Bio-inspired hemocompatible surface modifications for biomedical applications

https://doi.org/10.1016/j.pmatsci.2022.100997Get rights and content

Highlights

  • Preventing surface-induced thrombosis is necessary for maintaining device efficacy.

  • Thrombosis can lead to total device occlusion, inflammation, and device failure.

  • Antithrombotic biomimetic medical-grade surfaces aim for total hemocompatibility.

  • Biopassive, bioactive, and endothelialization surface strategies have been explored.

  • Current bio-inspired hemocompatible materials research is extensively discussed.

Abstract

When blood first encounters the artificial surface of a medical device, a complex series of biochemical reactions is triggered, potentially resulting in clinical complications such as embolism/occlusion, inflammation, or device failure. Preventing thrombus formation on the surface of blood-contacting devices is crucial for maintaining device functionality and patient safety. As the number of patients reliant on blood-contacting devices continues to grow, minimizing the risk associated with these devices is vital towards lowering healthcare-associated morbidity and mortality. The current standard clinical practice primarily requires the systemic administration of anticoagulants such as heparin, which can result in serious complications such as post-operative bleeding and heparin-induced thrombocytopenia (HIT). Due to these complications, the administration of antithrombotic agents remains one of the leading causes of clinical drug-related deaths. To reduce the side effects spurred by systemic anticoagulation, researchers have been inspired by the hemocompatibility exhibited by natural phenomena, and thus have begun developing medical-grade surfaces which aim to exhibit total hemocompatibility via biomimicry. This review paper aims to address different bio-inspired surface modifications that increase hemocompatibility, discuss the limitations of each method, and explore the future direction for hemocompatible surface research.

Introduction

Blood-contacting devices serve as a mainstay for intravenous drug administration, tissue engineering, extracorporeal circulation (ECC), and disease management (Fig. 1). Vascular bypass grafts, catheters, stents, pacemakers, and heart valves are widely used for the treatment of cardiovascular diseases, amounting to 17% of annual health expenditures in the US and the leading cause of death globally [1], [2]. By 2030, the American Heart Association projects that 40.5% of the population in the United States will have some form of cardiovascular disease [1], and failure of devices used for treatment will be catastrophic towards morbidity and mortality rates as well as patient cost. Between 2010 and 2030, direct and indirect medical costs attributed to cardiovascular disease are projected to amount to $818 and $276 billion, respectively [1]. One of the most common complications associated with indwelling cardiovascular devices, including peripherally inserted central catheters, is thrombosis (10–20% rate), which has direct implications on patient outcomes [3]. Therefore, improving the likelihood of successful device applications may significantly reduce the cost of treating cardiovascular diseases and improve patient outcomes.

Moreover, extracorporeal blood-contacting devices are critical for patients requiring cardiac and respiratory support or removal of excess water, solutes, or toxins from the blood. Chronic kidney disease affects 14.8% of adults in the US, and end-stage renal disease (ESRD) affects approximately 750,000 people in the US per year [4]. ESRD patients are limited to two treatment options: donor transplantation and dialysis. Dialysis requires on average three different 3–5 h long sessions per week, resulting in frequent ECC applications for circulatory support and subsequent risks of clot formation [4]. Extracorporeal membrane oxygenators (ECMO) are used as cardiopulmonary life-support through mechanical circulation outside the body to oxygenate the blood. In addition to neonates and pediatrics who compose the majority of ECMO patients, respiratory outbreaks such as the COVID-19 pandemic have continued to underline the importance of improving ECMO treatment. Both dialyzers and ECMO devices are extensively utilized for blood filtration but contain large surface areas that, without systemic anticoagulation, would induce widespread thrombosis [5].

Regulating host response upon exposure to the devices remains the largest challenge relating to blood-contacting devices. A major determining factor in the success of blood-contacting devices is their hemocompatibility. Preventing thrombus formation on the surface of devices is crucial for maintaining device functionality and patient safety. Despite the intensive research and development surrounding these devices, blood coagulation and thrombosis remain the largest limitation of many medical devices. When foreign surfaces are exposed to blood, thrombus formation spontaneously and abruptly occurs, ultimately leading to device failure in the absence of anticoagulant or antiplatelet therapies. Device-induced blood clots can impede device functionality, occlude vessels, or break off and move downstream, causing further complications such as pulmonary embolism, kidney failure, deep vein thrombosis, heart attack, or stroke. Thrombosis is the most common cause of vascular access failure in hemodialysis patients [6], and occurs at rates of up to 66% in long-term central venous catheters [7]. While systemic anticoagulation helps reduce the occurrence of device-induced thrombosis, these events still occur. The administration of anticoagulants can also lead to hemorrhaging. Thrombosis and bleeding have been linked to decreased survival rates by 33% and 40% in ECMO patients, respectively [8]. Even with anticoagulant therapy, stenting often leads to late-stage thrombotic occlusion of the stent, manifesting as restenosis and resulting in further systemic thromboembolism [9]. Late-stage restenosis after corrective surgery can lead to further cardiac events, often necessitating patient readmission. Therefore, the use of systemic anticoagulation and antiplatelet therapies requires careful monitoring to prevent device-induced thrombosis while minimizing the risk of bleeding.

In response, researchers have begun to develop surface modifications for medical devices that mimic hemocompatible natural phenomena to reduce the occurrence of device-induced thrombosis and dependence on systemic anticoagulation. This review will address different bio-inspired surface modifications within each category, as well as the limitations and future directions of these devices.

When exposed to blood, foreign surfaces are subjected to various complex reactions which can compromise the life span and usability of the device (Fig. 2). Under normal conditions, due to its antithrombotic properties, the endothelium can interact with blood without triggering clot formation [10]. However, when devices are introduced to the blood, the adsorption of physiological proteins initiates the activation of a number of biological processes like the coagulation cascade and inflammation. Overall, medical device-induced thrombosis is the result of fXIIa-mediated thrombin formation and platelet adhesion and aggregation which are both initiated by protein adsorption [11].

Proteins, which constitute a major part of the plasma, are considered to initiate thrombosis by rapidly adsorbing to the foreign surface immediately after it enters the blood [11]. The surface chemistry and physical properties of the device modulate which proteins are attracted to the surface and the strength at which they adsorb. Furthermore, the Vroman effect may occur, a process wherein proteins can be displaced by other proteins over time based on their relative affinity, size, and charge [11]. Generally, smaller proteins adsorb quickly to the surface and are eventually replaced by larger proteins or proteins with greater affinity [12]. Blood is composed of different plasma proteins, several of which play key roles in mediating platelet, leukocyte, and red blood cell attachment.

Platelets are essential for the maintenance of hemostasis, the formation of hemostatic plugs, and the releasing of pro-coagulant signals which ultimately assist in the transformation of prothrombin to thrombin [13]. Platelets interact with fibrinogen attached to the foreign surface by the integrin αIIbβ3 present on platelets [11]. Due to their high affinity to fibrinogen, platelets can adhere at adsorbed fibrinogen concentrations as small as 7 ng cm−2 [11], [14]. After adhering to fibrinogen, platelets begin to form dendritic pseudopodia and release agonists that further promote aggregation and adhesion of platelets [12]. Von Willebrand factor joins together activated platelets through the αIIbβ3 complex [15]. Adhered leukocytes can degranulate, releasing platelet-activating factor, interleukins, and TNFα, which further progress platelet activation. Red blood cells adhere independently from the protein monolayer and release adenosine diphosphate (ADP), which further promotes platelet aggregation [11].

Key factors composing the contact-phase system can also bind to the device surface and displace fibrinogen including factor XII (fXII), HMWK, prekallikrein (PK), and factor XI (fXI) [11], [16]. Bound fXII can autoactivate into fXIIa, which activates PK into active kallikrein and HMWK into bradykinin, both of which stimulate coagulation and inflammatory responses [11]. Through the intrinsic pathway, fXIIa begins a series of reactions that results in the activation of factor X, ultimately triggering thrombin generation and inflammation [11], [16]. Both the extrinsic and intrinsic pathways of coagulation, which share the activation of factor X, begin the conversion of prothrombin to thrombin and the transformation of fibrinogen to fibrin and platelet aggregation, resulting in a dense network of clot formation [11], [16].

Exposure of artificial surfaces to blood can also induce the complement system, a key pathway for immune response as the initial line of defense against foreign bodies. The complement system is initiated by three different pathways: classical, alternative, and mannose-binding lectin (MBL). Ultimately, these three pathways result in C3 convertase, which by cleaving C3 into C3a and C3b, promotes inflammation at the site. The generation of C5 convertase also cleaves C5 into C5a and C5b [16]. Together C3a and C5a increase the recruitment, attachment, and activation of leukocytes [11]. Moreover, C5b can subsequently bind to the surface and initiate the production of the membrane attack complex (MAC), triggering a series of inflammatory reactions [16].

In addition to coagulation complications, introducing a foreign material can also induce both acute and chronic inflammatory responses. Similar to medical device-induced thrombosis, inflammation is initially triggered through the adsorption of proteins (ex. complement components, fibrinogen, vWF, vascular cell adhesion molecule (ex. VCAM-1, P-selectin) on the surface, which enable inflammatory cell recruitment and attachment [17], [18]. Platelets that attach to the surface generate pro-inflammatory molecules including monomeric C-reactive protein and tissue factors that recruit inflammatory cells (ex. macrophages, polymorphonuclear leukocytes), promoting thrombosis [17], [19]. In addition to their roles in device-induced thrombosis, kallikrein, thrombin, and other coagulation enzymes stimulate a local inflammatory response [11]. Over time, monocyte-derived macrophages begin to replace polymorphonuclear leukocytes and degrade the device through the generation of reactive oxygen and nitrogen species as well as hydrolytic enzymes [19]. Fibrous encapsulation is facilitated by later-recruited macrophages, walling off the implant from the body and obstructing device functionality [19]. Excessive inflammatory responses can lead to several major complications including device failure, neointimal thickening, and tissue damage [18], [20].

To increase hemocompatibility, researchers are now modifying surfaces to prevent or disrupt the pathways described above. Hemocompatibility assessment guidelines provided by ISO 10993-4 are comprised of five distinct categories: thrombosis, coagulation, platelets, hematology, and immunology [16]. To alleviate undesired side effects from medical device exposure and minimize patient risk, the search for a biocompatible surface that prevents blood component activation in each of these categories has been initiated.

Current methods to prevent thrombus formation caused by medical devices fall under two categories: systemic anticoagulation/antiplatelet therapy and the usage of hemocompatible devices. Systemic administration of anticoagulants, mainly systemic heparinization, remains the most widely used technique to control clot formation. However, anticoagulant therapies are among the most common causes of adverse drug-related events and deaths in hospitalized patients. A surveillance study examining adverse drug events with hospitalized Medicare patients found that 13.6% of patients administered heparin and 8.2% of patients administered warfarin experienced an adverse drug event [21]. According to a comprehensive study conducted at Brigham and Women’s Hospital, of the nearly 500 anticoagulant-associated adverse drug events, 48.8% were due to medication errors, 30.5% were due to adverse drug reactions, and 20.7% were due to both medication errors and adverse drug reactions; as a result, death within 30 days of the adverse event occurred in 11% of patients [22]. Patients receiving anticoagulants are likely to have medical conditions (ex. heart failure, ischemic heart disease, chronic kidney disease, stroke) that increase their vulnerability to adverse drug events, increasing the likelihood of longer hospital stay, more complicated treatment requirements, and risk of death [22]. All forms of anticoagulants have been associated with the development of acute hemorrhaging [23]. Incidence rates of major bleeding events during systemic heparinization are reported to occur at 7.3 to 16.7 per 100 person-years [24]. Moreover, systemic heparinization has led to side effects including drug intolerance, thrombocytopenia, and osteopenia [25]. Even after discontinuation of systemic heparinization, 50% of patients that develop heparin-induced thrombocytopenia experience a thrombotic event, and thrombotic complications associated with heparin-induced thrombocytopenia are associated with a mortality rate between 20 and 30% [26], [27]. In response, researchers have set out to develop improved hemocompatible devices, averting the need for additional systemic administration of anticoagulants or antiplatelet therapies [28].

Significant research has been conducted in identifying physical, chemical, and biological surface properties that result in antithrombotic behavior. Characteristics including surface charge, the presence of hydrogen bond acceptors, polarity, surface roughness, and hydration forces alter the interactions between the device and blood [16], [29], [30]. However, even with these surface adaptions, achieving a biocompatible device that exhibits antiplatelet and protein-repulsive activity has proven to be difficult. One of the most widely explored surface modification techniques is the incorporation of polyethylene glycol (PEG). PEG-coated surfaces form tightly bound water layers at the interface that proteins are unable to displace as needed for protein adsorption [31]. Although PEG-incorporated surfaces significantly reduce thrombus formation [32], [33], incorporating PEG into polymers generates several drawbacks. PEG is not biodegradable and can trigger the complement pathway, resulting in an immediate or delayed immunological response [34], [35]. Although PEG incorporation is generally considered to suppress protein adsorption, exposure to some PEGylated therapeutics has resulted in the generation of anti-PEG antibodies, activation of the complement system, and caused hypersensitivity reactions [36]. However, the exact mechanisms of this are not well-understood.

Other synthetic materials and surface modifications such as the incorporation of poly(2-ethyl-2-oxazoline), titanium oxides/nitrides, polyethylene oxide (PEO), poly(vinyl chloride) (PVC), poly(ethylene), and polysulfone (PSF) have also been utilized to increase hemocompatibility, but despite initial promising results, each method has fallen short of reaching total blood compatibility [10], [12], [37], [38]. For this reason, researchers have turned to emulating hemocompatible and antifouling bodies found in nature (Table 1, [355], [356]). Bio-inspired technologies for improving hemocompatibility can be broken down into three categories based on their method of achieving blood compatibility: biopassive methods, bioactive methods, and promotion of endothelial cell growth. Biopassive surfaces do not interact with the environment or trigger an immune response, while bioactive coatings contain or release agents that actively interfere with components that promote thrombus formation and provoke an immune response [12]. More recently, the promotion of endothelial cell growth on the surface of medical devices has been recognized as a final method of preventing thrombus formation, forming a barrier that prohibits the interaction between the device and the surrounding environment, and is particularly necessary for long-term indwelling devices [39]. The remainder of this review will cover technologies developed in each category, the short-comings of each strategy, and future directions for bio-inspired hemocompatible devices.

Section snippets

Current biopassive methods for improving surface hemocompatibility

The fate of a biomaterial ultimately depends on its ability to prevent recognition by the foreign body response. Biopassive surfaces aim to minimize triggering large adverse reactions, effectively evading surface-induced coagulation by preventing protein adsorption and platelet adhesion (Fig. 3). These modifications invoke a low immune response from the body, but the effectiveness of these devices over long periods of exposure time is still a concern, limiting their use almost exclusively to

Current bioactive methods for improving surface hemocompatibility

Another method of mitigating clot formation is the incorporation of bioactive antithrombotic vehicles. Such agents present on or locally released from biomaterials can react with the surrounding environment, directly interfering with protein adsorption or platelet adhesion and aggregation, thereby preventing thrombus formation (Fig. 10). The following section will discuss bio-inspired bioactive surface additives that improve hemocompatibility, as well as some of the drawbacks and limitations of

Current promotion of endothelial cell growth strategies for improving surface hemocompatibility

There is no doubt that the native endothelial surface is the most hemocompatible surface that exists. Measuring at thicknesses as low as 0.2 µm, a healthy endothelium acts as a thin yet highly effective barrier between blood and tissues [284]. Endothelial cells regulate the release of NO, tissue factor, and thrombin inhibitors, effectively preventing thrombus formation. Often used as a final marker for the degree of wound healing, the endothelialization of biomaterials effectively blocks the

Conclusions and future directions

Medical implants routinely fail due to protein adsorption and platelet adhesion and activation, resulting in thrombus formation. Occlusive clot formation can prevent device function and result in surgical complications and local tissue necrosis. Additionally, large thrombi can embolize, leading to severe complications such as heart attack and stroke. To prevent thrombus formation, the current gold standard in clinical practice is the systemic administration of anticoagulants including heparin

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Funding for this work was provided by the National Institutes of Health, USA (grants R01HL134899 and R01HL151473).

Megan Douglass is a senior engineer at a leading medical device company. Megan received her Ph.D. from the University of Georgia in 2021 under the guidance of Dr. Hitesh Handa, where she focused on the development and evaluation of hemocompatible and antimicrobial surface modifications for medical devices.

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    Megan Douglass is a senior engineer at a leading medical device company. Megan received her Ph.D. from the University of Georgia in 2021 under the guidance of Dr. Hitesh Handa, where she focused on the development and evaluation of hemocompatible and antimicrobial surface modifications for medical devices.

    Mark Garren received his B.S. in Chemical and Biomolecular Engineering from the Georgia Institute of Technology in 2017. He is currently a PhD candidate under the guidance of Dr. Hitesh Handa at the University of Georgia. His research is focused on gasotransmitter and reactive species strategies for modulating biological responses to polymeric materials to improve infection resistance and hemocompatibility of medical devices.

    Ryan Devine is currently a R&D Engineer working on tissue engineered products in the private industry. Ryan received both his B.S. and Ph.D. degrees in Biomedical Engineering from the School of Chemical, Materials, and Biomedical Engineering at the University of Georgia in 2017 and 2022, respectively. Under the guidance of Dr. Hitesh Handa, Ryan's doctoral dissertation focused on the development and study of slippery, nitric oxide-releasing materials for the improvement of medical device hemocompatibility.

    Arnab Mondal received his Ph.D. in Engineering from the University of Georgia in 2021 under the direction of Dr. Hitesh Handa. He currently works with Dr. Elizabeth Brisbois as a postdoctoral researcher at the School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia. His research interest includes leveraging nitric oxide-based polymeric materials for developing medical devices for antimicrobial and hemocompatibility applications.

    Hitesh Handa is an associate professor in the School of Chemical, Materials and Biomedical Engineering at the University of Georgia. Dr. Handa's area of focus is in translational research for development of medical device coatings, wound healing materials, therapeutic nanoparticles, and microfluidic artificial lungs. With his experience in biomolecular interactions, materials/surface science, polymeric coatings, blood-surface interactions and animal models, his goal is to bridge the gap between the engineers and clinical researchers in the field of biocompatible materials.

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