Macromolecular Diffusion in Self-Assembling Biodegradable Thermosensitive Hydrogels (original) (raw)
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In-situ crosslinkable thermo-responsive hydrogels for drug delivery
Journal of Controlled Release, 2006
because rheological experiments indicate that the storage modulus of the gels (not exposed to additional buffer) does not change during the first two days. It was also noticed that the gels degrade in time. Degradation will lead to removal of physical crosslinks, increased swelling and final disintegration of the network. All these factors will influence the release behavior of the protein, like lysozyme. The release behavior at pH 5 (results not shown) was similar to that at pH 7. It has been shown that at pH 5 the hydrogel shows only negligible swelling and degradation over the release period . Apparently, at these conditions the mesh size of the gel is larger than the hydrodynamic diameter of lysozyme. shows that the release rate of IgG increases with decreasing polymer concentration, while increasing the PLA block length causes only a small increase in the release rate. The release of IgG, using corresponding gels, is much slower than the release of lysozyme. The same processes (swelling, degradation) will occur as with the gels used for lysozyme. In this case, the initial mesh size of the gels is smaller or close to the hydrodynamic diameter of IgG. After additional swelling and degradation, the protein can be released and for the gels at 12.5 w/v% polymer concentration the release rate in time does not vary much during the first 16 days. Hydrogels with a lower polymer concentration of 7.5 w/v% show a biphasic release, in which the release after 6 days is accelerated, probably because of dissolution of the polymer after degradation of the network. After 20 days, IgG is not completely retrieved, which may be due to partial denaturation or adsorption onto hydrophobic domains during the release experiment.
Biomacromolecules, 2005
A series of hydrogels with both thermoresponsive and completely biodegradable properties was developed for aqueous encapsulation and controlled release of hydrophilic drugs in response to temperature change. The hydrogels were prepared in phosphate-buffered saline (pH 7.4) through free radical polymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-2-hydroxyethyl methacrylate units (Dex-lactateHEMA). Swelling measurement results demonstrated that four gels with feeding weight ratios of NIPAAm:Dex-lactateHEMA ) 7:2, 6:3, 5:4, and 4:5 (w/w) were thermoresponsive by showing a lower critical solution temperature at approximately 32°C. The swelling and degradation of the hydrogels strongly depended on temperature and hydrogel composition. An empirical mathematical model was established to describe the fast water absorption at the early stage and deswelling at the late stage of the hydrogels at 37°C. Two hydrophilic model drugs, methylene blue and bovine serum albumin, were loaded into the hydrogels during the synthesis process. The molecular size of the drugs, the hydrophilicity and degradation of the hydrogels, and temperature played important roles in controlling the drug release.
In Situ Forming Injectable Thermoresponsive Hydrogels for Controlled Delivery of Biomacromolecules
Due to their relatively large molecular sizes and delicate nature, biologic drugs such as peptides, proteins, and antibodies often require high and repeated dosing, which can cause undesired side effects and physical discomfort in patients and render many therapies inordinately expensive. To enhance the efficacy of biologic drugs, they could be encapsulated into polymeric hydrogel formulations to preserve their stability and help tune their release in the body to their most favorable profile of action for a given therapy. In this study, a series of injectable, thermoresponsive hydrogel formulations were evaluated as controlled delivery systems for various peptides and proteins, including insulin, Merck proprietary peptides (glucagon-like peptide analogue and modified insulin analogue), bovine serum albumin, and immunoglobulin G. These hydrogels were prepared using concentrated solutions of poly(lactide-co-glycolide)−blockpoly(ethylene glycol)−block-poly(lactide-co-glycolide) (PLGA−PEG−PLGA), which can undergo temperature-induced sol−gel transitions and spontaneously solidify into hydrogels near the body temperature, serving as an in situ depot for sustained drug release. The thermoresponsiveness and gelation properties of these triblock copolymers were characterized by dynamic light scattering (DLS) and oscillatory rheology, respectively. The impact of different hydrogel-forming polymers on release kinetics was systematically investigated based on their hydrophobicity (LA/GA ratios), polymer concentrations (20, 25, and 30%), and phase stability. These hydrogels were able to release active peptides and proteins in a controlled manner from 4 to 35 days, depending on the polymer concentration, solubility nature, and molecular sizes of the cargoes. Biophysical studies via size exclusion chromatography (SEC) and circular dichroism (CD) indicated that the encapsulation and release did not adversely affect the protein conformation and stability. Finally, a selected PLGA−PEG−PLGA hydrogel system was further investigated by the encapsulation of a therapeutic glucagon-like peptide analogue and a modified insulin peptide analogue in diabetic mouse and minipig models for studies of glucose-lowering efficacy and pharmacokinetics, where superior sustained peptide release profiles and long-lasting glucoselowering effects were observed in vivo without any significant tolerability issues compared to peptide solution controls. These results suggest the promise of developing injectable thermoresponsive hydrogel formulations for the tunable release of protein therapeutics to improve patient's comfort, convenience, and compliance.
2010
The purpose of this research was to synthesize novel macroporous thermosensitive hydrogels and to characterise the produced hydrogel materials for controlled drug delivery applications. Twelve hydrogel polymers were synthesized based on the homo-, co-and/or terpolymers of N-isopropylacrylamide (NIPAAm), 2-hydroxyethyl methacrylate (HEMA) and ethyl methacrylates (EMA). The polymers were produced in the presence of varying amounts of water so as to generate porous structures of the hydrogels through a phase separation polymerization process. N, N'methylenebisacrylamide (mBAAm) was used as a crosslinking agent and ammonium persulfate (APS) was used an initiator. The morphology of these hydrogels was examined using scanning electron microscopy (SEM). The porous structure of the hydrogels was future evaluated by the polymer volume fraction at the equilibrium state at various temperatures. The swelling properties of hydrogels were also studied. These include the equilibrium swelling ratio (ESR) and the normalised volume change at different temperatures, the swelling kinetics, and the deswelling kinetics. Based on the porosities and the swelling properties, their responsiveness to the temperature changes, nine hydrogels were selected for the assessment of drug loading capacity and drug diffusion properties using a conventional antiinflammatory drug, predinisolone 21-hemisuccinate sodium salt. The influence of temperature, porosity and drug concentrations on the drug loading capacity and diffusion kinetics was also investigated. v BRIEF BIOGRAPHY OF THE AUTHOR Yuli Setiyorini graduated in Materials and Metallurgy Engineering of Sepuluh November Institute of Technology (ITS) Surabaya, Indonesia in 2003. She has three and a half years experience as a junior lecturer at ITS. She commenced her Master of Philosophy in January 2008 under the support of an Australian Development Scholarship (ADS).
Journal of Biomaterials Science, Polymer Edition, 2012
Physical polymeric hydrogels have significant potential for use as injectable depot drug/protein-delivery systems. In this study, a series of novel injectable, biodegradable and pH/temperature-sensitive multiblock co-polymer physical hydrogels composed of poly(ethylene glycol) (PEG) and poly(β-amino ester urethane) (PEU) was synthesized by the polyaddition between the isocyanate groups of 1,6-diisocyanato hexamethylene and the hydroxyl groups of PEG and a synthesized monomer BTB (or ETE) in chloroform in the presence of dibutyltin dilaurate as a catalyst. The synthesized co-polymers were characterized by nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy and gel-permeation chromatography. Aqueous solutions of the co-polymers showed a sol-to-gel phase transition with increasing pH and a gel-to-sol phase transition with increasing temperature. The gel regions covered the physiological conditions (37°C, pH 7.4) and could be controlled by changing the molecular weight of PEG, PEG/PEU ratio and co-polymer solution concentration. A gel formed rapidly in situ after injecting the co-polymer solution subcutaneously into SD rats and remained for more than 2 weeks in the body. The cytotoxicity tests confirmed the non-cytotoxicity of this co-polymer hydrogel. The controlled in vitro release of the model anticancer drug, doxorubicin, from this hydrogel occurred over a 7-day period. This hydrogel is a potential candidate for biomedical applications and drug/protein-delivery systems.
Strategies toward development of biodegradable hydrogels for biomedical applications
Polymer-Plastics Technology and Materials, 2020
Hydrogel is a macromolecular gel constructed of a network of cross-linked polymer chains. Hydrogels are class of materials that can be tuned toward the subjected stimuli and can be modified to imitate the extracellular environment of the body which makes hydrogel worthy of being used in tissue regeneration, drug delivery, and other fields of science. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, and biodegradability. Hydrogels are having various tissue engineering and drug delivery application due to its high loading with ensured molecule efficacy, high encapsulation, variable release profile, stable, and inexpensive.
Journal of controlled release : official journal of the Controlled Release Society, 2015
Thermosensitive injectable hydrogels have been used for the delivery of pharmacological and cellular therapies in a variety of soft tissue applications. A promising class of synthetic, injectable hydrogels based upon oligo(ethylene glycol) methacrylate (OEGMA) monomers has been previously reported, but these polymers lack reactive groups for covalent attachment of therapeutic molecules. In this work, thermosensitive, amine-reactive and amine-functionalized polymers were developed by incorporation of methacrylic acid N-hydroxysuccinimide ester or 2-aminoethyl methacrylate into OEGMA-based polymers. A model therapeutic peptide, bivalirudin, was conjugated to the amine-reactive hydrogel to investigate effects on the polymer thermosensitivity and gelation properties. The ability to tune the thermosensitivity of the polymer in order to compensate for peptide hydrophilicity and maintain gelation capability below physiological temperature was demonstrated. Cell encapsulation studies using ...