oxidation of the thioether groups of EG3SA becoming more hydrophilic, while the decrease of pH slightly reduced the KET released (0.25 mg/mL). This hydrophilic effect is more evident over time as the release of KET increased after 72 h. P[NIPAM70-co-MAA15-co-(EG3SA)15] hydrogels showed a similar behavior. The same trends were observed in the case of P[NIPAM40-co-MAA20-co-(EG3SA)40] hydrogels, although the concentration of KET released was much lower due to their higher cross-linking degree and consequently lower swelling capacity. Therefore, all hydrogels were thermo-, pH-, and ROS- responsive leading to tunable KET release profiles.

Figure 3

Figure 3. (a) Schematic representation of the ketoprofen (KET) release from P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels under different conditions of temperature, pH, and ROS. (b) Release of KET from P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels under nonoxidative conditions in PBS, and oxidative conditions in the presence of 9 mM H2O2, at 25 or 37 °C, and pH 5, 7.4, or 11 for 24 and 72 h. Diagrams include the mean and standard deviation (n = 3) and the ANOVA results. Different letters indicate statistically significant differences at a significance level of p < 0.05 using Tukey’s test. Bars with no common letters are significantly different (p < 0.05).

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The additive manufacturing by DLP 3D printing was initially studied by photorheology (Figure 4a). Before irradiation (0–60 s), the loss modulus (G′′) was higher than the storage modulus (G′), pointing out the liquid-like state of the copolymer inks. After 60 s, the UV light was switched and the photopolymerization process started reaching a solid-like state (G′ > G′′) in a few seconds. The photopolymerization time decreased with an increase in the EG3SA concentration from 20 s for P[NIPAM80-co-MAA15-co-(EG3SA)5] to 12 and 10 s for P[NIPAM70-co-MAA15-co-(EG3SA)15] and P[NIPAM40-co-MAA20-co-(EG3SA)40], respectively. As no significant differences were observed between hydrogels with 5% and 15% mol EG3SA, only hydrogels with the lowest and highest percentage of this monomer, 5% and 40% mol, were studied in further experiments. The copolymers with 5% and 40% mol EG3SA were successfully processed by DLP 3D printing to fabricate customized multihollow scaffolds (Figure 4b). Thanks to their stimuli-responsive properties, they became 4D-printable hydrogels. The printing resolution increased with the percentage of EG3SA monomer within the copolymers, but the hydrogels were more brittle. The mechanical properties in the presence of different stimuli were characterized by rheology. In all cases, G′ was higher than G′′, corroborating the hydrogel formation (Figure 4c). Three different conditions were tested to characterize the hydrogels based on the most representative biological conditions: (i) Physiological mimicking conditions (PBS, pH 7.4, 37 °C): G′ increased with NIPAM percentage within the hydrogels, from ≈2 × 104 Pa for P[NIPAM40-co-MAA20-co-(EG3SA)40] (Figure S3) to ≈6 × 104 Pa for P[NIPAM80-co-MAA15-co-(EG3SA)5] due to their higher contraction at physiological temperature making them less flexible. (ii) Oxidation in the presence of ROS (H2O2), which are present in inflammatory diseases, (32) at pH 7.4 and 37 °C (Figure 4d). The mechanical properties were highly influenced by the thermoresponse of NIPAM and ROS-response of EG3SA. G′ increased up to ≈1 × 105 Pa in P[NIPAM40-co-MAA20-co-(EG3SA)40] hydrogels due to the higher percentage of EG3SA that led to the formation of sulfoxides and sulfones, thus, allowing them to hold a high quantity of water and making them more brittle. (iii) Oxidation (H2O2) at pH 5 and 37 °C (Figure 4e). No significant differences were observed in G′ of P[NIPAM40-co-MAA20-co-(EG3SA)40] hydrogels between pH 7.4 and pH 5, probably because they reached the maximum swelling capacity before breaking. G′ of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels decreased to ≈3 × 104 Pa because of the less amount of cross-linker EG3SA and the higher elasticity of the oxidized chains.

Figure 4

Figure 4. (a) Photorheological properties to determine the gel point (G′ > G′′) when the inks are irradiated for 10–20 s (from 60 s), leading to P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels. (b) Schematic representation of the DLP process employed to print the hydrogels (left), and shape-defined 4D-printed P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogel scaffolds with pores (right). Rheological properties of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels in the presence of different stimuli: (c) PBS, pH 7.4, 37 °C, (d) H2O2, pH 7.4, 37 °C, and (e) H2O2, pH 5, 37 °C.

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The cytotoxicity of nonloaded and KET-loaded P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels was tested in vitro with mouse embryonic fibroblasts (NIH 3T3) and RAW 264.7 murine macrophage (RAW) cells. These cell lines were selected as representative models involved in inflammatory processes during tissue repair, (33−36) in which macrophages modulate inflammation and fibroblasts lay down a new extracellular matrix. P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels were not cytotoxic, showing NIH 3T3 and RAW cell viabilities higher than 90% (Figure 5a,b). However, P[NIPAM40-co-MAA20-co-(EG3SA)40] hydrogels reduced the viability of NIH 3T3 (≈ 85%) and RAW (≈ 65%) cells and were discarded for the next experiments. It was observed that the presence of the EG3SA within P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels favored the NIH 3T3 cell adhesion in comparison with P[NIPAM90-co-MAA10] hydrogels (Figure 5c,d). NIH 3T3 cell morphology was visualized by staining cell nuclei with Hoechst (blue staining) and cytoskeleton (F-actin fibers) with phalloidin-rhodamine (orange staining). On P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels, NIH 3T3 cells showed an elongated morphology and cell spreading, which was not observed in P[NIPAM90-co-MAA10] hydrogels where fibroblasts exhibited a round morphology forming clusters. It is known that cell adhesion is influenced by chemical groups present on the surface of the hydrogels (37) and specifically enhanced by sulfonic groups, (38) which induce a reorganization of the actin cytoskeleton of fibroblasts. (39,40) Thus, the thioether groups present on the EG3SA domains favored the cell adhesion on P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels. The anti-inflammatory properties of nonloaded and KET-loaded P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels were tested in contact with RAW cells, which can polarize to their pro-inflammatory phenotype (M1) when they are activated by lipopolysaccharide (LPS) and start to overproduce nitric oxide (NO). The anti-inflammatory capacity of the hydrogels was determined by measuring the NO production of LPS-activated RAW cells (LPS-RAW) seeded on the hydrogels for 24 h (Figure 5e) in comparison with LPS-RAW cells seeded on the well plate (positive control, inflammatory conditions untreated - ICU) and non-LPS-activated RAW cells seeded on the hydrogels (negative control, noninflammatory conditions - NIC). The NO released by LPS-RAW cells seeded on top of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels decreased up to 29.9 ± 2.6% after 24 h, reaching the basal value of non-LPS-activated RAW cells on the hydrogels (NIC = 32.3 ± 1.1%). Nonsignificant differences were detected in comparison with KET-loaded P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels that also decreased the NO production (30.1 ± 4.4%) up to basal values. To quantify the anti-inflammatory capacity of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels, NO values were compared with those of LPS-RAW cells seeded on a plate and brought in contact with different ketoprofen concentrations (Figure S4). Results showed that NO released by LPS-RAW cells decreased up to basal values from 0.3 mg/mL KET approximately. Overall, these results proved the excellent anti-inflammatory capacity of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels, per se, without encapsulating an anti-inflammatory drug (Figure 5e). At the initial stage, RAW cells are seeded on top of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels. They are in a noninflammatory stage and NO production is at the basal value. In the second stage, the inflammatory process is induced by activation of RAW cells with LPS and they start to overproduce NO (a type of ROS). Then, in the last stage, the ROS produced by LPS-RAW cells are trapped by the P[NIPAM80-co-MAA15-co-(EG3SOA)5] hydrogels in the oxidized EG3SA domains formed by sulfoxides and sulfones (EG3SOA), thus reducing the inflammatory process and the NO production by RAW cells up to basal values of noninflammatory conditions. This interesting achievement opens the route for the fabrication of 4D printable anti-inflammatory scaffolds in a customized manner with anti-inflammatory properties.

Figure 5

Figure 5. In vitro cytotoxicity tests of nonloaded and KET-loaded P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels in contact with (a) NIH 3T3 and (b) RAW cells for 24 and 48 h. (c) NIH 3T3 cell adhesion on (c) P[NIPAM90-co-MAA10] and (d) P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels. (e) Nitric oxide (NO) released by LPS-RAW cells seeded on the plate (ICU), non-LPS-RAW cells seeded on the plate (NIC), and LPS-RAW cells seeded on the hydrogels. Diagrams (a), (b), and (e) include the mean and standard deviation (n = 3) and the ANOVA results at significance levels of *p < 0.05 and ***p < 0.001 using Tukey’s test (ns means nonstatistically significant differences). (f) Schematic representation of the inflammatory process induced by the activation of RAW cells, growth on top of the hydrogels, with LPS leading to ROS production, and the anti-inflammatory properties of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels, which trapped ROS due to the oxidative capacity of the (EG3SA) block.

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In conclusion, triple-responsive hydrogels were synthesized by photopolymerization of thermoresponsive NIPAM, pH-responsive MAA, and ROS-responsive EG3SA monomers. Thus, it also allowed their additive manufacturing by DLP leading to 4D printed shape-defined hydrogels. The swelling properties of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels decreased with the temperature increase from 25 to 37 °C, due to the contraction of PNIPAM chains above their LCST, and with the pH decrease from 7.4 to 3, because of the protonation of the carboxylic groups of PMAA below their pKa. On the contrary, swelling increased with the pH increase from 7.4 to 11, due to the deprotonation of carboxylic groups, and with the presence of ROS (i.e., H2O2) because of the oxidation of the thioether groups in EG3SA into sulfoxides and sulfones making them more hydrophilic. P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels were used as carriers for the controlled release of ketoprofen. The mechanical properties of the hydrogels were characterized by rheology showing a variation of the initial G′ values (≈104 Pa) that depended on the applied stimuli and could reach up to ≈105 Pa. Cell tests pointed out P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels presented the optimal stimuli-responsive performance while being noncytotoxic, at the same time they possessed anti-inflammatory properties per se.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmacrolett.4c00404.

  • Materials and methods, 1H NMR spectra of EG3SA monomer in CDCl3, FTIR spectra of P[NIPAM70-co-MAA15-co-(EG3SA)15] hydrogels at different conditions, representative pictures of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels under different conditions and swelling comparison, rheological properties of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels in PBS at pH 7.4 and 25 °C, and nitric oxide (NO) released by RAW cells in the presence of different ketoprofen concentrations (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Maria Regato-Herbella - POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018, Donostia-San Sebastián, Spain;  Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA). Paseo de Miramón 194, 20014, Donostia-San Sebastián, Spain
    • Daniele Mantione - POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018, Donostia-San Sebastián, Spain;  Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
    • Agustín Blachman - Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Junín 956, 1113 Ciudad Autónoma de Buenos Aires, Buenos Aires C1053ABH, Argentina
    • Antonela Gallastegui - POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018, Donostia-San Sebastián, Spain
    • Graciela C. Calabrese - Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Junín 956, 1113 Ciudad Autónoma de Buenos Aires, Buenos Aires C1053ABH, Argentina;  Orcidhttps://orcid.org/0000-0001-5835-423X
  • Author Contributions

    The manuscript was written through the contributions of all authors. All authors have approved the final version of the manuscript. CRediT: Maria Regato-Herbella data curation, formal analysis, investigation, methodology, writing-original draft; Daniele Mantione investigation, methodology, writing-original draft; Agustín Blachman investigation, methodology, writing-original draft; Antonela Gallastegui investigation, methodology; Graciela Cristina Calabrese validation; Sergio E. Moya funding acquisition, validation, writing-review & editing; David Mecerreyes conceptualization, funding acquisition, project administration, supervision, writing-review & editing; Miryam Criado-Gonzalez conceptualization, data curation, formal analysis, investigation, methodology, supervision, writing-original draft, writing-review & editing.

  • Funding

    The authors acknowledge Grant PID2020-119026GB-I00 funded by MCIU/AEI/10.13039/501100011033. M.C.-G. thanks the Emakiker program of POLYMAT (UPV/EHU). S.E.M. thanks the PID2020-114356RB-I00 Project from the Ministry of Science and Innovation of the Government of Spain. D.M. thanks “Ayuda RYC2021-031668-I financiada por MCIN/AEI/10.13039/501100011033 y por la Unión Europea NextGenerationEU/PRTR”.

  • Notes
    The authors declare no competing financial interest.

References

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This article references 40 other publications.

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    Robinson, Daphne N.; Peppas, Nicholas A.
    Macromolecules (2002), 35 (9), 3668-3674CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Poly(methacrylic acid-g-ethylene glycol) (P(MAA-g-EG)) has been studied extensively in this lab. due to its extremely promising applications in the biomedical and pharmaceutical fields. It exhibits pH-responsive interpolymer complexes that make it a promising candidate as an oral carrier for peptide and protein drugs. We developed a photoinitiated free-radical pptn. polymn. method to produce P(MAA-g-EG) nanospheres with relatively narrow size distributions. The effect of various reaction parameters, such as total monomer concn. in water, comonomer molar feed ratios, crosslinking agent concn., and polymn. time, on the particle size and size distribution was investigated. P(MAA-g-EG) nanospheres with a relatively narrow size distribution could be produced in the size range 150-650 nm depending on the monomer concn. and comonomer molar feed ratio. The P(MAA-g-EG) nanospheres exhibited a pH-responsive swelling behavior. Increasing the concn. of the crosslinking agent during polymn. produced P(MAA-g-EG) nanospheres that swelled to a lesser degree. The morphol. of the P(MAA-g-EG) nanospheres was investigated by cryogenic SEM.
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  18. 18
    Gao, X.; Cao, Y.; Song, X.; Zhang, Z.; Xiao, C.; He, C.; Chen, X. pH- and thermo-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) copolymers and hydrogels with LCST dependent on pH and alkyl side groups. J. Mater. Chem. B 2013, 1 (41), 5578– 5587,  DOI: 10.1039/c3tb20901f
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    18
    pH- and thermo-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) copolymers and hydrogels with LCST dependent on pH and alkyl side groups
    Gao, Xiaoye; Cao, Yue; Song, Xiangfu; Zhang, Zhe; Xiao, Chunsheng; He, Chaoliang; Chen, Xuesi
    Journal of Materials Chemistry B: Materials for Biology and Medicine (2013), 1 (41), 5578-5587CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
    A series of pH- and temp.-responsive poly(N-isopropylacrylamide-co-acrylic acid deriv.) (P(NIPAM-co-AAD)) copolymers and hydrogels were prepd. The lower crit. soln. temps. (LCSTs) of the copolymers exhibited a dependence on both pH and the hydrophobicity of the AAD unit. The influence of pH and temp. on the equil. swelling ratio of the hydrogels was investigated. The hydrogels displayed a unique thermo-induced swelling-deswelling transition that can be self-regulated to occur at above or below the physiol. temp. in response to the environmental pH. Scanning electron microscopic (SEM) anal. revealed porous sponge-like microstructures of the hydrogels. Insulin was loaded into the hydrogels as a model protein, and the in vitro release profiles indicated that the loaded protein could be protected within the hydrogels in an acidic environment and selectively released in neutral medium. MTT assay proved that both the copolymers and hydrogels are nontoxic. After oral administration of the insulin-loaded hydrogels to streptozotocin-induced diabetic rats at 60 IU per kg, the fasting plasma glucose level was reduced continuously to 72.1% within 6 h. The bioavailability of hydrogel-encapsulated insulin via the oral administration to healthy rabbits reached 5.24%, which is much higher than that of pure insulin soln. given orally. These results showed that the smart copolymers and hydrogels may hold great promise for pH-triggered drug delivery systems.
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  19. 19
    Belman-Flores, C. E.; Herrera-Kao, W.; Vargas-Coronado, R. F.; May-Pat, A.; Oliva, A. I.; Rodríguez-Fuentes, N.; Vázquez-Torres, H.; Cauich-Rodríguez, J. V.; Cervantes-Uc, J. M. Synthesis and characterization of pH sensitive hydrogel nanoparticles based on poly(N-isopropyl acrylamide-co-methacrylic acid). J. Mater. Sci.: Mater. Med. 2020, 31 (8), 61,  DOI: 10.1007/s10856-020-06400-x
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    Han, Z.; Wang, P.; Mao, G.; Yin, T.; Zhong, D.; Yiming, B.; Hu, X.; Jia, Z.; Nian, G.; Qu, S.; Yang, W. Dual pH-Responsive Hydrogel Actuator for Lipophilic Drug Delivery. ACS Appl. Mater. Interfaces 2020, 12 (10), 12010– 12017,  DOI: 10.1021/acsami.9b21713
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    Dual pH-Responsive Hydrogel Actuator for Lipophilic Drug Delivery
    Han, Zilong; Wang, Peng; Mao, Guoyong; Yin, Tenghao; Zhong, Danming; Yiming, Burebi; Hu, Xiaocheng; Jia, Zheng; Nian, Guodong; Qu, Shaoxing; Wei, Yangph
    ACS Applied Materials & Interfaces (2020), 12 (10), 12010-12017CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    As one of the most promising drug delivery carriers, hydrogels have received considerable attention in recent years. Many previous efforts have focused on diffusion-controlled release, which allows hydrogels to load and release drugs in vitro and/or in vivo. However, it hardly applies to lipophilic drug delivery due to their poor compatibility with hydrogels. Herein, we propose a novel method for lipophilic drug release based on a dual pH-responsive hydrogel actuator. Specifically, the drug is encapsulated and can be released by a dual pH-controlled capsule switch. Inspired by the deformation mechanism of Drosera leaves, we fabricate the capsule switch with a double-layer structure that is made of two kinds of pH-responsive hydrogels. Two layers are covalently bonded together through silane coupling agents. They can bend collaboratively in a basic or acidic environment to achieve the "turn on" motion of the capsule switch. By incorporating an array of parallel elastomer stripes on one side of the hydrogel bilayer, various motions (e.g., bending, twisting, and rolling) of the hydrogel bilayer actuator were achieved. We conducted an in vitro lipophilic drug release test. The feasibility of this new drug release method is verified. We believe this dual pH-responsive actuator-controlled drug release method may shed light on the possibilities of various drug delivery systems.
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  21. 21
    Zhao, Y.; Shi, C.; Yang, X.; Shen, B.; Sun, Y.; Chen, Y.; Xu, X.; Sun, H.; Yu, K.; Yang, B.; Lin, Q. pH- and Temperature-Sensitive Hydrogel Nanoparticles with Dual Photoluminescence for Bioprobes. ACS Nano 2016, 10 (6), 5856– 5863,  DOI: 10.1021/acsnano.6b00770
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    pH- and Temperature-Sensitive Hydrogel Nanoparticles with Dual Photoluminescence for Bioprobes
    Zhao, Yue; Shi, Ce; Yang, Xudong; Shen, Bowen; Sun, Yuanqing; Chen, Yang; Xu, Xiaowei; Sun, Hongchen; Yu, Kui; Yang, Bai; Lin, Quan
    ACS Nano (2016), 10 (6), 5856-5863CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    This study demonstrates high contrast and sensitivity by designing a dual-emissive hydrogel particle system, whose two emissions respond to pH and temp. strongly and independently. It describes the photoluminescence (PL) response of poly(N-isopropylacrylamide) (PNIPAM)-based core/shell hydrogel nanoparticles with dual emission, which is obtained by emulsion polymn. with potassium persulfate, consisting of the thermo- and pH-responsive copolymers of PNIPAM and poly(acrylic acid) (PAA). A red-emission rare-earth complex and a blue-emission quaternary ammonium tetraphenylethylene deriv. (d-TPE) with similar excitation wavelengths are inserted into the core and shell of the hydrogel nanoparticles, resp. The PL intensities of the nanoparticles exhibit a linear temp. response in the range from 10 to 80 °C with a change as large as a factor of 5. In addn., the blue emission from the shell exhibits a linear pH response between pH 6.5 and 7.6 with a resoln. of 0.1 unit, while the red emission from the core is pH-independent. These stimuli-responsive PL nanoparticles have potential applications in biol. and chem., including bio- and chemosensors, biol. imaging, cancer diagnosis, and externally activated release of anticancer drugs.
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    Sies, H.; Jones, D. P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 2020, 21 (7), 363– 383,  DOI: 10.1038/s41580-020-0230-3
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    Reactive oxygen species (ROS) as pleiotropic physiological signalling agents
    Sies, Helmut; Jones, Dean P.
    Nature Reviews Molecular Cell Biology (2020), 21 (7), 363-383CODEN: NRMCBP; ISSN:1471-0072. (Nature Research)
    Abstr.: 'Reactive oxygen species' (ROS) is an umbrella term for an array of derivs. of mol. oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to mol. damage, denoted as 'oxidative distress'. Here we focus on ROS at physiol. levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiol. levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addn., several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodol. advances permit the assessment of mol. interactions of specific ROS mols. with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiol. and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low mol. mass antioxidant compds. was not successful in counteracting disease initiation and progression in clin. trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymic defense systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradn.).
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    Shields, H. J.; Traa, A.; Van Raamsdonk, J. M. Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies. Front. Cell Dev. Biol. 2021, 9, 628157,  DOI: 10.3389/fcell.2021.628157
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    23
    Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies
    Shields Hazel J; Traa Annika; Van Raamsdonk Jeremy M; Shields Hazel J; Traa Annika; Van Raamsdonk Jeremy M; Shields Hazel J; Traa Annika; Van Raamsdonk Jeremy M; Van Raamsdonk Jeremy M; Van Raamsdonk Jeremy M
    Frontiers in cell and developmental biology (2021), 9 (), 628157 ISSN:2296-634X.
    Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging. To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation. Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan. Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.
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    Xu, Q.; He, C.; Xiao, C.; Chen, X. Reactive Oxygen Species (ROS) Responsive Polymers for Biomedical Applications. Macromol. Biosci. 2016, 16 (5), 635– 646,  DOI: 10.1002/mabi.201500440
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    Reactive Oxygen Species (ROS) Responsive Polymers for Biomedical Applications
    Xu, Qinghua; He, Chaoliang; Xiao, Chunsheng; Chen, Xuesi
    Macromolecular Bioscience (2016), 16 (5), 635-646CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Reactive oxygen species (ROS) play important roles in cell signaling pathways, while increased prodn. of ROS may disrupt cellular homeostasis, giving rise to oxidative stress and a series of diseases. Utilizing these cell-generated species as triggers for selective tuning polymer structures and properties represents a promising methodol. for disease diagnosis and treatment. Recently, significant progress has been made in fabricating biomaterials including nanoparticles and macroscopic networks to interact with this dynamic physiol. condition. These ROS-responsive platforms have shown potential in a range of biomedical applications, such as cancer targeted drug delivery systems, cell therapy platforms for inflammation related disease, and so on.
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    Criado-Gonzalez, M.; Mecerreyes, D. Thioether-based ROS responsive polymers for biomedical applications. J. Mater. Chem. B 2022, 10 (37), 7206– 7221,  DOI: 10.1039/D2TB00615D
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    25
    Thioether-based ROS responsive polymers for biomedical applications
    Criado-Gonzalez, Miryam; Mecerreyes, David
    Journal of Materials Chemistry B: Materials for Biology and Medicine (2022), 10 (37), 7206-7221CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
    A review. Reactive oxygen species (ROS) play a key role in several biol. functions of living organisms such as regulation of cell signalling, prodn. of some hormones, modulation of protein function or mediation of inflammation. In this regard, ROS responsive polymers are ideal candidates for the development of stimuli-responsive biomaterials for target therapies. Among different ROS-responsive polymers, those contg. thioether groups are widely investigated in the biomedical field due to their hydrophobic to hydrophilic phase transition under oxidative conditions. This feature makes them able to self-assemble in aq. solns. forming micellar-type nanoparticles or hydrogels to be mainly used as drug carriers for local therapies in damaged body areas characterized by high ROS prodn. This review article collects the main findings about the synthesis of thioether-based ROS responsive polymers and polypeptides, their self-assembly properties and ROS responsive behavior for use as injectable nanoparticles or hydrogels. Afterward, the foremost applications of the thioether-based ROS responsive nanoparticles and hydrogels in the biomedical field, where cancer therapies are a key objective, will be discussed.
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    Napoli, A.; Valentini, M.; Tirelli, N.; Müller, M.; Hubbell, J. A. Oxidation-responsive polymeric vesicles. Nat. Mater. 2004, 3 (3), 183– 189,  DOI: 10.1038/nmat1081
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    Oxidation-responsive polymeric vesicles
    Napoli, Alessandro; Valentini, Massimiliano; Tirelli, Nicola; Mueller, Martin; Hubbell, Jeffrey A.
    Nature Materials (2004), 3 (3), 183-189CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    ABA block copolymer amphiphiles that self-assemble into unilamellar vesicles that can be further destabilized by oxidn., were prepd. Poly(ethylene glycol) (PEG) was used as the hydrophilic A block, owing to its resistance to protein adsorption and low toxicity. As hydrophobic B blocks, poly(propylene sulfide) (PPS) was used based on extreme hydrophobicity, low glass-transition temp., and most importantly, the ability for oxidative conversion from a hydrophobe to a hydrophile, poly(propylene sulfoxide) and ultimately poly(propylene sulfone). Thus, oxidative conversion is used to destabilize carriers. The oxidn.-responsive polymeric vesicles may find applications as nanocontainers in drug delivery, biosensors, etc.
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    Yan, B.; Zhang, Y.; Wei, C.; Xu, Y. Facile synthesis of ROS-responsive biodegradable main chain poly(carbonate-thioether) copolymers. Polym. Chem. 2018, 9 (7), 904– 911,  DOI: 10.1039/C7PY01908D
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    Facile synthesis of ROS-responsive biodegradable main chain poly(carbonate-thioether) copolymers
    Yan, Bingkun; Zhang, Yan; Wei, Chao; Xu, Yue
    Polymer Chemistry (2018), 9 (7), 904-911CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    Oxidn.-responsive thioether-functional polymers have emerged as potential materials for biomedical applications. Herein, we report the straightforward synthesis of a well-defined biodegradable thioether-contg. polycarbonate (mPEG-b-PS) based on the macrocyclic sulfur-substituted carbonate monomer (MS) using an enzyme-catalyzed ring-opening polymn. with the thioether groups situated on the backbone. NMR, FTIR and GPC techniques were employed to confirm the structure of the copolymers. Moreover, the thioether groups endowed the copolymers with rich ROS responsiveness and the oxidn. mechanism was clarified according to in situ1H-NMR, FTIR and TGA data. In addn., the water contact angles testified that the hydrophilicity of the copolymers was greatly improved during the H2O2 triggered oxidn. process. The thioether oxidn. to polar sulfone and sulfoxide groups enabled us to tailor the copolymer's soly. profile; thus, the size, morphol. and transmittance of the nanostructure changed according to the results obtained using DLS, TEM and UV techniques. Furthermore, CCK-8 assays showed that the thioether-contg. polycarbonate and their oxidized products were non-toxic up to a tested concn. of 250μg mL-1. Moreover, the mPEG-b-PS had a definite H2O2-triggered drug release behavior. Therefore, these results highlight a facile synthesis of biodegradable thioether-contg. polymers and provide a novel ROS responsive material platform for further cancer therapy and inflammation targeting.
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    Regato-Herbella, M.; Morhenn, I.; Mantione, D.; Pascuzzi, G.; Gallastegui, A.; Caribé dos Santos Valle, A. B.; Moya, S. E.; Criado-Gonzalez, M.; Mecerreyes, D. ROS-Responsive 4D Printable Acrylic Thioether-Based Hydrogels for Smart Drug Release. Chem. Mater. 2024, 36 (3), 1262– 1272,  DOI: 10.1021/acs.chemmater.3c02264
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    Liu, J.; Li, Y.; Chen, S.; Lin, Y.; Lai, H.; Chen, B.; Chen, T. Biomedical Application of Reactive Oxygen Species-Responsive Nanocarriers in Cancer, Inflammation, and Neurodegenerative Diseases. Front. Chem. 2020, 8, 838,  DOI: 10.3389/fchem.2020.00838
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    Biomedical application of reactive oxygen species-responsive nanocarriers in cancer, inflammation, and neurodegenerative diseases
    Liu, Jinggong; Li, Yongjin; Chen, Song; Lin, Yongpeng; Lai, Haoqiang; Chen, Bolai; Chen, Tianfeng
    Frontiers in Chemistry (Lausanne, Switzerland) (2020), 8 (), 838CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
    A review. Numerous pathol. conditions, including cancer, inflammatory diseases, and neurodegenerative diseases, are accompanied by overprodn. of reactive oxygen species (ROS). This makes ROS vital flagging mols. in disease pathol. ROS-responsive drug delivery platforms have been developed. Nanotechnol. has been broadly applied in the field of biomedicine leading to the progress of ROS-responsive nanoparticles. In this review, we focused on the prodn. and physiol./pathophysiol. impact of ROS. Particular emphasis is put on the mechanisms and effects of abnormal ROS levels on oxidative stress diseases, including cancer, inflammatory disease, and neurodegenerative diseases. Finally, we summarized the potential biomedical applications of ROS-responsive nanocarriers in these oxidative stress diseases. We provide insights that will help in the designing of new ROS-responsive nanocarriers for various applications.
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    Zhang, R.; Liu, R.; Liu, C.; Pan, L.; Qi, Y.; Cheng, J.; Guo, J.; Jia, Y.; Ding, J.; Zhang, J.; Hu, H. A pH/ROS dual-responsive and targeting nanotherapy for vascular inflammatory diseases. Biomaterials 2020, 230, 119605,  DOI: 10.1016/j.biomaterials.2019.119605
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    A pH/ROS dual-responsive and targeting nanotherapy for vascular inflammatory diseases
    Zhang, Runjun; Liu, Renfeng; Liu, Chao; Pan, Lina; Qi, Yuantong; Cheng, Juan; Guo, Jiawei; Jia, Yi; Ding, Jun; Zhang, Jianxiang; Hu, Houyuan
    Biomaterials (2020), 230 (), 119605CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Vascular inflammation is closely related to the pathogenesis of a diverse group of CVDs. Currently, it remains a great challenge to achieve site-specific delivery and controlled release of therapeutics at vascular inflammatory sites. Herein we hypothesize that active targeting nanoparticles (NPs) simultaneously responsive to low pH and high levels of reactive oxygen species (ROS) can serve as an effective nanoplatform for precision delivery of therapeutic cargoes to the sites of vascular inflammation, in view of acidosis and oxidative stress at inflamed sites. The pH/ROS dual-responsive NPs were constructed by combination of a pH-sensitive material (ACD) and an oxidn.-responsive material (OCD) that can be facilely synthesized by chem. functionalization of β-cyclodextrin, a cyclic oligosaccharide. Simply by regulating the wt. ratio of ACD and OCD, the pH/ROS responsive capacity can be easily modulated, affording NPs with varied hydrolysis profiles under inflammatory microenvironment. Using rapamycin (RAP) as a candidate drug, we first demonstrated in vitro therapeutic advantages of RAP-contg. NPs with optimal dual-responsive capability, i.e. RAP/AOCD NP, and a non-responsive nanotherapy (RAP/PLGA NP) and two single-responsive nanotherapies (RAP/ACD NP and RAP/OCD NP) were used as controls. In an animal model of vascular inflammation in rats subjected to balloon injury in carotid arteries, AOCD NP could accumulate at the diseased site after i.v. injection. Consistently, i. v. treatment with RAP/AOCD NP more effectively inhibited neointimal hyperplasia in rats with induced arterial injuries, compared to RAP/PLGA NP, RAP/ACD NP, and RAP/OCD NP. By surface decoration of AOCD NP with a peptide (KLWVLPKGGGC) targeting type IV collagen (Col-IV), the obtained Col-IV targeting, dual-responsive nanocarrier TAOCD NP showed dramatically increased accumulation at injured carotid arteries. Furthermore, RAP/TAOCD NP exhibited significantly potentiated in vivo efficacy in comparison to the passive targeting nanotherapy RAP/AOCD NP. Importantly, in vitro cell culture expts. and in vivo animal studies in both mice and rats revealed good safety for AOCD NP and RAP/AOCD NP, even after long-term treatment via i. v. injection. Consequently, our results demonstrated that the newly developed Col-IV targeting, pH/ROS dual-responsive NPs may serve as an effective and safe nanovehicle for precision therapy of arterial restenosis and other vascular inflammatory diseases.
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    Pardeshi, P. M.; Mungray, A. A. Photo-polymerization as a new approach to fabricate the active layer of forward osmosis membrane. Sci. Rep. 2019, 9 (1), 1937,  DOI: 10.1038/s41598-018-36346-8
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    Khan, A. Q.; Agha, M. V.; Sheikhan, K. S. A. M.; Younis, S. M.; Tamimi, M. A.; Alam, M.; Ahmad, A.; Uddin, S.; Buddenkotte, J.; Steinhoff, M. Targeting deregulated oxidative stress in skin inflammatory diseases: An update on clinical importance. Biomed. Pharmacother. 2022, 154, 113601,  DOI: 10.1016/j.biopha.2022.113601
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    Mescher, A. L. Macrophages and fibroblasts during inflammation and tissue repair in models of organ regeneration. Regeneration 2017, 4 (2), 39– 53,  DOI: 10.1002/reg2.77
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    Buechler, M. B.; Fu, W.; Turley, S. J. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity 2021, 54 (5), 903– 915,  DOI: 10.1016/j.immuni.2021.04.021
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    Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer
    Buechler, Matthew B.; Fu, Wenxian; Turley, Shannon J.
    Immunity (2021), 54 (5), 903-915CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)
    A review. Fibroblasts and macrophages are present in all tissues, and mounting evidence supports that these cells engage in direct communication to influence the overall tissue microenvironment and affect disease outcomes. Here, we review the current understanding of the mol. mechanisms that underlie fibroblast-macrophage interactions in health, fibrosis, and cancer. We present an integrated view of fibroblast-macrophage interactions that is centered on the CSF1-CSF1R axis and discuss how addnl. mol. programs linking these cell types can underpin disease onset, progression, and resoln. These programs may be tissue and context dependent, affected also by macrophage and fibroblast origin and state, as seen most clearly in cancer. Continued efforts to understand these cells and the means by which they interact may provide therapeutic approaches for the treatment of fibrosis and cancer.
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    Witherel, C. E.; Abebayehu, D.; Barker, T. H.; Spiller, K. L. Macrophage and Fibroblast Interactions in Biomaterial-Mediated Fibrosis. Adv. Healthc. Mater. 2019, 8 (4), 1801451,  DOI: 10.1002/adhm.201801451
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    Criado-Gonzalez, M.; Espinosa-Cano, E.; Rojo, L.; Boulmedais, F.; Aguilar, M. R.; Hernández, R. Injectable Tripeptide/Polymer Nanoparticles Supramolecular Hydrogel: A Candidate for the Treatment of Inflammatory Pathologies. ACS Appl. Mater. Interfaces 2022, 14 (8), 10068– 10080,  DOI: 10.1021/acsami.1c22993
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  • Abstract

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    Figure 1

    Figure 1. (a) Chemical route employed for the synthesis of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels by UV light at 365 nm for 3–5 min and using Darocur as a photoinitiator. (b) Pictures of the synthesized hydrogels with different monomer ratios.

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    Figure 2

    Figure 2. (a) Schematic representation of the swelling/shrinking behavior of each monomer within the P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels in response to external stimuli, temperature, pH, and/or ROS. (b) Swelling of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels at different pHs immersed in (b) PBS at 25 °C, (c) PBS at 37 °C, (d) 9 mM H2O2 at 25 °C, and (e) 9 mM H2O2 at 37 °C, for 24 h. Diagrams (b)–(e) include the mean and standard deviation (n = 3) and the ANOVA results. Different letters indicate statistically significant differences at a significance level of p < 0.05 using Tukey’s test. Bars with no common letters are significantly different (p < 0.05). (f) Representative pictures of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels after 24 h at different temperatures, pHs, and under nonoxidant (PBS) or oxidant (H2O2) conditions. Scale bars = 5 mm. (g) Swelling comparison of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels at different temperatures (25 and 37 °C) and pHs (3, 5, 7.4 and 11), in Phosphate Buffer Solution (PBS) or H2O2.

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    Figure 3

    Figure 3. (a) Schematic representation of the ketoprofen (KET) release from P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels under different conditions of temperature, pH, and ROS. (b) Release of KET from P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels under nonoxidative conditions in PBS, and oxidative conditions in the presence of 9 mM H2O2, at 25 or 37 °C, and pH 5, 7.4, or 11 for 24 and 72 h. Diagrams include the mean and standard deviation (n = 3) and the ANOVA results. Different letters indicate statistically significant differences at a significance level of p < 0.05 using Tukey’s test. Bars with no common letters are significantly different (p < 0.05).

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    Figure 4

    Figure 4. (a) Photorheological properties to determine the gel point (G′ > G′′) when the inks are irradiated for 10–20 s (from 60 s), leading to P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels. (b) Schematic representation of the DLP process employed to print the hydrogels (left), and shape-defined 4D-printed P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogel scaffolds with pores (right). Rheological properties of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels in the presence of different stimuli: (c) PBS, pH 7.4, 37 °C, (d) H2O2, pH 7.4, 37 °C, and (e) H2O2, pH 5, 37 °C.

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    Figure 5

    Figure 5. In vitro cytotoxicity tests of nonloaded and KET-loaded P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels in contact with (a) NIH 3T3 and (b) RAW cells for 24 and 48 h. (c) NIH 3T3 cell adhesion on (c) P[NIPAM90-co-MAA10] and (d) P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels. (e) Nitric oxide (NO) released by LPS-RAW cells seeded on the plate (ICU), non-LPS-RAW cells seeded on the plate (NIC), and LPS-RAW cells seeded on the hydrogels. Diagrams (a), (b), and (e) include the mean and standard deviation (n = 3) and the ANOVA results at significance levels of *p < 0.05 and ***p < 0.001 using Tukey’s test (ns means nonstatistically significant differences). (f) Schematic representation of the inflammatory process induced by the activation of RAW cells, growth on top of the hydrogels, with LPS leading to ROS production, and the anti-inflammatory properties of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels, which trapped ROS due to the oxidative capacity of the (EG3SA) block.

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      Spiegel, Christoph A.; Hackner, Maximilian; Bothe, Viktoria P.; Spatz, Joachim P.; Blasco, Eva
      Advanced Functional Materials (2022), 32 (51), 2110580CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A novel and versatile shape memory ink system allowing 4D printing with light at the macroscale as well as the microscale is presented. Digital light processing (DLP) and direct laser writing (DLW) are selected as suitable 3D printing technologies to cover both regimes. First, a system based on monofunctional isobornyl acrylate and two crosslinkers consisting of a soft and a hard diacrylate is identified and proven to be compatible with both printing techniques. Employing DLP, a large variety of structures exhibiting distinct complexity is printed. These structures range from simple frames to more demanding 3D geometries such as double platform structures, infinity rings, or cubic grids. The shape memory effect is demonstrated for all the 3D geometries. Excellent shape fixity as well as recovery and repeatability is shown. Furthermore, the formulation is adapted for fast 4D printing at the microscale using DLW. Importantly, the 4D printed microstructures display remarkable shape memory properties. The possibility of trapping and releasing microobjects, such as microspheres, is ultimately demonstrated by designing, smart box-like 4D microstructures that can be thermally actuated-evidencing the versatility and potential of the reported system.
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    12. 12
      Matsumoto, N. M.; Buchman, G. W.; Rome, L. H.; Maynard, H. D. Dual pH- and temperature-responsive protein nanoparticles. Eur. Polym. J. 2015, 69, 532– 539,  DOI: 10.1016/j.eurpolymj.2015.01.043
      12
      Dual pH- and temperature-responsive protein nanoparticles
      Matsumoto, Nicholas M.; Buchman, George W.; Rome, Leonard H.; Maynard, Heather D.
      European Polymer Journal (2015), 69 (), 532-539CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)
      Multiply responsive protein nanoparticles are interesting for a variety of applications. Herein, we describe the synthesis of a vault nanoparticle that responds to both temp. and pH. Specifically, poly(N-isopropylacrylamide-co-acrylic acid) with a pyridyl disulfide end group was prepd. by reversible addn.-fragmentation chain transfer (RAFT) polymn. The polymer had a lower crit. soln. temp. (LCST) of 31.9 °C at pH 5, 44.0 °C at pH 6 and above 60 °C at pH 7. The polymer was conjugated to human major vault protein (hMVP), and the resulting nanoparticle was analyzed by UV-Vis, dynamic light scattering (DLS) and electron microscopy. The data demonstrated that the poly(N-isopropylacrylamide-co-acrylic acid)-vault conjugate did not respond to temps. below 60 °C at pH 7, while the nanoparticles reversibly aggregated at pH 6. Furthermore, it was shown that the vault nanoparticle structure remained intact for at least three heat and cooling cycles. Thus, these dually responsive nanoparticles may serve as a platform for drug delivery and other applications.
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    13. 13
      Gao, Y.; Wei, M.; Li, X.; Xu, W.; Ahiabu, A.; Perdiz, J.; Liu, Z.; Serpe, M. J. Stimuli-responsive polymers: Fundamental considerations and applications. Macromol. Res. 2017, 25 (6), 513– 527,  DOI: 10.1007/s13233-017-5088-7
      13
      Stimuli-responsive polymers: Fundamental considerations and applications
      Gao, Yongfeng; Wei, Menglian; Li, Xue; Xu, Wenwen; Ahiabu, Andrews; Perdiz, Juliana; Liu, Zining; Serpe, Michael J.
      Macromolecular Research (2017), 25 (6), 513-527CODEN: MRAECT; ISSN:1598-5032. (Polymer Society of Korea)
      Stimuli-responsive polymers are capable of changing their chem. and/or phys. properties in response to environmental stimuli. This unique feature has allowed stimuli-responsive polymers to be used in a variety of applications. In this review, we present a basic introduction to the theories that have been developed to describe polymer chains, brushes, and networks. We then detail numerous examples of how stimuli-responsive polymers can be used for sensing and biosensing, drug delivery, and as artificial muscles. While we focus the review on these particular areas, there are numerous other demonstrations of the applications of these fascinating materials, and we are certain that many applications have yet to be discovered. [Figure not available: see fulltext.].
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    14. 14
      Reineke, T. M. Stimuli-Responsive Polymers for Biological Detection and Delivery. ACS Macro Lett. 2016, 5 (1), 14– 18,  DOI: 10.1021/acsmacrolett.5b00862
      14
      Stimuli-Responsive Polymers for Biological Detection and Delivery
      Reineke, Theresa M.
      ACS Macro Letters (2016), 5 (1), 14-18CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
      A review. Responsive polymers with properties designed to interact with their surrounding environment are enabling "smart" design features for custom biomaterials. Numerous applications are being innovated, ranging from diagnostics and imaging to tissue engineering and drug delivery. Herein, I feature a collection of research articles published in ACS Macro Letters that highlight an array of innovative chem. attributes such as pH-triggered hydrolytic degrdn., redn.-based release, photomodulation, glucose responsiveness, thermal sensitivity, and membrane permeating peptides. The chem., phys., mech., and morphol. properties of polymeric structures can be custom tailored to enhance numerous features such as biol. delivery, pharmaceutical potency and safety, disease diagnosis, and antigen/biomarker detection.
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    15. 15
      Beck, J. B.; Rowan, S. J. Multistimuli, Multiresponsive Metallo-Supramolecular Polymers. J. Am. Chem. Soc. 2003, 125 (46), 13922– 13923,  DOI: 10.1021/ja038521k
      15
      Multistimuli, Multiresponsive Metallo-Supramolecular Polymers
      Beck, J. Benjamin; Rowan, Stuart J.
      Journal of the American Chemical Society (2003), 125 (46), 13922-13923CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The use of metal ion-induced polymns. of a ditopic ligand offers a facile route to the prepn. of org./inorg. hybrid materials. Such metallo-supramol. polymers potentially offer the functionality of the metal ion along with the processibility of a polymer. The authors report, herein, the prepn. of gellike metallo-supramol. polymers prepd. from a monomer unit, which consists of a 2,6-bis-(benzimidazolyl)-4-hydroxypyridine unit attached to either end of a polyether chain, mixed with a transition metal ion (e.g., Co(II) or Zn(II)) and a small percentage of a lanthanoid metal (e.g., La(III), Eu(III)). Such materials show dramatic reversible responses to a variety of stimuli, including thermal, mech., chemo, and photo. The nature of the response can be controlled by the nature of the combination of transition metal ion and lanthanide metal ion used.
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    16. 16
      Cudjoe, E.; Khani, S.; Way, A. E.; Hore, M. J. A.; Maia, J.; Rowan, S. J. Biomimetic Reversible Heat-Stiffening Polymer Nanocomposites. ACS Cent. Sci. 2017, 3 (8), 886– 894,  DOI: 10.1021/acscentsci.7b00215
      16
      Biomimetic Reversible Heat-Stiffening Polymer Nanocomposites
      Cudjoe, Elvis; Khani, Shaghayegh; Way, Amanda E.; Hore, Michael J. A.; Maia, Joao; Rowan, Stuart J.
      ACS Central Science (2017), 3 (8), 886-894CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      Inspired by the ability of the sea cucumber to (reversibly) increase the stiffness of its dermis upon exposure to a stimulus, we herein report a stimuli-responsive nanocomposite that can reversibly increase its stiffness upon exposure to warm water. Nanocomposites comprised of cellulose nanocrystals (CNCs) that are grafted with a lower crit. soln. temp. (LCST) polymer embedded within a poly(vinyl acetate) (PVAc) matrix show a dramatic increase in modulus, for example, from 1 to 350 MPa upon exposure to warm water. The hypothesis being that grafting the polymers from the CNCs disrupts the interactions between the nanofibers and minimizes the mech. reinforcement of the film. However, exposure to water above the LCST leads to the collapse of the polymer chains and subsequent stiffening of the nanocomposite as a result of the enhanced CNC interactions. Backing up this hypothesis are Energy Conserving Dissipative Particle Dynamics (EDPD) simulations which show that the attractive interactions between CNCs are switched on upon the temp.-induced collapse of the grafted polymer chains, resulting in the formation of a percolating reinforcing network.
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    17. 17
      Robinson, D. N.; Peppas, N. A. Preparation and Characterization of pH-Responsive Poly(methacrylic acid-g-ethylene glycol) Nanospheres. Macromolecules 2002, 35 (9), 3668– 3674,  DOI: 10.1021/ma011525u
      17
      Preparation and Characterization of pH-Responsive Poly(methacrylic acid-g-ethylene glycol) Nanospheres
      Robinson, Daphne N.; Peppas, Nicholas A.
      Macromolecules (2002), 35 (9), 3668-3674CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Poly(methacrylic acid-g-ethylene glycol) (P(MAA-g-EG)) has been studied extensively in this lab. due to its extremely promising applications in the biomedical and pharmaceutical fields. It exhibits pH-responsive interpolymer complexes that make it a promising candidate as an oral carrier for peptide and protein drugs. We developed a photoinitiated free-radical pptn. polymn. method to produce P(MAA-g-EG) nanospheres with relatively narrow size distributions. The effect of various reaction parameters, such as total monomer concn. in water, comonomer molar feed ratios, crosslinking agent concn., and polymn. time, on the particle size and size distribution was investigated. P(MAA-g-EG) nanospheres with a relatively narrow size distribution could be produced in the size range 150-650 nm depending on the monomer concn. and comonomer molar feed ratio. The P(MAA-g-EG) nanospheres exhibited a pH-responsive swelling behavior. Increasing the concn. of the crosslinking agent during polymn. produced P(MAA-g-EG) nanospheres that swelled to a lesser degree. The morphol. of the P(MAA-g-EG) nanospheres was investigated by cryogenic SEM.
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    18. 18
      Gao, X.; Cao, Y.; Song, X.; Zhang, Z.; Xiao, C.; He, C.; Chen, X. pH- and thermo-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) copolymers and hydrogels with LCST dependent on pH and alkyl side groups. J. Mater. Chem. B 2013, 1 (41), 5578– 5587,  DOI: 10.1039/c3tb20901f
      18
      pH- and thermo-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) copolymers and hydrogels with LCST dependent on pH and alkyl side groups
      Gao, Xiaoye; Cao, Yue; Song, Xiangfu; Zhang, Zhe; Xiao, Chunsheng; He, Chaoliang; Chen, Xuesi
      Journal of Materials Chemistry B: Materials for Biology and Medicine (2013), 1 (41), 5578-5587CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
      A series of pH- and temp.-responsive poly(N-isopropylacrylamide-co-acrylic acid deriv.) (P(NIPAM-co-AAD)) copolymers and hydrogels were prepd. The lower crit. soln. temps. (LCSTs) of the copolymers exhibited a dependence on both pH and the hydrophobicity of the AAD unit. The influence of pH and temp. on the equil. swelling ratio of the hydrogels was investigated. The hydrogels displayed a unique thermo-induced swelling-deswelling transition that can be self-regulated to occur at above or below the physiol. temp. in response to the environmental pH. Scanning electron microscopic (SEM) anal. revealed porous sponge-like microstructures of the hydrogels. Insulin was loaded into the hydrogels as a model protein, and the in vitro release profiles indicated that the loaded protein could be protected within the hydrogels in an acidic environment and selectively released in neutral medium. MTT assay proved that both the copolymers and hydrogels are nontoxic. After oral administration of the insulin-loaded hydrogels to streptozotocin-induced diabetic rats at 60 IU per kg, the fasting plasma glucose level was reduced continuously to 72.1% within 6 h. The bioavailability of hydrogel-encapsulated insulin via the oral administration to healthy rabbits reached 5.24%, which is much higher than that of pure insulin soln. given orally. These results showed that the smart copolymers and hydrogels may hold great promise for pH-triggered drug delivery systems.
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    19. 19
      Belman-Flores, C. E.; Herrera-Kao, W.; Vargas-Coronado, R. F.; May-Pat, A.; Oliva, A. I.; Rodríguez-Fuentes, N.; Vázquez-Torres, H.; Cauich-Rodríguez, J. V.; Cervantes-Uc, J. M. Synthesis and characterization of pH sensitive hydrogel nanoparticles based on poly(N-isopropyl acrylamide-co-methacrylic acid). J. Mater. Sci.: Mater. Med. 2020, 31 (8), 61,  DOI: 10.1007/s10856-020-06400-x
      There is no corresponding record for this reference.
    20. 20
      Han, Z.; Wang, P.; Mao, G.; Yin, T.; Zhong, D.; Yiming, B.; Hu, X.; Jia, Z.; Nian, G.; Qu, S.; Yang, W. Dual pH-Responsive Hydrogel Actuator for Lipophilic Drug Delivery. ACS Appl. Mater. Interfaces 2020, 12 (10), 12010– 12017,  DOI: 10.1021/acsami.9b21713
      20
      Dual pH-Responsive Hydrogel Actuator for Lipophilic Drug Delivery
      Han, Zilong; Wang, Peng; Mao, Guoyong; Yin, Tenghao; Zhong, Danming; Yiming, Burebi; Hu, Xiaocheng; Jia, Zheng; Nian, Guodong; Qu, Shaoxing; Wei, Yangph
      ACS Applied Materials & Interfaces (2020), 12 (10), 12010-12017CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      As one of the most promising drug delivery carriers, hydrogels have received considerable attention in recent years. Many previous efforts have focused on diffusion-controlled release, which allows hydrogels to load and release drugs in vitro and/or in vivo. However, it hardly applies to lipophilic drug delivery due to their poor compatibility with hydrogels. Herein, we propose a novel method for lipophilic drug release based on a dual pH-responsive hydrogel actuator. Specifically, the drug is encapsulated and can be released by a dual pH-controlled capsule switch. Inspired by the deformation mechanism of Drosera leaves, we fabricate the capsule switch with a double-layer structure that is made of two kinds of pH-responsive hydrogels. Two layers are covalently bonded together through silane coupling agents. They can bend collaboratively in a basic or acidic environment to achieve the "turn on" motion of the capsule switch. By incorporating an array of parallel elastomer stripes on one side of the hydrogel bilayer, various motions (e.g., bending, twisting, and rolling) of the hydrogel bilayer actuator were achieved. We conducted an in vitro lipophilic drug release test. The feasibility of this new drug release method is verified. We believe this dual pH-responsive actuator-controlled drug release method may shed light on the possibilities of various drug delivery systems.
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    21. 21
      Zhao, Y.; Shi, C.; Yang, X.; Shen, B.; Sun, Y.; Chen, Y.; Xu, X.; Sun, H.; Yu, K.; Yang, B.; Lin, Q. pH- and Temperature-Sensitive Hydrogel Nanoparticles with Dual Photoluminescence for Bioprobes. ACS Nano 2016, 10 (6), 5856– 5863,  DOI: 10.1021/acsnano.6b00770
      21
      pH- and Temperature-Sensitive Hydrogel Nanoparticles with Dual Photoluminescence for Bioprobes
      Zhao, Yue; Shi, Ce; Yang, Xudong; Shen, Bowen; Sun, Yuanqing; Chen, Yang; Xu, Xiaowei; Sun, Hongchen; Yu, Kui; Yang, Bai; Lin, Quan
      ACS Nano (2016), 10 (6), 5856-5863CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      This study demonstrates high contrast and sensitivity by designing a dual-emissive hydrogel particle system, whose two emissions respond to pH and temp. strongly and independently. It describes the photoluminescence (PL) response of poly(N-isopropylacrylamide) (PNIPAM)-based core/shell hydrogel nanoparticles with dual emission, which is obtained by emulsion polymn. with potassium persulfate, consisting of the thermo- and pH-responsive copolymers of PNIPAM and poly(acrylic acid) (PAA). A red-emission rare-earth complex and a blue-emission quaternary ammonium tetraphenylethylene deriv. (d-TPE) with similar excitation wavelengths are inserted into the core and shell of the hydrogel nanoparticles, resp. The PL intensities of the nanoparticles exhibit a linear temp. response in the range from 10 to 80 °C with a change as large as a factor of 5. In addn., the blue emission from the shell exhibits a linear pH response between pH 6.5 and 7.6 with a resoln. of 0.1 unit, while the red emission from the core is pH-independent. These stimuli-responsive PL nanoparticles have potential applications in biol. and chem., including bio- and chemosensors, biol. imaging, cancer diagnosis, and externally activated release of anticancer drugs.
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    22. 22
      Sies, H.; Jones, D. P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 2020, 21 (7), 363– 383,  DOI: 10.1038/s41580-020-0230-3
      22
      Reactive oxygen species (ROS) as pleiotropic physiological signalling agents
      Sies, Helmut; Jones, Dean P.
      Nature Reviews Molecular Cell Biology (2020), 21 (7), 363-383CODEN: NRMCBP; ISSN:1471-0072. (Nature Research)
      Abstr.: 'Reactive oxygen species' (ROS) is an umbrella term for an array of derivs. of mol. oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to mol. damage, denoted as 'oxidative distress'. Here we focus on ROS at physiol. levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiol. levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addn., several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodol. advances permit the assessment of mol. interactions of specific ROS mols. with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiol. and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low mol. mass antioxidant compds. was not successful in counteracting disease initiation and progression in clin. trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymic defense systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradn.).
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    23. 23
      Shields, H. J.; Traa, A.; Van Raamsdonk, J. M. Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies. Front. Cell Dev. Biol. 2021, 9, 628157,  DOI: 10.3389/fcell.2021.628157
      23
      Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies
      Shields Hazel J; Traa Annika; Van Raamsdonk Jeremy M; Shields Hazel J; Traa Annika; Van Raamsdonk Jeremy M; Shields Hazel J; Traa Annika; Van Raamsdonk Jeremy M; Van Raamsdonk Jeremy M; Van Raamsdonk Jeremy M
      Frontiers in cell and developmental biology (2021), 9 (), 628157 ISSN:2296-634X.
      Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging. To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation. Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan. Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.
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    24. 24
      Xu, Q.; He, C.; Xiao, C.; Chen, X. Reactive Oxygen Species (ROS) Responsive Polymers for Biomedical Applications. Macromol. Biosci. 2016, 16 (5), 635– 646,  DOI: 10.1002/mabi.201500440
      24
      Reactive Oxygen Species (ROS) Responsive Polymers for Biomedical Applications
      Xu, Qinghua; He, Chaoliang; Xiao, Chunsheng; Chen, Xuesi
      Macromolecular Bioscience (2016), 16 (5), 635-646CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Reactive oxygen species (ROS) play important roles in cell signaling pathways, while increased prodn. of ROS may disrupt cellular homeostasis, giving rise to oxidative stress and a series of diseases. Utilizing these cell-generated species as triggers for selective tuning polymer structures and properties represents a promising methodol. for disease diagnosis and treatment. Recently, significant progress has been made in fabricating biomaterials including nanoparticles and macroscopic networks to interact with this dynamic physiol. condition. These ROS-responsive platforms have shown potential in a range of biomedical applications, such as cancer targeted drug delivery systems, cell therapy platforms for inflammation related disease, and so on.
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    25. 25
      Criado-Gonzalez, M.; Mecerreyes, D. Thioether-based ROS responsive polymers for biomedical applications. J. Mater. Chem. B 2022, 10 (37), 7206– 7221,  DOI: 10.1039/D2TB00615D
      25
      Thioether-based ROS responsive polymers for biomedical applications
      Criado-Gonzalez, Miryam; Mecerreyes, David
      Journal of Materials Chemistry B: Materials for Biology and Medicine (2022), 10 (37), 7206-7221CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
      A review. Reactive oxygen species (ROS) play a key role in several biol. functions of living organisms such as regulation of cell signalling, prodn. of some hormones, modulation of protein function or mediation of inflammation. In this regard, ROS responsive polymers are ideal candidates for the development of stimuli-responsive biomaterials for target therapies. Among different ROS-responsive polymers, those contg. thioether groups are widely investigated in the biomedical field due to their hydrophobic to hydrophilic phase transition under oxidative conditions. This feature makes them able to self-assemble in aq. solns. forming micellar-type nanoparticles or hydrogels to be mainly used as drug carriers for local therapies in damaged body areas characterized by high ROS prodn. This review article collects the main findings about the synthesis of thioether-based ROS responsive polymers and polypeptides, their self-assembly properties and ROS responsive behavior for use as injectable nanoparticles or hydrogels. Afterward, the foremost applications of the thioether-based ROS responsive nanoparticles and hydrogels in the biomedical field, where cancer therapies are a key objective, will be discussed.
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    26. 26
      Napoli, A.; Valentini, M.; Tirelli, N.; Müller, M.; Hubbell, J. A. Oxidation-responsive polymeric vesicles. Nat. Mater. 2004, 3 (3), 183– 189,  DOI: 10.1038/nmat1081
      26
      Oxidation-responsive polymeric vesicles
      Napoli, Alessandro; Valentini, Massimiliano; Tirelli, Nicola; Mueller, Martin; Hubbell, Jeffrey A.
      Nature Materials (2004), 3 (3), 183-189CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      ABA block copolymer amphiphiles that self-assemble into unilamellar vesicles that can be further destabilized by oxidn., were prepd. Poly(ethylene glycol) (PEG) was used as the hydrophilic A block, owing to its resistance to protein adsorption and low toxicity. As hydrophobic B blocks, poly(propylene sulfide) (PPS) was used based on extreme hydrophobicity, low glass-transition temp., and most importantly, the ability for oxidative conversion from a hydrophobe to a hydrophile, poly(propylene sulfoxide) and ultimately poly(propylene sulfone). Thus, oxidative conversion is used to destabilize carriers. The oxidn.-responsive polymeric vesicles may find applications as nanocontainers in drug delivery, biosensors, etc.
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    27. 27
      Yan, B.; Zhang, Y.; Wei, C.; Xu, Y. Facile synthesis of ROS-responsive biodegradable main chain poly(carbonate-thioether) copolymers. Polym. Chem. 2018, 9 (7), 904– 911,  DOI: 10.1039/C7PY01908D
      27
      Facile synthesis of ROS-responsive biodegradable main chain poly(carbonate-thioether) copolymers
      Yan, Bingkun; Zhang, Yan; Wei, Chao; Xu, Yue
      Polymer Chemistry (2018), 9 (7), 904-911CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      Oxidn.-responsive thioether-functional polymers have emerged as potential materials for biomedical applications. Herein, we report the straightforward synthesis of a well-defined biodegradable thioether-contg. polycarbonate (mPEG-b-PS) based on the macrocyclic sulfur-substituted carbonate monomer (MS) using an enzyme-catalyzed ring-opening polymn. with the thioether groups situated on the backbone. NMR, FTIR and GPC techniques were employed to confirm the structure of the copolymers. Moreover, the thioether groups endowed the copolymers with rich ROS responsiveness and the oxidn. mechanism was clarified according to in situ1H-NMR, FTIR and TGA data. In addn., the water contact angles testified that the hydrophilicity of the copolymers was greatly improved during the H2O2 triggered oxidn. process. The thioether oxidn. to polar sulfone and sulfoxide groups enabled us to tailor the copolymer's soly. profile; thus, the size, morphol. and transmittance of the nanostructure changed according to the results obtained using DLS, TEM and UV techniques. Furthermore, CCK-8 assays showed that the thioether-contg. polycarbonate and their oxidized products were non-toxic up to a tested concn. of 250μg mL-1. Moreover, the mPEG-b-PS had a definite H2O2-triggered drug release behavior. Therefore, these results highlight a facile synthesis of biodegradable thioether-contg. polymers and provide a novel ROS responsive material platform for further cancer therapy and inflammation targeting.
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    28. 28
      Regato-Herbella, M.; Morhenn, I.; Mantione, D.; Pascuzzi, G.; Gallastegui, A.; Caribé dos Santos Valle, A. B.; Moya, S. E.; Criado-Gonzalez, M.; Mecerreyes, D. ROS-Responsive 4D Printable Acrylic Thioether-Based Hydrogels for Smart Drug Release. Chem. Mater. 2024, 36 (3), 1262– 1272,  DOI: 10.1021/acs.chemmater.3c02264
      There is no corresponding record for this reference.
    29. 29
      Liu, J.; Li, Y.; Chen, S.; Lin, Y.; Lai, H.; Chen, B.; Chen, T. Biomedical Application of Reactive Oxygen Species-Responsive Nanocarriers in Cancer, Inflammation, and Neurodegenerative Diseases. Front. Chem. 2020, 8, 838,  DOI: 10.3389/fchem.2020.00838
      29
      Biomedical application of reactive oxygen species-responsive nanocarriers in cancer, inflammation, and neurodegenerative diseases
      Liu, Jinggong; Li, Yongjin; Chen, Song; Lin, Yongpeng; Lai, Haoqiang; Chen, Bolai; Chen, Tianfeng
      Frontiers in Chemistry (Lausanne, Switzerland) (2020), 8 (), 838CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
      A review. Numerous pathol. conditions, including cancer, inflammatory diseases, and neurodegenerative diseases, are accompanied by overprodn. of reactive oxygen species (ROS). This makes ROS vital flagging mols. in disease pathol. ROS-responsive drug delivery platforms have been developed. Nanotechnol. has been broadly applied in the field of biomedicine leading to the progress of ROS-responsive nanoparticles. In this review, we focused on the prodn. and physiol./pathophysiol. impact of ROS. Particular emphasis is put on the mechanisms and effects of abnormal ROS levels on oxidative stress diseases, including cancer, inflammatory disease, and neurodegenerative diseases. Finally, we summarized the potential biomedical applications of ROS-responsive nanocarriers in these oxidative stress diseases. We provide insights that will help in the designing of new ROS-responsive nanocarriers for various applications.
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    30. 30
      Zhang, R.; Liu, R.; Liu, C.; Pan, L.; Qi, Y.; Cheng, J.; Guo, J.; Jia, Y.; Ding, J.; Zhang, J.; Hu, H. A pH/ROS dual-responsive and targeting nanotherapy for vascular inflammatory diseases. Biomaterials 2020, 230, 119605,  DOI: 10.1016/j.biomaterials.2019.119605
      30
      A pH/ROS dual-responsive and targeting nanotherapy for vascular inflammatory diseases
      Zhang, Runjun; Liu, Renfeng; Liu, Chao; Pan, Lina; Qi, Yuantong; Cheng, Juan; Guo, Jiawei; Jia, Yi; Ding, Jun; Zhang, Jianxiang; Hu, Houyuan
      Biomaterials (2020), 230 (), 119605CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Vascular inflammation is closely related to the pathogenesis of a diverse group of CVDs. Currently, it remains a great challenge to achieve site-specific delivery and controlled release of therapeutics at vascular inflammatory sites. Herein we hypothesize that active targeting nanoparticles (NPs) simultaneously responsive to low pH and high levels of reactive oxygen species (ROS) can serve as an effective nanoplatform for precision delivery of therapeutic cargoes to the sites of vascular inflammation, in view of acidosis and oxidative stress at inflamed sites. The pH/ROS dual-responsive NPs were constructed by combination of a pH-sensitive material (ACD) and an oxidn.-responsive material (OCD) that can be facilely synthesized by chem. functionalization of β-cyclodextrin, a cyclic oligosaccharide. Simply by regulating the wt. ratio of ACD and OCD, the pH/ROS responsive capacity can be easily modulated, affording NPs with varied hydrolysis profiles under inflammatory microenvironment. Using rapamycin (RAP) as a candidate drug, we first demonstrated in vitro therapeutic advantages of RAP-contg. NPs with optimal dual-responsive capability, i.e. RAP/AOCD NP, and a non-responsive nanotherapy (RAP/PLGA NP) and two single-responsive nanotherapies (RAP/ACD NP and RAP/OCD NP) were used as controls. In an animal model of vascular inflammation in rats subjected to balloon injury in carotid arteries, AOCD NP could accumulate at the diseased site after i.v. injection. Consistently, i. v. treatment with RAP/AOCD NP more effectively inhibited neointimal hyperplasia in rats with induced arterial injuries, compared to RAP/PLGA NP, RAP/ACD NP, and RAP/OCD NP. By surface decoration of AOCD NP with a peptide (KLWVLPKGGGC) targeting type IV collagen (Col-IV), the obtained Col-IV targeting, dual-responsive nanocarrier TAOCD NP showed dramatically increased accumulation at injured carotid arteries. Furthermore, RAP/TAOCD NP exhibited significantly potentiated in vivo efficacy in comparison to the passive targeting nanotherapy RAP/AOCD NP. Importantly, in vitro cell culture expts. and in vivo animal studies in both mice and rats revealed good safety for AOCD NP and RAP/AOCD NP, even after long-term treatment via i. v. injection. Consequently, our results demonstrated that the newly developed Col-IV targeting, pH/ROS dual-responsive NPs may serve as an effective and safe nanovehicle for precision therapy of arterial restenosis and other vascular inflammatory diseases.
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    31. 31
      Pardeshi, P. M.; Mungray, A. A. Photo-polymerization as a new approach to fabricate the active layer of forward osmosis membrane. Sci. Rep. 2019, 9 (1), 1937,  DOI: 10.1038/s41598-018-36346-8
      There is no corresponding record for this reference.
    32. 32
      Khan, A. Q.; Agha, M. V.; Sheikhan, K. S. A. M.; Younis, S. M.; Tamimi, M. A.; Alam, M.; Ahmad, A.; Uddin, S.; Buddenkotte, J.; Steinhoff, M. Targeting deregulated oxidative stress in skin inflammatory diseases: An update on clinical importance. Biomed. Pharmacother. 2022, 154, 113601,  DOI: 10.1016/j.biopha.2022.113601
      There is no corresponding record for this reference.
    33. 33
      Mescher, A. L. Macrophages and fibroblasts during inflammation and tissue repair in models of organ regeneration. Regeneration 2017, 4 (2), 39– 53,  DOI: 10.1002/reg2.77
      There is no corresponding record for this reference.
    34. 34
      Buechler, M. B.; Fu, W.; Turley, S. J. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity 2021, 54 (5), 903– 915,  DOI: 10.1016/j.immuni.2021.04.021
      34
      Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer
      Buechler, Matthew B.; Fu, Wenxian; Turley, Shannon J.
      Immunity (2021), 54 (5), 903-915CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)
      A review. Fibroblasts and macrophages are present in all tissues, and mounting evidence supports that these cells engage in direct communication to influence the overall tissue microenvironment and affect disease outcomes. Here, we review the current understanding of the mol. mechanisms that underlie fibroblast-macrophage interactions in health, fibrosis, and cancer. We present an integrated view of fibroblast-macrophage interactions that is centered on the CSF1-CSF1R axis and discuss how addnl. mol. programs linking these cell types can underpin disease onset, progression, and resoln. These programs may be tissue and context dependent, affected also by macrophage and fibroblast origin and state, as seen most clearly in cancer. Continued efforts to understand these cells and the means by which they interact may provide therapeutic approaches for the treatment of fibrosis and cancer.
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    35. 35
      Witherel, C. E.; Abebayehu, D.; Barker, T. H.; Spiller, K. L. Macrophage and Fibroblast Interactions in Biomaterial-Mediated Fibrosis. Adv. Healthc. Mater. 2019, 8 (4), 1801451,  DOI: 10.1002/adhm.201801451
      There is no corresponding record for this reference.
    36. 36
      Criado-Gonzalez, M.; Espinosa-Cano, E.; Rojo, L.; Boulmedais, F.; Aguilar, M. R.; Hernández, R. Injectable Tripeptide/Polymer Nanoparticles Supramolecular Hydrogel: A Candidate for the Treatment of Inflammatory Pathologies. ACS Appl. Mater. Interfaces 2022, 14 (8), 10068– 10080,  DOI: 10.1021/acsami.1c22993
      36
      Injectable Tripeptide/Polymer Nanoparticles Supramolecular Hydrogel: A Candidate for the Treatment of Inflammatory Pathologies
      Criado-Gonzalez, Miryam; Espinosa-Cano, Eva; Rojo, Luis; Boulmedais, Fouzia; Aguilar, Maria Rosa; Hernandez, Rebeca
      ACS Applied Materials & Interfaces (2022), 14 (8), 10068-10080CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Supramol. peptide-based hydrogels attract great attention in several fields, i.e., biomedicine, catalysis, energy, and materials chem., due to the noncovalent nature of the self-assembly and functional tunable properties defined by the amino acid sequence. In this work, we developed an injectable hybrid supramol. hydrogel whose formation was triggered by electrostatic interactions between a phosphorylated tripeptide, Fmoc-FFpY (F: phenylalanine, pY: phosphorylated tyrosine), and cationic polymer nanoparticles made of vinylimidazole and ketoprofen (poly(HKT-co-VI) NPs). Hydrogel formation was assessed through inverted tube tests, and its fibrillary structure, around polymer NPs, was obsd. by transmission electron microscopy. Interestingly, peptide self-assembly yields the formation of nontwisted and twisted fibers, which could be attributed to β-sheets and α-helix structures, resp., as characterized by CD and IR spectroscopies. An increase of the elastic modulus of the Fmoc-FFpY/polymer NPs hybrid hydrogels was obsd. with peptide concn. as well as its injectability property, due to its shear thinning behavior and self-healing ability. After checking their stability under physiol. conditions, the cytotoxicity properties of these hybrid hydrogels were evaluated in contact with human dermal fibroblasts (FBH) and murine macrophages (RAW 264.7). Finally, the Fmoc-FFpY/polymer NPs hybrid hydrogels exhibited a great nitric oxide redn. (∼67%) up to basal values of pro-inflammatory RAW 264.7 cells, thus confirming their excellent anti-inflammatory properties for the treatment of localized inflammatory pathologies.
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    37. 37
      Tallawi, M.; Rosellini, E.; Barbani, N.; Cascone, M. G.; Rai, R.; Saint-Pierre, G.; Boccaccini, A. R. Strategies for the chemical and biological functionalization of scaffolds for cardiac tissue engineering: a review. J. R. Soc. Interface. 2015, 12 (108), 20150254,  DOI: 10.1098/rsif.2015.0254
      37
      Strategies for the chemical and biological functionalization of scaffolds for cardiac tissue engineering: a review
      Tallawi Marwa; Rosellini Elisabetta; Barbani Niccoletta; Cascone Maria Grazia; Rai Ranjana; Saint-Pierre Guillaume; Boccaccini Aldo R
      Journal of the Royal Society, Interface (2015), 12 (108), 20150254 ISSN:.
      The development of biomaterials for cardiac tissue engineering (CTE) is challenging, primarily owing to the requirement of achieving a surface with favourable characteristics that enhances cell attachment and maturation. The biomaterial surface plays a crucial role as it forms the interface between the scaffold (or cardiac patch) and the cells. In the field of CTE, synthetic polymers (polyglycerol sebacate, polyethylene glycol, polyglycolic acid, poly-l-lactide, polyvinyl alcohol, polycaprolactone, polyurethanes and poly(N-isopropylacrylamide)) have been proven to exhibit suitable biodegradable and mechanical properties. Despite the fact that they show the required biocompatible behaviour, most synthetic polymers exhibit poor cell attachment capability. These synthetic polymers are mostly hydrophobic and lack cell recognition sites, limiting their application. Therefore, biofunctionalization of these biomaterials to enhance cell attachment and cell material interaction is being widely investigated. There are numerous approaches for functionalizing a material, which can be classified as mechanical, physical, chemical and biological. In this review, recent studies reported in the literature to functionalize scaffolds in the context of CTE, are discussed. Surface, morphological, chemical and biological modifications are introduced and the results of novel promising strategies and techniques are discussed.
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    38. 38
      Kolluru, G. K.; Shen, X.; Kevil, C. G. Reactive Sulfur Species. Arterioscler. Thromb. Vasc. Biol. 2020, 40 (4), 874– 884,  DOI: 10.1161/ATVBAHA.120.314084
      38
      Reactive Sulfur Species: A New Redox Player in Cardiovascular Pathophysiology
      Kolluru, Gopi K.; Shen, Xinggui; Kevil, Christopher G.
      Arteriosclerosis, Thrombosis, and Vascular Biology (2020), 40 (4), 874-884CODEN: ATVBFA; ISSN:1079-5642. (Lippincott Williams & Wilkins)
      A review. Hydrogen sulfide has emerged as an important gaseous signaling mol. and a regulator of crit. biol. processes. However, the physiol. significance of hydrogen sulfide metabolites such as persulfides, polysulfides, and other reactive sulfur species (RSS) has only recently been appreciated. Emerging evidence suggests that these RSS mols. may have similar or divergent regulatory roles compared with hydrogen sulfide in various biol. activities. However, the chem. nature of persulfides and polysulfides is complex and remains poorly understood within cardiovascular and other pathophysiol. conditions. Recent reports suggest that RSS can be produced endogenously, with different forms having unique chem. properties and biol. implications involving diverse cellular responses such as protein biosynthesis, cell-cell barrier functions, and mitochondrial bioenergetics. Enzymes of the transsulfuration pathway, CBS (cystathionine beta-synthase) and CSE (cystathionine gamma-lyase), may also produce RSS metabolites besides hydrogen sulfide. Moreover, CARSs (cysteinyl-tRNA synthetase) are also able to generate protein persulfides via cysteine persulfide (CysSSH) incorporation into nascently formed polypeptides suggesting a new biol. relevant amino acid. This brief review discusses the biochem. nature and potential roles of RSS, assocd. oxidative stress redox signaling, and future research opportunities in cardiovascular disease.
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    39. 39
      Kowalczyńska, H. M.; Inkielman, M.; Nowak-Wyrzykowska, M.; Stołowska, L.; Doroszewski, J. Interaction of L1210 cells with sulfonated polystyrene in the absence of serum: adhesion and three-dimensional cell shape. Colloids Surf. B Biointerfaces 2003, 30 (3), 193– 206,  DOI: 10.1016/S0927-7765(03)00086-9
      There is no corresponding record for this reference.
    40. 40
      Wilson, C. G.; Sisco, P. N.; Gadala-Maria, F. A.; Murphy, C. J.; Goldsmith, E. C. Polyelectrolyte-coated gold nanorods and their interactions with type I collagen. Biomaterials 2009, 30 (29), 5639– 5648,  DOI: 10.1016/j.biomaterials.2009.07.011
      40
      Polyelectrolyte-coated gold nanorods and their interactions with type I collagen
      Wilson, Christopher G.; Sisco, Patrick N.; Gadala-Maria, Francis A.; Murphy, Catherine J.; Goldsmith, Edie C.
      Biomaterials (2009), 30 (29), 5639-5648CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Gold nanorods (AuNRs) have unique optical properties for numerous biomedical applications, but the interactions between AuNRs and proteins, particularly those of the extracellular matrix (ECM), are poorly understood. Here the effects of AuNRs on the self-assembly, mechanics, and remodeling of type I collagen gels were examd. in vitro. AuNRs were modified with polyelectrolyte multilayers (PEMs) to minimize cytotoxicity, and AuNRs with different terminal polymer chemistries were examd. for their interactions with collagen by turbidity assays, rheol. tests, and microscopy. Gel contraction assays were used to examine the effects of the PEM-coated AuNRs on cell-mediated collagen remodeling. Polyanion-terminated AuNRs significantly reduced the lag (nucleation) phase of collagen self-assembly and significantly increased the dynamic shear modulus of the polymd. gels, whereas polycation-terminated AuNRs had no effect on the mech. properties of the collagen. Both polyanion- and polycation-terminated AuNRs significantly inhibited collagen gel contraction by cardiac fibroblasts, and the nanoparticles were localized in intra-, peri-, and extracellular compartments, suggesting that PEM-coated AuNRs influence cell behavior via multiple mechanisms. These results demonstrate the significance of nanoparticle-ECM interactions in detg. the bioactivity of nanoparticles.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmacrolett.4c00404.

    • Materials and methods, 1H NMR spectra of EG3SA monomer in CDCl3, FTIR spectra of P[NIPAM70-co-MAA15-co-(EG3SA)15] hydrogels at different conditions, representative pictures of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels under different conditions and swelling comparison, rheological properties of P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels in PBS at pH 7.4 and 25 °C, and nitric oxide (NO) released by RAW cells in the presence of different ketoprofen concentrations (PDF)


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