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![Synthesis of gelatin based hydrogel via photo-initiated thiol-ene reaction cross-linking thiolated gelatin and acrylated gelatin. Adapted from Li et al. [132].](publication/347892843/figure/fig5/AS:974714642133002@1609401488704/Synthesis-of-gelatin-based-hydrogel-via-photo-initiated-thiol-ene-reaction-cross-linking.jpg)
Synthesis of gelatin based hydrogel via photo-initiated thiol-ene reaction cross-linking thiolated gelatin and acrylated gelatin. Adapted from Li et al. [132].
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This review focuses on the synthesis of hydrogel networks using thiomers such as thiolated hyaluronic acid, chitosan, cyclodextrin, poly(ethylene glycol) and dextran that are cross-linked via their thiol substractures. Thiomers have been widely investigated as matrix of hydrogels due to the high reactivity of these sulfhydryl moieties. They are wel...
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... support, attachment, adhesion and proliferation of cells [135]. Another injectable and photocurable gelatin-based hydrogel was recently prepared for corneal injuries repair. The hydrogel consisted of acrylated-gelatin and thiolated-gelatin cross-linked by a photo-initiated thiol-ene reaction using Irgacure 2959 as photo-initiator as shown in Fig. 13 The resulting hydrogel had a high transparency being required for ocular hydrogels in order to avoid blurred vision. The hydrogel was shown to be degraded in presence of collagenase, which is present in the tear fluid and its cytocompatibility was demonstrated both in vitro and in vivo. In vivo studies in rabbits demonstrated a faster ...
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... Exploiting the potential of thiols to form disulfide bonds with endogenous thiols or disulfides, thiomers have been widely investigated as matrices for mucoadhesive hydrogels (Summonte et al., 2021;Fürst et al., 2022Fürst et al., , 2023Shahzadi et al., 2020). The application of such mucoadhesive hydrogels in drug delivery, however, is still limited by a too rapid release of active pharmaceutical ingredients (APIs) from such gels. ...
... Applying citric acid as a crosslinker with phosphoric acid as a catalyst, clear and stable hydrogels were formed at 100 • C even within just 30 min. Former thiolated hydrogels were designed by using free thiol groups for crosslinking, but in this study, the sulfhydryl moieties were previously protected by MESNA (Summonte et al., 2021). Consequently, the crosslinking with citric acid affects neither the extent of available thiol moieties nor their reactivity. ...
... Following this, in the subsequent stage, a pre-polymerized polymer is submerged into the aforementioned solution. This specific class of materials has improved surface and pore characteristics that possess the capability to increase the control and monitoring of medication release conditions, along with mechanical properties [89]. ...
... The swelling response to changes in temperature, pH and ionic strength is another important property of these materials [4,5]. Crosslinked hydrogels prepared from different hydrophilic monomers have been widely utilized in different fields, including contact lenses, drug delivery, diagnostics, pharmaceutical, wound dressing, gene delivery, agriculture, thermo sensitive materials, and food industry [6][7][8][9]. Among them, hydrogels prepared from acrylamide derivatives have been used in various fields such as linear polymers, tissue engineering, film making, smart polymers, heavy metal removal, and dye removal [10][11][12][13][14][15]. ...
By radical polymerization, two series of superabsorbent hydrogels of hydroxybutyl acrylate and acrylamide copolymers, poly(HBA-co-AAm), were obtained. In the first series, the ratio of hydroxybutyl acrylate to acrylamide was optimized with a constant amount of methylene bisacrylamide (MBA) as a cross-linking agent. In the second series, the amount of MBA was changed at a fixed monomer ratio. The structure of the copolymers was confirmed by the FTIR method. Swelling parameters and mechanical properties were tested. Hydrogels with a high Young’s modulus and a high degree of swelling were selected for the study of adsorption properties towards Co2+, Ni2+ and Cd2+ ions. The influence of basic factors such as adsorbent dose, exposure time and pH on adsorption efficiency was also investigated. The ability to adsorb heavy metal ions changed as follows: Co2+> Ni2+> Cd2+.
... In addition, our previous work has shown that GelAGE synthesis allows for tailored MW's which can be used to control thermal gelling properties [10], which are important for biofabrication processes' such as microfluidics and subsequent bioassembly [10,24,25]. Combining this control over precursory material properties with thiol-ene crosslinking allow for great control of crosslinking mechanisms while facilitating the incorporation of thiolated molecules with high conversion rates [9,10,21,[26][27][28]. Despite the strengths of these materials, there are still many hurdles left to overcome for biofabrication of large-scale constructs, especially relating to oxygenation, where the lack of a continuous oxygen supply leads to tissue dysfunction and potential necrosis [29][30][31][32][33]. ...
The delivery of oxygen within tissue engineered constructs is essential for cell survivability; however, achieving this within larger biofabricated constructs poses a significant challenge. Efforts to overcome this limitation often involve the delivery of synthetic oxygen generating compounds. The application of some of these compounds is problematic for the biofabrication of living tissues due to inherent issues such as cytotoxicity, hyperoxia and limited structural stability due to oxygen inhibition of radical-based crosslinking processes. This study aims to develop an oxygen delivering system relying on natural-derived components which are cytocompatible, allow for photopolymerization and advanced biofabrication processes, and improve cell survivability under hypoxia (1% O2). We explore the binding of human hemoglobin (Hb) as a natural oxygen deposit within photopolymerizable allylated gelatin (GelAGE) hydrogels through the spontaneous complex formation of Hb with negatively charged biomolecules (heparin, hyaluronic acid, and bovine serum albumin). We systematically study the effect of biomolecule inclusion on cytotoxicity, hydrogel network properties, Hb incorporation efficiency, oxygen carrying capacity, cell viability, and compatibility with 3D-bioassembly processes within melt electrowritten (MEW) scaffolds. All biomolecules were successfully incorporated within GelAGE hydrogels, displaying controllable mechanical properties and cytocompatibility. Results demonstrated efficient and tailorable Hb incorporation within GelAGE-Heparin hydrogels. The developed system was compatible with microfluidics and photopolymerization processes, allowing for the production of GelAGE-Heparin-Hb spheres. Hb-loaded spheres were assembled into MEW polycaprolactone scaffolds, significantly increasing the local oxygen levels. Ultimately, cells within Hb-loaded constructs demonstrated good cell survivability under hypoxia. Taken together, we successfully developed a hydrogel system that retains Hb as a natural oxygen deposit post-photopolymerization, protecting Hb from free-radical oxidation while remaining compatible with biofabrication of large constructs. The developed GelAGE-Heparin-Hb system allows for physoxic oxygen delivery and thus possesses a vast potential for use across broad tissue engineering and biofabrication strategies to help eliminate cell death due to hypoxia.
... Notably, this particular combination has not been previously documented in the available research. Both homopolymerization [29] and the microemulsion technique, which are ecologically friendly experimental procedures, were used in the synthesis of the EHMC-pEGDMA microgel. The SEM analysis in Figure 1 revealed that the EHMC-pEDGMA microgel exhibited an irregularly spherical shape. ...
Ethylhexyl methoxycinnamate (EHMC) is frequently employed as a photoprotective agent in sunscreen formulations. EHMC has been found to potentially contribute to health complications as a result of its propensity to produce irritation and permeate the skin. A microgel carrier, consisting of poly(ethylene glycol dimethacrylate) (pEDGMA), was synthesized using interfacial polymerization with the aim of reducing the irritation and penetration of EHMC. The thermogravimetric analysis (TGA) indicated that the EHMC content accounted for 75.72% of the total composition. Additionally, the scanning electron microscopy (SEM) images depicted the microgel as exhibiting a spherical morphology. In this study, the loading of EHMC was demonstrated through FTIR and contact angle tests. The UV resistance, penetration, and skin irritation of the EHMC-pEDGMA microgel were additionally assessed. The investigation revealed that the novel sunscreen compound, characterized by limited dermal absorption, had no irritant effects and offered sufficient protection against ultraviolet radiation.
... As shown in Fig. S5e-f, disulfide bonds can be reduced to sulfhydryl groups resulting in a transition from gel to solution. Subsequently, disulfide bonds were formed by oxidation of free thiols by oxygen H 2 O 2 to form gel [29]. The ADA hydrogels displayed excellent self-healing and injectable capacities, which could be locally injected to fill the tissue defects with minimally invasive procedures for bridging the damaged area and providing an ideal microenvironment for nerve regeneration [30]. ...
... Hydrogels are cross-linked, porous networks of hydrophilic polymer chains that serve as outstanding and effective 3D platforms with high water uptake capacity [1]. They allow the conjugation of various therapeutics, like drug molecules and peptide-based biomolecules, to either end groups or side chains due to the presence of functional moieties, such as amine, hydroxyl, carboxylic acid, maleimide, etc., in their structures [2][3][4][5]. Although their physicochemical properties are mainly affected by their swelling ratio for controlled delivery of encapsulated therapeutic agents inside, chemically or physically cross-linked smart polymers also contribute to the development of hydrogels with diverse stimuli responsiveness to temperature, pH, biomolecules, light, magnetic fields, etc. [6][7][8][9]. ...
... Size and PDI values were measured in ddH 2 O by DLS instrument.2 Surface charge values were measured using 1:10 dilution factor (v/v) in 1 mM NaCl.3 Encapsulation efficiency values were measured by LC-MS/MS instrument. ...
As therapeutic agents that allow for minimally invasive administration, injectable biomaterials stand out as effective tools with tunable properties. Furthermore, hydrogels with responsive features present potential platforms for delivering therapeutics to desired sites in the body. Herein, temperature-responsive hydrogel scaffolds with embedded targeted nanoparticles were utilized to achieve controlled drug delivery via local drug administration. Poly(N-isopropylacrylamide) (pNIPAM) hydrogels, prepared with an ethylene-glycol-based cross-linker, demonstrated thermo-sensitive gelation ability upon injection into environments at body temperature. This hydrogel network was engineered to provide a slow and controlled drug release profile by being incorporated with curcumin-loaded nanoparticles bearing high encapsulation efficiency. A core (alginate)–shell (chitosan) nanoparticle design was preferred to ensure the stability of the drug molecules encapsulated in the core and to provide slower drug release. Nanoparticle-embedded hydrogels were shown to release curcumin at least four times slower compared to the free nanoparticle itself and to possess high water uptake capacity and more mechanically stable viscoelastic behavior. Moreover, this therapy has the potential to specifically address tumor tissues over-expressing folate receptors like ovaries, as the nanoparticles target the receptors by folic acid conjugation to the periphery. Together with its temperature-driven injectability, it can be concluded that this hydrogel scaffold with drug-loaded and embedded folate-targeting nanoparticles would provide effective therapy for tumor tissues accessible via minimally invasive routes and be beneficial for post-operative drug administration after tumor resection.
... 1 PEG macromers can be functionalized with different end groups and crosslinked under mild conditions to form hydrogels. 2,3 Organic reactive groups such as alkenes, alkynes, azides, N-hydroxysuccinimide esters, or norbornenes 4−6 or enzymatically crosslinkable groups such as tyramines or sortase-sensitive peptides are examples of cross-linkable functionalities, 7,8 Among them, thiol-based cross-linking chemistries are a frequent choice since they occur without the need of catalysts or light and allow paralell biofunctionalization of the hydrogel with bioactive thiolated molecules. 9 PEG-vinyl sulfone (VS), 10 PEG-maleimide (MAL) 11,12 and PEG-Acrylate (AC) 13−15 macromers can react with thiol-terminated cross-linkers to form hydrogels that are nontoxic for cells and usable for in vitro cell encapsulation when functionalized with degradable sequences, cell adhesive peptides and bioactive factors. In vivo, PEG-SH macromers cross-linked with PEG-AC (2-arm, 3 kDa, 10 wt %) or PEG-norbornene (8-arm, 20 kDa, 6 wt %) have been shown to be stable on a month time scale, even if they incorporate cell-degradable cross-linkers and embedded cells. ...
Methylsulfone derivatized poly(ethylene) glycol (PEG) macromers can be biofunctionalized with thiolated ligands and cross-linked with thiol-based cross-linkers to obtain bioactive PEG hydrogels for in situ cell encapsulation. Methylsulfonyl-thiol (MS-SH) reactions present several advantages for this purpose when compared to other thiol-based cross-linking systems. They proceed with adequate and tunable kinetics for encapsulation, they reach a high conversion degree with good selectivity, and they generate stable reaction products. Our previous work demonstrated the cytocompatibility of cross-linked PEG-MS/thiol hydrogels in contact with fibroblasts. However, the cytocompatibility of the in situ MS-SH cross-linking reaction itself, which generates methylsulfinic acid as byproduct at the cross-linked site, remains to be evaluated. These studies are necessary to evaluate the potential of these systems for in vivo applications. Here we perform an extensive cytocompatibility study of PEG hydrogels during in situ cross-linking by the methylsulfonyl-thiol reaction. We compare these results with maleimide-thiol cross-linked PEGs which are well established for cell culture and in vivo experiments and do not involve the release of a byproduct. We show that fibroblasts and endothelial cells remain viable after in situ polymerization of methylsulfonyl-thiol gels on the top of the cell layers. Cell viability seems better than after in situ cross-linking hydrogels with maleimide-thiol chemistry. The endothelial cell proinflammatory phenotype is low and similar to the one obtained by the maleimide-thiol reaction. Finally, no activation of monocytes is observed. All in all, these results demonstrate that the methylsulfonyl-thiol chemistry is cytocompatible and does not trigger high pro-inflammatory responses in endothelial cells and monocytes. These results make methylsulfonyl-thiol chemistries eligible for in vivo testing and eventually clinical application in the future.
... Based on their high responsiveness to ROS, disulfide bonds are often used as reactive linkers for drug delivery systems and are widely used to construct ROS-responsive hydrogel systems. 23,24 Disulfide bond cross-linked hydrogels must be generated under mild conditions, making the gels biocompatible. Many hydrogels containing disulfide bonds have been available with good biocompatibility. ...
Coronary atherosclerosis is closely related to inflammation and oxidative stress. Owing to poor biocompatibility, lack of personalized treatment, and late toxic side effects, traditional drug-eluting stent intervention, releasing antiproliferative drugs, can delay endothelial repair and cause late thrombosis. The inflammation caused by atherosclerosis results in an acidic microenvironment and oxidative stress, which can be considered as triggers for precise and intelligent treatment. Here, we used catechol hyaluronic acid (C-HA) and cystamine (Cys) to prepare C-HA-Cys hydrogel coatings by amide reaction. The H2S-releasing donor allicin was loaded in the hydrogel to form an intelligent biomimetic coating. The disulfide bond of Cys made the cross-linked network redox-responsive to the inflammation and oxidative stress in the microenvironment by releasing the drug and H2S intelligently to combat the side effects of stent implantation. This study evaluated the hemocompatibility, anti-inflammatory capacity, vascular wall cytocompatibility, and in vivo histocompatibility of this intelligent hydrogel coating. Furthermore, the effect of H2S released from the coating on atherosclerosis-related signaling pathways such as CD31 and cystathionine γ-lyase (CSE), CD36, and ACAT-1 was investigated. Our results indicate that the C-HA-Cys-Allicin hydrogel coating could be manufactured on the surface of vascular interventional devices to achieve a precise response to the microenvironment of the lesion to release drug, which can attain the purpose of prevention of in-stent restenosis and ensure the effectiveness and safety of the application of interventional devices.
... In these reviews the various chemical categories of mucoadhesive polymers together with the relevant physical-chemical (MW, hydrophilicity, cross-links) and mechanical (cohesiveness) properties are discussed as well as their possible applications in the biomedical field. Furthermore, chemical functionalization of native polymers, such as thiolation (Duggan et al., 2017;Leichner et al., 2019;Federer et al., 2021;Knoll et al., 2021;Summonte et al., 2021), conjugation with boronate groups (Surendranath et al., 2022) and methacrylation (Agibayeva et al., 2020) has also been proposed to improve the mucoadhesive properties. ...
The paper is intended to deal with the regulatory status of the family of substance-based medical devices (SB-MD) which contain mucoadhesive polymers. Mucoadhesive formulations are mainly intended for oral/buccal, gastro-esophageal, nasal, or vaginal administration routes. They contain one or more substances/polymers of either natural, synthetic or semi-synthetic origin endowed with mucoadhesive properties. These are complex substances whose chemical-physical properties are in general well characterized. Hydration and water retaining properties, gel formation, lubricating properties are example of functional characteristics that may be involved in mucosal interaction. However, there are still uncertainties as to the underlaying mechanisms. The idea is to provide support, to the understanding of the prevailing mechanisms of action of the family of SB-MD that exploit mucoadhesion phenomenon to exert the intended therapeutic action. A case study on Hyaluronic acid as a typical representative of mucoadhesive polymers, is presented. The correct understanding of the mechanism of action of the substances/polymers involved in SB-MD is pivotal to a smooth and successful submission to the involved regulatory bodies to a positive assessment and to the final approval.
