Pulsatile peptide release from multi-layered hydrogel formulations consisting of poly(ethylene glycol)-grafted and ungrafted dextrans

Multi-layered hydrogel formulations consisting of poly(ethylene glycol)-grafted dextran (PEG-g-Dex) and ungrafted Dex were investigated as a model of Pulsatile drug release. In these formulations, it is considered that the grafted PEG domains act as a drug reservoir dispersed in the Dex matrix based on aqueous polymer two-phase systems. The formulations exhibited surface-controlled degradation by dextranase, and insulin release was observed in a pulsatile manner because of the multi-layered structure, PEG-g-Dex hydrogel layers containing insulin and insulin-free Dex hydrogel layers. Thus, it is suggested that the multi-layered hydrogel formulations using PEG-g-Dex and Dex are feasible for chronopharmacological drug delivery systems.     

Solute transport analysis in pH-responsive,complexing hydrogels of poly(methacrylic acid-g-ethylene glycol)

We report on the preparation and properties of hydrogels of poly(methacrylic acid-g-ethylene glycol) that exhibit pH-responsive swelling behavior due to the reversible formation/dissociation of interpolymer complexes. Because of their nature, these materials may be useful in drug delivery applications. In this work, we studied the diffusional behavior of three solutes of varying molecular size in the complexing hydrogels as a function of solution pH. The ability of these gels to control the solute diffusion rates was strongly dependent on the molecular size of the solute and the environmental pH. The diffusion coefficients for solutes were calculated as a function of pH and were lower in acidic than neutral or basic media due to the formation of interpolymer complexes in the gels. However, the ratio of the solute radius to the network mesh size also was a significant factor in the overall behavior of these gels. The diffusion coefficient of the smallest solute, proxyphylline, studied only changed by a factor of five between the complexed and uncomplexed state. However, for the largest solute, FITC-dextran, which has a molecular radius ten times greater than proxyphylline, the diffusion coefficients of the drugs in complexed and uncomplexed gels varied by almost two orders of magnitude. These results are explained in terms of mesh size characteristics of the gels.     

Adaptable poly(ethylene glycol) microspheres capable of mixed-mode degradation

A simple, degradable poly(ethylene glycol) (PEG) microsphere system formed from a water-in-water emulsion process is presented. Microsphere network degradation and erosion were controlled by adjusting the number of hydrolytically labile sites, by varying the PEG molecular weight, and by adjusting the emulsion conditions. Microsphere size was also controllable by adjusting the polymer formulation. Furthermore, it is demonstrated that alternative degradation and erosion mechanisms, such as proteolytic degradation, can be incorporated into PEG microspheres, resulting in mixed-mode degradation. Owing to the adaptability of this approach, it may serve as an attractive option for emerging tissue engineering, drug delivery and gene delivery applications.     

Molecular calculations of poly(ethylene glycol) transport across a swollen poly (acrylic acid)/mucin interface

The transport of poly(ethylene glycol) chains than can promote mucoadhesion across the interface between lightly cross-linked poly(acrylic acid) and mucin may be analyzed as a function of molecular characteristics using theories of chain penetration in a dilute network. The fracture energy for the ensuing adhesive bond is proportional to the number of polymer chains crossing the interface, which, in turn, is related to the polymer volume fraction, the chain diffusion coefficient, and the degree of polymerization. Relevant calculations were performed for a number of cross-linked poly(acrylic acid) gels and three different types of poly(ethylene glycol) chains.     

Altering the release of tobramycin by incorporating poly(ethylene glycol) into model silicone hydrogel contact lens materials

Abstract

Delivery of drugs from contact lens materials is attractive for a number of reasons. However, the controlled delivery of hydrophilic drugs can be difficult to achieve due to the burst release of drug that is associated with materials of high water content, such as hydrogels. Silicone hydrogels have significant potential for drug delivery due to their increased hydrophobicity and the tortuous nature of the pores, overcoming some of the limitations associated with conventional hydrogel materials. The aim of this study was to examine the potential of model poly(ethylene glycol) (PEG) containing silicone hydrogels for delivery of hydrophilic aminoglycoside antibiotics. It was hypothesized that PEG, a polymer that has seen extensive use in biomedical applications, will provide in addition to hydrophilicity and protein repulsion, a mechanism for controlling the delivery of this hydrophilic antibiotic. PEG was combined with the macromer TRIS to create the model silicone hydrogel materials. The optical and physical properties of the novel TRIS-co-PEG silicone hydrogels exhibited excellent transparency, appropriate refractive index and high transmittance indicating minimal phase separation. Desirable properties such as wettability and protein repulsion were maintained across a wide range of formulations. The water content was found to be highly correlated with the ethylene oxide content. Drug release could be influenced through PEG content and was found to fit Higuchi-like kinetics. Overall, the study demonstrates that incorporation of PEG into a model silicone hydrogel could be used to control the release of a hydrophilic compound. Data suggests this is related to the unique structure and properties of PEG, which alter the types of water found in each formulation and the water content.     

Extracellular matrix-mimetic poly(ethylene glycol) hydrogels engineered to regulate smooth muscle cell proliferation in 3-D

The goal of this project is to engineer a defined, synthetic poly(ethylene glycol) (PEG) hydrogel as a model system to investigate smooth muscle cell (SMC) proliferation in three-dimensions (3-D). To mimic the properties of extracellular matrix, both cell-adhesive peptide (GRGDSP) and matrix metalloproteinase (MMP) sensitive peptide (VPMSMRGG or GPQGIAGQ) were incorporated into the PEG macromer chain. Copolymerization of the biomimetic macromers results in the formation of bioactive hydrogels with the dual properties of cell adhesion and proteolytic degradation. Using these biomimetic scaffolds, the authors studied the effect of scaffold properties, including RGD concentration, MMP sensitivity, and network crosslinking density, as well as heparin as an exogenous factor on 3-D SMC proliferation. The results indicated that the incorporation of cell-adhesive ligand significantly enhanced SMC spreading and proliferation, with cell-adhesive ligand concentration mediating 3-D SMC proliferation in a biphasic manner. The faster degrading hydrogels promoted SMC proliferation and spreading. In addition, 3-D SMC proliferation was inhibited by increasing network crosslinking density and exogenous heparin treatment. These constructs are a good model system for studying the effect of hydrogel properties on SMC functions and show promise as a tissue engineering platform for vascular in vivo applications.     

Thermoresponsive UCST‐Type Behavior of Interpolymer Complexes of Poly(ethylene glycol) and Poly(poly(ethylene glycol) methacrylate) Brushes with Poly(acrylic acid) in Isopropanol

Upper critical solution temperature (UCST)‐type thermoresponsive behavior of poly(ethylene glycol)–poly(acrylic acid) (PEG–PAA) and poly(poly(ethylene glycol) methacrylate)–poly(acrylic acid) (PPEGMA–PAA) interpolymer complexes has been observed in isopropanol. For these investigations, PPEGMA and PAA with various average molecular weights have been synthesized by atom transfer radical polymerization. It has been found that both the PEG and PPEGMA have lower cloud point temperatures (T _cp) than its mixed polymer solutions with PAA, whereas PAA does not show such behavior in the investigated temperature range. These findings indicate the reversible formation of interpolymer complexes with variable structure and composition in the solutions of the polymer mixtures in isopropanol. Increasing the ethylene glycol/acrylic acid molar ratio or the molecular weight of either the PAA or the H‐acceptor PEG component of the interpolymer complexes increases the UCST‐type cloud point temperatures of these interpolymer systems. The polymer–polymer interactions by hydrogen bonds between PAA and PEG or PPEGMA and the correlations between T _cp and structural parameters of the components revealed in the course of these investigations may be utilized for exploring well‐defined UCST‐type material systems for various applications.

     

Controlling the migration behaviors of vascular smooth muscle cells by methoxy poly(ethylene glycol) brushes of different molecular weight and density

Cell migration is an important biological activity. Regulating the migration of vascular smooth muscle cells (VSMCs) is critical in tissue engineering and therapy of cardiovascular disease. In this work, methoxy poly(ethylene glycol) (mPEG) brushes of different molecular weight (Mw 2 kDa, 5 kDa and 10 kDa) and grafting mass (0-859 ng/cm²) were prepared on aldehyde-activated glass slides, and were characterized by X-ray photoelectron spectrometer (XPS) and quartz crystal microbalance with dissipation (QCM-d). Adhesion and migration processes of VSMCs were studied as a function of different mPEG Mw and grafting density. We found that these events were mainly regulated by the grafting mass of mPEG regardless of mPEG Mw and grafting density. The VSMCs migrated on the surfaces randomly without a preferential direction. Their migration rates increased initially and then decreased along with the increase of mPEG grafting mass. The fastest rates (∼24 μm/h) appeared on the mPEG brushes with grafting mass of 300-500 ng/cm² depending on the Mw. Cell adhesion strength, arrangement of cytoskeleton, and gene and protein expression levels of adhesion related proteins were studied to unveil the intrinsic mechanism. It was found that the cell-substrate interaction controlled the cell mobility, and the highest migration rate was achieved on the surfaces with appropriate adhesion force.     

Enhanced hydrogel adhesion by polymer interdiffusion: Use of linear poly(ethylene glycol) as an adhesion promoter

The fracture energy required to separate layers of hydrogel films was investigated to evaluate the impact of bulk polymer diffusion on hydrogel/hydrogel adhesion and to obtain molecular information on the fracture energy in polymer mucoadhesion. Poly(ethylene glycol) (PEG) was incorporated in a hydrogel and was used as an adhesion promoter. The influence of PEG molecular weight and contact time on PEG diffusion across the hydrogel/hydrogel interface was investigated by using tensiometric studies and near-field FTIR microscopy. These experiments indicated that linear PEG diffusion enhanced the adhesion between the two hydrogel layers. The enhanced adhesion could not be explained by surface wetting phenomena alone. These results indicated that bulk diffusion of linear polymers such as PEG (adhesion promoter) incorporated into polymer networks (hydrogels) was an effective technique for enhancing gel/gel adhesion in various applications including polymer/mucus interactions in mucoadhesion and development of mucoadhesive controlled drug delivery systems.     

Factors affecting size and swelling of poly(ethylene glycol) microspheres formed in aqueous sodium sulfate solutions without surfactants

The LCST behavior of poly(ethylene glycol) (PEG) in aqueous sodium sulfate solutions was exploited to fabricate microspheres without the use of other monomers, polymers, surfactants or organic solvents. Reactive PEG derivatives underwent thermally induced phase separation to produce spherical PEG-rich domains that coarsened in size pending gelation, resulting in stable hydrogel microspheres between ≈1 and 100 microns in size. The time required to reach the gel point during the coarsening process and the extent of crosslinking after gelation both affected the final microsphere size and swelling ratio. The gel point could be varied by pre-reaction of the PEG derivatives below the cloud point, or by controlling pH and temperature above the cloud point. Pre-reaction brought the PEG derivatives closer to the gel point prior to phase separation, while the pH and temperature influenced the rate of reaction. Dynamic light scattering indicated a percolation-to-cluster transition about 3–5 min following phase separation. The mean radius of PEG-rich droplets subsequently increased with time to the 1/4th power until gelation. PEG microspheres produced by these methods with controlled sizes and densities may be useful for the production of modular scaffolds for tissue engineering.     

Double-stimuli-responsive degradation of hydrogels consisting of oligopeptide-terminated poly(ethylene glycol) and dextran with an interpenetrating polymer network

Biodegradable hydrogels consisting of oligopeptide-terminated poly(ethylene glycol) (PEG) and dextran (Dex) with an interpenetrating polymer network (IPN) structure were prepared as models of novel biomaterials exhibiting a double-stimuli-response function. The IPN-structured hydrogels were synthesized by sequential cross-linking reaction of N-methacryloyl-glycylglycylglycyl-terminated PEG and Dex. In vitro degradation of the IPN-structured hydrogels was examined using papain and dextranase as model enzymes of hydrolyzing oligopeptide and Dex, respectively. Specific degradation in the presence of papain and dextranase was observed in the IPN-structured hydrogel with a particular composition of oligopeptide-PEG and Dex. This same hydrogel was not degraded by one of the two enzymes. The IPN-structured hydrogels were characterized by water content, thermal mechanical analysis, and wide-angle X-ray diffraction, and the results were compared with those of co-cross-linked hydrogels consisting of N-methacryloyl-glycylglycylglycyl-terminated PEG and methacryloyl Dex. The results suggest that the IPN-structured hydrogels contain physical chain entanglements between networks as well as chemical cross-linked networks. It is concluded that the double-stimuli-responsive degradation observed in the IPN-structured hydrogel is achieved by controlling the chain entanglements between the two biodegradable polymers. Such degradation property of the IPN-structured hydrogel can be useful as a fail-safe system for guaranteed drug delivery and/or medical micromachines.     

Hyper-branched poly(poly(ethylene glycol)methacrylate)-grafted surfaces by photo-polymerization with iniferter for bioactive interfaces

A new hyper-branched surface in which three species of architectures were constructed as stem chain, branched stem and twig chain-grafted branched chain of poly(poly(ethylene glycol)methacrylate) (poly(PEGMA)) by photo-polymerization using dithiocarbamyl group (DC) as iniferter was prepared and characterized. For these surfaces, radical copolymerization of styrene and an iniferter-activated chain that was previously synthesized was performed for using as base materials for surface coating. On a DC-activated surface, hyper-branched poly(PEGMA) was introduced by photo-polymerization and dithiocarbamylation. All modified surfaces were analyzed by X-ray photoelectron spectroscopy (XPS) and water contact angle measurements. Our results demonstrated that a highly hyper-branched graft architecture of poly(PEGMA) can be constructed on PU surface by photo-polymerization using dithiocarbamyl group as iniferter, in which first, second and third generation gave stem chain, branched chain and twig chain of poly(PEGMA), respectively. Our hyper-branched surfaces could be regulated by photo-irradiation time and might be controlled by feed amounts or other reaction conditions. This highly dense architecture of PEG chain with hydrophilicity and chain mobility, grafted on surface, is expected to be effectively utilized in bio-implantable substrates or micro- or nano-patterned surfaces for immobilization of bioactive molecules in biomedical fields.     

Preparation and antibacterial activity of silver-loaded poly(oligo(ethylene glycol) methacrylate) brush

Herein, we report on a robust approach to fabricate antibacterial nanocomposite coating simply by immersing poly(oligo(ethylene glycol) methacrylate) (POEGMA) brush into a silver perchlorate solution without using any external reducing agents. The POEGMA brush of 48.3?nm in thickness is prepared via surface-initiated atom transfer radical polymerization method. Field-emission scanning electron microscope and Raman measurements indicate that silver nanoparticles of 14?～?25?nm in diameter are successfully embedded into the POEGMA brush. Antibacterial activities of the resultant silver-loaded POEGMA brushes against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus are measured by zone of inhibition and colony-counting methods, respectively. The results show that the silver-loaded POEGMA coatings exhibit enhanced antibacterial efficiency compared to bare POEGMA brush. In order to elucidate their antibacterial mechanism, silver release behaviors of these silver-loaded POEGMA brushes are monitored via inductively coupled plasma mass spectrometry.     

Preparation of anionic poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) copolymeric nanoparticles as basic protein antigen carrier

It is an useful method for polymeric nanoparticles to load protein by electrostatic method to improve the immunogenicity of protein antigen. In this article, anionic poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) nanoparticles were prepared by modified emulsion solvent evaporation method, and human basic fibroblast growth factor (bFGF), as a model protein, was absorbed onto its surface due to electrostatic interaction. The prepared anionic PCEC nanoparticles, with mean diameter of 136.9 nm, had zeta potential of ? 33.14 mV. The surface charge and particle size of bFGF/nanoparticles complex increased with increase of bFGF/nanoparticles mass ratio. The encapsulated bFGF could be released slowly from bFGF/nanoparticle complexes. The animal experiment indicated that the humoral immunity induced by bFGF/PCEC complex was improved greatly than that created by naked bFGF. Otherwise, the cytotoxicity of anionic PCEC nanoparticles was also evaluated by 293 cell viability. The prepared anionic PCEC nanoparticles might have great potential application as basic protein vaccine delivery system.     

Synthesis of degradable poly(L-lactide-co-ethylene glycol) porous tubes by liquid-liquid centrifugal casting for use as nerve guidance channels

Biodegradable nerve guidance channels are advantageous, obviating the need for their removal after regeneration; however, most channels lack the appropriate mechanical properties for soft tissue implantation and/or degrade too quickly, resulting in reduced regeneration and necessitating the need for the design of polymers with tunable degradation profiles and mechanical properties. We designed a series of biodegradable polymeric hydrogel tubes consisting of L-lactide (LLA) and polyethylene glycol (PEG) where both the ratio of LLA to PEG and PEG molar mass were varied. By adjusting the PEG:LLA ratio and the molecular weight of the PEG oligomer we were able to control degradation and mechanical properties of our polymers. By incorporating methacrylate (MA) groups on both termini of the linear oligomers, porous tubes were synthesized by a redox-initiated free radical mechanism during a liquid-liquid centrifugal casting process. The tube wall had a bead-like morphology, as determined by SEM, which was reminiscent of previous porous hydrogel tubes synthesized by the same method. Tubes swelled with degradation to 160 vol%, or 640 wt%, and an increased radius calculated at 1.26 times. Those tubes with greater PEG content and PEG molar mass degraded faster than those with greater LLA content, as was expected. Interestingly, the wall morphology changed with degradation to a fiber-like structure and the mechanical properties decreased with degradation. By correlating the accelerated degradation study to a physiologic one, these porous hydrogel tubes were stable for an equivalent of 1.5 months, after which the mechanical properties began to deteriorate. This study demonstrates how porous hydrogel tubes can be designed to meet tissue regeneration criteria by tuning the formulation chemistry and specifically how the ratio of hydrophobic/crystalline LLA and hydrophilic/amorphous PEG impact tube properties.     

聚乙二醇在聚砜膜上的接枝与表征

对用紫外辐照法在聚砜膜表面接枝的聚乙二醇作了初步的研究。通过静态水接触角测定、X射线-光电子能谱分析以及原子力学显微镜等测试手段，对接枝前后聚砜膜表面的性能进行了测定，证明采用同步接枝法和二步接枝法在聚砜材料表面接上了聚乙二醇，表面亲水性大大提高，两种接枝方法的接枝覆盖率分别为77．3％和41．9％，表面形貌、相位图等参数较接枝前变化明显，说明用同步法在聚砜膜表面产生了分枝的聚乙二醇层，而二步法在聚砜膜表面产生了薄煎饼状的聚乙二醇层。这一研究为下一步拟在聚砜中空纤维膜表面接上聚乙二醇刷分子层打下了基础。     

Linking the foreign body response and protein adsorption to PEG-based hydrogels using proteomics

Poly(ethylene glycol) (PEG) hydrogels with their highly tunable properties are promising implantable materials, but as with all non-biological materials, they elicit a foreign body response (FBR). Recent studies, however, have shown that incorporating the oligopeptide RGD into PEG hydrogels reduces the FBR. To better understand the mechanisms involved and the role of RGD in mediating the FBR, PEG, PEG-RGD and PEG-RDG hydrogels were investigated. After a 28-day subcutaneous implantation in mice, a thinner and less dense fibrous capsule formed around PEG-RGD hydrogels, while PEG and PEG-RDG hydrogels exhibited stronger, but similar FBRs. Protein adsorption to the hydrogels, which is considered the first step in the FBR, was also characterized. In vitro experiments confirmed that serum proteins adsorbed to PEG-based hydrogels and were necessary to promote macrophage adhesion to PEG and PEG-RDG, but not PEG-RGD hydrogels. Proteins adsorbed to the hydrogels in vivo were identified using liquid chromatography-tandem mass spectrometry. The majority (245) of the total proteins (≥300) that were identified was present on all hydrogels with many proteins being associated with wounding and acute inflammation. These findings suggest that the FBR to PEG hydrogels may be mediated by the presence of inflammatory-related proteins adsorbed to the surface, but that macrophages appear to sense the underlying chemistry, which for RGD improves the FBR.     

Physicochemical and biological properties of poly(ethylene glycol)-coupled immunoglobulin G. Part II. Effect of molecular weight of poly(ethylene glycol)

In order to obtain a stable human immunoglobulin G (IgG) preparation for clinical use, the chemical coupling of different molecular weights of poly(ethylene glycol)s (PEGs) to IgG molecules was achieved. The abilities of PEG-coupled IgGs (PEG-IgG hybrids) to aggregate were examined when they were subjected to such physicochemical treatments as interfacial exposure, heating, lyophilization, and acid treatment. It was found that the higher the molecular weight of PEG coupled, the more stable was the PEG-IgG hybrid obtained concerning interfacial exposure and heating. The hybrid was stable against lyophilization and acid treatment and its stability was independent of the PEG molecular weight. The decrease in antigen binding ability was suppressed as much as possible by the use of a small amount of PEG of higher molecular weight. The PEG-IgG hybrids were further assessed as a stabilizer for IgG. A limited degree of PEG coupling was required for the hybrids to achieve the most efficient stabilization of IgG: the optimal PEG contents of the hybrid were > 20 wt% (interfacial exposure), about 5'wt,?o (heating), 20 wt% (lyophilization), and 10 wt% (acid treatment) for PEG 5600. It was also confirmed that the PEG-IgG hybrid was superior to PEG and human serum albumin as a stabilizer.