Biodegradable Microgels Research Articles

Biodegradable Dextrin-Based Microgels for Slow Release of Dual Fertilizers for Sustainable Agriculture.

In this research, we report dextrin-based biodegradable microgels (PDXE MGs) having phosphate-based cross-linking units for slow release of urea and a potential P source to improve fertilization. PDXE MGs (∼200 nm) are synthesized by cross-linking the lauroyl-functionalized dextrin chains with sodium tripolyphosphate. The developed PDXE MGs exhibit high loading (∼10%) and encapsulation efficiency (∼88%) for urea. It is observed that functionalization of PDXE MGs with lauroyl chains slows down the release of urea (90% in ∼24 days) as compared to nonfunctionalized microgels (PDX MGs) (99% in ∼17 days) in water. Further studies of the developed formulation display that Urea@PDXE MGs significantly boost maize seed germination and overall plant growth as compared to pure urea fertilizer. Moreover, analysis of maize leaves obtained from plants treated with Urea@PDXE MGs reveals 3.5 ± 0.3% nitrogen content and 90 ± 0.7 mg/g chlorophyll content. These values are significantly higher than 1.4 ± 0.6% nitrogen content and 48 ± 0.05 mg/g chlorophyll content obtained by using bare urea. Further, acid phosphatase activity in roots is reduced upon treatment with PDXE MGs and Urea@PDXE MGs, suggesting the availability of P upon degradation of PDXE MGs by the amylase enzyme in soil. These experimental results present the developed microgel-based biodegradable formulation with a slow release feature as a potential candidate to move toward sustainable agriculture practices.

Degradation Kinetics of Disulfide Cross-Linked Microgels: Real-Time Monitoring by Confocal Microscopy.

Although biodegradable microgels represent a useful drug delivery system, questions remain regarding the kinetics of gel degradation and subsequent drug release. Spherical microgels (~Ø10-300 µm) were synthesized using an inverse suspension polymerization method. Specifically, acrylamide and acrylonitrile monomers were thermally co-polymerized with N,N'-bis(acryloyl)cystamine as a cross-linker with disulfide bridges. The kinetics and mechanism of degradation of these cross-linked, degradable, fluorescently labeled microgels (PAAm-AN-BAC-FA) were quantitatively studied under confocal microscopy at various concentrations of glutathione (reducing agent) ranging from 0.06 to 91.8 mM. It was found that polymer network degradation via the cleavage of disulfide bonds was accompanied by two overlapping processes: diffusion-driven swelling and dissolution-driven erosion. A slow increase in microgel size (swelling) resulted from partial de-cross-linking in the bulk of the microgel, whereas a faster decrease in fluorescence intensity (erosion) resulted from the complete cleavage of disulfide bonds and the release of uncleaved polymeric chains from the microgel immediate surface into the solution. Swelling and erosion exhibited distinct kinetics and characteristic times. Importantly, the dependence of kinetics on glutathione concentration for both swelling and erosion suggests that degradation would occur faster in cancer cells (higher concentration of reductants) than in normal cells (lower concentration of reductants), such that drug release profiles would be correspondingly different. A greater comprehension of microgel degradation kinetics would help in (i) predicting the drug release profiles for novel multifunctional drug delivery systems and (ii) using redox-sensitive degradable hydrogel particles to determine the concentrations of reducing agents either in vitro or in vivo.

Electroactive and degradable supramolecular microgels.

In this work, we synthesized electroactive and degradable microgels based on biomacromolecular building blocks, which enable the controlled release of therapeutic drugs. Functional chitosan-poly(hydroquinone) (Ch:PHQ) microgels exhibiting redox-active and pH-sensitive properties were synthesized by an oxidative polymerization in an inverse miniemulsion system. Physically crosslinked microgels were formed by polymerization of hydroquinone in the presence of chitosan through the formation of hydrogen bonds between PHQ and Ch. A series of microgel samples with variable Ch : PHQ ratios were synthesized. These obtained microgels exhibit pH-responsive properties due to the protonation/deprotonation of amino-groups of chitosan in the microgel system. Poly(hydroquinone) is a redox-active polymer exhibiting a two-electron/proton-transfer behavior and conveys this property to the microgels as confirmed by cyclic voltammetry. In addition, the microgels can be switched by electrochemical means: they swell in the oxidized state or shrink in the reduced state. In the presence of urea or lysozyme, the microgels undergo a fast degradation due to the disruption of hydrogen bonds acting as physical crosslinks in the microgel networks or due to the cleavage of glucosidic linkages of the incorporated chitosan scaffold, respectively. Doxorubicin (DOX), an anticancer drug, could be effectively encapsulated into the microgels and released in the presence of an enzyme, indicating that these biodegradable microgels could be used as drug delivery vehicles for tumor cells.

Sealing hyaluronic acid microgels with oppositely-charged polypeptides: A simple strategy for packaging hydrophilic drugs with on-demand release

A simple route to deliver on demand hydrosoluble molecules such as peptides, packaged in biocompatible and biodegradable microgels, is presented. Hyaluronic acid hydrogel particles with a controlled structure are prepared using a microfluidic approach. Their porosity and their rigidity can be tuned by changing the crosslinking density. These negatively-charged polyelectrolytes interact strongly with positively-charged linear peptides such as poly-l-lysine (PLL). Their interactions induce microgel deswelling and inhibit microgel enzymatic degradability by hyaluronidase. While small PLL penetrate the whole volume of the microgel, PLL larger than the mesh size of the network remain confined at its periphery. They make a complexed layer with reduced pore size, which insulates the microgel inner core from the outer medium. Consequently, enzymatic degradation of the matrix is fully inhibited and non-affinity hydrophilic species can be trapped in the core. Indeed, negatively-charged or small neutral peptides, without interactions with the network, usually diffuse freely across the network. By simple addition of large PLL, they are packaged in the core and can be released on demand, upon introduction of an enzyme that degrades selectively the capping agent. Single polyelectrolyte layer appears as a simple generic method to coat hydrogel-based materials of various scales for encapsulation and controlled delivery of hydrosoluble molecules.

Dual Responsive Poly(N-vinylcaprolactam) Based Degradable Microgels for Drug Delivery

Poly(N-vinylcaprolactam)-based biodegradable microgels are prepared for drug delivery application via precipitation polymerization using diacetone acrylamide (DAAM) and dimethyl itaconate (IADME) as comonomers. The microgel particles are subsequently crosslinked by addition of adipic acid dihydrazide, which reacts with the ketone groups of DAAM. Itaconic acid (IA) groups are generated by the hydrolysis of IADME units inside the microgels resulting into both pH and temperature sensitive microgel particles. Volume phase transition temperature of the obtained microgels is influenced by both IA content and pH of the surrounding medium. Due to the incorporation of hydrazone linkages, the microgels show degradation under acidic conditions. These microgels can effectively encapsulate doxorubicin (DOX) as a model drug and show low DOX leakage under physiological conditions while rapid DOX release is observed at low pH. The results of the cytotoxicity assay further display that the DOX-loaded microgels exhibit effective antitumor activity against HeLa cells demonstrating their great potential as drug delivery carriers for cancer therapy.

Controlled uptake and release of lysozyme from glycerol diglycidyl ether cross-linked oxidized starch microgel.

A biodegradable microgel system based on glycerol-1,3-diglycidyl ether (GDGE) cross-linked TEMPO-oxidized potato starch polymers was developed for controlled uptake and release of proteins. A series of microgels were prepared with a wide range of charge density and cross-link density. We found both swelling capacity (SWw) and lysozyme uptake at saturation (Γsat) increased with increasing degree of oxidation (DO) and decreasing cross-link density. Microgel of DO100% with a low cross-link density (RGDGE/polymer (w/w) of 0.025) was selected to be the optimum gel type for lysozyme absorption; Γsat increased with increasing pH and decreasing ionic strength. It suggests that the binding strength was the strongest at high pH and low ionic strength, which was recognized as the optimum absorption conditions. The lysozyme release was promoted at low pH and high ionic strength, which were considered to be the most suitable conditions for triggering protein release. These results may provide useful information for the controlled uptake and release of proteins by oxidized starch microgels.

Poly(vinylcaprolactam)-Based Biodegradable Multiresponsive Microgels for Drug Delivery

Poly(vinylcaprolactam) (PVCL)-based biodegradable microgels were prepared for the biomedical application as drug delivery system via precipitation polymerization, where N,N-bis(acryloyl) cystamine (BAC) served as cross-linker, methacrylic acid (MAA) and polyethylene glycol (PEG) methyl ether methacrylate acted as comonomers. The microgels with excellent stability had distinct temperature sensitivity as largely observed in the case of PVCL-based particles and their volume phase transition temperature (VPTT) shifted to higher temperature with increasing MAA content and ambient pH. In the presence of reducing agent glutathione (GSH) or dithiothreitol (DTT), the microgels could be degraded into individual linear polymer chains by the cleavage of the disulfide linkages coming from the cross-linker BAC. The microgels could effectively encapsulate Doxorubicin (DOX) inside and presented stimuli-triggered drug release in acidic or reducing environment. The results of the cytotoxicity assays further demonstrated that the blank microgels were nontoxic to normal cells while DOX-loaded microgels presented efficient antitumor activity to HeLa cells.

Facile synthesis of thermo- and pH-responsive biodegradable microgels

A novel and facile strategy has been designed to prepare biodegradable microgels with thermo- and pH-responsive property. The microgels were synthesized by the crosslinking of N-isopropylacrylamide with vinyl groups functionalized poly(L-glutamic acid) (PGA). The resultant microgels exhibited pH-dependent phase transition behaviors in aqueous solutions and underwent abrupt lower critical solution temperature decrease when the pH was reduced below the pK a of PGA. Dynamic light scattering measurement revealed that the microgels exhibited shrinkage as the temperature increased or the pH decreased.

Facile Preparation of Chemically Cross-Linked Microgels by Irradiation of Visible Light at Room Temperature

We report on the facile preparation of chemically cross-linked microgels in mild conditions by using the reversed microemulsion technique. Sodium alginate has been modified by partially grafting phenol groups to the backbone, on the basis of which microgels have been prepared by the irradiation of visible light in the presence of catalyst Ru(II) complex at room temperature. The irradiation of visible light instead of UV light or gamma rays brings many advantages. The mean diameters of the microgels are 15-40 microm in aqueous solution and 5-15 microm in the dried state. Although the size of the microgel is sensitive to the environment change, it presents excellent size stability in a broad range that covers the physiological condition. The applications of this biocompatible and biodegradable microgel in biology are greatly anticipated.

Preparation and Characterization of Oxidized Starch Polymer Microgels for Encapsulation and Controlled Release of Functional Ingredients

A novel biocompatible and biodegradable microgel system has been developed for controlled uptake and release of especially proteins. It contains TEMPO-oxidized potato starch polymers, which are chemically cross-linked by sodium trimetaphosphate (STMP). Physical chemical properties have been determined for microgels of different weight ratios of cross-linker to polymer (0.10, 0.15, 0.20, 0.30, and 0.40) and degrees of oxidation (30, 50, 70, and 100%). The charge density of the microgels as determined by proton titration is found to be in good agreement with the expected degree of oxidation (DO). The electrophoretic mobility of the microgel particles is used as a qualitative indicator of the pore size and scales with microgel swelling capacity as expected. The swelling capacity increases with increasing pH and decreasing salt concentration. Preliminary data for the uptake of the globular protein lysozyme by the microgels show it increases with increasing DO and decreasing cross-linker to polymer ratio. Highly charged microgels with intermediate cross-linker to polymer ratios (0.15 and 0.2) are found to be optimal for encapsulating lysozyme.

Pulsed in vitro release and in vivo behavior of exploding microcapsules

Drug delivery systems which can generate multiple drug pulses after a single injection can be of major importance for e.g. the delivery of vaccines which often require multiple booster injections to generate sufficient immunity. In this paper, we report self-exploding microcapsules which can release their content in a pulsed fashion after a certain incubation time at physiological conditions. The system is based on a biodegradable microgel core surrounded by a bio-polyelectrolyte membrane. When the microgel core degrades, the swelling pressure increases and finally ruptures the membrane leading to release of the encapsulated materials. We show that the explosion time and subsequent release of 50 nm latex nanoparticles (used as a model), can be tailored by varying the cross-link density of the microgels. Further we also address the biocompatibility in vivo after subcutaneous injection of the microcapsules in mice.

Preparation of thermosensitive microgels via suspension polymerization using different temperature protocols

A thermosensitive and biodegradable microgel for protein drug release was synthesized from a thermosensitive macromer via inverse suspension polymerization. Preparation was made under a constant temperature or under variable temperatures. In the latter protocol, dispersion was performed at a low temperature below lower critical solution temperature of the macromer aqueous solution and polymerization was performed at a high temperature above lower critical solution temperature. According to the experiments, the constant-temperature method was not suitable for preparation of microgels when the macromer concentration was high, because early physical gelation at the preparation temperature seriously influenced formation of dispersed droplets. If the macromer concentration was low, both temperature protocols resulted in spherical hydrogel microparticles, but the properties of the resulting microgels were different to a certain degree. In both cases, the model protein bovine serum albumin was loaded into microgels by a postfabrication encapsulation technique, which takes advantage of the microgels' negative thermosensitivity. The results demonstrate that, in microgel preparation, the variable-temperature protocol is useful in suspension polymerization of negatively thermosensitive macromers at a wide rage of monomer concentrations.

Preparation of a thermosensitive and biodegradable microgel via polymerization of macromonomers based on diacrylated Pluronic/oligoester copolymers

Abstract A novel biodegradable and thermosensitive hydrogel microparticle was prepared via suspension polymerization of a kind of block copolymer macromonomers. According to the molecular design, the macromonomer is composed of a thermosensitive triblock copolymer poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) and two oligomers of biodegradable polyester such as oligo(lactic acid) or oligo(e-caprolactone), and end-capped with acryloyl groups. Microgels were obtained by inverse suspension polymerization of the macromonomer aqueous droplets initiated by a redox initiator. Thermosensitivity and in vitro biodegradation of the resultant microgels were confirmed. The gel microparticles in an aqueous solution were swollen at low temperature and shrunken at high temperature (human body temperature). Degradation rate could be adjusted by controlling the composition and the degree of polymerization of oligoester. Thus, the microgels exhibit combinatory and tunable properties.

A novel microgel and associated post-fabrication encapsulation technique of proteins

A novel negatively thermo-sensitive and biodegradable microgel was prepared by combination of macromer synthesis and inverse suspension polymerization. A new post-fabrication encapsulation technique based upon this kind of intelligent microgel was developed. Model proteins (hemoglobin, bovine serum albumin and insulin) were encapsulated into the microgels at 4 °C and released in vitro at 37 °C. Relatively high loading levels and sustained release profiles demonstrate the feasibility of the encapsulation strategy. Since the encapsulation of proteins was performed at low temperature and after the preparation of microgels, organic solvent and high temperature were completely avoided in drug encapsulation. FTIR, Raman and circular dichroism measurements confirmed that the ordered structure of proteins was not destroyed during encapsulation and after release. Thus, the post-fabrication encapsulation technique in this paper is much unique and beneficial for controlled release of biomacromolecular drugs.