生物材料血液相容性综合评价体系的研究

本文提出由四个体外和半体内试验综合评价生物材料血液相容性的体系,同时用此综合评价体系评价了六种用于心血管系统的聚氨酯材料和一种硅橡胶材料的血液相容性。试验结果表明本文提出的四参数综合评价体系可较真实地评价生物材料对血液的急性反应,并可对生物材料的血液相容性进行粗筛。     

骨替代材料的生物相容性评价研究进展

生物安伞性的评价在于预测生物材料或医疗器械在与人体接触使用过程中的潜在危害性,保证牛物材料的应用安全性.骨替代材料的应用越来越广泛,需要进行一系列实验证明材料的安全性.文章对骨替代材料的生物相容性实验研究方法 进行了详细的论述,包括细胞相容性实验、全身毒性实验、血液相容性实验、皮肤致敏实验、刺激实验、遗传毒理学实验、体内植入实验.     

抗血栓形成医用高分子材料及血液相容性评价

作为生物材料,尤其是植入型材料,它们同机体组织和血液的相容性能是很重要的性质.而这两者在任何一种材料的实际使用中却又是有着密切的联系,但对于不同用途的材料其侧重点又不全相同.以植入型生物材料为例,按其接触对象的不同可分为与血液接触和与其它组织接触(如皮肤、结缔、骨组织)两大类,本文拟就同血液相接触的医用高分子材料抗血栓性能与其表面结构的关系、材料表面血栓形成的机制以及材料血液相容性的一般评价方法进行阐述.     

生物材料血液相容性评价研究的进展

生物材料从本世纪五十年代至八十年代已发展到了第三代,即高功能医用生物材料阶段。用于心血管系统的生物材料在研制时及临床使用之前,首先要准确地评价其与血液接触后的血液相容性。六十年代初,美国国立卫生研究院(NIH)率先对用于人工器官的生物材料进行了血液相容性评价,但由于多年来对凝血及抗凝血机理还末完全了解,故迄今为止,国内外还没有形成一个公认的统一的血液相容性评价体系,各试验室采用的评价方法、途径各不相同,评价结果也相差甚远,无法相互比较。NIH1985年最新版的“血液与材料相互作用指南”一书对以前的血液相容性评价方法已做了较全面的     

生物材料血液相容性评价中血小板减少的测定

在生物材料体外的血液相容性评价中,血小板计数是常规指标。但通常血液与材料接触前后的计数无法区别是由于血小板粘附或聚集而减少的数量。本文把Wu和Hoak用病人血定量测定循环的聚集血小板方法加以改进,建立了一种能区别血小板粘附及聚集的新方法。作者用EDTA使血小板分散,防止其聚集并用EDTA福尔马林混合液将聚集的血小板固定.对血液和数种聚酰胺材料接触前后的血小板进行了四项指标测定:En及Et分别为与材料接触前和后血液中加EDTA的血小板计数;     

生物材料血液相容性评价研究进展

随着医学的进步,包括人工血管在内的生物材料在人类心血管系统疾病的防治中越来越重要.用于心血管系统的生物材料在研制时和临床使用之前,首先要准确评价其与血液接触后的血液相容性.早在六十年代初,美国国立卫生研究院(NIH)就对用于人工器官的生物材料进行血液相容性评价[1],但由于凝血及抗凝血机理未完全明了,故现在国内外尚无统一的血液相容性评价体系,各实验室采用的评价方法、途径各不相同,评价结果也相差甚远,故无法相互比较.     

聚氨酯的血液相容性评价

血液相容性是生物材料研究领域里最受关注的问题之一。血液相容性是一个涉及血液和生物医学材料表面作用的复杂现象 ,影响因素繁多。对材料的血液相容性的测试和评价同样是一个复杂问题 ,涉及到多学科、多领域的技术和方法。本文以聚氨酯为例 ,对生物材料血液相容性的概念、生物医学材料表面和血液的相互作用以及评价方法作一综述     

生物材料体外评价方法研究进展

引言 在生物材料与人体体液、组织和器官的接触应用中，对材料进行生物学评价是至关重要的。生物学评价通常包括体外和体内两种测试途径。体外实验是将材料或其浸提液在体外环境下与细胞或组织接触，观察材料对细胞数量、形态及分化的影响。体内实验则是将材料直接与动物体接触，观察植入体周围组织反映的状况，这类实验模拟了人体生理环境，与材料的最终应用状况接近。目前，动物体内植入仍是生物材料安全性和有效性评价的主要手段。体内实验也有一定的缺点，如在体内环境中，     

人工材料与人工脏器的生物相容性

目前临床上使用的许多装置都是用金属、玻璃、陶瓷和高分子等材料制作的,现在一般把这些医用材料统称为“生物材料”(Biomaterial)。研究这些材料,首先遇到的问题是如何快速、准确地评价材料的生物相容性,这对于研究新生物材料和加快研究周期将起着重要的作用。但只有少数体外试验能对表面进行很好的表征,并与体内试验结果有相关性。因此,本文结合作者的研究工作,简要介绍生物材料与血液的生物相容性以及生物相容性的评价方法。     

生物材料与细胞的相互作用

在上个世纪,生物医用材料被定义为"一类以诊断、治疗为目的,用于与活体组织接触,且具有功能的无生命材料".由于生物材料需与活体组织接触,材料的毒性、生物相容性、血液相容性受到特别的重视.即在诊断与治疗过程中,生物材料对人体必须是安全的,是生理惰性的,属于无生命材料.     

Bioengineering of improved biomaterials coatings for extracorporeal circulation requires extended observation of blood-biomaterial interaction under flow

Extended use of cardiopulmonary bypass (CPB) systems is often hampered by thrombus formation and infection. Part of these problems relates to imperfect hemocompatibility of the CPB circuitry. The engineering of biomaterial surfaces with genuine long-term hemocompatibility is essentially virgin territory in biomaterials science. For example, most experiments with the well-known Chandler loop model, for evaluation of blood-biomaterial interactions under flow, have been described for a maximum duration of 2 hours only. This study reports a systematic evaluation of two commercial CPB tubings, each with a hemocompatible coating, and one uncoated control. The experiments comprised (i) testing over 5 hours under flow, with human whole blood from 4 different donors; (ii) measurement of essential blood parameters of hemocompatibility; (iii) analysis of the luminal surfaces by scanning electron microscopy and thrombin generation time measurements. The dataset indicated differences in hemocompatibility of the tubings. Furthermore, it appeared that discrimination between biomaterial coatings can be made only after several hours of blood-biomaterial contact. Platelet counting, myeloperoxidase quantification, and scanning electron microscopy proved to be the most useful methods. These findings are believed to be relevant with respect to the bioengineering of extracorporeal devices that should function in contact with blood for extended time.     

Complement profile and activation mechanisms by different LDL apheresis systems

Extracorporeal removal of low-density lipoprotein (LDL) cholesterol by means of selective LDL apheresis is indicated in otherwise uncontrolled familial hypercholesterolemia. During blood-biomaterial interaction other constituents than the LDL particles are affected, including the complement system. We set up an ex vivo model in which human whole blood was passed through an LDL apheresis system with one of three different apheresis columns: whole blood adsorption, plasma adsorption and plasma filtration. The concentrations of complement activation products revealed distinctly different patterns of activation and adsorption by the different systems. Evaluated as the final common terminal complement complex (TCC) the whole blood system was inert, in contrast to the plasma systems, which generated substantial and equal amounts of TCC. Initial classical pathway activation was revealed equally for both plasma systems as increases in the C1rs-C1inh complex and C4d. Alternative pathway activation (Bb) was most pronounced for the plasma adsorption system. Although the anaphylatoxins (C3a and C5a) were equally generated by the two plasma separation systems, they were efficiently adsorbed to the plasma adsorption column before the "outlet", whereas they were left free in the plasma in the filtration system. Consequently, during blood-biomaterial interaction in LDL apheresis the complement system is modulated in different manners depending on the device composition.     

The short-term blood biocompatibility of poly(hydroxyethyl methacrylate-co-methyl methacrylate) in an in vitro flow system measured by digital videomicroscopy

An in vitro flow system for short-term blood biocompatibility testing of solution-castable polymeric biomaterials was developed. This system was relatively free of artefacts resulting from blood contact with materials other than the test material itself. In conjunction with epifluorescence videomicroscopy and digital image processing, this method provided a high resolution, quantitative, continuous analysis of platelet adhesion, aggregation, thrombus formation, and embolization on the biomaterial surface. This system was well suited for performing biochemical assays on post-contact blood for assessment of platelet activation and release as additional measures of the thrombogenicity of the test material. This method for biomaterials evaluation in vitro was demonstrated by a detailed examination of copolymers of hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA). Videomicroscopic analysis of fluorescently labelled platelets adhering per unit area of the polymer surface after 5 min of flow at a wall shear rate of 500 s-1 showed a dramatic decrease with increasing HEMA fraction in the polymer. The release of serotonin and thromboxane A2 by platelets decreased with increasing HEMA fraction. Reflection interference contrast microscopy was used to examine focal contacts of platelets on the copolymer surfaces as a qualitative measure of the platelet-surface interaction. A polymer-dependent gradation in contact extent and morphology was observed, ranging from large contacts on P(MMA) to none on P(HEMA).     

Standardized methods to quantify thrombogenicity of blood-contacting materials via thromboelastography

Blood coagulation is the most significant complication of vascular biomaterials. A straightforward, sensitive, and standard measure of the compatibility of these materials with whole blood (hemocompatibility) is necessary to avoid coagulation. Current techniques used quantify only individual clotting components and are poor predictors of coagulation. The thromboelastograph (TEG) provides a measure of overall clot formation from whole blood. Although TEG is very common in clinical settings, its application to biomaterials is limited partly due to difficulty in sample preparation. In this protocol, whole blood samples are incubated with (1) biomaterials (tube with clamped ends) and (2) endothelial cells cultured on biomaterial surfaces (12-well plate) under controlled shearing conditions (10 rpm on rocker, at 37°C), and then the blood is transferred to the TEG to measure clot formation. TEG clearly discriminates among the R-times (time until initial clot formation) of expanded poly(tetrafluoroethylene), poly(urethane), and Tygon tubing. Marked differences in R-time are also seen when endothelial cells are cultured on various extracellular matrix proteins and proteoglycans. Thus, R-time provides a robust metric of overall thrombogenicity of biomaterials, and these procedures provide a standardized method for TEG to facilitate direct comparison among candidate biomaterials undergoing in-vitro testing.     

The effect of high-density-lipoprotein on thrombus formation on and endothelial cell attachement to biomaterial surfaces

Cardiovascular implants such as vascular grafts fail frequently because they lack genuine blood-compatibility. The blood-contacting surface should simultaneously prevent thrombus formation and promote formation of a confluent endothelial cell layer, to achieve sustained haemostasis. Contact activation and endothelialization are known to be determined by the plasma proteins which adsorb onto virtually all synthetic surfaces almost immediately upon contact with blood. A common approach in blood-compatibility research is, therefore, to use hydrophilic biomaterials, which are sometimes claimed to be "protein-repellent". We report here that, for synthetic polymeric surfaces, hydrophilicity is by no means synonymous to protein-repellency. We discovered that significant amounts of proteins, especially high-density lipoprotein, adsorb to hydrophilic surfaces. Pre-incubation of hydrophilic synthetic surfaces with high-density lipoprotein provides a blood-biomaterial interface, which inhibits thrombin generation and subsequent thrombus formation, and also accommodates overgrowth with a confluent endothelial layer. This approach may open the way to truly functional small-caliber arterial prostheses, and may also be relevant to cardiovascular tissue engineering in which de novo vascular tissues are cultured on or within a biomaterial scaffold.     

Interaction of heparinized polymer materials with plasma proteins and platelets

Conclusion A negative correlation was found between adsorption of plasma proteins and surface affinity for AT-III. This correlation suggests that maximal activity of surface-bound HP and, therefore, maximal hemocompatibility of polymer material can be attained by minimization of adsorbed plasma proteins. The adsorbed layer is also enriched with AT-III. In addition, a negative correlation in the AT-III-RNAP pair shows that this condition is also necessary for decreasing risk of thrombosis, because it reduces the number of adhered platelets.Thus, high concentration of AT-III in the adsorbed layer is the specific feature of heparinized biomaterials which exerts a fundamental effect on cellular and molecular mechanisms of the interaction of blood with polymer materials.Scientific-Research Institute for Transplantology and Artificial Organs, Russian Ministry of Health, Moscow. Translated from Meditsinskaya Tekhnika, No. 2, pp. 18–22, March–April, 1994.     

Nuclear methods to characterize biomaterials

Techniques using X-rays are often used to study biomaterials fields. However, when one is interested by quantitative and very sensitive measurements, it is valuable to develop nuclear instruments and methods, in addition and complement with others. Fast neutron activation is appropriate for non-destructive analysis. Thermal neutron activation can evaluate trace elements as a reference. Proton-induced X-rays emission is applied to cartography of heavy elements. If necessary, proton-induced gamma-rays emission and charged particles scattering are suitable for evaluation and cartography of light elements. Radioactivated nuclei and labelled molecules can tag element transfers and biofunctionality. In our work, these methods are related to biomaterials field.     

Blood cell and plasma protein repellent properties of star-PEG-modified surfaces

The implantation of biomaterials, medical devices or prostheses can instigate a rejection response or initiate an undesirable adsorption of plasma proteins, as well as blood cells on the implant surface, thus triggering diverse defense mechanisms against the supposed pathologic invader. The extent of this inflammatory reaction depends in part on the biocompatibility of the used materials or coatings. Although adsorption and coagulation responses can appear during the total in vivo lifetime of the implant, they are initially and crucially formed within the first 2-4 weeks of implantation. This early phase is of decisive importance for the consecutive in-growth and healing process. The present study was intended to elucidate the effects of blood contact to surfaces modified with reactive six-arm star-shaped poly(ethylene glycol-stat-propylene glycol) pre-polymers (Star PEG). Taken together, for Star-PEG-covered substrates we could demonstrate a profound reduction of various blood-biomaterial interactions compared to non-coated substrates, indicating the promising potential of this material as future coating for biomaterials with blood contact.     

Recent advances in the diagnosis of drug allergy

PURPOSE OF REVIEW: The present review addresses the most recent literature regarding the diagnosis of drug hypersensitivity reactions, which can be classified as immediate or nonimmediate according to the time interval between the last drug administration and the onset. Immediate reactions occur within 1 h; nonimmediate ones occur after more than 1 h. RECENT FINDINGS: Clinical and immunological studies suggest that type-I (IgE-mediated) and type-IV (cell-mediated) pathogenic mechanisms are involved in most immediate and nonimmediate reactions, respectively. New diagnostic tools, such as the basophil activation test and the lymphocyte activation test, have been developed and are under validation. SUMMARY: In diagnosis, the patient's history is fundamental; the allergologic examination includes in-vivo and in-vitro tests selected on the basis of the clinical features. Prick, patch, and intradermal tests are the most readily available forms of allergy testing. Determination of specific IgE levels is still the most common in-vitro method for diagnosing immediate reactions. The sensitivity of allergologic tests is not 100%; in selected cases, therefore, provocation tests are necessary. The routine use of the basophil activation test and the lymphocyte activation test could increase the sensitivity of diagnostic work-ups, thus reducing the need for drug provocation tests.     

Problems and artefacts in the evaluation of polymeric materials for medical uses

The terms ‘biocompatibility’, ‘blood compatibility’, and ‘thrombogenicity’ are often used interchangeably which leads to confusion in the scientific and medical literatures. No single test can reliably predict the ‘blood compatibility’ of materials, and tests for thrombogenicity are not necessarily indicators of blood compatibility. Although the toxicological screening of biomaterials is important, the absence of adverse effects does not assure biocompatibility. Acute toxicological screenings should be carried out early in the biological evaluation phases of biomaterials, but the results should be interpreted with caution because polymers degrade in the physiological environment by time-dependent mechanisms leading to the formation of potentially toxic products, including carcinogens. Increased efforts are needed to screen potential biomaterials for carcinogenesis and mutagenesis. Biological tests should be conducted with animals whose haematological profile closely resembles that of humans rather than rely on results obtained with species such as dogs and calves. Accelerated fatigue testing of elastomers must be conducted under conditions that closely approximate the properties of the biological environment to avoid catastrophic failures.