Dextran Methacrylate Research Articles

Novel injectable and in situ cross-linkable hydrogels of dextran methacrylate and scleroglucan derivatives: Preparation and characterization

In this paper mixtures of two biocompatible polymers, dextran methacrylate (DEX-MA) with different molecular weights and scleroglucan (Scl), in its native form and as carboxymethyl derivative (Scl-CM), were tested as injectable and in situ cross-linkable systems. Rheological and texture analyses were carried out to better investigate the behavior of this kind of matrices. The combination of these polymers is able to assure adequate mechanical properties, suitable for biomedical applications. In addition swelling studies and in vitro release studies of three different biomolecules were also carried out.

Cryo-copolymerization preparation of dextran-hyaluronate based supermacroporous cryogel scaffolds for tissue engineering applications

Dextran-hyaluronate (Dex-HA) based supermacroporous cryogel scaffolds for soft tissue engineering were prepared by free radical cryo-copolymerization of aqueous solutions containing the dextran methacrylate (Dex-MA) and hyaluronate methacrylate (HA-MA) at various macromonomer concentrations under the freezing condition. It was observed that the suitable total concentration of macromonomers for the preparation of Dex-HA cryogel scaffold with satisfied properties was 5% (w/w) at the HA-MA concentration of 1% (w/v), which was then used to produce the test scaffold. The obtained cryogel scaffold with 5% (w/w) macromonomer solution had high water permeability (5.1 × 10−12 m2) and high porosity (92.4%). The pore diameter examined by scanning electron microscopy (SEM) was in a broad range of 50–135 μm with the mean pore diameter of 91 μm. Furthermore, the cryogel scaffold also had good elastic nature with the elastic modulus of 17.47±1.44 kPa. The culture of 3T3-L1 preadipocyte within the scaffold was investigated and observed by SEM. Cells clustered on the pore walls and grew inside the scaffold indicating the Dex-HA cryogel scaffold could be a promising porous biomaterial for applications in tissue engineering.

Calcium alginate/dextran methacrylate IPN beads as protecting carriers for protein delivery

In the present study, mechanical and protein delivery properties of a system based on the interpenetration of calcium-alginate (Ca-Alg) and dextran-methacrylate (Dex-MA) networks are shown. Interpenetrated hydrogels beads were prepared by means of the alginate chains crosslinking with calcium ions, followed by the exposure to UV light that allows the Dex-MA network formation. Optical microscope analysis showed an average diameter of the IPN beads (Ca-Alg/Dex-MA) of 2mm. This dimension was smaller than that of Ca-Alg beads because of the Dex-MA presence. Moreover, the strength of the IPN beads, and of their corresponding hydrogels, was influenced by the Dex-MA concentration and the crosslinking time. Model proteins (BSA and HRP) were successfully entrapped into the beads and released at a controlled rate, modulated by changing the Dex-MA concentration. The enzymatic activity of HRP released from the beads was maintained. These novel IPN beads have great potential as protein delivery system.

Preparation of cationic biodegradable dextran microspheres loaded with BSA and study on the mechanism of protein loading

Aim: The aim of this study was to investigate the feasibility of cationic biodegradable dextran microspheres loaded with bovine serum albumin (BSA) posterior to gel formation (postloading).Method: Positively charged microspheres were prepared by polymerization of hydroxylethyl methacrylate–derivatized dextran (dex-HEMA) and dimethyl aminoethyl methacrylate (DMAEMA) in an aqueous two-phase system and net positive surface charge increased with increasing amounts of DMAEMA. Loading efficiency of dextran microspheres for BSA was analyzed through fluorescence microscopy and measured. The BSA release from the cationic dextran microspheres in vitro was investigated.Results: BSA could penetrate into cationic dextran microspheres, but neutral dextran microspheres could not. Protein-loading efficiency (98.1–100%) by postloading was higher compared with by preloading (60.2–75.9%), when the incubated protein concentration was below 1.5 mg/ml. Even though BSA is incorporated in the hydrogel network based on electrostatic interaction, a controlled release can be achieved by varying the initial network density of the microspheres.Conclusion: These findings suggest that it is a feasible method to prepare dextran microspheres with high surface-charge density to efficiently adsorb oppositely charged protein based on electrostatic interactions.

Glucose-responsive insulin delivery microhydrogels from methacrylated dextran/concanavalin A: preparation and in vitro release study.

Glucose-responsive systems are very important for self-regulated insulin delivery. The aim of the present study was to evaluate the potential of insulin loaded microhydrogels fabricated from methacrylate derivatives of dextran (Dex-G) and concanavalin A (Con A-E) as a insulin delivery system releasing insulin in response to different glucose levels. Insulin-loaded microhydrogels were prepared through a reversed-phase emulsion crosslinking method. The morphology and size of obtained microhydrogels were characterized by SEM, fluorescence microscope and dynamic light scattering, which showed that these microhydrogels were formed with sphere-like shape and diameters less than 5 μm. In vitro release of insulin from these microhydrogels and release kinetics were studied. The results indicated that insulin release was reversible in response to different glucose concentrations and the released insulin was shown to remain active since the tertiary structure was not destroyed. The degree of substitution (DS) of dextran methacrylate derivatives had effects on the release rate and surface burst release of the microhydrogels and high DS of Dex-G (DS 32) restricted the glucose sensitivity of the microhydrogels. The MTT assay from L929 cell line indicated that these microhydrogels possessed noncytotoxicity. The results suggested that these microhydrogels might be suitable for self-regulated insulin delivery and find potential applications in biomedical fields.

Enzymatically degradable nanogels by inverse miniemulsion copolymerization of acrylamide with dextran methacrylates as crosslinkers

Polyacrylamide nanogels crosslinked with dextran methacrylate were prepared by free radical copolymerization in inverse miniemulsion and their degradation by enzymatic cleavage of the polysaccharide chains was investigated.

Mesh size distribution determination of interpenetrating polymer network hydrogels

The importance of Interpenetrating Polymer Networks (IPNs) in biomedical and pharmaceutical fields is continuously growing because of their mechanical and drug carrier tailoring opportunities. This paper deals with the physico-chemical characterization of an IPN hydrogel based on calcium-alginate and a dextran methacrylate derivative. The attention is focused on the determination of IPN mesh size distribution. For this purpose, two different approaches were applied, namely using a combination of rheological and low field NMR characterization, and cryoporosimetry. Appropriate mathematical models were developed for the interpretation of the experimental data. Both approaches led to a mono-modal mesh size distribution spanning the same size range but characterized by different mean values (25 nm, Rheo-NMR; 44 nm, cryoporosimetry). This is probably due to mesh widening upon water freezing. Moreover, release experiments of a model protein – myoglobin – from the IPN were performed and the obtained data were combined with the results of the two above mentioned approaches. Release tests yielded an estimation of the mean mesh size that is closer to that obtained according to the rheology–NMR approach than that resulting from cryoporosimetry measurements.

Glucose-responsive microhydrogels based on methacrylate modified dextran/concanavalin A for insulin delivery

Summary Glucose-responsive microhydrogels based on methacrylate derivatives of dextran and concanavalin A have been prepared and used for self-regulated insulin delivery. Insulin release from these microhydrogels was in response to different glucose concentrations in the medium and the glucose sensitivity was reversible. The released insulin was proved to remain active without destroying the tertiary structure. The degree of substitution (DS) of the dextran methacrylate derivative had effect on the glucose sensitivity of the microhydrogels.

Synthesis of Photopolymerizable Hydrophilic Macromers and Evaluation of Their Applicability as Reactive Resin Components for the Fabrication of Three‐Dimensionally Structured Hydrogel Matrices by 2‐Photon‐Polymerization

AbstractTwo‐photon polymerization (2‐PP) is a promising new photolithographic technique to fabricate three‐dimensional (3D), micro‐ and nano‐structured tissue engineering scaffolds from photopolymerizable monomers. Although various photo resins are known for the use in 2‐PP, there is currently a need for photo‐curable monomers processable by 2‐PP to generate biocompatible 3D‐structured hydrogel materials for soft or cartilage tissue regeneration. In the present work hydrophilic methacrylate monomers and macromers based on synthetic poly(glycerine) and poly(ethylene glycol) urethanes as well as on the biopolymers dextran and hyaluronan is prepared. The photopolymerization behavior of these substances are investigated and formed hydrogel networks are studied with regard to their mechanical properties, cytocompatibility, and hydrolytic degradation. Based on these examinations simple 3D model structures are fabricated from these photo‐curable monomers and macromers by 2‐PP. It is shown that both the synthetic monomers and the dextran methacrylate macromer are efficient 2‐PP starting materials whereas the hyaluronan methacrylate can be used for 2‐PP only in combination with suitable water‐soluble co‐monomers. No cytotoxic effects are found in preliminary chondrocyte cultivation experiments on 2‐PP‐fabricated scaffolds but initial cell adhesion on the hydrophilic scaffold surfaces is rather low and has to be further improved to apply these structures in tissue engineering.

Effect of varying molecular weight of dextran on acrylic-derivatized dextran and concanavalin A glucose-responsive materials for closed-loop insulin delivery

Aim: Dextran methacrylate (dex-MA) and concanavalin A (con A)-methacrylamide were photopolymerized to produce covalently cross-linked glucose-sensitive gels for the basis of an implantable closed-loop insulin delivery device. Methods: The viscoelastic properties of these polymerized gels were tested rheologically in the non-destructive oscillatory mode within the linear viscoelastic range at glucose concentrations between 0 and 5% (w/w). Results: For each cross-linked gel, as the glucose concentration was raised, a decrease in storage modulus, loss modulus and complex viscosity (compared at 1 Hz) was observed, indicating that these materials were glucose responsive. The higher molecular weight acrylic-derivatized dextrans [degree of substitution (DS) 3 and 8%] produced higher complex viscosities across the glucose concentration range. Conclusions: These studies coupled with in vitro diffusion experiments show that dex-MA of 70 kDa and DS (3%) was the optimum mass average molar mass to produce gels that show reduced component leach, glucose responsiveness, and insulin transport useful as part of a self-regulating insulin delivery device.

Preparation of hydrogels via ultrasonic polymerization

Several acrylic hydrogels were prepared via ultrasonic polymerization of water soluble monomers and macromonomers. Ultrasound was used to create initiating radicals in viscous aqueous monomer solutions using the additives glycerol, sorbitol or glucose in an open system at 37 °C. The water soluble additives were essential for the hydrogel production, glycerol being the most effective. Hydrogels were prepared from the monomers 2-hydroxyethyl methacrylate, poly(ethylene glycol) dimethacrylate, dextran methacrylate, acrylic acid/ethylene glycol dimethacrylate and acrylamide/bis-acrylamide. For example a 5% w/w solution of dextran methacrylate formed a hydrogel in 6.5 min in a 70% w/w solution of glycerol in water at 37° C with 20 kHz ultrasound, 56 W cm −2. The ultrasonic polymerization method described here has a wide range of applications such a biomaterial synthesis where initiators are not desired.

Fabrication of a biodegradable polysaccharide hydrogel with riboflavin, vitamin B2, as a photo‐initiator and L‐arginine as coinitiator upon UV irradiation

The objective of this study is to develop a completely natural material based photo-initiation system for fabricating biologically compatible hydrogels, that is, free of any synthetic materials like conventional synthetic photo-initiators. The resulting biodegradable hydrogels would be completely free of conventional toxic synthetic substances. Dextran-based precursor was used as a model system for this study. The natural material based photo-initiation system used riboflavin (vitamin B2) as photo-initiator and L-arginine as a coinitiator. Dextran-methacrylate precursor was prepared to introduce photosensitive unsaturated moieties into dextran for subsequent photo-induced gel formation. Riboflavin alone could not initiate the photo-crosslinking reaction of the dextran methacrylate solution upon UV irradiation. L-arginine, which can act as an electron donor in the photo-initiation process, was used as a coinitiator. The optimum gel formulation conditions in terms of the concentrations of riboflavin and L-arginine as well as different pH media were extensively investigated. The dextran-methacrylate hydrogels were formed well and fast at low riboflavin concentration range (0.2-1 wt %), and L-arginine promoted the photo-initiation at all concentrations. The gelation was promoted most in the neutral pH and the least in the alkaline pH. The turbidity of the dextran-methacrylate hydrogel precursor solution affected the polymerization because UV penetration was significantly hindered as the opacity of the solution increased. The swelling property and structural visualization of the prepared hydrogels were also investigated.

Injectable and in situ gelling hydrogels for modified protein release

A novel injectable polysaccharide system based on calcium Alginate (Ca-Alg) hydrogel and two Dextran methacrylate derivatives (DexMA) was recently developed. The resulting Interpenetrating Polymer Network showed a synergistic mechanical behavior that can be exploited to target the hydrogel properties towards specific biomedical needs. In the present paper, hydrogels composed of 3% (w/v) Ca-Alg and Dextran (Mw 40 x 10(4) and 500 x 10(4)), derivatized with methacrylic groups (derivatization degrees 5 and 30%) at concentrations 5% (w/v), were characterized. The data reported here evidenced that Mw and derivatization degree of Dex chains can deeply affect the mechanical as well a model protein (Horseradish peroxidase) delivery rate. The enzymatic activity of such model protein was never significantly altered by the adopted experimental conditions.

In Situ Cross-Linkable Novel Alginate-Dextran Methacrylate IPN Hydrogels for Biomedical Applications: Mechanical Characterization and Drug Delivery Properties

In situ polymerizable hydrogels are extensively investigated to implement new biomedical and pharmaceutical approaches. In the present paper a novel polysaccharidic matrix based on calcium alginate (Ca(II)-Alg) hydrogel and dextran methacrylate derivative (Dex-MA), showing potential applicability in the field of pharmaceutics is described. The semi-interpenetrating polymer system (semi-IPN) obtained by a dispersion of Dex-MA chains into a Ca(II) hydrogel leads to a hydrogel with rheological properties quite different from those of Ca(II)-Alg, allowing to inject the semi-IPN easily through an hypodermic needle. The UV curing of the semi-IPN, by cross-linking of the methacrylate moieties, leads to an IPN strong hydrogel that can be used for a modulated delivery of bioactive molecules. In the present paper, rheological and mechanical behaviors of the semi-IPN and of the IPN are discussed. The release of model molecules, including a protein, are also presented to show the suitability of the novel system as a drug delivery system.

UV Cross-Linked Dextran Methacrylate—Concanavalin A Methacrylamide Gel Materials for Self-Regulated Insulin Delivery

In this study, the successful acrylic derivatization of dextran and concanavalin A (con A) to form dextran methacrylate and con A methacrylamide is shown. These derivatized acrylic monomers are then photopolymerized in the presence of a water soluble photoinitiator Irgacure® under various conditions to form covalently bonded glucose-responsive gel materials, which undergo a transformation to sol in the presence of free glucose. Rheological data have revealed that as the degree of substitution for dextran methacrylate is increased, a more elastic material is produced due to the increased covalent linkages. Some of these gel systems show negligible component loss in in vitro diffusion experiments used to simulate the behavior of the cross-linked gel, as would be used in a self-regulated insulin delivery device.

Development of a reversed-phase high-performance liquid chromatography method for the analysis of components from a closed-loop insulin delivery system

A reversed-phase HPLC method has been developed which enables separation of the three components of a closed-loop insulin delivery system, namely concanavalin A methacrylamide (Con A-MA), dextran methacrylate (Dex-MA) and bovine insulin. The analysis of Con A-MA represents a significant challenge due to the formation of multiple conformations on contact with the chromatographic surface and the mobile phase. The extent of conformational change is shown to be dependent on a number of parameters: column temperature, mobile phase pH, contact time with the chromatographic surface, salt type and concentration and the organic modifier. By manipulation of these variables, protein denaturation can be minimised and recovery improved.

Solid lipid nanoparticles incorporated in dextran hydrogels: A new drug delivery system for oral formulations

Solid lipid nanoparticles (SLN) containing or not ( S)-(+)-2-(4-isobutylphenyl)propionic acid (ibuprofen) were prepared with Preciol ATO 5 as lipid phase by the hot homogenization technique and characterized through particle size analyses and zeta potential measurements. DSC experiments carried out on the freeze-dried samples of loaded SLN showed a shift of the melting endotherm of the lipid phase, with the maximum at a temperature value higher then that of the“empty” SLN. 1H NMR of the nanosuspension allowed to calculate the encapsulation efficiency of the particles that was 52 ± 3%. By adding dextran methacrylate (DEX-MA) to the aqueous phase and submitting the mixture to UV irradiation, systems of SLN (drug-loaded and unloaded) incorporated into a dextran hydrogel were prepared. Finally, dissolution studies of ibuprofen from the freeze-dried samples were performed. The comparison among the release profiles of ibuprofen from SLN, DEX-MA hydrogel and SLN/DEX-MA-hydrogel allows to affirm that this last system, retaining about 60% of the drug after 2 h in acid medium and releasing it slowly in neutral solution, is suitable for modified delivery oral formulations.

The effect of degree of acrylic derivatisation on dextran and concanavalin A glucose-responsive materials for closed-loop insulin delivery

Formulations of dextran methacrylate (dex-MA) and concanavalin A methacrylamide (con A-MA) were photo-polymerized to produce covalently cross-linked glucose-responsive materials for the basis of a closed-loop insulin delivery device. The viscoelastic properties of these polymerised materials were tested rheologically in the non-destructive oscillatory mode within the linear viscoelastic range at glucose concentrations between 0% and 5% w/w. The degree of acrylic substitution was varied for the dex-MA and con A-MA, and as the formulation glucose concentration was raised, a graded decrease in storage modulus, loss modulus and complex viscosity when compared at 1 Hz was observed for each cross-linked material. Increasing the degree of substitution (DS) of the derivatised dextran produced viscosity profiles at higher values throughout the glucose concentration range. A comparison with non-polymerised mixtures shows similar rheological properties but at much lower values across the chosen glucose concentration range. High-pressure liquid chromatography analyses and in vitro diffusion experiments showed that there were optimum degrees of derivatisation to minimise dex-MA and con A-MA component leach from the material. The in vitro diffusion experiments also showed that differential delivery of insulin in response to glucose was possible with candidate polymerised glucose-responsive formulations, thus highlighting the potential of such a novel glucose-sensitive material to be used as part of implantable closed-loop insulin delivery device.

On the release of proteins from degrading dextran methacrylate hydrogels and the correlation with the rheologic properties of the hydrogels.

To study the release of macromolecules of different sizes (bovine serum albumin, immunoglobulin G) from degrading (addition of dextranase) dextran methacrylate (dex-MA) hydrogels and to correlate the release with the evolution of the rehologic properties of the hydrogels during degradation. The size of the macromolecules, the degree of substitution (i.e., number of methacrylates per 100 glycopyranose residues) of the dex-MA and the dextranase concentration in the hydrogels was varied. The rheologic properties were measured with a controlled stress rheometer. The release from dex-MA hydrogels without dextranase was very small [7-20% (time frame up to 180 days)] showing that most of the molecules were entrapped within the hydrogel network. The release from degrading dex-MA hydrogels followed zero-order kinetics for all molecules during a substantial period of the release. This was explained by a liberation and an increasing diffusivity of the proteins in the course of the degradation. The total amount released and the release rates could be well correlated with the rheologically observed degradation rates. It was shown that rheology can be a useful tool to help explain the release from degrading hydrogels.

Influence of the Degradation Mechanism of Hydrogels on Their Elastic and Swelling Properties during Degradation

The aim of this study was to investigate the degradation of hydrogels that degrade through different mechanisms. As models, two types of dextran-based hydrogels were investigated. Dextran methacrylate (dex-MA) hydrogels that are degraded by entrapped dextranase were used as a model for hydrogels that degrade by hydrolysis of the polymer backbone. Dextran hydroxyethyl methacrylate (dex-HEMA) hydrogels were used as a model for hydrogels that degrade by hydrolysis of the cross-links. The degradation was characterized rheologically and analytically by determination of the degradation products and by the swelling behavior of the hydrogels. The degradation kinetics as observed from the various characterization techniques were distinctively different and depended on both the composition of the hydrogels and the degradation mechanism. Combining all the results, a qualitative understanding could be proposed for the degradation of the polymer networks of both types of hydrogels. The insight obtained can help the de...