Thromboresistant Materials Research Articles

Effect of Temperature on Thrombogenicity Testing of Biomaterials in an In Vitro Dynamic Flow Loop System.

To develop and standardize a reliable in vitro dynamic thrombogenicity test protocol, the key test parameters that could impact thrombus formation need to be investigated and understood. In this study, we evaluated the effect of temperature on the thrombogenic responses (thrombus surface coverage, thrombus weight, and platelet count reduction) of various materials using an in vitro blood flow loop test system. Whole blood from live sheep and cow donors was used to assess four materials with varying thrombogenic potentials: negative-control polytetrafluoroethylene (PTFE), positive-control latex, silicone, and high-density polyethylene (HDPE). Blood, heparinized to a donor-specific concentration, was recirculated through a polyvinyl chloride tubing loop containing the test material at room temperature (22-24°C) for 1 hour, or at 37°C for 1 or 2 hours. The flow loop system could effectively differentiate a thrombogenic material (latex) from the other materials for both test temperatures and blood species ( p < 0.05). However, compared with 37°C, testing at room temperature appeared to have slightly better sensitivity in differentiating silicone (intermediate thrombogenic potential) from the relatively thromboresistant materials (PTFE and HDPE, p < 0.05). These data suggest that testing at room temperature may be a viable option for dynamic thrombogenicity assessment of biomaterials and medical devices.

Prostheses from the decellularized aorta and bioresorbable material in vivo

Modern vascular prostheses are prone to thrombosis and infections. Effective anticoagulant antibacterial therapy approaches and the development of other prostheses materials are very relevant today. In this context, prostheses from the decellularized vessel and bioresorbable material, polylactide for example, are of great interest due to the high probability of endogenous endothelization induced by the extracellular protein matrix, followed by the formation of the autogenic matrix of the vessel. Such blood vessels are characterized by atrombogenicity, porosity of the structure, prone to integration with the vascular wall of the recipient, endothelization, matrix and vessel formation. We would like to emphasize that such prostheses are capable of growth and are suitable not only for adults, but also for children with cardiovascular defects. However, our study of these prostheses in the dynamics of the posttransplantation period did not match the expected results: the prosthesis from the decellularized aorta turned out to be unsuitable within the first month after transplantation. The prosthesis from the bioresorbable material didn’t cause complications but conceal the risk of spontaneous insolvency caused by predetermined bioresorption and postponement formation of extracellular matrix. We assumed that the hybrid biosynthetic prosthesis consisting of two layers: the inner one made of a bioresorbable thrombo-resistant material and the outer one – from a decellularized vessel may be the decision. The internal bioresorbable layer will remove the problems of thrombosis, the formation of an aneurysm, and the external layer from the vascular matrix will ensure the migration into the prosthesis of the cells of the precursors of endotheliocytes and myocytes.

Crosslinking decreases the hemocompatibility of decellularized, porcine small intestinal submucosa

Decellularized tissues have been widely used as scaffolds for biomedical applications due to their presentation of adhesion peptide sequences and growth factors, which facilitate integration with surrounding tissue. One of the most commonly used decellularized tissues is derived from porcine small intestinal submucosa (SIS). In some applications, SIS is crosslinked to modulate the mechanical properties or degradation rate of the scaffold. Despite the widespread use of SIS, there has been no mechanistic characterization of blood reactions with SIS, or how crosslinking affects these reactions. Therefore, we characterized the effect of SIS and carbodiimide-crosslinked SIS (cSIS) on plasma coagulation, including targeted assessments of the intrinsic and extrinsic coagulation pathways, and thrombus formation using flowing whole blood. SIS inhibited plasma coagulation initiated by recalcification, as well as low concentrations of thrombin or tissue factor. SIS prolonged the activated partial thromboplastin time by 14.3±1.54s, indicating inhibition of the intrinsic coagulation pathway. Carbodiimide crosslinking abrogated all anticoagulant effects of SIS, as did heparinase I and III treatment, suggesting that heparin and heparan sulfate are predominantly responsible for SIS anticoagulant effects. Inhibiting contact activation of the intrinsic pathway prevented cSIS-mediated coagulation. When tubular SIS devices were connected to a nonhuman primate arteriovenous shunt loop, which enables whole blood to flow across devices without the use of anticoagulants, SIS demonstrated remarkably limited platelet accumulation and fibrinogen incorporation, while cSIS initiated significantly higher platelet and fibrinogen accumulation. These results demonstrate that SIS is a thromboresistant material and crosslinking markedly reduces the hemocompatibility of SIS.

Self-organization and aggregation of amphiphilic block copolymers of N-vinylpyrrolidone—block-2,2,3,3-tetrafluoropropylmethacrylate at interfaces

The physicochemical characteristics of monolayer formation of amphiphilic block copolymers of N-vinylpyrrolidone—block-2,2,3,3-tetrafluoropropylmethacrylate (PVP—block-PFMA) with different molecular weights (Mw) at the water-air interface and on the solid support (quartz, silicon) were studied. It was shown by UV and IR spectroscopy, analysis of the θ—S compression isotherms, and imaging by atomic force microscopy (AFM) that the state of PVP—block-PFMA monolayers on the aqueous subphase and solid support is determined by the ratio of Mw of comonomer blocks Mw(PFMA)/Mw(PVP), the aggregation of copolymers in solution and in the surface layer (surface micellation and phase isolation). Gibb’s surface energy of the films calculated in the Wendt—Good—Kaelbly—Dan—Fowkes approximation increases up to 30–33 mJ m−2 from 21 mJ m−2 (PFMA). The values of adhesion work Wadh(monolayer—water droplet—air) and Wadh(monolayer—water in octanol) and AFM imaging characterize the lipophilicity and surface topology of the films as optimal for thromboresistant materials.

Blood compatible materials: state of the art.

Devices that function in contact with blood are ubiquitous in clinical medicine and biotechnology. These devices include vascular grafts, coronary stents, heart valves, catheters, hemodialysers, heart-lung bypass systems and many others. Blood contact generally leads to thrombosis (among other adverse outcomes), and no material has yet been developed which remains thrombus-free indefinitely and in all situations: extracorporeally, in the venous circulation and in the arterial circulation. In this article knowledge on blood-material interactions and "thromboresistant" materials is reviewed. Current approaches to the development of thromboresistant materials are discussed including surface passivation; incorporation and/or release of anticoagulants, antiplatelet agents and thrombolytic agents; and mimicry of the vascular endothelium.

Novel thromboresistant materials

The development of a clinically durable small-diameter vascular graft as well as permanently implantable biosensors and artificial organ systems that interface with blood, including the artificial heart, kidney, liver, and lung, remain limited by surface-induced thrombotic responses. Recent breakthroughs in materials science, along with a growing understanding of the molecular events that underlay thrombosis, has led to the design and clinical evaluation of a variety of biologically active coatings that inhibit components of the coagulation pathway and platelet responses by surface immobilization or controlled release of bioactive agents. This report reviews recent progress in generating synthetic thromboresistant surfaces that inhibit (1) protein and cell adsorption, (2) thrombin and fibrin formation, and (3) platelet activation and aggregation.

Use of the affinity chromatography principle in creating new thromboresistant materials

The principle of affinity chromatography was used for preparation of thromboresistant bilayer coatings. The outer biospecific layer containing ε-aminocaproic acid residues (from 2.2 up to 5.5 nmol/cm 2) was synthesized using a copolymer of maleic anhydride with N-vinylpyrrolidone and l-lysine dihydrochloride or N-ε- tert-BOC- l-lysine. This surface can selectively adsorb plasminogen (fibrinolytic zymogen) from blood. The biospecific layer (from 2.0 up to 3.6 μg/cm 2) was applied for covering chitosan (native or modified) or albumin interlayer. Such bilayer coatings (BCs) were stable and represented the insoluble polyelectrolyte complexes. BCs were proposed for bilayer modification of synthetic vascular grafts, polyethylene, and other materials contacting with blood. This technique allowed us to significantly reduce thrombogenic properties of polyethylene surfaces.

Platelets are deposited early post-operatively on the leaflet of a mechanical heart valve in sheep without post-operative anticoagulants or antiplatelet agents. A scanning electron microscopic observation of the pyrolytic carbon surface in a mechanical heart valve.

Pyrolytic carbon has been used for mechanical heart valves as a thromboresistant, wear resistant, and fatigue resistant material. Thrombosis and thromboembolism, however, remain major mechanical heart valve associated complications and may frequently occur during the early post-operative period. In depth morphologic studies on blood-pyrolytic carbon surface interactions are limited. The purpose of this study was to evaluate the blood compatibility of the pyrolytic carbon surface of St. Jude Medical mechanical heart valves that were implanted in the mitral position of sheep without the administration of post-operative anticoagulants or antiplatelet agents for 2, 4, and 6 weeks. Almost the entire leaflet and orifice ring surfaces were observed by scanning electron microscopy. Although the surfaces appeared clean macroscopically, when observed by electron microscopy, the surface were mottled, mainly by solitary platelets and aggregations. There were only a few leukocytes or red blood cells observed. No fibrin clots were observed on the leaflets. The density of platelet deposition was higher in the vicinity of the pivots and near the edges of the leaflets. The sizes of the platelet aggregations decreased with longer duration. The outer surfaces of the pivot guards were covered by various amounts of deposition composed of platelet aggregations and thrombi. Thus, the administration of antiplatelet agents is recommended during the early post-operative period after mechanical heart valve implantation.

Hypercoagulable state induced by thrombocytapheresis.

The influence of the continuous-flow automated blood cell separator. Fenwal CS-3000, on blood coagulation and the fibrinolytic system in blood donors was studied. Blood samples were taken from the collection line of donors undergoing extracorporeal circulation, before and after platelet pheresis. Of the molecular markers, prothrombin fragment-F1 + 2 (PF1 + 2) markedly increased from 0.8 +/- 0.3 to 2.9 +/- 2.0 nM/ml (P < .004), thrombin antithrombin III complex (TAT) also markedly increased from 2.6 +/- 1.3 to 56.0 +/- 24.0 micrograms/L (P < .001), fibrinopeptide A (FPA) increased slightly from 0.8 +/- 0.9 to 3.8 +/- 4.2 micrograms/L (P < .05), and alpha 2-plasmin inhibitor (alpha 2-PI) decreased slightly from 95 +/- 8 to 91 +/- 9% (P < .05). In one donor with the highest level of PF1 + 2, TAT, FPA, and plasmin inhibitor complex after platelet pheresis, protein C, protein S, C4b-binding protein, ATIII, plasminogen, alpha 2-PI, and coagulation factors were decreased. In blood donors undergoing platelet pheresis using the continuous-flow automated blood cell separator, Fenwal CS-3000, a hypercoagulable state was observed. Changing the materials of the plastic disposables to a more thromboresistant material may prevent the hypercoagulable state in donors induced by platelet pheresis using the blood cell separator.

Protein-Polymer Interaction: Changes With Plasma Components, Vitamins, and Antiplatelet Drugs at the Interface

Abstract Medical devices like catheters, hemodialyzers, oxygenators, heart valves, and blood vessel prostheses are frequently used in man as a consequence of natural and accidental causes of deterioration of his body. The formation of thrombi on the surfaces of artificial materials occurs upon contact with blood. Progress made over the last 25 years in the area of blood-biomaterial compatibility has been impressive. However, we still do not have a satisfactory thromboresistant material to replace a coronary artery.

Recent advances in thromboresistant materials.

There are strong demands for innovative antithrombogenic materials, because of their necessity in fabricating artificial organs and progressive surgical prostheses. This paper reviews the recent advances in thromboresistant materials. Special emphasis is placed on the novel feature of the surface characterization of thromboresistant materials by X-ray photoelectron spectroscopy and its biomedical implications. Essential role of crystalline-amorphous microstructured surface in thromboresistant property of semicrystalline segmented copolymer is also discussed in detail.

Adsorption of proteins in the processes of interaction of polymers with blood and model solutions

The adsorption of plasma proteins plays an important role in the processes of interaction of polymers with the blood. The composition of the proteinized polymer surface determines the intensity of adhesion of the thrombocytes to it and the subsequent formation of a thrombus. The thermodynamic aspect of adsorption is considered. The existence of two types of adsorption of protein is demonstrated one of which (strongly adsorbed) is characterized by considerable conformational changes in the globules. The architecture and the structural aspects of proteins on non-physiological surface must determine the choice of the thromboresistant materials.

Preliminary evaluation of the thromboresistance of polymer materials

An experimental analysis was made of three express methods (the time of blood coagulation, the number of thrombocytes adhered and the degree of albuminization) used for sampling thromboresistant polymer materials in vitro. It was shown that the usefullness of the method of blood coagulation is limited.

The effect of thromboresistent surfaces on the development of blood emboli and hemolysis.

Heparinized dog blood was sheared in conicylindrical test cells which had been coated with thrombo-resistant materials. Hemolysis and blood emboli formation in the coated cells were as great or greater than in uncoated polycarbonate cells. These results suggest that materials which resist the buildup of thrombi may still be stimulating emboli formation and red cell damage.

Carbon biomedical devices

Isotropic pyrolytic carbon (LTI carbon) offers a unique combination of properties that has made it the material of choice for use in the construction of artificial heart valves. The biocompatibility of LTI carbon, in particular its thromboresistance, together with its resistance to degradation by wear and fatigue in the biological environment, has greatly reduced the incidence of thromboembolic complications and mechanical failures of prosthetic valves. Since 1969, more than 200,000 valves that use LTI carbon have been implanted. The morphological and/or surface chemical characteristics responsible for the compatibility of LTI carbon with blood remain unidentified. Its surface energy, greater than 50 ergs/cm 2, is unusually high for a thromboresistant material, yet LTI carbon surfaces are able to interface with blood through a weakly adsorbed proteinaceous layer without activating clotting via the intrinsic mechanism. The solid carbons have elastic moduli that are in the range often quoted for bone. Thus, for load-bearing applications in dentistry for endosseous dental implants and in orthopedics for joint replacement, the match of moduli provides biomechanical compatibility which can minimize the stress concentrations that often result when stiffer materials such as metals and ceramics are used in bone. The biochemical compatibility and wear resistance of the silicon-alloyed variety of LTI carbon, together with its strength and elastic match with bone, provide an ideal combination of properties for applications in orthopedics as a joint replacement material. Complex shapes not fabricable from isotropic pyrolytic carbon can be fabricated from metals and then coated with a thin, impermeable layer of carbon by vapor deposition. Flexible materials may be obtained by carbon coating thin polymeric sheets or fabrics by vapor deposition or through the use of glassy carbon fibers. The ability of carbon to perform percutaneously is being utilized, for example, in devices used to gain access to the blood stream for dialysis.

An introduction to blood compatible polymer surfaces for use in artificial internal organs

AbstractWhile the body is a hostile environment for all types of polymers, an even more serious problem is that of thrombus formation induced by all foreign surfaces, including polymeric surfaces. This is a still largely unsolved problem which hinders the development of artificial internal organs. The thromboresistant materials presently proposed and used in artificial organs include heparinized surfaces and materials found to be thromboresistant in certain implantation cites. In this article tissue‐polymer interactions are first discussed and then followed by a discussion of blood‐polymer interactions. The mechanism of thrombus formation is presented and some of the possible interactions of blood with surfaces are suggested. Representative nonthrombogenic and thromboresistant materials are discussed.

Biocompatibie materials for use in the vascular system.

AbstractTechniques are presented which result in the production of thromboresistant materials which can be used to interface with blood in the vascular system. Three useful processes for the heparinization of materials are presented and data are given on characteristics of attachment, the blood compatibility, and environmental stability of these surfaces. At this point, applications of heparinized surfaces via a simple one‐step process should be limited to siturations where low blood shear rates are involved, such as the venous system. Intitial data indicate significant loss of surface heparin in situations where high blood flow rates are involved such as A‐V shunts.

759. Some technical and metallurgical aspects of the application of the RH process: M Wahster and H-H Reichel,Steel Times, Nov 1967, 195, 459–468

Isotropic pyrolytic carbon (LTI carbon) offers a unique combination of properties that has made it the material of choice for use in the construction of artificial heart valves. The biocompatibility of LTI carbon, in particular its thromboresistance, together with its resistance to degradation by wear and fatigue in the biological environment, has greatly reduced the incidence of thromboembolic complications and mechanical failures of prosthetic valves. Since 1969, more than 200,000 valves that use LTI carbon have been implanted. The morphological and/or surface chemical characteristics responsible for the compatibility of LTI carbon with blood remain unidentified. Its surface energy, greater than 50 ergs/cm2, is unusually high for a thromboresistant material, yet LTI carbon surfaces are able to interface with blood through a weakly adsorbed proteinaceous layer without activating clotting via the intrinsic mechanism.The solid carbons have elastic moduli that are in the range often quoted for bone. Thus, for load-bearing applications in dentistry for endosseous dental implants and in orthopedics for joint replacement, the match of moduli provides biomechanical compatibility which can minimize the stress concentrations that often result when stiffer materials such as metals and ceramics are used in bone. The biochemical compatibility and wear resistance of the silicon-alloyed variety of LTI carbon, together with its strength and elastic match with bone, provide an ideal combination of properties for applications in orthopedics as a joint replacement material.Complex shapes not fabricable from isotropic pyrolytic carbon can be fabricated from metals and then coated with a thin, impermeable layer of carbon by vapor deposition. Flexible materials may be obtained by carbon coating thin polymeric sheets or fabrics by vapor deposition or through the use of glassy carbon fibers. The ability of carbon to perform percutaneously is being utilized, for example, in devices used to gain access to the blood stream for dialysis.

Blood sampling by a chronic artificial external arteriovenous shunt in dogs.

ArticleBlood sampling by a chronic artificial external arteriovenous shunt in dogs.W G Frasher JrW G Frasher JrPublished Online:01 Feb 1967https://doi.org/10.1152/jappl.1967.22.2.348MoreSectionsPDF (889 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByChronic Artificial External Arterio-Venous ShuntVascular Access in Large Laboratory AnimalsParallel flow arteriovenous shunt for theex vivo evaluation of heparinized materialsJournal of Biomedical Materials Research, Vol. 19, No. 2The microcirculatory society Eugene M. Landis award lectureMicrovascular Research, Vol. 23, No. 2Heparinized Polymers as Thromboresistant Biomaterials5 December 2006 | Polymer-Plastics Technology and Engineering, Vol. 16, No. 2AN EX VIVO METHOD FOR THE EVALUATION OF BIOMATERIALS IN CONTACT WITH BLOODAnnals of the New York Academy of Sciences, Vol. 283, No. 1 The BehaviorAn intravascular test device for thromboresistant materials: Analysis and preliminary experimental evaluationAnnals of Biomedical Engineering, Vol. 3, No. 3Pharmacological Features of Peripheral Vascular Beds of BeaglesJapanese Journal of Pharmacology, Vol. 24, No. 5Compatibility Problems in Artificial Organs11 July 2009 | Biomaterials, Medical Devices, and Artificial Organs, Vol. 1, No. 1Platelet Adhesion to Heparin-Bonded and Heparin-Free Surfaces11 July 2009 | Biomaterials, Medical Devices, and Artificial Organs, Vol. 1, No. 1In vivo rheology of dog blood after infusions of low molecular-weight dextran or salineMicrovascular Research, Vol. 4, No. 4Permanent Implantation of Arterial and Venous Catheters and Lymphatic ShuntsJournal of Dairy Science, Vol. 55, No. 8The effects of fibrination on the in vivo rheology of dog bloodMicrovascular Research, Vol. 4, No. 1 More from this issue > Volume 22Issue 2February 1967Pages 348-51 https://doi.org/10.1152/jappl.1967.22.2.348PubMed6017907History Published online 1 February 1967 Published in print 1 February 1967 Metrics