Publications (32)111.43 Total impact
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Article: Nanostructuring PEG-fibrinogen hydrogels to control cellular morphogenesis.
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ABSTRACT: The nanostructuring of hydrogel scaffolds used in tissue engineering aims to provide an ability to control cellular morphogenesis through defined cell-matrix interactions. Toward this objective, we developed a method that alters the molecular network structure of biosynthetic hydrogel scaffolds made from crosslinked poly(ethylene glycol)-fibrinogen conjugates (PEG-fibrinogen, PF). The modifications were based on Pluronic(®) F127 micelles that were formed in the hydrogel precursor solution and that altered the hydrogel network assembly during photopolymerization crosslinking. Two variations of the cell-encapsulating hydrogels (high and low crosslinking density) were prepared with three concentrations of Pluronic(®) F127 (3%, 7%, 10% w/v). Quantitative morphometrics were used to characterize fibroblast shape parameters (both transient and stable) in all hydrogels, and rheological characterizations were used to measure the elastic (storage) component of the complex shear modulus of these hydrogels. The morphometric data was then correlated to both the nanostructure and modulus of the hydrogels for day 1 and day 4 in culture. These correlations revealed that structural features imparted by the Pluronic(®) F127 micelles were able to reverse the normally strong correlations found between indicators of cell spreading and the hydrogel's mechanical properties. Therefore, the data supports the conclusion that nanostructural features in the encapsulating hydrogel culture environment can facilitate better cell spreading in a dense hydrogel milieu, simply by introducing imperfections into the network structure. This research also provides further prospective regarding biocompatible approaches toward making structural modifications to hydrogel scaffolds for the purpose of 3-D cell culture and tissue engineering.Biomaterials 11/2011; 32(31):7839-46. · 7.40 Impact Factor -
Article: Nanostructuring biosynthetic hydrogels for tissue engineering: a cellular and structural analysis.
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ABSTRACT: The nanostructuring of hydrogel scaffolds used in tissue engineering provides the ability to control cellular fate and tissue morphogenesis through cell-matrix interactions. Here we describe a method to provide nanostructure to a biosynthetic hydrogel scaffold made from crosslinked poly(ethylene glycol)-fibrinogen conjugates (PEG-fibrinogen), by modifying them with the block-copolymer Pluronic® F127. The copolymeric additive self-assembled into micelles at certain concentrations and temperatures, thereby creating nanostructures within the crosslinked hydrogel. Small-angle X-ray scattering (SAXS) and transmission electron microscopy at cryogenic temperature were used to detect Pluronic® F127 micelles embedded within the crosslinked PEG-fibrinogen hydrogels. The density and order of the micelles within the hydrogel matrix increased as the relative Pluronic® F127 concentration was raised. The transient stability of the micelles within the hydrogel network was analyzed using time-dependent swelling and Pluronic® F127 release measurements. These characterizations revealed that most of the Pluronic® F127 molecules diffuse out of the hydrogels after 4 days in aqueous buffer and SAXS analysis confirmed a significant change in the structure and interactions of the micelles during this time. Cell culture experiments evaluating the three-dimensional fibroblast morphology within the matrix indicated a strong correlation between cell spreading and the hydrogel's characteristic mesh size. The present research thereby provides a more quantitative understanding of how structural features in an encapsulating hydrogel environment can affect cell morphogenesis towards tissue regeneration.Acta biomaterialia 08/2011; 8(1):51-60. · 3.98 Impact Factor -
Article: Physical and structural characteristics of acrylated poly(ethylene glycol)-alginate conjugates.
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ABSTRACT: Transmucosal delivery of therapeutic agents is a non-invasive approach that utilizes human entry paths such as the nasal, buccal, rectal and vaginal routes. Mucoadhesive polymers have the ability to adhere to the mucus layer covering those surfaces and by that promote drug release, targeting and absorption. We have recently demonstrated that acrylated polymers display enhanced mucoadhesive properties due to their ability to covalently attach to mucus type glycoproteins. We have synthesized an acrylated poly(ethylene glycol)-alginate conjugate (alginate-PEGAc), a molecule which combines the gelation ability of alginate with the mucoadhesion properties arising from both the characteristics of poly(ethylene glycol) and the acrylate functionality. In the current investigation we introduce an in-depth characterization of the thermal, mechanical and structural properties of alginate-PEGAc aimed at gaining a better knowledge of its structure-function relations. The thermal stability, evaluated by thermal gravimetric analysis and differential scanning calorimetry, was compared with that of alginate and the intermediate product thiolated alginate. Dehydration at temperatures up to 200 °C was detected for all samples, followed by distinctive decomposition steps arising from the decomposition of the polymer backbone and side-chains. The nanostructure of the solutions and gels was evaluated from small angle X-ray scattering patterns, to which the "broken rod linked by flexible chain" model was fitted, and from rheology measurements. The maxima arising from electrostatic repulsion between the highly charged alginate chains was diminished for both modified alginate samples, suggesting that modification led to electrostatic screening. Alginate, thiolated alginate and alginate-PEGAc cross-linked with calcium ions demonstrated similar scattering patterns. However, different scattering intensities, gel strengths, and gelation kinetics were observed, suggesting a decrease in the cross-linking density in the order alginate>thiolated alginate>alginate-PEGAc. These results were attributed to the increased size of the grafted side groups, which interfere with the gelation process. Examining the effect of the method of alginate-PEGAc gelation (physical or chemical) has shown that additional UV irradiation of calcium cross-linked gels did not cause a significant change in the network structure and strength. It seems that the concentration of the acrylated end group is not high enough to create a chemically cross-linked network.Acta biomaterialia 07/2011; 7(7):2817-25. · 3.98 Impact Factor -
Article: Stimulus-responsive hydrogels made from biosynthetic fibrinogen conjugates for tissue engineering: structural characterization.
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ABSTRACT: Nanostructured hydrogels based on "smart" polymer conjugates of poloxamers and protein molecules were developed in order to form stimulus-responsive materials with bioactive properties for 3-D cell culture. Functionalized Pluronic F127 was covalently attached to a fibrinopeptide backbone and cross-linked into a structurally versatile and mechanically stable polymer network endowed with bioactivity and temperature-responsive structural features. Small angle X-ray scattering and transmission electron microscopy combined with rheology were used to characterize the structural and mechanical features of this biosynthetic conjugate, both in solution and in hydrogel form. The temperature at which the chemical cross-linking of F127-fibrinopeptide conjugates was initiated had a profound influence on the mechanical properties of the thermo-responsive hydrogel. The analysis of the scattering data revealed modification in the structure of the protein backbone resulting from increases in ambient temperature, whereas the structure of the polymer was not affected by ambient temperature. The hydrogel cross-linking temperature also had a major influence on the modulus of the hydrogel, which was rationally correlated to the molecular structure of the polymer network. The hydrogel structure exhibited a small mesh size when cross-linked at low temperatures and a larger mesh size when cross-linked at higher temperatures. The mesh size was nicely correlated to the mechanical properties of the hydrogels at the respective cross-linking temperatures. The schematic charts that model this material's behavior help to illustrate the relationship that exists between the molecular structure, the cross-linking temperature, and the temperature-responsive features for this class of protein-polymer conjugates. The precise control over structural and mechanical properties that can be achieved with this bioactive hydrogel material is essential in designing a tissue-engineering scaffold for clinical applications.Langmuir 06/2011; 27(11):6977-86. · 4.19 Impact Factor -
Article: Alginate-PEGAc: a new mucoadhesive polymer.
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ABSTRACT: We have synthesized a novel mucoadhesive polymer, alginate-polyethylenglycol acrylate (alginate-PEGAc), in which an alginate backbone carries acrylated polyethylenglycol. This polymer combines the strength, simplicity and gelation ability of alginate with the mucoadhesion properties arising from the characteristics and acrylate functionality of PEG. The strong bonding to the mucus results from a combination of PEG's ability to interpenetrate the mucus surface and a Michael-type addition reaction between an acrylate end group on a polymer and the sulfide end group of the mucin-type glycoprotein. We have synthesized alginate-PEGAc, verified the formation of the desired product by nuclear magnetic resonance, demonstrated the lack of cytotoxicity, and evaluated the ability of this polymer to function as a novel mucoadhesive material for controlled drug release. Based on our findings we believe that modifying other polymers with PEG-acrylate can open the way for the development of many other multifunctional biomaterials for a variety of biotechnological and biomedical applications.Acta biomaterialia 02/2011; 7(2):625-33. · 3.98 Impact Factor -
Chapter: Drug Delivery Systems Based On Mucoadhesive Polymers
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ABSTRACT: Transmucosal delivery of therapeutic agents is a non-invasive approach that utilizes human entry paths such as the nasal, buccal, rectal and vaginal routs. Mucoadhesive polymers have the ability to adhere to the mucus layer covering those surfaces and by that promote drug release, targeting and absorption. Mucoadhesive polymers commonly interact with mucus through non-covalent bonds such as hydrogen bonds, ionic interactions and/or chain entanglement. This chapter reviews variety of mucoadhesive polymeric systems with a special emphasis on recent developments in the field. In particular, a new class of covalently interacting mucoadhesive polymers termed acrylated mucoadhesive polymers is described in detail. Acrylated mucoadhesive polymers are macromolecules which carry at least one double bond therefore are capable of forming covalent link with thiol groups on mucin type glycoproteins, the main component of mucus. To date, two acrylated mucoadhesive polymers were synthesized, and their ability to act as a mucoadhesive drug release vehicle was characterized and compare to other covalently binding mucoadhesive polymers. This approach opens a way to additional clinical applications that will benefit from the administration of drugs through the mucosa surface.12/2010: pages 439-456; -
Article: Composite alginate hydrogels: An innovative approach for the controlled release of hydrophobic drugs.
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ABSTRACT: We present an innovative methodology for the sustained delivery of hydrophobic drugs using composite hydrogels, prepared by embedding oil-in-water microemulsions in hydrophilic hydrogels. The hydrophobic nature of the microemulsion core enhances the solubilization of hydrophobic drugs, while the crosslinked matrix could be readily used as a solid controlled delivery vehicle. A microemulsion was formulated from pharmaceutical accepted components; the droplets diameter was shown to be about 10nm by dynamic light scattering, cryo-transmission electron microscopy and small-angle X-ray scattering (SAXS). Combining the microemulsion with alginate solution and crosslinking with calcium ions resulted in a clear hydrogel. A model hydrophobic drug, Ketoprofen, precipitated from the alginate hydrogel, but the drug-containing composite hydrogel was clear and macroscopically homogeneous. The nanostructure was investigated by SAXS; scattering plots indicate that oil droplets exist in the composite hydrogel. Release profiles of the drug from the composite hydrogel with various concentrations of polymer and crosslinker demonstrate the applicability of this system as a controlled delivery vehicle, and suggest that the release rate is governed not by the microemulsion structure but, rather, by the network properties. Furthermore, it was demonstrated that the release rate could be tailored for a specific application utilizing different alginate and calcium concentrations. The generalization of the methodology of including hydrophobic drugs in composite gels is discussed.Acta biomaterialia 12/2010; 6(12):4642-9. · 3.98 Impact Factor -
Article: Proteolytically Degradable Photo‐Polymerized Hydrogels Made From PEG–Fibrinogen Adducts
Advanced Engineering Materials 06/2010; 12(6):B200 - B209. · 1.18 Impact Factor -
Article: Molecularly imprinted hydrogel displaying reduced non-specific binding and improved protein recognition.
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ABSTRACT: A novel approach for enhancing protein recognition in molecularly imprinted hydrogel (MIH) is presented. This approach was developed based on the hypothesis that the number of specific binding sites created in the previously described MIH is very small, thus attempts to enhance the capacity result in most cases in additional non-specific binding and loss of selectivity. Thus, blocking the non-specific binding sites could lead to higher capacities and better selectivity. To test this hypothesis, MIH interpenetrating networks designed to block non-specific binding sites were synthesized using two separate stages of polymerization. Re-binding of the template protein (lysozyme) and a competitor protein (cytochrome C) was measured, and the results were compared with the similar experiment performed using a control non-imprinted hydrogel and a "conventional" MIH. The imprinting efficacy of the MIH interpenetrating network was found to be much higher than that of the controls. Furthermore, competitive adsorption assays have demonstrated the superiority of the new formulation.Journal of Separation Science 06/2010; 33(11):1673-81. · 2.73 Impact Factor -
Article: Novel mucoadhesive system based on sulfhydryl-acrylate interactions.
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ABSTRACT: We propose a novel cross-linked mucoadhesive system that can interact covalently with mucin type glycoprotein, thus providing both strong bonding to mucosa as well as ability to function as a sustained release matrix. The strong bonding results from Michael type addition reaction between an acrylate end group on a polymer and the sulfide end group of the mucin type glycoprotein. A proof of concept is provided using a polyehtylene glycol hydrogel formed in situ from polyehtylene glycol di-acrylate (PEG-DA) macromers. The ability of PEG-DA to create interactions with mucin type glycoproteins was verified using nuclear magnetic resonance (NMR) and rheology experiments. NMR studies have detected disappearance of the PEG-DA's vinyl protons upon mucin addition, whereas rheology measurements have shown a viscosity increase. These results provide an evidence for the formation of mucin-polymer covalent bond. The ability PEG-DA to attach to mucus and promote mucoadhesion was evaluated by tensile measurements. PEG-DA adhered at strength comparable to other covalently interacting mucoadhesive polymers. Furthermore, PEG-DA was found to be a suitable candidate for sustained release of the hydrophilic drug Ibuprofen.Journal of Materials Science Materials in Medicine 04/2010; 21(7):2027-34. · 2.32 Impact Factor -
Article: Mucoadhesion: a review of characterization techniques.
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ABSTRACT: Mucoadhesive drug delivery vehicles attract much attention owing to benefits such as extended residence time of the drug at the site of application, a relatively rapid uptake of a drug into the systemic circulation, and enhanced bioavailability of therapeutic agents. Mucoadhesion, defined as the ability to adhere to the mucus gel layer covering organs that are exposed to the outer surface of the body yet are not covered with skin, such as the mouth and the respiratory tract, is a key element in the design of these drug delivery systems. This review focuses on the numerous experimental methods that have been proposed over the years for mucoadhesion characterization. These techniques are categorized into directs methods, which measure the force or time required to detach the mocoadhesive from a mucus, and indirect methods, which asses the interactions between the mucoadhesive and mucin type glycoproteins. The comprehensive description of the available techniques could facilitate the selection of a characterization method that meets the requirements of a specific study. Moreover, a comparison between the results obtained in different laboratories is given whenever possible. The challenge of adopting a universal test method that could be used to compare data from different research groups and rank new mucoadhesion candidates has not yet been met.Expert Opinion on Drug Delivery 02/2010; 7(2):259-71. · 4.90 Impact Factor -
Article: Structural investigation of PEG-fibrinogen conjugates.
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ABSTRACT: Controllable bio-synthetic polymeric hydrogels made from fibrinogen-poly(ethylene glycol) adducts have been successfully employed in tissue engineering. The structural consequences of PEG conjugation to fibrinogen (i.e., PEGylation) in such a hydrogel network are not fully understood. The current investigation details the structural alterations caused to the reduced fibrinogen polypeptides by the covalent attachment of linear or branched PEG chains. The structure of PEGylated fibrinogen polypeptides were comprehensively characterized using small angle X-ray scattering, light scattering, and cryo-transmission electron microscopy. These characterizations concur that the bio-synthetic hybrids self-assemble into elongated objects, having a protein core of about 50 A in diameter decorated with multiple PEG chains. Conjugates with branched PEG chains were shorter, and have lower average molecular weight compared to conjugates with linear chains. The diameter of the protein core of both samples was similar, suggesting a tail-to-head aggregation of the PEGylated fibrinogen polypeptide. A more complete understanding of this unique structural arrangement can provide further insight into the full extent of biofunctional accessibility in a biomaterial that combines the advantages of synthetic polymers with bioactive proteins.Journal of Materials Science Materials in Medicine 09/2009; 21(1):73-80. · 2.32 Impact Factor -
Article: Nanostructuring of PEG-fibrinogen polymeric scaffolds.
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ABSTRACT: Recent studies have shown that nanostructuring of scaffolds for tissue engineering has a major impact on their interactions with cells. The current investigation focuses on nanostructuring of a biocompatible, biosynthetic polymeric hydrogel scaffold made from crosslinked poly(ethylene glycol)-fibrinogen conjugates. Nanostructuring was achieved by the addition of the block copolymer Pluronic F127, which self-assembles into nanometric micelles at certain concentrations and temperatures. Cryo-transmission electron microscopy experiments detected F127 micelles, both embedded within PEGylated fibrinogen hydrogels and in solution. The density of the F127 micelles, as well as their ordering, increased with increasing block copolymer concentration. The mechanical properties of the nanostructured hydrogels were investigated using stress-sweep rheological testing. These tests revealed a correlation between the block copolymer concentration and the storage modulus of the composite hydrogels. In vitro cellular assays confirmed that the increased modulus of the hydrogels did not limit the ability of the cells to form extensions and become spindled within the three-dimensional (3-D) hydrogel culture environment. Thus, altering the nanostructure of the hydrogel may be used as a strategy to control cellular behavior in 3-D through changes in mechanical properties of the environment.Acta biomaterialia 08/2009; 6(7):2518-24. · 3.98 Impact Factor -
Article: Evaluating the mucoadhesive properties of drug delivery systems based on hydrated thiolated alginate.
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ABSTRACT: Mucoadhesive polymers have been proposed as drug delivery carriers due to their ability to adhere to the mucus layer. A relatively new class of mucoadhesive polymers, termed thiomers, was suggested as an improved carrier capable of creating disulfide covalent bond with the mucus. Since the wet physiological environment is likely to cause any delivery system to adsorb water and arrive hydrated to its target, studying the performance of mucoadhesive systems in their hydrated form is of major importance. Model thiomer, alginate-thiol, were synthesized and characterized the product using Nuclear Magnetic Resonance (NMR), Fourier Transform Infra Red spectroscopy (FTIR). The swelling behavior was determined gravimetrically and found to be affected from the thiolation. Interactions between the alginate-thiol and mucin glycoproteins, which are believed to be an outcome of disulfide bonds, were verified using rheology experiments. Adhesion of hydrated tablets with different cross linking densities to porcine's fresh small intestine tissue were characterized using a Lloyd Tensile Machine. It was shown that the thiolation did not improve the adhesion properties of hydrated tablets. It appears that the benefit achieved by adding thiol group to the polymer in dry tablet form was flawed in hydrated form due to formation of inter-molecular disulfide junctions.Journal of Controlled Release 03/2009; 136(1):38-44. · 5.73 Impact Factor -
Article: Phloroglucinol-based biomimetic adhesives for medical applications.
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ABSTRACT: An adhesive that functions well under moist conditions could facilitate many surgical procedures. In recent studies we designed novel biomimetic glues which mimic the adhesion mechanism of algae, renowned for their remarkable adherence to wet surfaces. Here we extend our previous studies and propose biomimetic formulations, composed of alginate gel and native phloroglucinol, that do not induce cell cytotoxicity. Characterization of the adherence to tissues showed that adhesion was directly related to the mechanical strength of the cross-linked alginate. Therefore the adhesion strength can be altered by changing the source of the calcium cross-linker, the alginate G-content or the molecular weight of the alginate. The adhesion strength was comparable to that of Tisseel, a commercial tissue adhesive.Acta biomaterialia 11/2008; 5(5):1582-7. · 3.98 Impact Factor -
Article: Novel biomimetic adhesives based on algae glue.
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ABSTRACT: Inspired by the remarkable adhesive capabilities to wet surfaces of the secretes of the brown alga Fucus serratus, novel glues have been designed and characterized. Formulations composed of phloroglucinol, alginate, and calcium ions are capable of adhering to a variety of surfaces. Rheological data show that the presence of phloroglucinol lowers the amount of Ca(2+) ions required for sol-gel transition, which indicates interactions between the alginate and the phloroglucinol. SAXS data support this claim. The phloroglucinol adhesive binds porcine tissues together with an adhesive strength of 17-25 kPa, which indicates appropriate mechanical properties for application as a soft tissue adhesive.Macromolecular Bioscience 06/2008; 8(5):393-400. · 3.89 Impact Factor -
Article: Defining the role of matrix compliance and proteolysis in three-dimensional cell spreading and remodeling.
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ABSTRACT: Recent studies have identified extracellular matrix (ECM) compliance as an influential factor in determining the fate of anchorage-dependent cells. We explore a method of examining the influence of ECM compliance on cell morphology and remodeling in three-dimensional culture. For this purpose, a biological ECM analog material was developed to pseudo-independently alter its biochemical and physical properties. A set of 18 material variants were prepared with shear modulus ranging from 10 to 700 Pa. Smooth muscle cells were encapsulated in these materials and time-lapse video microscopy was used to show a relationship between matrix modulus, proteolytic biodegradation, cell spreading, and cell compaction of the matrix. The proteolytic susceptibility of the matrix, the degree of matrix compaction, and the cell morphology were quantified for each of the material variants to correlate with the modulus data. The initial cell spreading into the hydrogel matrix was dependent on the proteolytic susceptibility of the materials, whereas the extent of cell compaction proved to be more correlated to the modulus of the material. Inhibition of matrix metalloproteinases profoundly affected initial cell spreading and remodeling even in the most compliant materials. We concluded that smooth muscle cells use proteolysis to form lamellipodia and tractional forces to contract and remodel their surrounding microenvironment. Matrix modulus can therefore be used to control the extent of cellular remodeling and compaction. This study further shows that the interconnection between matrix modulus and proteolytic resistance in the ECM may be partly uncoupled to provide insight into how cells interpret their physical three-dimensional microenvironment.Biophysical Journal 05/2008; 94(7):2914-25. · 3.65 Impact Factor -
Article: Development of nanostructure in resistant starch type III during thermal treatments and cycling.
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ABSTRACT: The effect of recrystallization temperature on the lamellar structure of RSIII samples was studied using XRD and SAXS. The polymorph type could be manipulated in a controlled manner, independently of the plant source. In RSIII from corn starch and from high-amylose corn starch, retrogradation at a low temperature led to the formation of polymorph B with lamellas arranged in long-range periodicity, whereas retrogradation at a high temperature led to the formation of polymorphs A and V with no defined periodicity. The retrogradation temperature of wheat starch did not have a major effect on its nanostructure. For both polymorphs, the enzymatic degradation decreased as the degree of order within the crystal increased.Macromolecular Bioscience 03/2008; 8(2):163-70. · 3.89 Impact Factor -
Article: The influence of halide-mediated oxidation on algae-born adhesives.
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ABSTRACT: Adhesive materials extracted from the brown algae Fucus Serratus were studied. These adhesives are composed of cross-linked alginate and polyphenols oxidized in the presence of KI or KBr. All formulations were capable of adhering to a variety of surfaces, however the adhesion properties were influenced by the halide used. SAXS and TEM experiments revealed that oxidized polyphenols self-assemble into chain-like objects, irrespective of the oxidation conditions. Yet, slight differences in the aggregate size were detected. QCM-D results showed that the kinetics of the oxidation was faster with iodide than with bromide. Moreover, oxidation with iodide generates stiffer networks, suggesting that the interaction between the alginate and the polyphenol could be the cause of the reduced adhesion.Macromolecular Bioscience 01/2008; 7(12):1280-9. · 3.89 Impact Factor -
Article: Study of the interactions between protein-imprinted hydrogels and their templates.
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ABSTRACT: The interactions between lysozyme-imprinted hydrogel and their template protein were studied using adsorption measurements, competitive adsorption experiments, and isothermal titration calorimetry (ITC). The results were compared to the interactions between the imprinted polymer and a reference protein, cytochrome c. Experimental adsorption isotherms and competitive adsorption studies detected better affinity and higher capacity of the imprinted polymer toward the template protein. Moreover, analysis of ITC data identified major differences in the binding enthalpy of lysozyme when the imprinted and the non-imprinted polymers were compared. On the other hand, cytochrome C did not exhibit any major changes in the adsorption enthalpy when comparing the imprinted and the non-imprinted polymers. This is the first thermodynamic evidence for the creation of new binding sites in the process of protein imprinting.Langmuir 06/2007; 23(11):6329-35. · 4.19 Impact Factor
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2004–2011
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Technion - Israel Institute of Technology
Haifa, Haifa District, Israel
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