Synthesis and Anticoagulant Function of Heparin Containing Block Copolymers On Polystyrene Microspheres (original) (raw)
Related papers
International Journal of Biological Macromolecules, 2010
Thiol (-SH) groups were introduced into unfractionated heparin by reaction of carboxyl groups in its uronic acid residues with 3,3 dithiobis(propanoic)hydrazide. Thiolated heparin derivatives were then linked to pyridyl disulfide-activated polyethylene oxide-polypropylene oxide-polyethylene oxide triblocks, which had previously been coated onto the surfaces of 1.15 m polystyrene microspheres. The heparin immobilization reaction was monitored spectrophotometrically as colored pyridine-2-thione was released. In addition, the zeta potentials of uncoated, triblock-coated, and heparin-containing microsphere suspensions were recorded to demonstrate the successful attachment of heparin on the surface. However this "side-on" attachment of heparin to pendant, polyethylene oxide chains did not significantly increase the anticoagulant or anti-Factor Xa activity of microsphere suspensions.
Importance of Uniform Heparin Coating on Biopolymers
Artificial Organs, 2000
Cardiopulmonary surgeries need connectors for extracorporeal circulation. The patient's blood in contact with the tube surfaces modifies its plasmatic proteins, promotes platelet aggregation, and activates the complement system, unleashing thrombus formation. Thus, it becomes necessary for an anticoagulant to keep the circuit free from these events. Heparin is the anticoagulant used even after reports about its disadvantages. Platelet adherence seems to be very dependent on the quality from the surfaces that can promote cellular proliferation, aggregation, and
Heparin-containing block copolymers
Journal of Materials Science: Materials in Medicine, 1993
Newly synthesized heparin-containing block copolymers, consisting of a hydrophobic block of polystyrene (PS), a hydrophilic spacer-block of poly(ethylene oxide) (PEO) and covalently bound heparin (Hep) as bioactive block, were coated on aluminium, glass, polydimethylsiloxane (PDMS), PS or Biomer substrates. Surfaces of coated materials were characterized by transmission electron microscopy (TEM), contact angle measurements and X-ray photoelectron spectroscopy for chemical analysis (XPS), It was demonstrated by TEM that thin films of PS-PEO and PS-PEO-Hep block copolymers consisted of heterogeneous microphase separated structures. Using sessile-drop and Wilhelmy plate dynamic contact angle measurements, insight was provided into the hydrophilicity of the surfaces of the coatings. Measurements with hydrated coatings of PS-PEO and PS-PEO-Hep block copolymers revealed that the surfaces became more hydrophilic during immersion in water, due to relaxation/reorientation, or swelling of PEO or PEO-Hep domains, respectively. XPS results for PS, PEO, heparin and PS-PEO as powder agreed well with qualitative and quantitative predictions. XPS results for films of PS-PEO and PS-PEO-Hep block copolymers showed enrichments of PEO in the top layers of the coatings. This effect was more pronounced for hydrated surfaces. Only small amounts of heparin were detected at the surface of coatings of PS-PEO-Hep block copolymers.
Journal of Biomedical Materials Research Part A, 2008
Poor compatibility between blood and metallic coronary artery stents is one reason for arterial restenosis; however, the immobilization of anticoagulant agents on the surface of the stent is a feasible method of improving stent compatibility. Heparin, a well-known anticoagulant, has been frequently used to coat the surfaces of certain biomaterials to attain blood compatibility. The compound 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide has often been utilized for the immobilization of heparin, but the critical carboxyl groups of heparin (with regards to heparin's anticoagulant activity) will be reduced by this method. This study examined possible methods of heparin immobilization without consuming these carboxyl groups. The 316L stainless steel surface was first activated with hexamethylene diisocyanate and then coupled with bis-amine-terminated poly (ethylene glycol) (BA-PEG) so as to create active amine groups. Sodium periodate (NaIO 4 ; SP) was then used to oxidize heparin to form aldehyde groups. The treated heparin could then be grafted onto the activated surface of the test material without losing its carboxyl groups. Effective surface modification of the hexamethylene diisocyanate-activated and BA-PEG-grafted 316L SS surface was confirmed using Fourier Transform Infrared Spectroscopy, electron spectroscopy for chemical analysis and a water contact angle test. After the heparin was immobilized on the BA-PEG-grafted 316L SS surface by SP, the surface showed an improvement in antithrombrin III (AT III) binding ability, its anticoagulant property, and hemocompatibility in comparison with heparin grafted by 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide.
Journal of Biomaterials Science, Polymer Edition, 1993
Appropriate surface modification has significantly improved the blood compatibility of polymeric biomaterials. This article reviews methods of surface modification with water-soluble polymers, such as polyethylene oxide (PEO), albumin, and heparin. PEO is a synthetic, neutral, watersoluble polymer, while albumin and heparin are a natural globular protein and an anionic polysaccharide, respectively. When grafted onto the surface, all three macromolecules share a common feature to reduce thrombogenicity of biomaterials. The reduced thrombogenicity is due to the unique hydrodynamic properties of the grafted macromolecules. In aqueous medium, surface-bound water-soluble polymers are expected to be highly flexible and extend into the bulk solution. Biomaterials grafted with either PEO, albumin, or heparin are able to resist plasma porotein adsorption and platelet adhesion predominantly by a steric repulsion mechanism.
Journal of Biomaterials Applications, 2002
Antenna coupling microwave plasma enables a highly oxidative treatment of the outmost surface of polypropylene (PP) nonwoven fabric within a short time period. Subsequently, grafting copolymerization with acrylic acid (AAc) makes the plasma-treated fabric durably hydrophilic and excellent in water absorbency. With high grafting density and strong water affinity, the pAAc-grafted support greatly becomes feasible as an intensive absorbent and as a support to promote heparin immobilization through amide bonds. For heparin immobilized in acidic condition, the carbonate groups of the molecule tend to dissolve and passive encapsulation of the molecule prevents its functional groups from bonding with the carboxylic acid of pAAc. This effect leads to inhibit the immobilization process and consequently reduces the quantity as well as the bioactivity of the immobilized heparin. In alkaline processing environment, the oxidized uronic acid residues in heparin-related glycans are presumably cleaved and the removal of some oxidized residuals before immobilization process is likely to reduce the chain length of heparin. In the latter case, anticoagulant Factors X and XII, but not thrombin, are unaffected. Anticoagulant activity test using activated partial thromboplastin time (aPTT) is more sensitive in assessing heparin-immobilized surfaces, since it corresponds to Factor X and initiates the inhibition of Factor XII and thrombin. Likewise, platelets adhesion on the surfaces decreases as the process shifted from acidic to alkaline condition, whereas the hydrophilic character of the grafted pAAc markedly contributes to extend physical insertion of platelets. The immobilized heparin has a great part of original bioactivity, depending on the pH of the processing environment and the immobilized quantity. Relative bioactivity based upon aPTT tests is partially held longer than 90 days for the sample prepared in the alkaline or neutral environment.
Effect of PEG–PDMAEMA Block Copolymer Architecture on Polyelectrolyte Complex Formation with Heparin
Biomacromolecules, 2016
Heparin is a naturally occurring polyelectrolyte consisting of a sulfated polysaccharide backbone. It is widely used as an anticoagulant during major surgical operations. However, the associated bleeding risks require rapid neutralization after the operation. The only clinically approved antidote for heparin is protamine sulfate, which is however ineffective against low molecular weight heparin and can cause severe adverse reactions in patients. In this study, the facile synthesis of cationic-neutral diblock copolymers and their effective heparin binding is Page 1 of 34 ACS Paragon Plus Environment Biomacromolecules presented. Poly(ethylene glycol)-poly(2-(dimethylamino)ethyl methacrylate) (PEG-PDMAEMA) block copolymers were synthetized in two steps via atom-transfer radical polymerization (ATRP) using PEG as a macroinitiator. Solution state binding between heparin and a range of PEG-PDMAEMA block copolymers and one homopolymer was studied with dynamic light scattering and methylene blue displacement assay. Also in vitro binding in plasma was studied by utilizing a chromogenic heparin anti-Xa assay. Additionally, quartz crystal microbalance and multi-parametric surface plasmon resonance were used to study the surface adsorption kinetics of the polymers on a heparin layer. It was shown that the block copolymers and heparin form electrostatically bound complexes with varying colloidal properties, where the block lengths play a key role in controlling the heparin binding affinity, polyelectrolyte complex size and surface charge. With the optimized polymers (PEG 114 PDMAEMA 52 and PEG 114 PDMAEMA 100), heparin could be neutralized in dose-dependent manner, and bound efficiently into small neutral complexes, with a hydrodynamic radius less than 100 nm. These complexes did not have an effect on cell viability. Based on these studies, our approach paves the way for the development of new polymeric heparin binding agents.
A nonelutable low-molecular weight heparin stent coating for improved thromboresistance
Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2012
Low-molecular weight heparin (LMWH) has been widely used as a systemic anticoagulant during percutaneous coronary intervention. In this study, LMWH was covalently immobilized to the surface of a cobalt chromium reservoirbased sirolimus-eluting stent to create a nonelutable nanoscale coating for enhanced thromboresistance. Toludine-blue stained stents revealed uniform heparin coverage on all surfaces of the stent. Scanning electron microscopy of stent strut cross-sections showed identical coating thickness on all sides; while the thickness was determined to be 320 nm by a focus-ion beam system. Secondary ion mass spectrometry showed constant concentrations of O, N, and S atoms throughout the depth of the surface, confirming the uniformity of the heparin coating. The nonelutable nature of the coating was confirmed in a modified Factor Xa inhibition assay which showed the stent had an equivalent of 3-5 heparin units/cm 2 , while no elutable heparin was detected in wash solutions. The antithrombin binding capacity of the immobilized heparin was determined to be 60-80 pmol/cm 2 in an antithrombin uptake assay. The enhanced thromboresistance of the heparin coating was demonstrated in an in-vitro bovine blood flow loop which showed minimal visual thrombus accumulation and 95% reduction in platelet deposition compared to uncoated control stents. Drug-eluting stents with such nonelutable LMWH coating would represent a significant advance in the treatment of patients with complex lesions who are at increased risk of developing stent thrombosis. V C 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B:
Heparin-Mimicking Polymers: Synthesis and Biological Applications
Biomacromolecules, 2016
Heparin is a naturally occurring, highly sulfated polysaccharide that plays a critical role in a range of different biological processes. Therapeutically, it is mostly commonly used as an injectable solution as an anticoagulant for a variety of indications, although it has also been employed in other forms such as coatings on various biomedical devices. Due to the diverse functions of this polysaccharide in the body, including anticoagulation, tissue regeneration, anti-inflammation, and protein stabilization, and drawbacks of its use, analogous heparin-mimicking materials are also widely studied for therapeutic applications. This review focuses on one type of these materials, namely, synthetic heparin-mimicking polymers. Utilization of these polymers provides significant benefits compared to heparin, including enhancing therapeutic efficacy and reducing side effects as a result of fine-tuning heparin-binding motifs and other molecular characteristics. The major types of the various ...