Reducible polyethylenimine hydrogels with disulfide crosslinkers prepared by michael addition chemistry as drug delivery carriers: Synthesis,properties, and in vitro release

Degradable hydrogels crosslinked with disulfide bonds were prepared by Michael addition between amine groups of branched polyethylenimine and carbon–carbon double bonds of N,N′‐bis(acryloyl)cystamine. The influences of the chemical composition of the resulted hydrogels on their properties were examined in terms of morphology, surface area, swelling kinetics, and degradation. The hydrogels were uniformly crosslinked and degraded into water‐soluble polymers in the presence of the reducing agent of dithiothreitol, which improved the control over the release of encapsulated drug. The degradation of hydrogels can trigger the release of encapsulated molecules, as well as facilitate the removal of empty vehicles. Results obtained from in vitro drug release suggested that the disulfide crosslinked hydrogels exhibited an accelerated release of encapsulated drug in dithiothreitol‐containing PBS buffer solution. Moreover, the drug release rate decreased gradually with increasing crosslinking density. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4074–4082, 2009     

Synthesis,characterization and evaluation of semi‐IPN hydrogels consisted of poly(methacrylic acid) and guar gum for colon‐specific drug delivery

The semi‐IPN hydrogels consisting of poly(methacrylic acid) and guar gum (GG) are prepared at room temperature using water as solvent. 5‐aminosalicylic acid (5‐ASA) is entrapped in the hydrogel in the synthesis of hydrogel and all entrapment efficiencies are found above 85%. The hydrogel shows excellent pH‐sensitivity. It exhibited minimum swelling in an acidic pH medium through the formation of a complex hydrogen‐bonded structure and maximal swelling due to the electrostatic repulsion due to the ionization of the carboxylic groups in pH 7.4 medium. The degradation in vitro shows that the degree of degradation (R%) depended on the concentration of cross‐linking agent and content of GG. The hydrogel shows a minimum release of 5‐ASA due to the complex hydrogen bonded structure of the hydrogels in the medium of pH 2.2. The enzymatic degradation of hydrogels by cecal bacteria can accelerate the release of 5‐ASA entrapped in the hydrogel in pH 7.4 medium. Copyright © 2007 John Wiley & Sons, Ltd.     

Influence of the amine structure on the polymerization of methyl methacrylate photoinitiated by aromatic ketone/amine

The polymerization of methyl methacrylate photoinitiated by 2‐chlorothioxanthone in the presence of amines of different structures has been investigated. The photoinitiation efficiency of these systems is highly dependent on the structure of the amine. The polymerization rate increases with the amine concentration, reaching a constant value in an amine concentration range of 10–30 mM. At these amine concentrations, aliphatic hydroxyalkyl amines are more efficient photoinitiators than the corresponding alkyl‐substituted compounds. Dimethylanilines with electron‐acceptor substituents in the 4‐position give higher polymerization rates than electron‐donor‐substituted anilines. The photophysics of these photoinitiation systems has been studied in the polymerization medium. These data show that the singlet and triplet excited states of thioxanthones are efficiently deactivated by the amine. Rate constants are well correlated to the oxidation potential of the amine. These studies have allowed us to simulate the dependence of the photoinitiation efficiency with the amine concentration and indicate that the active radicals are produced from the interaction of the ketone triplet with the amine. Also, photochemical studies have allowed us to establish that the dependence of the polymerization rate on structural features of amines is mainly due to differences in the fraction of produced active radicals that add to the monomer. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 2888–2893, 2002     

Antibacterial poly(ethylene glycol) hydrogels from combined epoxy‐amine and thiol‐ene click reaction

Antibacterial hydrogels containing quaternary ammonium (QA) groups were prepared via a facile thiol‐ene “click” reaction using multifunctional poly(ethylene glycol) (PEG). The multifunctional PEG polymers were prepared by an epoxy‐amine ring opening reaction. The chemical and physical properties of the hydrogels could be tuned with different crosslinking structures and crosslinking densities. The antibacterial hydrogel structures prepared from PEG Pendant QA were less well‐defined than those from PEG Chain‐End QA. Furthermore, functionalization of the PEG‐type hydrogels with QA groups produced strong antibacterial abilities against Staphylococcus aureus, and therefore has the potential to be used as an anti‐infective material for biomedical devices. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 656–667     

pH‐Sensitive Mechanical Properties of Elastin‐Based Hydrogels

Ionizable amino acids in protein‐based hydrogels can confer pH‐responsive behavior. Because elastin‐like polypeptides (ELPs) have an established sequence and can crosslink to form hydrogels, they are an ideal system for creating pH‐sensitive materials. This study examines different parameters that might affect pH‐sensitive behavior and characterizes the mechanical and physical properties between pH 3 and 11 of three ELP‐based crosslinked hydrogels. The first finding is that varying the amount of crosslinker affects the overall stiffness and resilience of the hydrogels but does not strongly affect water content, swelling ratio, or pH sensitivity. Second, the choice of two popular tag sequences, which vary in histidine and aspartic acid content, does not have a strong effect on pH‐sensitive properties. Last, selectively blocking lysine and tyrosine residues through acetylation significantly decreases the pH‐sensitive zeta potential. Acetylated hydrogels also demonstrate different behavior at low pH values with reduced swelling, reduced water content, and higher stiffness. Overall, this work demonstrates that ELP hydrogels with ionizable groups are promising materials for environmentally‐responsive applications such as drug delivery, tissue engineering, and microfluidics.     

Synthesis of thermosensitive guar‐based hydrogels with tunable physico‐chemical properties by click chemistry

Thermosensitive guar‐based hydrogels are obtained in water solutions by copper‐catalyzed 1,3‐dipolar cycloaddition between alkyne‐functionalized guars and α,ω‐diazido‐poly[(ethylene glycol)‐co‐(propylene glycol)]. Characterization by TGA, HR‐MAS ¹H NMR, and rheology have shown that hydrogels with tunable physico‐chemical properties, such as crosslinking density, viscoelasticity, swelling ratio, and so forth, could be obtained by varying the guar molar mass, the degree of alkyne functionality, the guar/crosslinker weight ratio, and the reaction temperature. Based on swelling measurements, it has been shown that the thermal sensitiveness of guar‐based hydrogels is fast, reversible, and intimately related to the weight fraction of the thermosensitive crosslinker in the network. Finally, the monitoring of doxorubicin hydrochloride release has demonstrated the potential of these hydrogels as temperature‐dependent drug release devices. The robust, efficient, and orthogonal approach described herein represents a general approach towards the development of well‐controlled guar‐based hydrogels using α,ω‐diazido crosslinkers. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2733–2742, 2010     

Biomimetic Strain‐Stiffening Self‐Assembled Hydrogels

Supramolecular structures with strain‐stiffening properties are ubiquitous in nature but remain rare in the lab. Herein, we report on strain‐stiffening supramolecular hydrogels that are entirely produced through the self‐assembly of synthetic molecular gelators. The involved gelators self‐assemble into semi‐flexible fibers, which thereby crosslink into hydrogels. Interestingly, these hydrogels are capable of stiffening in response to applied stress, resembling biological intermediate filaments system. Furthermore, strain‐stiffening hydrogel networks embedded with liposomes are constructed through orthogonal self‐assembly of gelators and phospholipids, mimicking biological tissues in both architecture and mechanical properties. This work furthers the development of biomimetic soft materials with mechanical responsiveness and presents potentially enticing applications in diverse fields, such as tissue engineering, artificial life, and strain sensors.     

Precursor‐involved and Conversion Rate‐controlled Self‐assembly of a 'Super Gelator' in Thixotropic Hydrogels for Drug Delivery

Enzymatic hydrogelation is a totally different process to the heating‐cooling gelation process, in which the precursors of the gelators can be involved during the formation of self‐assembled structures. Using thixotropic hydrogels formed by a super gelator as our studied system, we demonstrated that the enzyme concentration/conversion rate of enzymatic reaction had a strong influence on the morphology of resulting self‐assembled nanostructures and the property of resulting hydrogels. The principle demonstrated in this study not only helps to understand and elucidate the phenomenon of self‐assembly triggered by enzymes in biological systems, but also offers a unique methodology to control the morphology of self‐assembled structures for specific applications such as controlled drug release.     

Synthesis and Evaluation of Biocompatible pH‐Sensitive Hydrogels as Colon‐Specific Drug Delivery Systems

Because of the growing importance of pH‐sensitive hydrogels as drug delivery systems, biocompatible copolymeric hydrogels based N‐vinyl‐2‐pyrrolidinone (NVP) and methacrylic acid (MAA) were designed and synthesized. These hydrogels were investigated for oral drug delivery. Radical copolymerizations of N‐vinyl‐2‐pyrrolidinone (NVP) and methacrylic acid (MAA) with the various ratios of cross‐linking agent were carried out at 70 °C. Azabisisobutyronitrile (AIBN) was the free‐radical initiator employed and Cubane‐1,4‐dicarboxylic acid (CDA) linked to two 2‐hydroxyethyl methacrylate (HEMA) group was the crosslinking agent (CA) used for hydrogel preparations. The hydrogels were characterized by differential scanning calorimetry and FT‐IR. Equilibrium swelling studies were carried out in enzyme‐free simulated gastric and intestinal fluids (SGF and SIF, respectively). A model drug, olsalazine [3,3′‐azobis (6‐hydroxy benzoic acid)] (OSZ) as an azo derivative of 5‐aminosalicylic acid (5‐ASA), was entrapped in these gels and the in‐vitro release profiles were established separately in both enzyme‐free SGF and SIF. The drug‐release profiles indicated that the amount of drug released depended on the degree of swelling. The swelling was modulated by the amount of crosslinking of the polymer bonded drug (PBDs) prepared. Based on the great difference in hydrolysis rates at pH 1 and 7.4, these pH‐sensitive hydrogels appear to be good candidates for colon‐specific drug delivery.     

Hybrid cross‐linked hydrogels as a technology platform for in vitro release of cephradine

Hydrogel‐based drug delivery systems can leverage therapeutically favorable upshots of drug release and found clinical uses. Hydrogels offer temporal and spatial control over the release of different therapeutic agents. Because of their tailor made controllable degradability, physical properties, and ability to prevent the labile drugs from degradation, hydrogels provide platform on which diverse physicochemical interactions with entrapped drugs cause to control drug release. Herein, we report the fabrication of novel vinyltrimethoxy silane (VTMS) cross‐linked chitosan/polyvinyl pyrrolidone hydrogels. Swelling in distilled water in conjunction with different buffer and electrolyte solutions was performed to assess the swellability of hydrogels. Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and X‐ray diffraction (XRD) analysis were further conducted to investigate the possible interactions between components, thermal stability, and crystallinity of as‐prepared hybrid hydrogels, respectively. In vitro time‐dependent biodegradability, antimicrobial study, and cytotoxicity were also carried out to evaluate their extensive biocompatibility and cytotoxic behavior. More interestingly, in vitro drug release study allowed for the controlled release of cephradine. Therefore, this facile strategy developed the novel biocompatible and biodegradable hybrid hydrogels, which could significantly expand the scope of these hydrogels in other biomedical applications like scaffolds, skin regeneration, tissue engineering, etc.     

Increasing the hydrophilicity of star‐shaped amphiphilic co‐networks by using of PEG and dendritic s‐PCL cross‐linkers

New hyperbranched hydrophobic cross‐linkers with peripheral azide groups were synthesized as follows: First, star‐shaped polycaprolactones (sPCL) were synthesized by ring‐opening polymerization of caprolactone in the presence of pentaerythritol and tin (II) octoate. In the next step, sequential acrylation, Micheal addition, tosylation, and azidation by acryloyl chloride, diethanol amine, tosyl chloride, and sodium azide were respectively exploited to synthesize azide‐functionalized hyperbranched star‐shaped polycaprolactones which were named sPCL‐acrylate‐diethanolamine‐azide (sPCL‐AC‐DEA‐N₃) and sPCL‐acrylate‐diethanolamine‐acrylate‐diethanolamine‐azide (sPCL‐AC‐DEA‐AC‐N₃). All steps were thoroughly characterized by FT‐IR and ¹H NMR spectroscopy. The GPC analysis showed that the molecular weight of sPCL increased after two azide functionalizations. Amphiphilic hydrogels based on sPCL‐AC‐DEA‐N₃ (M_n = 8130 g/mol) and sPCL‐AC‐DEA‐AC‐N₃ (M_n = 10112 g/mol) with linear alkyne‐terminated polyethylene glycols (PEG) (M_n = 2000, 4000, and 6000 g/mol) were synthesized through click coupling between azide and alkyne groups. In both hydrogels, the swelling ratio increased by increasing the molecular weight of PEG. The obtained results showed that the branching of the cross‐linker, significantly affected the swelling ratio of hydrogels. For instance, the swelling ratio of sPCL‐AC‐DEA‐AC‐N₃ and PEG‐6000 (Q = 900) was higher than sPCL‐AC‐DEA‐N₃ and PEG‐6000 (Q = 600). Despite the high cross‐linking density of sPCL‐AC‐DEA‐AC‐DEA‐N₃–based hydrogels, the amount of released theophylline was higher than sPCL‐AC‐DEA‐N₃–based hydrogels, due to the high content of PEG in these hydrogels.     

Drug‐Loaded Elastin‐Like Polypeptide–Collagen Hydrogels with High Modulus for Bone Tissue Engineering

Emphasizing the role of hydrogel stiffness and cellular differentiation, this study develops collagen and elastin‐like polypeptide (ELP)–based bone regenerative hydrogels loaded with recombinant human bone morphogenetic protein‐2 (rhBMP‐2) and doxycycline with mechanical properties suitable for osteogenesis. The drug‐incorporated collagen–ELP hydrogels has significantly higher modulus of 35 ± 5 kPa compared to collagen‐only hydrogels. Doxycycline shows a bi‐phasic release with an initial burst release followed by a gradual release, while rhBMP‐2 exhibits a nearly linear release profile for all hydrogels. The released doxycycline shows anti‐microbial activity against Pseudomonas aeruginosa, Streptococcus sanguinis, and Escherichia coli. Microscopic observation of the hydrogels reveals their interconnected, macroporous, 3D open architecture with pore diameters between 160 and 400 µm. This architecture supports human adipose–derived stem cell attachment and proliferation from initial days of cell seeding, forming a thick cellular sheath by day 21. Interestingly, in collagen and collagen–ELP hydrogels, cell morphology is elongated with stretched slender lamellipodial formation, while cells assemble as spheroidal aggregates in crosslinked as well as drug‐loaded hydrogels. Osteogenic markers, alkaline phosphatase and osteocalcin, are expressed maximally for drug‐loaded hydrogels compared to those without drugs. The drug‐loaded collagen–ELP hydrogels are thus promising for combating bacterial infection and promoting guided bone regeneration.     

Dual thermo‐ and pH‐sensitive network‐grafted hydrogels formed by macrocrosslinker as drug delivery system

Dual thermo‐ and pH‐sensitive network‐grafted hydrogels made of poly(N,N‐dimethylaminoethyl methacrylate) (PDMAEMA) network and poly(N‐isopropylacrylamide) (PNIPAM) grafting chains were successfully synthesized by the combination of atom transfer radical polymerization (ATRP), reversible addition‐fragmentation chain transfer (RAFT) polymerization, and click chemistry. PNIPAM having two azide groups at one chain end [PNIPAM‐(N₃)₂] was prepared with an azide‐capped ATRP initiator of N,N‐di(β‐azidoethyl) 2‐chloropropionylamide. Alkyne‐pending poly(N,N‐dimethylaminoethyl methacrylate‐co‐propargyl acrylate) [P(DMAEMA‐co‐ProA)] was obtained through RAFT copolymerization using dibenzyltrithiocarbonate as chain transfer agent. The subsequent click reaction led to the formation of the network‐grafted hydrogels. The influences of the chemical composition of P(DMAEMA‐co‐ProA) on the properties of the hydrogels were investigated in terms of morphology and swelling/deswelling kinetics. The dual stimulus‐sensitive hydrogels exhibited fast response, high swelling ratio, and reproducible swelling/deswelling cycles under different temperatures and pH values. The uptake and release of ceftriaxone sodium by these hydrogels showed both thermal and pH dependence, suggesting the feasibility of these hydrogels as thermo‐ and pH‐dependent drug release devices. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Double Hydrogen‐Bonding pH‐Sensitive Hydrogels Retaining High‐Strengths Over a Wide pH Range

Traditional pH‐sensitive hydrogels inevitably suffer strength deterioration while the responsive weak acid or base groups are in the ionized state. In this study, we report on a facile approach to fabricate a novel pH‐sensitive high‐strength hydrogel from copolymerization of two hydrogen‐bonding motif‐containing monomers, 3‐acrylamidophenylboronic acid and 2‐vinyl‐4,6‐diamino‐1,3,5‐triazine with a crosslinker N,N‐methylenebisacrylamide through hydrophilic optimization of the comonomer oligo(ethylene glycol) methacrylate. The double hydrogen bonding hydrogel exhibits both high tensile and compressive strengths over a broad pH range due to the unique ability to maintain at least one type of hydrogen‐bonding crosslink over the whole course of pH change.     

Biodegradable thermo‐ and pH‐responsive hydrogels for oral drug delivery

In this article, novel smart hydrogels based on biodegradable pH sensitive poly(L ‐glutamic acid‐g‐2‐hydroxylethyl methacrylate) (PGH) chains and temperature‐sensitive hydroxypropylcellulose‐g‐acrylic acid (HPC‐g‐AA) segments were designed and synthesized. The influence of pH and temperature on the equilibrium swelling ratios of the hydrogels was discussed. The optical transmittance of the hydrogels was also changed as a function of temperature, which reflecting that the HPC‐g‐AA part of the hydrogels became hydrophobic at the temperature above the lower critical solution temperature (LCST). At the same time, the LCST of the hydrogels had a visible pH‐dependent behavior. Scanning electron microscopic analysis revealed the morphology of the hydrogels before and after enzymatic degradation. The biodegradation rate of the hydrogels was directly related to the PGH content and the pH value. The in vitro release of bovine serum albumin from the hydrogels were investigated. The release profiles indicated that both the HPC‐g‐AA and PGH contents played important roles in the drug release behaviors. These results show that the smart hydrogels seem to be of great promise in pH–temperature oral drug delivery systems. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

A novel sodium carboxymethylcellulose/poly(N‐isopropylacrylamide)/Clay semi‐IPN nanocomposite hydrogel with improved response rate and mechanical properties

A novel semi‐IPN nanocomposite hydrogel (CMC/PNIPA/Clay hydrogel) based on linear sodium carboxymethylcellulose (CMC) and poly(N‐isopropylacrylamide) (PNIPA) crosslinked by inorganic clay was prepared. The structure and morphology of these hydrogels were investigated and their swelling and deswelling kinetics were studied in detail. TEM images showed that the clay was substantially exfoliated to form nano‐dimension platelets dispersed homogeneously in the hydrogels and acted as a multifunctional crosslinker. The CMC/PNIPA/Clay hydrogels swell faster than the corresponding PNIPA/Clay hydrogels at pH 7.4, whereas they swell slower than the PNIPA/Clay hydrogels at pH 1.2. The CMC/PNIPA/Clay nanocomposite hydrogels showed much higher deswelling rates, which was ascribed to more passway formed in these hydrogels for water to diffuse in and out. The deswelling process of the hydrogels could be approximately described by the first‐order kinetic equation and the deswelling rate decreased with increasing clay content. The mechanical properties of the CMC/PNIPA/Clay nanocomposite hydrogels were analyzed based on the theory of rubber elasticity. It was found that with increasing clay content, the effective crosslink chain density, v_e, increased whereas the molecular weight of the chains between crosslinks M_c decreased. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 1546–1555, 2008     

Out‐of‐Water Constitutional Self‐Organization of Chitosan–Cinnamaldehyde Dynagels

An investigation of the constitutional adaptive gelation process of chitosan/cinnamaldehyde ( C / Cy ) dynagels is reported. These gels generate timely variant macroscopic organization across extended scales. In the first stage, imine‐bond formation takes place “in‐water” and generates low‐ordered hydrogels. The progressive formation of imine bonds further induces “ out‐of‐water” increased reactivity within interdigitated hydrophobic self‐assembled layers of Cy , with a protecting environmental effect against hydrolysis and that leads to the stabilization of the imine bonds. The hydrophobic swelling due to Cy layers at the interfaces reaches a critical step when lamellar self‐organized hybrids are generated (24 hours). This induces an important restructuration of the hydrogels on the micrometric scale, thus resulting in the formation of highly ordered microporous xerogel morphologies of high potential interest for chemical separations, drug delivery, and sensors.     

Synthesis of dual responsive cyclotriphosphazene‐based IPN hydrogels for controlled release of chemotherapeutic agent

Dual responsive cyclotriphosphazene (CTP)‐based hydrogels have been synthesized for a controlled release of FU, a hydrophilic drugs. These hydrogels composed of mono (methacryloyl‐2‐ethoxy)‐pentakis(N¹,N¹‐dimethylpropane‐1,3‐diamino)‐cyclotriphosphazene (HEMA (DMPDA)₅CP), acryl amide and pectin were synthesized by free radical polymerization method using methylenebisacrylamide cross linker. The CTP hydrogels were characterized to understand the structure, drug nature in the network and morphology by FTIR, DSC, XRD and SEM, respectively. In this paper, the swelling (dynamic and equilibrium) properties of cyclotriphosphazene hydrogels were investigated, showing dual (pH and thermo) responsiveness and large variation in the swelling capacity. Based on these results the structural parameters of the hydrogel networks such as the average molecular weight between cross‐links (M_c) and polymer–solvent interaction parameter (χ) were determined. The CTP hydrogels has high FU loading efficiency 65 ± 0.5. In‐vitro FU release of these hydrogels was controlled for about 24 hr also hydrogel showed a distinct initial burst. The CTP hydrogels are bearing both hydrophilic groups of pectin and hydrophobic groups of CTP exhibited dual responsive behaviors with pH and temperature. Copyright © 2015 John Wiley & Sons, Ltd.     

Release of theophylline and aminophylline from acrylic acid/n‐alkyl methacrylate hydrogels

The swelling capacity and release rate of two homologous drugs, theophylline and aminophylline, from acrylic acid/n‐alkyl methacrylate hydrogels have been studied. The maximum equilibrium swelling increases as the molar fraction of acrylic acid or the chain length of the methacrylate in the hydrogels increases. Water diffusion to the hydrogels is non‐Fickian. Both drugs are released from the fully swollen hydrogels according to Fick's law. However, the drug release from xerogels deviates from Fick's law, especially for aminophylline. As expected because of its larger size, aminophylline diffuses more slowly than theophylline under similar experimental conditions. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2756–2765, 2004     

Elucidation of the Mechanism of Enhanced Insulin Uptake and Release from pH Responsive Hydrogels

Summary: Environmentally responsive hydrogels composed of poly(methacrylic acid-g-ethylene glycol) (P(MAA-g-EG)) have shown promise for oral insulin delivery due to their pH responsive complexation behavior. A series of hydrogel formulations were polymerized with varying amounts of crosslinker and varying monomer volume fraction. The mesh size of the network depended primarily on pH, varying from 8.0 to 27.2 nm. Insulin loading efficiency varied directly with crosslink density, ranging from 42.7 to 84.9% of available insulin loaded into the hydrogels. The release of insulin was performed with each polymer formulation at 5 pH levels ranging from 2.7 to 6.8. Insulin release was less than 20% for all formulations tested with insulin for the duration of the 3 hour release study for all pH levels considered except when the pH was 6.8, at which point the release occurred as a burst. Loading studies performed with insulin glargine, an insulin analog with an increased pI, showed the same trends as native insulin. However, the release of insulin glargine only occurred at a pH level above that of the pI of the protein. These results indicate that hydrogen bonds and ionic interactions between the protein and P(MAA-g-EG) may strongly influence its loading and release behavior in vitro.