In vitro blood compatibility of polymeric biomaterials through covalent immobilization of an amidine derivative

Gouzy, Marie-Françoise; Sperling, Claudia; Salchert, Katrin; Pompe, Tilo; Streller, Uwe; Uhlmann, Petra; Rauwolf, Cordula; Simon, Frank; Böhme, Frank; Voit, Brigitte; Werner, Carsten

doi:10.1016/j.biomaterials.2003.10.091

Cited by 47 publications

(30 citation statements)

References 30 publications

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“…As the main components of the introduced gel materials are already medically approved and widely used, the described system is considered attractive for clinical translation. Similar bio-responsive gels with sensitivity to the more upstream coagulation factor FXa or delivery of direct—synthetic—coagulation inhibitors instead of heparin offer promising variations of the introduced design concept35.…”

Section: Discussionmentioning

confidence: 99%

Bio-responsive polymer hydrogels homeostatically regulate blood coagulation

et al. 2013

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Bio-responsive polymer architectures can empower medical therapies by engaging molecular feedback-response mechanisms resembling the homeostatic adaptation of living tissues to varying environmental constraints. Here we show that a blood coagulation-responsive hydrogel system can deliver heparin in amounts triggered by the environmental levels of thrombin, the key enzyme of the coagulation cascade, which—in turn—becomes inactivated due to released heparin. The bio-responsive hydrogel quantitatively quenches blood coagulation over several hours in the presence of pro-coagulant stimuli and during repeated incubation with fresh, non-anticoagulated blood. These features enable the introduced material to provide sustainable, autoregulated anticoagulation, addressing a key challenge of many medical therapies. Beyond that, the explored concept may facilitate the development of materials that allow the effective and controlled application of drugs and biomolecules.

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Section: Discussionmentioning

confidence: 99%

Bio-responsive polymer hydrogels homeostatically regulate blood coagulation

et al. 2013

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“…However, the anticoagulant properties of the immobilized PPACK were worse than those found previously for immobilized benzamidine-type inhibitors. 4 A direct comparison between these two types of inhibitors are intended for a further study. Reversible inhibitors typically form the enzyme-inhibitor complex faster than irreversible inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…After immobilization, samples were washed with 10 mM HCl to remove nonimmobilized PPACK for 1 h. Details of the immobilization are described elsewhere. 4,17 Unmodified, hydrolyzed PP-MA served as reference surface, and further control surfaces consisted of PEG with immobilized bovine serum albumin (BSA). The efficiency of the PPACK immobilization method was probed by X-ray photoelectron spectroscopy (XPS; Amicus spectrometer, Kratos Analytical, UK) and by highperformance liquid chromatography (HPLC) after hydrolysis of the immobilized material according to a previously described method.…”

Section: Methodsmentioning

confidence: 99%

“…Their inhibitor characteristics have been determined in solution, and the efficiency as immobilized molecules in whole blood incubation has been demonstrated. 4,5 Benzamidines belong to the high-affinity, competitive inhibitors of thrombin. They interact noncovalently with Asp 189 in the binding pocket of thrombin and have no interaction with the reactive triad of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

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Immobilization of the irreversible thrombin inhibitor D‐Phe‐Pro‐Arg‐chloromethylketone: A concept for hemocompatible surfaces?

Maitz

Sperling

Werner

2010

J Biomedical Materials Res

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The irreversible thrombin inhibitor D-Phe-Pro-Arg-chloromethylketone (PPACK) was covalently immobilized to PEGylated polymer thin films at its primary alpha-amino group. Activity assays and capture of radioconjugated thrombin reveal that the PPACK-decorated surfaces could bind thrombin forming up to 30% of a monolayer density. Back-calculation of this high thrombin-inhibiting capacity indicated that the surface immobilization of the inhibitor was still associated with more than two orders of magnitude of loss of activity; increasing activity was observed at higher surface densities. PPACK-containing polymer films almost duplicated the plasma coagulation time when compared with the reference substrate without inhibitor. In whole blood, however, the anticoagulant properties were below those previously found for benzamidine-type reversible thrombin inhibitors; in addition, the surface exhibited inflammatory properties. It is concluded that immobilized reversible thrombin inhibitors are more effective by passivating higher amounts of thrombin in a cooperative action with antithrombin III.

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“…Informed consent was obtained from donors prior to blood donation. Heparin is a commonly used anticoagulant in blood compatibility testing of biomaterials in vitro 9,31 and was selected as the anticoagulant for TAT generation studies. Unfractionated heparin (UFH) binds antithrombin and converts it into a more efficient inhibitor of thrombin and other coagulation factors such as factor Xa, factor IXa, and factor XIIa 11.…”

Section: Methodsmentioning

confidence: 99%

Hemocompatibility of Silicon-Based Substrates for Biomedical Implant Applications

et al. 2011

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Silicon membranes with highly uniform nanopore sizes fabricated using microelectromechanical systems (MEMS) technology allow for the development of miniaturized implants such as those needed for renal replacement therapies. However, the blood compatibility of silicon has thus far been an unresolved issue in the use of these substrates in implantable biomedical devices. We report the results of hemocompatibility studies using bare silicon, polysilicon, and modified silicon substrates. The surface modifications tested have been shown to reduce protein and/or platelet adhesion, thus potentially improving biocompatibility of silicon. Hemocompatibility was evaluated under four categories—coagulation (thrombin–antithrombin complex, TAT generation), complement activation (complement protein, C3a production), platelet activation (P-selectin, CD62P expression), and platelet adhesion. Our tests revealed that all silicon substrates display low coagulation and complement activation, comparable to that of Teflon and stainless steel, two materials commonly used in medical implants, and significantly lower than that of diethylaminoethyl (DEAE) cellulose, a polymer used in dialysis membranes. Unmodified silicon and polysilicon showed significant platelet attachment; however, the surface modifications on silicon reduced platelet adhesion and activation to levels comparable to that on Teflon. These results suggest that surface-modified silicon substrates are viable for the development of miniaturized renal replacement systems.Electronic supplementary materialThe online version of this article (doi:10.1007/s10439-011-0256-y) contains supplementary material, which is available to authorized users.

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In vitro blood compatibility of polymeric biomaterials through covalent immobilization of an amidine derivative

Cited by 47 publications

References 30 publications

Bio-responsive polymer hydrogels homeostatically regulate blood coagulation

Bio-responsive polymer hydrogels homeostatically regulate blood coagulation

Immobilization of the irreversible thrombin inhibitor D‐Phe‐Pro‐Arg‐chloromethylketone: A concept for hemocompatible surfaces?

Hemocompatibility of Silicon-Based Substrates for Biomedical Implant Applications

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