用于心血管医疗装置的聚合物表面构建与生物相容性研究Ⅲ——聚合物生物材料表面的凝血及抗凝血涂层改性

doi:10.3969/j.issn.2095-4344.2015.08.024

摘要/Abstract

摘要：

背景：用于心血管医疗的生物材料在血液接触性条件下必须具有抗血栓性、对抗生物降解性与抗感染性。

目的：研制用于心血管组织工程的新型植(介)入型聚合物材料(表面)，从聚合物生物材料表面的凝血及抗凝血涂层改性方面考察各种相应改性表面的生物相容性、血液相容性和细胞相容性。

方法：检索1983至2014年PubMed数据库及万方数据库。英文检索词为“biocompatibility, blood compatibility, biomedical materials, biomedical polymer materials”，中文检索词为“生物相容性材料；血液相容性材料；生物医用材料；医用高分子材料”。排除与研究目的相关性差及内容陈旧、重复的文献，保留与生物医用高分子材料的血液相容性研究，进行归纳总结。

结果与结论：通过对血液与植入物间的相互作用和生物材料表面的抗凝血涂层改性两个方面的归纳分析，从聚合物生物材料表面的凝血及抗凝血涂层改性方面考察了各种相应改性表面的生物相容性、血液相容性和细胞相容性。研制用于心血管组织工程的新型植(介)入型聚合物材料(表面)关键在于对聚合物生物材料表面的凝血及抗凝血涂层改性以及对其相应生物相容性与内皮细胞相容性的研究。通过对心血管医疗用聚合物生物材料的种类与应用及其心血管医疗器件和可植入性软组织替代物的深入研究可以发现表面与本体的差别则将体现在从表面向本体延伸的很多层分子上，而2种主要因素决定了其包括本体/表面差异及表面相分离在内的本体/表面行为，即表面能和分子运动性。如果考虑到对本体-表面的组成差异的理解，则还必须追加另以附加决定因素，即各组分的结晶行为。

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

全文链接：

关键词: 生物材料, 材料相容性, 聚合物材料, 聚合物生物材料, 生物医用聚合物材料, 生物相容性, 血液相容性, 细胞相容性, 抗凝血涂层改性

Abstract:

BACKGROUND: As the cardiovascular device, biomaterials applied under the blood-contact conditions should have anti-thrombotic, anti-biodegradable and anti-infective properties.

OBJECTIVE: To develop novel polymer materials for implantation and intervention in cardiovascular tissue engineering and to explore the biocompatibility, blood compatibility and cytocompatibility of the surface-modified polymer biomaterials based on the coagulant and anti-coagulant coating modification.

METHODS: We retrieved PubMed and WanFang databases for relevant articles publishing from 1983 to 2014. The key words were "biocompatibility, blood compatibility, biomedical materials, biomedical polymer materials" in English and Chinese, respectively. Those unrelated, outdated and repetitive papers were excluded. Literatures addressing the blood compatibility of biomedical polymer materials were summarized.

RESULTS AND CONCLUSION: The blood-implant interaction and the anti-coagulant surface modification of biomaterials were analyzed. The biocompatibility, blood compatibility and cytocompatibility of the surface-modified polymer biomaterials were determined based on the coagulant and anti-coagulant coating modification. The coagulant and anti-coagulant surface modification of polymer biomaterials and the research on their biocompatibility and endothelial cell compatibility are crucial for developing novel polymer materials for implantation and intervention in cardiovascular tissue engineering. Through in-depth studies of the types and applications of polymer biomaterials, cardiovascular medical devices and implantable soft tissue substitutes, the differences between the surface and the body will be reflected in the many layers of molecules extending from the surface to the body. Two major factors, surface energy and molecular mobility, determine the body/surface behaviors that include body/surface differences and phase separation. Considering the difference between the body/surface composition, an additional determinant is indispensable, that is the crystallization behavior of each component.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

全文链接：

Key words: Polymers, Coat Materials, Biocompatible, Blood Coagulation, Thrombosis

中图分类号:

R318

陈宝林，王东安. 用于心血管医疗装置的聚合物表面构建与生物相容性研究Ⅲ——聚合物生物材料表面的凝血及抗凝血涂层改性[J]. 中国组织工程研究, 2015, 19(8): 1277-1283.

Chen Bao-lin, Wang Dong-an. Phase III study on surface construction and biocompatibility of polymer materials as cardiovascular devices: coagulant and anti-coagulant surface modification[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(8): 1277-1283.

图/表（结果） 2

The interaction between the implant and the blood

All synthetic implants (including so-called "inert material") are present as endogenous substances in the contact with the host blood environment, and may cause different levels of host response, such as deposition of plasma proteins and platelets, infiltration of neutrophils and monocytes, as well as migration of endothelial cells and smooth muscle cells. In fact these host responses have very complex mechanisms, which play a crucial role on the in vivo implantation^[2].

Protein adsorption

When the implants are in contact with the blood, plasma proteins are immediately deposited on the surface of the implants. A large amount of serum proteins such as albumin, fibrinogen and immunoglobulin G may adsorb to the material surface. According to the Vroman effect, these proteins are redistributed due to different biochemical affinities and charge affinities on the material surface. Both platelets and blood cells are binding with the proteins, rather than the implants directly, so the concentration of the ligand expressed on the protein surface plays a crucial role on the viability of the inhibitors. Fibrin, fibronectin, laminin and vitronectin contain Arg-Gly-Asp (RGD) sequence region, which binds with the GIIb/IIIa receptor complex on the platelet surface^[3]. Therefore, the activation of platelet deposition may be affected by protein adsorption that occur previously. Other plasma proteins including complement components may also be activated on the implant surface.

Platelet deposition

Early platelet deposition is the result of mutual interactions between the surface protein receptors and the proteins adhered to the implant surface, it also includes pure physical absorption. The formation of platelet/protein complexes is mediated by platelet membrane glycoprotein of von Wilkbrand factor. Platelet conformations begin to change after deposition and release a series of biologically active substances, including serotonin, adrenocorticotropic hormone, ADP and thromboxane A₂. These substances can activate other platelets and increase thrombin generation^[4].

Infiltration of neutrophils and monocytes

Acute inflammation is caused by the neutrophils adsorbed onto the surface of the artificial implants, which is mediated by C₅a, Leukotrienc B₄ and other strong chemoattractants. Neutrophils can be adsorbed to the agglutinators that are encapsulated in and out of implants, and also adhere to the endothelial cells around the anastomosis stoma through the strong adhesion of the leukocyte-endothelial cell adhesion molecule. The activated neutrophils release oxygen free radicals and protease, which can cause the substrate degradation and protein vascular graft from complete endothelialization. Furthermore, the monocytes in blood circulation are prone to adsorb to wounds or endothelium regeneration site. There are many kinds of activating factors in plasma, due to these factors, monocytes differentiate into macrophages and participate in the host chronic inflammatory response. Macrophages release oxygen free radicals and proteases, which can function in the tissue/implant/blood interface for a long term, some materials are even phagocytized by macrophages. At the same time, macrophages release mitogens to stimulate the proliferation of smooth muscle cells, endothelial cells and fibroblasts at quiescent stage^[5-19].

Ingrowth of endothelial cells and smooth muscle cells

Autologous vascular endothelial cells are arranged orderly and secrete bioactive substances to prevent thrombosis, meanwhile initialize fibrin dissolution, prevent the proliferation of smooth muscle cells and maintain normal blood flow. However, artificial implants often appeared endothelial ingrowth, in which the depth does not exceed 1.0-2.0 cm over the anastomosis stoma. There are some damaged or unfused endothelial cells around the anastomosis stoma, but the biochemical properties change and are like to induce thrombus and promote the growth of smooth muscle. The proliferation and thickening of subintimal smooth muscle cells are more evident at the anastomosis stoma, where chronic cell retrograde and chronic inflammation occur. Smooth muscle cells, inflammatory mononuclear phagocytes and foreign macrophages also produce a series of growth regulating substances (factors), which continuously stimulate the proliferation of smooth muscle cells and produce extracellular matrix components. The hyperplasia of smooth muscle cells is usually considered as the leasing cause of endometrial hypertrophy^[3].

Anti-coagulant surface modification of biomaterials

As mentioned above, when the untreated synthetic materials are in contact with the blood, they produce a series of biochemical reactions, which certainly cause serious harm on the host, even life-threatening^[20]. To solve this situation, patients need anticoagulant drugs such as heparin during the interventional treatment or artificial graft implantation. However, the administration induces very serious adverse reactions, even fatal consequences. Therefore, improving anticoagulant properties of the implants is a radical approach. Changing the nature of the materials can improve blood compatibility and inevitably affect their physical-mechanical properties and chemical properties. Therefore, surface modification method that fully retains the material properties has been widely used. Among the surface modification methods, purely physical modification is the dominant due to simple operation, low cost, and less harmful residue. The schematic diagram of surface modification to improve blood compatibility of the catheters is shown in Figure 1.

Anti-coagulant surface coatings can be divided into short-term, long-term and permanent according to the duration of exposure to blood.

Anti-adhesion coating

Anti-adhesion coating is a kind of short-term coating, which is mainly used to exclude the adhesion of platelets, proteins and other coagulation substances^[21]. Due to the short-term use, this coating requires no heparin and other bioactive substances.

Such short-term anti-coagulant coating materials have been introduced into commercial production, such as Slip-Coat polymer coating (STS Biopolymers Company, Henrietta, NY, USA), light grafting hydrogel surface system (SurModics Company, Eden Prairie, MN, USA), SPI-Polymer (Spire Corp Company, Bedford, MA, USA), and Hydromer (Hydromer Company, Branchburg, NJ, USA). These products are consisted of surface-anticoagulant coronary catheter, guiding catheter, angioplasty catheter, balloon dilator, guider, as well as topical intubation.

As the interventional catheters, the surface smoothness^[22-28] is also essential in addition to anticoagulant surface modification. A previous study of Target Therapeutics (Fremont, CA, USA) has shown that, improving surface smoothness of the catheter can not only reduce the damage to surrounding tissue in the catheter insertion process, but also reduce surface adhesion of blood tangible materials. The photosensitive hydrogel coating has an antiplatelet adhesion effect and even exceeds the surface modification through the heparin fixation (without special smoothing process)^[4].

Bioactive coating

Bioactive coating contains heparin and other bioactive factors, and allows a long-term utilization of interventional therapy. Generally speaking, bioactive coating has a better anticoagulant effect than simple anti-adhesion surface modification, and the beneficial effect is more apparent for the interventional therapy. The heparin-contained surface coating avoids the presence of microthromb shedding and the blockage of cardiovascular vessels caused by conventional coating. The heparinized coating-modified medical devices include coronary bypass oxygenator, central venous catheters, coronary stents and hemolytic balancing device^[4].

Heparin itself is a highly charged molecule and can disrupt the interaction between thrombin and factor Xa in the “waterfall model” generated by coagulant fibrinogen^{[21, 29-31]}, so the heparinized coating prevents platelet adhesion and activation (Figure 2). Heparinized coating is shown to inhibit overall degree of coagulation and prolong acute coagulant time in clinical experiments^{[4, 32]}. Heparinized coating materials have been commercially produced, such as Carmeda BioActive Surface (CBAS; Carmeda AB Company, Stocknolm), surgical Duraflo surface systems (Baxter International Company, Deerfield, IL, USA), PhotoLink coating (SurModics) and Medi-Coat hydrogel surface system (STS).

Surface coating promoting the growth of host cells

The surface coating modification of permanent implantable medical devices (such as vascular grafts, vascular stents and heart valves sutural margin) requires anti-coagulation functions and strong anti-immune recognition functions. The most direct way to hinder the immune system in human body is to modify and form “novel” material surface in contact with the human body, using the autologous tissue cells. In brief, human endothelial cells are introduced to the inner wall of artificial blood vessel through a tissue engineering method, to impede anticoagulant and immune response; in order to stimulate the proliferation and migration of endothelial cells and prevent excessive proliferation of smooth muscle cells, it is feasible to stimulate excessive secretion of growth factors and growth inhibiting factors from endothelial cells, by transgenic technology^[33-39]. Such engineered blood vessel is different from human blood vessel, because the engineered vessels need prosthesis support to maintain its structure and do not contain elastin^[40-42]. The surface morphology of biomaterials by endothelial tissue engineered modification (including uncoated graft) is shown in Figure 3^[43-48].

Other blood compatible coatings

Other blood compatible coatings include the phosphorylcholine-contained surface coating, albumin surface coating, and the plasminogen activator-contained surface coating. Wherein phosphorylcholine itself is present as an alternative to the outer membrane of a cell in the blood, and can inhibit the adhesion and activation of serum proteins and platelets^[49-53]. Such surface coating materials have been produced by Biocompatibles International plc (Farnham, Surrey, UK). Albumin surface coating is also good and efficious anticoagulant coating. Albumin surface can effectively inhibit acute adhesion of fibrinogen both in vivo and in vitro, thus blocking platelet aggregation and fibrin formation. Another study demonstrated that the albumin-modified polyurethane surface are good blood compatible. The plasminogen activator-contained surface coating can cleavage the thrombus in vivo, because the plasminogen activator has fibrinolytic function. The plasminogen activators include fibrin plasminogen, polylysine, streptokinase and urokinase.

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引言

Biomaterials are often used in medical devices, particularly for temporary or permanent implantation in the human body. It is defined as: any substance and complex (rather than a drug), synthetic or natural, that can be used as a system or part of a system that treats, augments, or replaces any tissue, organ, or function of the body^[1]. Blood-contact materials served for cardiovascular medical use include extracorporeal devices for blood transfusion and collection, vascular interventional devices and permanently implantable devices. Permanently implantable devices are mainly used as soft tissue substitutes for the improvement and regeneration of human soft tissue.

Generally speaking, polymer materials used for in vivo implantation should have two basic properties, namely medical functionality and biocompatibility. In fact, these two properties also cover the other properties of the materials, such as the physical and mechanical properties, chemical stability, toxicity, formability and other requirements. Medical functionality refers to diagnostic or therapeutic effects achieved by a combination of materials

and living tissues. The biocompatibility refers to the degree of mutual accommodation between materials and living tissues, and it contains two meanings: blood compatibility and tissue compatibility. Biocompatibility is the most important feature of biomaterials different from other materials, which is the fundamental basis for evaluating the feasibility of a material in biomedicine field. Therefore, biocompatibility is one of the central topics of biomaterial research.

As a branch of the Key Project named “Interfacial Behavior of Living Systems and Non-Living Systems and Relevant Mechanism of Interaction”, new implantable polymer biomaterials should be developed so as to meet the design and manufacturing needs for cardiovascular devices. The key of this work lies in the coagulant and anti-coagulant surface modification of polymer biomaterials, as well as the corresponding biocompatibility and endothelial cell compatibility. In this paper, we analyze the biocompatibility, blood compatibility and cell compatibility of different surface-modified polymer biomaterials for implantation and intervention in cardiovascular tissue engineering, based on the coagulant and anti-coagulant surface modification. The modification includes the following aspects: the blood-implant interactions and the anti-coagulant surface modification of biomaterials.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程
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材料方法

讨论

The biocompatibility is a very important problem for clinical application of biological materials. To prepare a high polymer material suitable for cell implantation, cell culture and cell growth on the material surface is the fundamental way to achieve a good biocompatibility of the material. Therefore, research on the biomaterials suitable for cell growth is not only significant for the in-depth understanding of the cell-material interaction mechanism, but also of great value for developing the clinical application of histocompatible and blood compatible materials. To solve the biocompatibility of materials is the key for the biomedical application of biomaterials. For a long time, increasing studies have focused on surface modification, such as the development of materials with blood compatibility that is to modify the surface hydrophilicity and hydrophobicity, introduce charged and bioactive substances by surface molecule designation to minimize the formation of thrombus and improve blood compatibility of materials. However, surface modification is limited to improve the blood compatibility because the contact with body fluids, presence of organic molecules, enzymes, free radicals, and other cells, as well as very complex biological environment.

In this study, we analyzed the blood-implant interaction and the anticoagulant coating modification on the surface of biomaterials, and detected the biocompatibility, blood compatibility and cell compatibility of polymer biomaterials after modification. The bio-functional surface construction of polymer biomaterials is very important for the development of new implantable polymer materials for cardiovascular tissue engineering, as well as their corresponding biocompatibility and endothelial cell compatibility. Through the in-depth study of the types and application of cardiovascular medical polymers, cardiovascular medical devices and implantable soft tissue substitutes, we can find that the difference between the surface and the body will be reflected on various molecular levels extending from the surface to the body. Surface energy and molecular mobility are two main factors that determine the body/surface behaviors involving the body/surface differences and surface phase separation. Considering the difference between body/surface composition, an additional determinant is indispensable, that is the crystallization behavior of each component. Furthermore, angle-dependent X-ray photoelectron spectroscopy technique is used to measure the content of end groups of the modifier at different surface layers, and to investigate the effect of interaction between end groups and PEO bridging at different molecular sizes on the surface conformation. The model of typical PEO annular conformation can be established for short MSPEO in the aqueous phase. Compared with the body blending system, the surface coating system strengthens the poor compatibility between the modifier and the substrate, while weakens the dynamic resistance originated from surface enrichment caused by self-migration.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程
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