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.     

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.     

The effects of varying poly(ethylene glycol) hydrogel crosslinking density and the crosslinking mechanism on protein accumulation in three-dimensional hydrogels

Matrix stiffness has been shown to play an important role in modulating various cell fate processes such as differentiation and cell cycle. Given that the stiffness can be easily tuned by varying the crosslinking density, poly(ethylene glycol) (PEG) hydrogels have been widely used as an artificial cell niche. However, little is known about how changes in the hydrogel crosslinking density may affect the accumulation of exogenous growth factors within 3-D hydrogel scaffolds formed by different crosslinking mechanisms. To address such shortcomings, we measured protein diffusivity and accumulation within PEG hydrogels with varying PEG molecular weight, concentration and crosslinking mechanism. We found that protein accumulation increased substantially above a critical mesh size, which was distinct from the protein diffusivity trend, highlighting the importance of using protein accumulation as a parameter to better predict the cell fates in addition to protein diffusivity, a parameter commonly reported by researchers studying protein diffusion in hydrogels. Furthermore, we found that chain-growth-polymerized gels allowed more protein accumulation than step-growth-polymerized gels, which may be the result of network heterogeneity. The strategy used here can help quantify the effects of varying the hydrogel crosslinking density and crosslinking mechanism on protein diffusion in different types of hydrogel. Such tools could be broadly useful for interpreting cellular responses in hydrogels of varying stiffness for various tissue engineering applications.     

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.     

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.     

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.

     

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.     

聚乙二醇单甲醚-聚(D,L-乳酸)嵌段共聚物的研究

采用熔融缩聚反应合成一系列聚（D，L-乳酸）（PDLLA）／聚乙二醇单甲醚（mPEG）两亲性二嵌段共聚物（PEDLLA），采用IR、^1H-NMR、DSC、WAXD和TEM等手段分析和研究PEDLLA的结构与性能。实验结果表明，PEDLLA的结构和组成与设计相一致，结晶度和熔点均低于均聚物，且随着PEDLLA中PDLLA含量的增加，mPEG嵌段熔点降低，随着PDLLA嵌段相对分子质量的增大，PEDLLA降解速率增大。载药纳米粒呈核壳结构，载药量达30％。     

Synthesis and properties of novel block copolymers containing poly(lactic-glycolic acid) and poly(ethyleneglycol) segments

A synthetic process for obtaining high-molecular-weight block copolymers containing poly(lacticglycolic acid) and poly(ethylene glycol) segments has been established. This process involves the reaction of poly(ethylene glycols) with phosgene, followed by polycondensation of the resulting ,ω-bis (chloroformates) with poly(lactic-glycolic acid) oligomers. The copolymers have been characterized for their molecular weight, solubility properties, water absorption and preliminarily thermal behaviour. All evidence points to the conclusion that the process described is a general one, enabling biodegradable polymers to be obtained tailor-made according to specific requirements.     

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.     

Effect of poly(dimethylsiloxane)-block-poly(oligo (ethylene glycol) methacrylate) amphiphilic block copolymers on dermal fibroblast viability and proliferation

Abstract

In this work, well-defined poly(dimethylsiloxane)-b-poly(oligo (ethylene glycol) methacrylate) (PDMS-b-POEGMA) amphiphilic block copolymers were synthesized and their effect on human dermal fibroblast were investigated. Anionic ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP) were used to synthesis the block copolymers. The molecular weight of synthesized copolymers ranged from 1000 to 2300?Da by changing the number of both PDMS and POEGMA units. It was found that the copolymer having low molecular weight decreased the fibroblast viability and proliferation by inducing apoptosis. It was proved by flow cytometry and TUNEL assay that human dermal fibroblast experienced apoptosis after exposure to synthesized amphiphilic copolymers. The results of this work suggest the use of PDMS-b-POEGMA amphiphilic copolymers with low molecular weight for hypertrophic scars remediation.     

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.     

Hydrolytically and Reductively Degradable High‐Molecular‐Weight Poly(ethylene glycol)s

Reductively degradable multiblock polymers for gene and drug delivery were synthesised by oxidative polycondensation of poly(ethylene glycol)‐cysteine derivatives containing ester or urethane bonds. Hydrolysis of the polymers at pH = 5.5, 7.4 and 8.0 and reductive degradation with glutathione and dithiothreitol were studied. The hydrolysis rate of polymer esters increased with increase in pH; the hydrolysis of polymer urethanes was negligible. Chemical substitution of the pendant COOH or NH₂ groups significantly affected the rate of the polymer degradation. Surface modification of poly(L ‐lysine)‐DNA complexes with PEG‐cystine multiblocks led to the formation of reductively degradable nanoparticles.

     

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.     

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.     

Clickable Poly(ethylene glycol)‐Microsphere‐Based Cell Scaffolds

Clickable poly(ethylene glycol) (PEG) derivatives are used with two sequential aqueous two‐phase systems to produce microsphere‐based scaffolds for cell encapsulation. In the first step, sodium sulfate causes phase separation of the clickable PEG precursors and is followed by rapid geleation to form microspheres in the absence of organic solvent or surfactant. The microspheres are washed and then deswollen in dextran solutions in the presence of cells, producing tightly packed scaffolds that can be easily handled while also maintaining porosity. Endothelial cells included during microsphere scaffold formation show high viability. The clickable PEG‐microsphere‐based cell scaffolds open up new avenues for manipulating scaffold architecture as compared with simple bulk hydrogels.

     

Refined control of thermoresponsive swelling/deswelling and drug release properties of poly(N-isopropylacrylamide) hydrogels using hydrophilic polymer crosslinkers

Thermoresponsive poly(N-isopropylacrylamide) (PNIPAm)-based hydrogels are widely investigated for their ability to alter their physical properties (e.g. dimensions, swelling/deswelling) in response to change in temperature. Despite extensive research efforts, it is still challenging to control various aspects of thermoresponsive physical properties of PNIPAm hydrogels in an efficient and comprehensive manner using conventional small molecular crosslinkers due to their limited solubility and functional groups. Herein, thermoresponsive swelling/deswelling behavior of PNIPAm hydrogels is tuned in a wide range by hydrophilic polymeric crosslinkers with varying chain lengths. The concentration and molecular weight of the poly(ethylene glycol) (PEG) crosslinker are varied to control the swelling/deswelling behavior, drug release, and lower critical solution temperature (LCST) of PNIPAm-PEG hydrogels. Compared with PNIPAm hydrogels crosslinked with a conventional small molecular crosslinker, N,N′-methylenebisacrylamide, greater degree and range of thermoresponsive swelling/deswelling as well as tunable LCST are demonstrated for PNIPAm-PEG hydrogels. In addition, more swelling-controlled PNIPAm-PEG hydrogels displayed more sustained and variable thermoresponsive drug release based on their crosslinking density, by modulating the hydrophobic transition of PNIPAm chains with hydrophilic PEG chains. In sum, various thermoresponsive properties of PNIPAm hydrogels could be controlled by hydrophilic polymeric crosslinkers, and this strategy could be applied to various hydrogel systems to control their physical properties for biomedical applications.     

Effect of end segment on physicochemical properties and platelet compatibility of poly(propylene glycol)-initiated poly(methyl methacrylate)

It is well known that polyether-based copolymers have good blood compatibility, although many mechanisms have been proposed to explain their favorable performance. Our objective in carrying out the present study was to obtain a better understanding of the effect of the (poly)ether segment on blood compatibility. Therefore, we synthesized poly(propylene glycol) (PPG)-based initiators for atom transfer polymerization, where the number of propylene glycol (PG) units in the PPG (Pn(PG) was varied from 1 to 94. Methyl methacrylate (MMA) was polymerized using the initiators, resulting in the formation of polyMMAs with a PG-based ether part at the polymer terminal. We mainly investigated the effects of Pn(PG) on the surface properties and platelet compatibility of the PPG-polyMMA. X-ray photoelectron spectroscopy and surface contact angle (CA) analysis revealed the exposure of the PG units at the surface of the polymer. The platelet compatibility of the polymers was improved compared with a commercial polyMMA, even when Pn(PG)?=?1. These results suggest that PG units have an important influence on favorable blood compatibility, regardless of the Pn(PG) value. We also investigated protein adsorption behavior in terms of the amount and deformation of fibrinogen adsorbed on the polymer surface.