Konjac glucomannan‐graft‐acrylic acid hydrogels containing azo crosslinker for colon‐specific delivery

In this article, the synthesis and characterization of novel hydrogel systems designed for colon‐targeting drug delivery are reported. The gels were composed of konjac glucomannan, copolymerized with acrylic acid, and crosslinked by the aromatic azo agent bis(methacryloylamino)‐azobenzene. The influence of various parameters on the dynamic and equilibrium swelling ratios (SRs) of the hydrogels was investigated. It is shown that the SR was inversely proportional to the grafting degree of acrylic acid and the content of bis(methacryloylamino)‐azobenzene. The dependence of SR on the pH indicates that obtained hydrogels are potential for drug delivery to colon. It was possible to modulate the degree of swelling and the pH sensitivity of the gels by changing crosslinking density of the polymer. The main chain of hydrogels can be degraded by β‐glycosidase which is abundant in colon. They can be in vitro degraded for 73% in a month by Cereflo® and 86% in 20 days by Mannaway25L. We have also prepared the hydrogels that loaded with bovine serum albumin about 1.5%, 3%, 9%, and 20% by weight. In vitro release of model drug bovine serum albumin was studied in the presence of Mannaway25L or Fungamyl®800L in pH 7.4 phosphate buffer at 37 °C. The drug release can be controlled by the biodegradation of the hydrogels. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4370–4378, 2004     

Synthesis and Unusual Swelling Behavior of Combined Cationic/Non‐Ionic Hydrogels Based on Chitosan

Hydrogel‐forming copolymers based on chitosan grafted with different amounts of polyacrylamide were synthesized and its swelling capacity determined in distilled water, sodium chloride solutions, as well as in buffer solutions at pH 1.2 and 8.0. The resulting products are highly efficient as hydrogel‐forming materials with swelling at equilibrium going approximately from 300 to 3 000 times the volume of the dry solid polymer in all the investigated media. The products, different to usual hydrogels, swells considerably more and quickly in electrolyte‐containing solutions compared to in distilled water. This has been attributed to their structure that contains non‐ionic polyacrylamide macromolecules grafted onto the trunk polymer chitosan, which is cationic in nature. In‐vitro drug‐release behavior of formulations containing grafted copolymers have been tested using theophylline as a water‐soluble drug and the results were compared with similar formulations containing unmodified chitosan. It was found that tablets based on formulations containing grafted chitosan show higher erosion and swelling compared with those of the matrix based on unmodified chitosan, leading to a higher fraction of theophylline released. It can be concluded that formulations based on the synthesized copolymers are potentially useful for fluid absorbency and as prolonged drug‐release matrices.

The swelling of one of the hydrogels studied here.     

Synthesis,characterization, and evaluation of enzymatically degradable poly(N‐isopropylacrylamide‐co‐acrylic acid) hydrogels for colon‐specific drug delivery

The enzymatically degradable poly(N‐isopropylacrylamide‐co‐acrylic acid) hydrogels were prepared using 4,4^′‐bis(methacryloylamino)azobenzene (BMAAB) as the crosslinker. It was found that the incorporated N‐isopropylacrylamide (NIPAAm) monomer did not change the enzymatic degradation of hydrogel, but remarkably enhanced the loading of protein drug. The hydrogels exhibited a phase transition temperature between 4°C (refrigerator temperature) and 37°C (human body temperature). Bovine serum albumin (BSA) as a model drug was loaded into the hydrogels by soaking the gels in a pH 7.4 buffer solution at 4°C, where the hydrogel was in a swollen status. The high swelling of hydrogels at 4°C enhanced the loading of BSA (loading capability, ca. 144.5 mg BSA/g gel). The drug was released gradually in the pH 7.4 buffer solution at 37°C, where the hydrogel was in a shrunken state. In contrast, the enzymatic degradation of hydrogels resulted in complete release of BSA in pH 7.4 buffer solution containing the cecal suspension at 37°C (cumulative release: ca. 100 mg BSA/g gel after 4 days). Copyright © 2008 John Wiley & Sons, Ltd.     

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.     

Non‐Osmotic Hydrogels: A Rational Strategy for Safely Degradable Hydrogels

Hydrogels are promising materials for biomedical applications, where timely degradation is often preferred. In the conventional design, however, the cleavage of polymer networks essentially causes considerable morphological changes (i.e., degradation‐induced swelling), triggering various medical complications. Herein, we report a rational strategy to suppress the degradation‐induced swelling based on the synthetic control of the polymer–solvent interaction parameter (χ) of constituent polymer networks. The resultant hydrogels with an optimal χ parameter (χ_{37 °C}≈0.53; non‐osmostic hydrogels) displayed the capability to retain their original shape and degrade without generating significant swelling pressure under physiological conditions (Π_{37 °C}<1 kPa). This concept of the safely degradable non‐osmotic hydrogel is theoretically universal, and can be exploited for other types of synthetic hydrogels in various settings.     

Electrospun nanofibers for drug delivery applications: Methods and mechanism

Electrospinning procedures such as blend electrospinning, coaxial electrospinning, and emulsion electrospinning have been used for the fabrication of electrospun nanofibers (ENFs) for biomedical applications. These ENFs are attracted great interest especially in drug delivery applications due to their small size, high surface area-to-volume, and porosity. The aim of this review is to focus on the controlled release mechanism among the different electrospinning methods, and the selectivity of hydrophilic, water-soluble polymers as a carrier for drug. The mechanism for the drug delivery depends mainly on the method of drug loading, polymeric interactions, and the nature of polymer swelling, erosion, or degradation. This review compressed on the literature survey about the fabrication of nanofibers by different electrospinning methods, factors affecting the nanofiber morphologies, selectivity of polymeric blends for successful controlled release behavior, and the mechanism involved in the drug release steps.     

Development of Injectable Biodegradable Multi-Arms PEG-Based Hydrogels: Swelling and Degradation Investigations

Summary : Injectable biodegradable hydrogels have been developed to determine the efficacy of biomaterials for the treatment of periodontitis through control delivery of bone-healing bioactives. The hydrogels were prepared from the PEG-ylated macromer of Boltorn™ H20 (BH20) and an acrylated triblock copolymer of polylactide-polyethylene glycol (2k)-polylactide (PLA) in various molar ratios using ammonium persulfate and sodium ascorbate as a free radical initiating system. Preliminary investigations involving the synthesis of PLA hydrogels with different PLLA block lengths were studied in order to determine the swelling ratios and degradation rates of the biodegradable component of the hydrogels prior to copolymerization with BH20. The swelling and degradation studies of PLA with PEG diacrylate (FW 700) hydrogels were established in phosphate buffered saline (PBS) at 37 °C, pH 7.4 and in water (pH ∼5.5). They have been shown to have low swelling ratios (Q_max = 4.4 to 3.6) and degradation times of 20–30 days. The swelling and degradation parameters were found to be dependent on the molar ratio of the PEG diacrylate to PLA in the copolymer.     

UV-photocrosslinking of inulin derivatives to produce hydrogels for drug delivery application

In this work, INU, a natural polysaccharide, has been chemically modified in order to obtain new photocrosslinkable derivatives. To reach this goal, INU has been derivatized with MA thus obtaining four samples (INU-MA derivatives) as a function of the temperature and time of reaction. An aqueous solution of the derivative INU-MA1 was irradiated by using a UV lamp with an emission range from 250 to 364 nm and without using photoinitiators. The obtained hydrogel showed a remarkable water affinity but it underwent a partial degradation in simulated gastric fluid. To overcome this drawback, INU-MA1 was derivatized with SA thus obtaining the INU-MA1-SA derivative designed to produce a hydrogel showing a low swelling and an increased chemical stability in acidic medium. Ibuprofen, as a model drug, was loaded by soaking into INU-MA1 and INU-MA1-SA hydrogels and its release from these matrices was evaluated in simulated gastrointestinal fluids. INU-MA1 hydrogel showed the ability to quickly release the entrapped drug thus indicating its potential as a matrix for an oral formulation. INU-MA1-SA hydrogel showed a pH-responsive drug delivery. Therefore it is a promising candidate for controlled drug release in the intestinal tract.     

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     

Structural Selection in G‐Quartet‐Based Hydrogels and Controlled Release of Bioactive Molecules

A guanosine‐5′‐hydrazide can entrap biologically interesting molecules such as acyclovir, vitamin C, and vancomycin into its hydrogel network. Controlled release of these molecules was monitored by ¹H NMR spectroscopy. The hydrazide may potentially form mixed G–G quartets with analogous compounds containing a guanine group. ¹H NMR spectroscopy was used to study the inclusion of various guanine derivatives into the hydrogel. The structural selectivity was found to depend strongly on both the shape and the charge of the additive and may arise from the strong cohesion of the supramolecular architecture of the gel and the resulting resistance to perturbation by foreign bodies. Hydrogels thus offer a promising medium for highly selective, controlled release of bioactive substances.     

A novel pH‐ and thermo‐sensitive PVP/CMC semi‐IPN hydrogel: Swelling,phase behavior,and drug release study

Poly(N‐vinyl‐pyrrolidone) (PVP) hydrogel has been considered as a very interesting and promising thermosensitive material. The most vital shortcoming of PVP hydrogel as thermosensitive material is that it does not exhibit thermosensitivity under usual conditions. In this work, semi‐interpenetrating polymer network (semi‐IPN) hydrogels based on PVP and carboxymethylcellulose (CMC) were prepared. The volume phase transition temperature (VPTT) of the hydrogels was determined by swelling behavior and differential scanning calorimetry (DSC). The results showed that the VPTT was significantly dependent on CMC content and the pH of the swelling medium. The amount of CMC in the semi‐IPN hydrogels was 0.050, 0.075, and 0.100 g, the VPTT in buffer solution of pH 1.2 was 29.9 °C, 27.5 °C and 24.5 °C, respectively. In addition, the VPTT occurred in buffer solution of pH 1.2, but did not appear in alkaline medium. Bovine serum albumin (BSA) as a model drug was loaded and the in vitro release studies were carried out in different buffer solutions and at different temperatures. The results of this study suggest that PVP/CMC semi‐IPN hydrogels could serve as potential candidates for protein drug delivery in the intestine. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 48: 1749–1756, 2010     

Synthesis and characterization of poly(ethylene glycol)‐based thermo‐responsive polyurethane hydrogels for controlled drug release

The thermo‐responsiveness, swelling and mechanical properties of a series of novel poly(ester‐ether urethane) hydrogels have been investigated. These thermo‐sensitive hydrogels were obtained by combining hydrophobic biodegradable poly(ε‐caprolactone) diols and hydrophilic two‐, three‐ and four‐arm hydroxyl terminated poly(ethylene glycol) (PEG) of various molecular weights, using hexamethylene diisocyanate, dichloroethane as solvent and a tin‐based catalyst. The use of multifunctional PEGs leads to the formation of covalent crosslinking points allowing an additional control of the swelling capability. Thus, it was found that tuning the hydrophilic/hydrophobic balance and the crosslinking degree by changing the composition, the swelling and the thermo‐responsive behavior of these hydrogels could be modulated. The obtained hydrogels showed a volume transition at around room temperature. Therefore, and taking into account their biocompatibility, these hydrogels show promising properties for biomedical applications, such as drug delivery. Thus, the loading and release of diltiazem hydrochloride, an antihypertensive drug used as model, were investigated. These new PEG polyurethane hydrogels were able to incorporate a high amount of drug providing a sustained release after an initial burst effect. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis and characterization of a starch‐modified hydrogel as potential carrier for drug delivery system

Synthesis and characterization of a new hydrogel were carried out using a chemically modified starch (starch‐M) consisting of coupling C?C bounds coming from glycidil methacrylate (GMA) onto the polysaccharide structure. ¹³C NMR, ¹H NMR, and FT‐IR spectroscopies were used to confirm the incorporation of such groups onto the starch‐M. The hydrogel was prepared by a crosslinking polymerization of starch‐M using sodium persulfate as an initiating agent. The starch‐M hydrogel shows morphology clearly different from that of the raw starch film due to the presence of voids on its surface. The swelling process of the starch‐M hydrogel was not significantly affected by changes on the temperature or on pH of the surrounding liquid, indicating the such behavior can be then understood by a diffusional process, resulting from its physical–chemical interactions with the solvent. The values of the diffusional exponent n were on the order of 0.45–0.49 for the range of pHs investigated, demonstrating that the water transport mechanism of starch‐M hydrogel is more dependent on Fickian diffusion, that is, controlled by water diffusion. Such starch‐M hydrogel is a promising candidate to be used in transporting and in preserving acid‐responsive drugs, such as corticoids, for the treatment of colon‐specific diseases, for example, Crohn's disease. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2567–2574, 2008     

Effect of Chemical Crosslinking on the Swelling and Shrinking Properties of Thermal and pH‐Responsive Chitosan Hydrogels

The ability to form a gel through the physical or chemical crosslinking of chitosan has been well documented. In an attempt to mimic biological systems, thermal and pH‐sensitive chitosan cylindrical hydrogels were produced by a combination of physical and chemical crosslinking processes. To this end, chitosan hydrogels prepared from alkali chitin were molded in cylinders and, once washed, were further crosslinked with glutaraldehyde at stoichiometric ratios, R (= [? CH?O]/[? NH₂]), of 1.61 and 3.22 × 10^?2. Variation in swelling as a result of stepwise changes in temperature between 40 and 2 °C at pH values of 7.0, 7.6, and 8.0 revealed that the system responds in markedly different manners dependent upon the pH. At pH 7.0, cooling from 40 to 2 °C results in contraction of the gel network structure. While raising the temperature from 2 to 40 °C leads to a rapid swelling response (i.e., ca. a twofold increase in the amount of solvent uptake). Subsequent cooling to 2 °C is accompanied by a new contraction cycle. At pH ≥ 7.6 the temperature dependence of the swelling–contraction behavior is exactly the opposite of that observed at pH 7.0. Very similar trends were observed for the gels at both degrees of crosslinking. The swelling–shrinking behavior observed in gels of pH ≥ 7.6, is similar in kind to that of uncrosslinked gels and is interpreted in terms of a lower critical solution temperature (LCST) volume phase transition, driven by hydrophobic association, presumably involving residual acetyl groups in the chitin. The results at pH 7.0 suggest that the slight ionization of the ? NH groups leads to destruction of the hydrophobic hydration thus effectively reversing the negative thermal shrinking.

Evolution of the swelling ratio, S, as a function of time and temperature for crosslinked chitosan hydrogels. Circles represent S values recorded at pH 7.0 and triangles those at pH 7.6.     

Investigation of drug release from thermo‐ and pH‐sensitive poly(N‐isopropylacrylamide/itaconic acid) copolymeric hydrogels

N‐Isopropylacrylamide/itaconic acid copolymeric hydrogels were prepared by irradiation of the ternary mixtures of N‐isopropylacrylamide/itaconic acid/water by γ‐rays at ambient temperature. The dependence of swelling properties and phase transitions on the comonomer concentration and temperature were investigated. The hydrogels showed both temperature and pH responses. The effect of comonomer concentration on the uptake and release behavior of the hydrogels was studied. Methylene blue (MB) was used as a model drug for the investigation of drug uptake and release behavior of the hydrogels. The release studies showed that the basic parameters affecting the drug release behavior of the hydrogels were pH and temperature of the solution. Copyright © 2004 John Wiley & Sons, Ltd.     

Poly(2‐oxazoline) Hydrogels: State‐of‐the‐Art and Emerging Applications

The synthesis of poly(2‐oxazoline)s has been known since the 1960s. In the last two decades, they have risen in popularity thanks to improvements in their synthesis and the realization of their potential in the biomedical field due to their “stealth” properties, stimuli responsiveness, and tailorable properties. Even though the bulk of the research to date has been on linear forms of the polymer, they are also of interest for creating network structures due to the relatively easy introduction of reactive functional groups during synthesis that can be cross‐linked under a variety of conditions. This opinion article briefly reviews the history of poly(2‐oxazoline)s and examines the in vivo data on soluble poly(2‐oxazoline)s to date in an effort to predict how hydrogels may perform as implantable materials. This is followed by an overview of the most recent hydrogel synthesis methods and emerging applications, and is concluded with a section on the future directions predicted for these fascinating yet underutilized polymers.     

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     

Hydrogels: From soft contact lenses and implants to self‐assembled nanomaterials

Hydrogels were the first biomaterials designed for clinical use. Their discovery and applications as soft contact lenses and implants are presented. This early hydrogel research served as a foundation for the expansion of biomedical polymers research into new directions: design of stimuli sensitive hydrogels that abruptly change their properties upon application of an external stimulus (pH, temperature, solvent, electrical field, biorecognition) and hydrogels as carriers for the delivery of drugs, peptides, and proteins. Finally, pathways to self‐assembly of block and graft copolymers into hydrogels of precise 3D structures are introduced. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5929–5946, 2009     

pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogels via aza‐michael addition for anticancer drug delivery

A pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogel containing “acetals” as pH‐sensitive groups and “disulfides” as reducible linkages was designed and synthesized via aza‐Michael addition reaction between PAMAM and PEGDA diacrylates. The pore size and swelling ratio of hydrogels was varied from 14 ± 3 to 19 ± 4 μm and 214 ± 13 to 300 ± 19 μm, respectively, with varying ethylene glycol repeating units in diacrylates. The swelling ratio of PEGDA/PAMAM network hydrogel increased with increase in the molecular weight of PEG and with decrease in pH. The presence of different cationizable amino‐functionalities in PEGDA/PAMAM network hydrogel helped to enhance the swelling ability of hydrogel under the acidic conditions. The continuous increase in metabolically active live HeLa cells with time in MTT assay implied biocompatibility/noncytotoxicity of the synthesized PEGDA/PAMAM injectable network hydrogel. Furthermore, the prepared PEGDA/PAMAM hydrogel showed higher degradation at lower pH and at higher concentration of DTT. The burst release of doxorubicin from PEGDA/PAMAM hydrogel under the environment of the lower pH and in presence of DTT compared to the release at normal physiological pH and in absence of DTT suggested the potential ability of this model hydrogel system for targeted and selective anticancer drug release at tumor tissues. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2080–2095