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![Figure 1. Blood-material interactions. Adapted from [1].](profile/Maria-Tanzi/publication/7475675/figure/fig1/AS:601765300953095@1520483436310/Blood-material-interactions-Adapted-from-1_Q320.jpg)
The contact of any biomaterial with blood gives rise to multiple pathophysiologic defensive mechanisms such as activation of the coagulation cascade, platelet adhesion and activation of the complement system and leukocytes. The reduction of these events is of crucial importance for the successful clinical performance of a cardiovascular device. Thi...
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... Modification of medical device surfaces to improve blood compatibility has been pursued to reduce device-related thrombus formation and inflammatory reactions. Surface modification technologies can be assigned into two broad categories: (a) passivation of material surfaces and (b) bioactive surface treatments and coatings (Biran & Pond, 2017;Tanzi, 2005). Passive approaches are aimed at reducing the inherent thrombogenicity of the material surface by establishing a barrier at the device-blood interface through modification of surface chemistry (e.g. ...
... topography). Bioactive strategies employ direct pharmacological inhibition of the coagulation response by local drug delivery or permanent immobilisation of an active agent (Sin et al., 2012;Tanzi, 2005). ...
Mechanical circulatory support (MCS) devices, such as left ventricular assist devices (LVADs) are very useful in improving outcomes in patients with advanced-stage heart failure. Despite recent advances in LVAD development, pump thrombosis is one of the most severe adverse events caused by LVADs. The contact of blood with artificial materials of LVAD pumps and cannulas triggers the coagulation cascade. Heat spots, for example, produced by mechanical bearings are often subjected to thrombus build-up when low-flow situations impair washout and thus the necessary cooling does not happen. The formation of thrombus in an LVAD may compromise its function, causing a drop in flow and pumping power leading to failure of the LVAD, if left unattended. If a clot becomes dislodged and circulates in the bloodstream, it may disturb the flow or occlude the blood vessels in vital organs and cause internal damage that could be fatal, for example, ischemic stroke. That is why patients with LVADs are on anti-coagulant medication. However, the anti-coagulants can cause a set of issues for the patient-an example of gastrointestinal (GI) bleeding is given in illustration. On account of this, these devices are only used as a last resort in clinical practice. It is, therefore, necessary to develop devices with better mechanics of blood flow, performance and hemocompatibility. This paper discusses the development of LVADs through landmark clinical trials in detail and describes the evolution of device design to reduce the risk of pump thrombosis and achieve better hemocompatibility. Whilst driveline infection, right heart failure and arrhythmias have been recognised as LVAD-related complications, this paper focuses on complications related to pump thrombosis, especially blood coagulopathy in detail and potential strategies to mitigate this complication. Furthermore, it also discusses the LVAD implantation techniques and their anatomical challenges.
... Heparin-coated systems for ECLS were developed to reduce the hemorrhagic risk by lowering the systemic heparinization [62][63][64][65]. The first heparin coating to become commercially available was developed by the company Carmeda in 1983 [66,67]. From that time on, several new coatings with different bonding techniques have been developed and became available in the market. ...
... Phosphorylcholine (PC) is anti-thrombogenic, protein resistant, antibacterial, and has anti-fouling properties [67]. Coatings with phosphorylcholine (PC) have been developed as an alternative to heparin-bound systems. ...
The use of extracorporeal life support (ECLS) devices has significantly increased in the last decades. Despite medical and technological advancements, a main challenge in the ECLS field remains the complex interaction between the human body, blood, and artificial materials. Indeed, blood exposure to artificial surfaces generates an unbalanced activation of the coagulation cascade, leading to hemorrhagic and thrombotic events. Over time, several anticoagulation and coatings methods have been introduced to address this problem. This narrative review summarizes trends, advantages, and disadvantages of anticoagulation and coating methods used in the ECLS field. Evidence was collected through a PubMed search and reference scanning. A group of experts was convened to openly discuss the retrieved references. Clinical practice in ECLS is still based on the large use of unfractionated heparin and, as an alternative in case of contraindications, nafamostat mesilate, bivalirudin, and argatroban. Other anticoagulation methods are under investigation, but none is about to enter the clinical routine. From an engineering point of view, material modifications have focused on commercially available biomimetic and biopassive surfaces and on the development of endothelialized surfaces. Biocompatible and bio-hybrid materials not requiring combined systemic anticoagulation should be the future goal, but intense efforts are still required to fulfill this purpose.
... A suitable biomaterial substrate should display adequate pore size, open porosity, mechanical strength, degradation properties, and biocompatibility. In addition, when in contact with blood, it should present adequate thrombus resistance [4]. ...
... Over the years, studies on biofunctionalization of biomaterial substrates (i.e., modification with biologically active molecules) have gained importance [5]. Among the considered strategies to overcome thrombogenesis, one of the best approaches has been the immobilization of heparin onto the synthetic surface [4]. Heparin is a highly negatively charged glycosaminoglycan (GAG) containing sulphonic and carboxylic groups and also one of the most commonly used natural anticoagulant drugs for treatment and prevention of blood clotting and thrombus formation [6]. ...
... Among several approaches for heparin immobilization [4], the development of polymeric structures able to interact and strongly retain heparin appeared very promising. In particular, linear polymers carrying tertiary amino groups in alternation with amido groups (TAG-AG), named poly-amido-amines (PAAs), demonstrated the ability to form stables complexes with heparin, via strong ionic and electrostatic interactions owing to their protonation behaviour at physiological pH [8]. ...
... Blood contact causes the release of the ionic complex from the surface, but the presence of the surfactant slows the rate of heparin release. Other elution-based technologies have been described in previous reviews [180]. ...
Heparinoid is the generic term that is used for heparin, heparan sulfate (HS), and heparin-like molecules of animal or plant origin and synthetic derivatives of sulfated polysaccharides. Various biological activities of heparin/HS are attributed to their specific interaction and regulation with various heparin-binding cytokines, antithrombin (AT), and extracellular matrix (ECM) biomolecules. Specific domains with distinct saccharide sequences in heparin/HS mediate these interactions are mediated and require different highly sulfated saccharide sequences with different combinations of sulfated groups. Multivalent and cluster effects of the specific sulfated sequences in heparinoids are also important factors that control their interactions and biological activities. This review provides an overview of heparinoid-based biomaterials that offer novel means of engineering of various heparin-binding cytokine-delivery systems for biomedical applications and it focuses on our original studies on non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) and polyelectrolyte complex-nano/microparticles (N/MPs), in addition to heparin-coating devices.
... Surface modification strategies enable the combination of a material's bulk properties with desired biological attributes, and it has become a focus strategy for preventing cruor. This surface modification strategy could be realized in many ways, for instance, surface biopassive, surface bioactive, and biomimetic modification [14][15][16]. One of the most well-known methods is developing heparin-grafted materials. ...
Nowadays, a variety of materials are employed to make numerous medical devices, including metals, polymers, ceramics, and others. Blood-contact devices are one of the major classes of these medical devices, and they have been widely applied in clinical settings. Blood-contact devices usually need to have good mechanical properties to maintain clinical performance. Metal materials are one desirable candidate to fabricate blood-contact devices due to their excellent mechanical properties and machinability, although the blood compatibility of existing blood-contact devices is better than other medical devices, such as artificial joints and artificial crystals. However, blood coagulation still occurs when these devices are used in clinical settings. Therefore, it is necessary to develop a new generation of blood-contact devices with fewer complications, and the key factor is to develop novel biomaterials with good blood compatibility. In this work, one albumin biopassive polyallylamine film was successfully established onto the 316L stainless steel (SS) surface. The polyallylamine film was prepared by plasma polymerization in the vacuum chamber, and then polyallylamine film was annealed at 150 °C for 1 h. The chemical compositions of the plasma polymerized polyallylamine film (PPAa) and the annealed polyallylamine film (HT-PPAa) were characterized by Fourier transform infrared spectrum (FTIR). Then, the wettability, surface topography, and thickness of the PPAa and HT-PPAa were also evaluated. HT-PPAa showed increased stability when compared with PPAa film. The major amino groups remained on the surface of HT-PPAa after annealing, indicating that this could be a good platform for numerous molecules’ immobilization. Subsequently, the bovine serum albumin (BSA) was immobilized onto the HT-PPAa surface. The successful introduction of the BSA was confirmed by the FTIR and XPS detections. The blood compatibility of these modified films was evaluated by platelets adhesion and activation assays. The number of the platelets that adhered on BSA-modified HT-PPAa film was significantly decreased, and the activation degree of the adhered platelets was also decreased. These data revealed that the blood compatibility of the polyallylamine film was improved after BSA immobilized. This work provides a facile and effective approach to develop novel surface treatment for new-generation blood-contact devices with improved hemocompatibility.
... Odex-APs and Odex-HbMPs fabricated by One-pot formulation have a size in the submicron range, uniform morphology and negative surface charge. The coating of the particles with human serum albumin improves significantly their blood compatibility by reducing the adsorption of other proteins as well the interaction with platelets and leukocytes [33]. Due to the covalent binding of albumin to haemoglobin the stability of the coating is sufficient to protect the particles during their circulation in the blood stream against non-specific adsorption of other plasma proteins. ...
Blood compatibility is a key requirement to fulfil for intravenous administration of drug and oxygen carrier system. Recently, we published the fabrication of oxidised-dextran (Odex)-crosslinked protein particles by one-pot formulation. In the current study we investigate the haemocompatibility of these Odex - particles including albumin particles (Odex-APs) and haemoglobin particles (Odex-HbMPs). Odex-APs and Odex-HbMPs have a submicron size ranged 800–1000 nm with peanut-like shape and a negative surface charge. In vitro haemocompatibility assays included haemolysis test, indirect phagocytosis test and platelet activation test in human blood. Odex-APs and Odex-HbMPs did not provoke any undesirable effects on the blood cells. Firstly, the ratio of haemolysis after contacted with Odex-crosslinked protein particles were less than 5% and therefore the particles may be considered non-haemolytic. Secondly, the incubation of leukocyte with Odex-APs/HbMPs did not influence the phagocytosis of leukocyte. We conclude that our particles are not recognized by monocytes or granulocytes. Finally, exposure of Odex-APs/HbMPs to platelets did not cause an activation of platelets. Additionally, Odex-HbMP/AP did not enhance or attenuate agonist-induced platelet activation. We conclude that Odex-crosslinked protein particles exhibit a very good haemocompatibility and represent highly promising carriers for drugs or oxygen.
... Novel techniques of stent surface modifications to resolve the problem of undesired clinical outcomes of intravascular implants are still an ongoing research area. Surface modification technologies can be divided into two main categories: passive and bioactive material surface and coatings [18]. Passive approaches are aimed at modification of surface chemistry or material physical structure [19]. ...
Stainless steel 316L is a material commonly used in cardiovascular medicine. Despite the various methods applied in stent production, the rates of in-stent restenosis and thrombosis remain high. In this study graphene was used to coat the surface of 316L substrate for enhanced bio- and hemocompatibility of the substrate. The presence of graphene layers applied to the substrate was investigated using cutting-edge imaging technology: energy-filtered low-voltage FE-SEM approach, scanning electron microscopy (SEM), Raman spectroscopy, and atomic force microscopy (AFM). The potential of G-316L surface to influence endothelial cells phenotype and endothelial-to-mesenchymal transition (EndoMT) has been determined. Our results show that the bio- and hemocompatible properties of graphene coatings along with known radial force of 316L make G-316L a promising candidate for intracoronary implants.
... Exposure of the bulk-modified material to the biological, aqueous environment ideally drives the migration of hydrophilic "protein repellant" blocks to the surface whereas the hydrophobic blocks interact with the base polymer to inhibit leaching. 56 LbL and SMAs have been shown to be promising platforms for some of the new chemistries and strategies of protein resistance discussed below. ...
Toward improving implantable medical devices as well as diagnostic performance, the development of polymeric biomaterials having resistance to proteins remains a priority. Herein, we highlight key strategies reported in the recent literature that have relied upon improvement of surface hydrophilicity via direct surface modification methods or with bulk modification using surface modifying additives (SMAs). These approaches have utilized a variety of techniques to incorporate the surface hydrophilization agent, including physisorption, hydrogel network formation, surface grafting, layer-by-layer (LbL) assembly and blending base polymers with SMAs. While poly(ethylene glycol) (PEG) remains the gold standard, new alternatives have emerged such as polyglycidols, poly(2-oxazoline)s (POx), polyzwitterions, and amphiphilic block copolymers. While these new strategies provide encouraging results, the need for improved correlation between in vitro and in vivo protein resistance is critical. This may be achieved by employing complex protein solutions as well as strides to enhance the sensitivity of protein adsorption measurements.
... blending), are intended to migrate to the air or solution interface to affect surface modification. 44,45 SMA strategies are an attractive option for surface modification, as they avoid the complications associated with poor adhesion of the coatings to substrates and complex surface grafting methods. SMAs have been reported for several base polymers and are typically amphiphilic diblock or triblock oligomers where the hydrophobic block has an affinity to the base polymer. ...
... SMA efficacy may be limited by its ability to restructure to the aqueous interface as well as its tendency to leach from the base polymer during prolonged exposure to water. 44,45 While the PEO-silane amphiphile (a-(EtO) 3 Si-(CH 2 ) 3 -ODMS 13 -block-PEO 8 -OCH 3 ) demonstrated excellent efficacy as a silicone SMA, questions remain regarding its capacity to retain protein resistance during prolonged aqueous exposure. Moreover, the contributions of its diblock architecture and cross-linkable Teos end group are not understood. ...
Surface modifying additives (SMAs), which may be readily blended into silicones to improve anti-fouling behavior, must have excellent surface migration potential and must not leach into the aqueous environment. In this work, we evaluated the efficacy of a series of poly(ethylene oxide) (PEO)-based SMA amphiphiles which varied in terms of crosslinkability, siloxane tether length (m) and diblock versus triblock architectures. Specifically, crosslinkable, diblock PEO-silane amphiphiles with two oligodimethylsiloxane (ODMS) tether lengths [(EtO)3Si-(CH2)3-ODMS
m
-PEO8, m = 13 and 30] were compared to analogous non-crosslinkable, diblock (H-Si-ODMS
m
-PEO8) and triblock (PEO8-ODMS
m
-PEO8) SMAs. Prior to water conditioning, while all modified silicone coatings exhibited a high degree of water-driven surface restructuring, that prepared with the non-crosslinkable diblock SMA (m = 13) was the most hydrophilic. After conditioning, all modified silicone coatings were similarly hydrophilic and remained highly protein resistant, with the exception of PEO8-ODMS
30
-PEO8. Notably, despite twice the PEO content, triblock SMAs were not superior to diblock SMAs. For diblock SMAs, it was shown that water uptake and leaching were also similar whether or not the SMA was crosslinkable.
... Modification of medical device surfaces to improve blood compatibility has been sought to reduce device-related thrombus formation and inflammatory reactions. Surface modification technologies can be assigned into two broad categories: passivation of material surfaces and bioactive surface treatments and coatings [3]. Passive approaches are aimed at reducing the inherent thrombogenicity of the material surface through modification of surface chemistry (e.g. ...
... It was observed that by temporarily immobilizing the anticoagulant drug heparin at the device surface, there was marked reduction in thrombus formation on materials implanted into the vena cava. Numerous approaches to hemocompatible surface modifications have been described since [1][2][3], including a number of heparin-based surface modifications [5][6][7][8]. ...
... Blood contact causes release of the ionic complex from the surface, but the presence of the surfactant slows the rate of heparin release. Other elution-based technologies have been described in previous reviews [3,6]. ...
Blood contact with biomaterials triggers activation of multiple reactive mechanisms that can impair the performance of implantable medical devices and potentially cause serious adverse clinical events. This includes thrombosis and thromboembolic complications due to activation of platelets and the coagulation cascade, activation of the complement system, and inflammation. Numerous surface coatings have been developed to improve blood compatibility of biomaterials. For more than thirty years, the anticoagulant drug heparin has been employed as a covalently immobilized surface coating on a variety of medical devices. This review describes the fundamental principles of non-eluting heparin coatings, mechanisms of action, and clinical applications with focus on those technologies which have been commercialized. Because of its extensive publication history, there is emphasis on the Carmeda® Bioactive Surface (CBAS® Heparin Surface), a widely used commercialized technology for the covalent bonding of heparin.
