To elucidate the effect of fiber structure on the properties of the electrospun gelatin/PCL hybrid membranes, three types of fibers with different structures, i.e., core-shell, blend, and mixed fibers were fabricated. The crystallinity, wettability, swelling degree, and mechanical properties of the hybrid membranes were compared. It was found that the crystalline characteristics of PCL in the core-shell fibers were different from the fibers fabricated by the other two methods. That is, the orientation degree of the PCL chains in the core-shell fibers was higher than that in both blend and mixed fibers. The wettability of the hybrid membrane was dependent on both the composition and structure of the electrospun fibers. Blended fibers exhibited the highest hydrophobicity because of the enrichment of PCL at the fiber surface. Contrarily, the mixed fibers possessed the highest mechanical strength of 3–5.18 MPa. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
A novel type of reduction-sensitive graft copolymers, chitosan-S-S-poly(ε-caprolactone) (CS-S-S-PCL, here -S-S- means PCL was conjugated onto chitosan backbone through disulfide linkage), was synthesized through a convenient route using dithiodipropionic anhydride (DTDPA) as a disulfide donor. Reaction of hydroxy-terminated poly(ε-caprolactone) (PCL) with DTDPA quantitatively yielded DTDPA functionalized PCL (PCL-S-S-COOH). The disulfide-containing polyester was regioselectively conjugated onto the hydroxy groups of chitosan under mild and homogeneous conditions, utilizing dodecyl sulfate-chitosan complexes (SCC) as an intermediate. The self-assembly and Doxorubicin (Dox) release behavior of the copolymers were investigated. Spherical micelles could be formed through self-assembly of CS-S-S-PCL in aqueous media. The reduction-sensitive behavior of CS-S-S-PCL micelles was investigated by using Dithiothreitol (DTT) as a reductive reagent. In the presence of 10 mM DTT, the micelles gradually lost their aggregation stability and were precipitated out after four days. In addition, the Dox release was accelerated when the micelles were treated with DTT. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Chitosan-based tricomponent copolymers, chitosan-g-poly(ε-caprolactone)-(g-poly(oligo(ethylene glycol) methacrylate)) (CS-PCL-POEGMA, CPP), are synthesized as multifunctional nanocarriers for antitumor therapy. 2-Bromoisobutyric acid and PCL are first site-specifically conjugated onto the hydroxy groups of chitosan backbone through conventional coupling chemistry to give CS-PCL-Br using sodium dodecyl sulfate–chitosan complex as an organosoluble intermediate. CPP-PCL-Br is further used for initiating the single electron transfer-living radical polymerization of OEGMA in the mixed solvent of dimethyl sulfoxide and lactic acid, yielding CPP. One-pot reaction of CPP with a small amount of NaN3 under the catalysis of Cu(I)Br/tris-(2-dimethylaminoethyl)amine converts the bromo ends of POEGMA grafts to azide functionality, which is used for conjugation of folic acid targeting moiety via azide–alkyne click reactions. The resultant tricomponent copolymers can assemble into spherical micelles with the capacity of coincorporating indocyanine green and Doxorubicin through electrostatic and hydrophobic interactions, respectively. The dual-agent-loaded micelles display a combined effect for combating HepG2 cells when irradiated with near-infrared laser. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012
The size and surface property of nanomaterial-based delivery systems administered intravenously play important roles in their cell uptake and in vivo distribution. Both of them should be capable of self-evolution in order to achieve efficient targeting performance. A facile strategy was proposed to manipulate both the size and surface property of polymeric micelles. It was found that the hierarchical assembly between trimethylated chitosan-g-poly(ε-caprolactone) (TMC-PCL) micelles and carboxyethyl chitosan-g-poly(ethylene glycol) (CEC-PEG) could produce onion-like micelles with enlarged size and PEGylated surface. The onion-like micelles could withstand the ionic strength of plasma and competitive exchange with BSA, and abruptly disassemble into the pristine TMC-PCL micelles via a small change in pH. By varying the degree of carboxyethylation, the disassembly pH could be modulated to the range of the tumoral microclimate pH. In contrast with TMC-PCL micelles, which displayed high cytotoxicity and endocytic ability towards C6 glioma cells, the onion-like micelles were cell-friendly and internalized by the cells at a very low level. Doxorubicin was used as a model chemotherapeutic agent and incorporated within TMC-PCL micelles. Dox release from both TMC-PCL micelles and the onion-like micelles was very slow under normal physiological conditions and displayed excellent pH sensitivity. Cell viability of Dox-loaded micelles was also investigated.
Biodegradable tri-component graft copolymers, chitosan-poly(ε-caprolactone)-poly(ethylene glycol) (CPP), were synthesized via a mild route, using sodium dodecyl sulfate-chitosan complex (SCC) as a precursor. Both PCL and PEG could be conveniently conjugated to the hydroxyl sites of chitosan without the need of tedious chemical protection/deprotection processes, thereby leaving the amino groups of chitosan intact. The self-assembly and release behavior of the copolymer micelles were investigated. Paclitaxel and rutin were used as model drugs. Spherical micelles could be formed through self-assembly of CPP in aqueous media. The micelle diameter increased with PEGylation degree and ranged from 30 to 45 nm. The incorporation of drugs into the micelles significantly raised the micelle diameter and diversified the micelle morphologies. The micelles were further subjected to glutaraldehyde treatment to prolong the release of the incorporated drugs. It was found that the crosslinking process shrunk the drug-loaded micelles. In addition, the micelles were endowed with self-luminescent properties after crosslinked with glutaraldehyde. By increasing crosslinking density, the release duration of the model drugs could be prolonged. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2010.
A novel type of well-defined graft copolymer, succinylated chitosan-O-poly(oligo(ethylene glycol)methacrylate) (SC-POEGMA), was developed for pH-reversible poly(ethylene glyocol) (PEG) shielding of cationic nanocarriers. Chitosan-O-POEGMA (CS-POEGMA) was first synthesized via single electron transfer-living radical polymerization of oligo(ethylene glyol) methacrylate (OEGMA) using O-brominated chitosan (CS-Br) as a macromolecular initiator and Cu(I)Br/1,1,4,7,10,10-hexamethyltriethylenetetramine as a catalyst. The subsequent succinylation of the chitosan backbone gave the titled copolymers. The content of POEGMA in CS-POEGMA could be widely modulated by varying the degree of bromination and feed ratio of OEGMA to CS-Br, without compromising the amino density of chitosan backbone. The hierarchical assembly between SC-POEGMA and trimethylated chitosan-O-poly(ε-caprolactone) (TMC-PCL) micelles was further studied. At pH 7.4, the stoichiometric interactions between SC and TMC segments to form polyampholyte–polyelectrolyte complexes led to the formation of PEG-shielded micelles. The hierarchially assembled micelles could be disassembled into the pristine TMC-PCL micelles, when the medium pH was below a certain pH (pHφ). By varying the degree of succinylation of SC-POEGMA, the pHφ value could be facilely modulated from 6.5 to 3.5 to meet the needs for specific biomedical applications. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011
Structurally well-defined trimethylated chitosan-O-poly(ε-caprolactone) (TMC-O-PCL) was synthesized under mild homogeneous conditions, using sodium dodecyl sulfate-dimethylated chitosan complex (SDC) as an organosoluble intermediate. The effect of chitosan molecular weight (MW) on the preparation, organosolubility, self-assembly, and cytotoxicity of the copolymers was investigated. The copolymers with low-MW chitosan backbone had improved solubility in common organic solvents. Spherical micelles with average diameter of 25–55 nm and uniform morphology were formed through self-assembly of TMC-O-PCL in pH 7.4 PBS. When trimethylation degree of the copolymers was above 44%, the micelles could remain stable in neutral aqueous media. The critical aggregation concentration of TMC-O-PCL slightly increased with a decrease in the MW of chitosan backbone. The cytotoxicity of the cationic micelles could be suppressed by increasing PCL grafting levels, reducing trimethylation degree, and MW of the chitosan backbone. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2011.
Coaxial electrospinning was proved to be a facile method to produce multifunctional fibrous matrices which could essentially emulate certain features of native extracellular matrix. In order to further confer capability of immobilizing diverse macromolecular bioactive agents to the fibers, composite membranes composed of cationized gelatin-coated polycaprolactone (PCL) fibers were prepared by coaxial electrospinning. Gelatin was cationized by derivation with N,N-dimethylethylenediamine. The cationized gelatin (CG) was used as a shell material for constructing a core–shell fibrous membrane. PCL formed the core section of the core–shell fibers thereby improving the mechanical properties of nanofibrous CG hydrogel. The outer CG layer was crosslinked by exposing the membranes in glutaraldehyde vapor. The adsorption behaviors of FITC-labeled bovine serum albumin (FITC–BSA) or FITC–heparin onto the fibers were investigated. The core–shell fibers could effectively immobilize the two types of agents under mild conditions. The adsorption amount could reach about 12 μg of BSA per mg of membrane and 23 μg mg−1 for heparin. Furthermore, vascular endothelial growth factor (VEGF) could be conveniently impregnated into the fibers through specific interactions with the adsorbed heparin in the outer CG layer. Sustained release of bioactive VEGF could be achieved for more than 15 days.
Electrospun zein membranes were prepared using DMF as solvent. By changing the solution concentration, the electrospinning voltage and the distance between the spinneret and collector, nanofibrous meshes without bead defects could be obtained. In order to improve the mechanical strength of the hydrated zein meshes, core-shell-structured nanofibrous membranes with PCL as the core material and zein forming the shell were prepared by coaxial electrospinning. The core-shell structure of the composite fibers was confirmed by SEM characterization of the fibers, either extracted with chloroform to remove the inner PCL, or elongated to expose their cross-section. The composition and average diameter of the composite fibers could be modulated by the feed rate of the inner PCL solution. It was found that the core-shell fibrous membranes have similar wettability to the electrospun zein mesh. The presence of PCL in the fibers could significantly improve the mechanical properties of the zein membrane.
A facile coaxial electrospinning technique was devised to prepare biodegradable core-shell fibrous scaffolds with poly(ϵ-caprolactone) (PCL) comprising the core structure and gelatin forming the coating of the fibers. The effect of the feed rate of the inner dope on the electrospinning process and fiber morphology was investigated. The results indicated that core-shell fibers with narrow size distribution and smooth surface morphology could be obtained when the feed rate was below 8 mL/h. An increase of the feed rate resulted in analogous increase in the diameters of both the inner PCL fiber core and the entire core-shell fibers. XPS analyses revealed that the surface of the core-shell fibers was tainted with a small amount of PCL. The outer gelatin layer in the core-shell fibers was crosslinked with glutaraldehyde. By optimizing the glutaraldehyde/gelatin feed ratio, crosslinked scaffolds with high porosity were obtained. The mechanic strength of the hydrated, crosslinked core-shell fibrous scaffolds was significantly enhanced because of the presence of hydrophobic PCL in the core region of the fibers. Results of cell culture studies suggested that the crosslinked, core-shell fibrous scaffold were nontoxic and capable of supporting fibroblast adhesion and proliferation. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res 2007
Biodegradable poly(aspartic acid) (PASP) hydrogel and PASP/gelatin complex were prepared to evaluate their potential application as pH-sensitive matrices for controlled protein release. Entrapment of myoglobin (Mb) and its release were compared between the two types of carriers. It was found that incorporation of Mb into PASP hydrogel strongly depended on the medium pH and NaCl concentration, and was time-consuming. However, complete entrapment of Mb into PASP/gelatin complex was found within pH ranged from 2.5 to 4.0, which was concomitant with the formation of PASP/gelatin complex. By adjusting Mb feed ratio, Mb entrapment in the complex can be up to 31.54% (by weight) with high loading efficiency (96.2%). Gradual release of Mb from PASP hydrogel was observed within pH 2.0–7.4, while Mb release from PASP/gelatin complex was negligible within pH 2.0–4.2 for 4 days. In addition, pulsatile Mb release can be achieved by combining polyanhydride with pH-sensitive PASP/gelatin complex, while the device composed of polyanhydride and PASP hydrogel is mechanically unstable. PASP/gelatin complex formed by electrostatic interactions is superior to the single-component PASP hydrogel synthesized by chemical cross-linking as pH-sensitive matrices for controlled protein release when entrapment of proteins and pH-sensitivity of protein release are concerned. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006
In this work, two kinds of diacid monomers were synthesized by a convenient scheme, where 4-hydroxy-3-methoxybenzoic acid (vanillic acid) or 4-hydroxy-3,5-dimethoxybenzoic acid (syringic acid) directly condensated with succinic chloride. Corresponding polyanhydrides were obtained by melt polycondensation. Copolyanhydrides composed of the new monomers and sebacic acid (SA) were further prepared and characterized by NMR, DSC, and fluorometer. The two new kinds of polyanhydride emit strong fluorescence and have similar fluorescent spectra to poly(di(p-carboxyphenyl) succinate anhydride) (P(dCPS)). The emission wavelength (λem) of the copolymers could be tuned by the excitation wavelength (λex). Degradation rate of the copolyanhydrides decreased as dMOCPS or ddMOCPS fraction increased, and the degradation duration could be modulated from several days to more than 3 months. It addition, the copolyanhydrides displayed typical surface-degradation characteristics. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 1214–1221, 2006
Biodegradable core–shell structured fibers with poly(ε-caprolactone) as shell and bovine serum albumin (BSA)-containing dextran as core were prepared by coaxial electrospinning for incorporation and controlled release of proteins. BSA loading percent in the fibers and its release rate could be conveniently varied by the feed rate of the inner dope during electrospinning. With the increase in the feed rate of the inner dope, there was an associated increase in the loading percent and accelerated release of BSA. Poly(ethylene glycol) (PEG) was added to the shell section of the fibers to further finely modulate the release behavior of BSA. It was revealed that the release rate of BSA increased with the PEG percent in the shell section. By varying the feed rate of the inner dope and PEG content, most of BSA could be released from the core–shell structured fibers within the period of time ranging from 1 week to more than 1 month. The effect of the feed rate of the inner dope and addition of PEG into the shell section on the fiber morphology was also examined by scanning electron microscope. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Summary: An ampholytic N-carboxyethyl chitosan (CEC), with various isoelectric points (IPs), was synthesized by grafting acrylic acid on chitosan utilizing Michael's reaction. Compared to native chitosan, CEC has enhanced water solubility and dramatically accelerated enzymatic degradation; the rate of degradation is proportional to the degree of substitution (DS). The results from turbidimetric titration and fluorescence studies revealed that CEC formed complexes with either hyaluronic acid (HA) or bovine serum albumin (BSA) within a certain pH range. The HA/CEC/BSA ternary complexes could be prepared by colloid titration with quantitative yield and BSA entrapment. The rate of BSA release from the complexes was affected by pH, ionic strength, DS of CEC, and the molecular weight (MW) of HA. The endurance of BSA release from the complexes could be extended up to 20 d by formulating them with high-MW HA and CEC with low DS.
Summary: In this work, a novel diacid monomer was synthesized in a very convenient scheme. The monomer is derived from naturally occurring products and emits strong fluorescence when polymerized to polyanhydride. The chemical structure of the monomer dCPS is as follows: HOC(O)ArOC(O)(CH2)2C(O)OArCOOH. Copolyanhydrides composed of dCPS and sebacic acid were further prepared by melt copolycondensation, and characterized by IR, NMR, UV-Vis, DSC and fluorometry. The emission wavelength (λem) of the copolymers could be tuned by the excitation wavelength (λex). Fluorescence intensity increased with the increase of dCPS content. The microspheres fabricated from the copolymer with dCPS content as low as 10% could be clearly visualized with fluorescence microscopy. Either blue or green images of the microspheres could be captured with an excitation of UV and visible light. The degradation rate of the copolyanhydrides decreased as the dCPS fraction increased, and the degradation duration could be modulated from several days to more than three months. In addition, it was found that the copolyanhydrides displayed surface degradation characteristics. In view of the advantages of the novel copolyanhydrides, such as easy preparation, unique inherent luminescent properties, and widely adjustable degradation rate, they might be useful for biomedical engineering.
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