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    Drug Delivery Nanosystems for Biomedical Applications
    Drug Delivery Nanosystems for Biomedical Applications
    Drug Delivery Nanosystems for Biomedical Applications
    Ebook930 pages10 hours

    Drug Delivery Nanosystems for Biomedical Applications

    By Chandra P. Sharma

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    About this ebook

    Drug Delivery Nanosystems for Biomedical Application reviews some of the most challenging nanosystems with different routes of delivery that are useful for specific drugs, from both efficacy and bioavailability points-of-view. The chapters explore how this area is developing, the present state of the field, and future developments, in particular, inorganic, metallic, polymeric, composite and lipid nanosystems and their possible evolution to clinical applications. The book is a valuable research reference for both researchers and industrial partners who are not only interested in learning about this area, but also want to gain insights on how to move towards translational research.

    • Focuses on applications, including tissue engineering and regenerative technologies, showing how nanosystems are used in practice
    • Explores how nanosystems are used to deliver a variety of drugs, including peptides, hormone growth factors and genes
    • Assesses the safety and nanotoxicity aspects of drug delivery nanosystems
    LanguageEnglish
    PublisherElsevier Science
    Release dateAug 22, 2018
    ISBN9780323509237
    Drug Delivery Nanosystems for Biomedical Applications

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      Drug Delivery Nanosystems for Biomedical Applications - Chandra P. Sharma

      Australia

      Chapter 1

      Drug delivery nanosystems—An introduction

      Hindumathi R. Dhanasekaran⁎; Chandra Prakash Sharma†; Prathap Haridoss⁎    ⁎ Indian Institute of Technology Madras, Chennai, India

      † Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India

      Abstract

      Nanosystems mainly help in safe delivery of drug molecules to the target site, by minimizing the side effects. A wide range of drugs, genes, and other therapeutic molecules can be loaded onto the nanosystems, targeting various sites of action and various diseases. The use of nanosystems has facilitated the growth of drug delivery systems with multimodal functionality, which involve a combination of therapeutic molecules, therapy techniques or site of action, etc. This short review is aimed at giving a brief introduction to the different forms of nanosystems, their classification, and their future scope when applied for drug delivery systems aimed at treating cancer and other diseases.

      Keywords

      Nanosystems; Colloidal nanoparticles; Inorganic nanoparticles; Nanoemulsions; Nanocapsules; Multifunctional nanosystems; Self-assembly; Self-degradation

      Chapter Outline

      1.1Foreword

      1.2Different Forms of Drug Delivery Vehicles

      1.2.1Colloidal Nanoparticles and Nanocapsules

      1.2.2Nonspherical and Inorganic Nanoparticles

      1.2.3Polymeric Micelles and Other Nanoparticles

      1.3Classification of Drug Delivery Nanosystems

      1.4Versatality to the Target Site

      1.5Perspectives

      References

      1.1 Foreword

      Numerous microscale and nanoscale systems have been developed as part of the efforts to find efficient carrier systems for the delivery of drugs, genes, and antigens to specific sites in the human body, with minimal side effects. The biocompatible nanosuspensions in aqueous base as a drug carrier mainly increase the dispersibility of the hydrophobic drug, transport it safely to the target site, and are able to release the drug in a controlled manner depending on the various stimuli.

      Spherical and nonspherical nanosystems of hydrodynamic diameter 10–200 nm are preferred for drug delivery [1]. Interestingly, most of the recently reported nanosystems fall in this range. Metal nanoparticles can be designed with size less than 100 nm, while liposomes and polymeric nanoparticles are generally above 100 nm. In the last decade, several nanoparticles including carbon nanotubes and other nonspherical inorganic nanoparticles were vigorously tested for their biocompatibility, with contradictory results on their toxicity reported by various researchers. Ignoring the physicochemical properties of the nanoparticles was the reason for inconsistent results. The focus was then on the surface chemistry and the ability for functionalization, and it was learned that functionalization with biocompatible materials could largely reduce the toxicity of these materials. Subsequently, importance of the particle dimension was also recognized, and the physical aspects of the nanoparticles started showing up in publications. Advancements in microscopy techniques for characterizing nanomaterials have made this possible. The advantages of nanosystems are largely preserved in composite nanostructures which are in present focus. They provide additional versatility in developing multicomponent and multifunctional drug delivery systems involving multiple drugs, antibodies, and gene delivery.

      External stimuli such as the electromagnetic force, temperature, light, radiation, and ultrasound have proven to be clinically beneficial both in triggering drug release and by synergistically improving the therapeutic property of the drug. Nanosystems are also being designed to respond to internal stimuli such as pH, redox potential, enzymatic activity, and temperature [2–6]. Because of the acidic microenvironment of solid tumors, pH-stimulated delivery is the most used strategy among various stimuli [2]. Biomolecule-based nanosystems and polymers could protect the SiRNA and DNA from in vivo degradation till they are safely transported to the target site [7]. Hence, nanosystems are also widely explored for gene delivery.

      1.2 Different Forms of Drug Delivery Vehicles

      The different types of drug-loaded nanoparticles depending on their form or structure are shown in Fig. 1.1. Drug and other therapeutic molecules could be either embedded or attached to the surface of the colloidal nanoparticles as shown in Fig. 1.1A and B. Both the core and the shell component of the nanocapsule-type nanoparticle can be embedded with drug molecules as in Fig. 1.1C. Drugs can be attached to the surface of the nonspherical nanoparticles either with or without the help of functionalizing groups (Fig. 1.1D). Amphiphilic block co-polymers with both hydrophilic and hydrophobic reactive components can form micelle-like arrangement with hydrophobic drugs and aqueous solution (Fig. 1.1E). Emulsion-type drug delivery systems mostly contain oils and surfactants, which could enhance the intestinal absorption of poorly water-soluble drugs, and hence is being used in developing oral drug delivery systems [8].

      Fig. 1.1 Various forms of drug-loaded nanoparticles: (A) drug -embedded solid colloidal nanoparticle, (B) drug- adhered solid colloidal nanoparticle, (C) drug-embedded nanocapsules, (D) inorganic nanoparticles, and (E) micelle-type nanoassembly.

      1.2.1 Colloidal Nanoparticles and Nanocapsules

      Drug-loaded biocompatible nanoparticles with a wide range of materials and size can be formed as colloids. For example, curcumin-loaded PLGA-PEG nanoparticles of size less than 200 nm were obtained using a single emulsion solvent evaporation technique, with an encapsulation efficiency of more than 70% [9]. Curcumin could also be loaded onto PLGA particles alone, and the carrier also contributes to the enhanced anticancer activity of the formulation [10,11]. Protein-loaded PLGA nanoparticles were formed using PEG 400 as a solvent, maintaining the integrity of the protein [12]. High-pressure homogenization helps in the formation of pluronic nanosuspensions of particle size of about 300 nm, with a novel anticancer drug Q39 (3-(4-bromopheny l)-2-(ethyl-sulfonyl)-6-methylquinoxaline1, 4-dioxide) [13]. PLGA nanoparticles of about 200 nm size showed colloidal stability when tested in different biological fluids [14]. Unique core-shell-type silica nanostructures with drug-carrying small mesopores in the core and gene-carrying medium-sized mesopores in the shell is intended for combination therapy, where the genes are first released from the shell and downregulate the cancer-progressing genes and the drug in the core is released next for effective killing of cancer cells [15].

      1.2.2 Nonspherical and Inorganic Nanoparticles

      Inorganic nanoparticles have a wide range of physical and chemical properties suitable for various drug delivery applications [16]. In addition to drug loading and release, they could also serve as imaging agents and therapeutic molecules responding to external stimuli such as light, temperature, and electromagnetic radiation. Toxicity is the main issue with these nanoparticles but with considerable research, the physical property requirements of nontoxic, inorganic nanoparticles have been identified and suitable modifications have been made in terms of functionalization for the attachment of hydrophobic drug molecules and for controlled release at the target site. For example, the highest entrapment efficiency of doxorubicin was observed in a CNT-based formulation when compared with nanoparticle-based formulation, liposome, and dendrimers [17]. Loading doxorubicin to nanoparticles and liposomes also drastically reduced the hemolytic activity of the drug, thus minimizing the side effects of the drug. But optimizing the shape, length, diameter, and wall thickness are critical in deciding the physical characteristic requirements of CNTs suitable for a drug delivery system which is nontoxic to normal cells.

      1.2.3 Polymeric Micelles and Other Nanoparticles

      Polymeric micelles are highly water soluble with enhanced stability, nontoxic, have large cargo capacity, and show controlled drug release [18–20]. Though cyclodextrin- based systems are largely explored for oral drug delivery because of the ease of modification and supramolecular systems construction, like many other nanosystems, the ability to be transferred into clinically useful products remains a challenge [21]. Dendrimers, liposomes, phospholipids, and cyclodextrins form highly biocompatible nanoemulsions [5,17,21–25]

      1.3 Classification of Drug Delivery Nanosystems

      Depending on the carrier used, the drug delivery system may be lipid based [22–25], polymer derived, inorganic nanocarriers [16,26], or peptide derived [27]. Inorganic nanocarriers such as metal oxides, gold nanorods, and silica nanoparticles have unique advantages where they can be designed to respond to external stimuli like electromagnetic radiation and magnetic field, facilitating imaging and therapy [15,26]. The therapeutic molecules to be delivered range from antiinflammatory, anticancerous, antibacterial, antifungal, and antiviral drugs, herb-based drugs, viral and nonviral vectors, and genes. Demetzos and Pippa have rightly classified the drug delivery nanosystems with modulatory controlled release profiles as conventional and advanced [28]. Liposomes, nanotubes, and micelles either functionalized or nonfunctionalized are examples of conventional systems, while advanced systems combine different modalities with different kinds of biomaterials, with multimodal functionality, as shown in Fig. 1.2.

      Fig. 1.2 Examples of conventional and advanced drug delivery nanosystems.

      Multimodal functionality can involve a combination of one or more of the following different actions—targeting one or more cells, diagnosis, improving therapeutic efficiency, improving biocompatibility, controlled release, photothermal therapy, drug and gene delivery, multiple site of action, biodegradability, etc. [3,25,29]. For example, core-shell type poly (methacrylic acid)—Fe3O4 nanoparticles loaded with doxorubicin showed dual modality imaging (sensitive to both ultrasound and magnetic resonance imaging, MRI), control-release under pH, redox and ultrasound, in addition to biodegradability [30]. Hybrid nanosystems with natural polymers chitosan, carrageenan, and tripolyphosphate were associated with bovine serum albumin protein and the complex was stable and biocompatible. The complex could be successfully microencapsulated by spray drying to make them suitable for pulmonary delivery [31]. Fluorescent silica nanoparticles were conjugated with multiwalled carbon nanotubes (MWCNTs), polyacrylic acids, and 3-aminopropyl-trimethoxysilane to obtain nanocomposites with enhanced fluorescent emission and photostability, which can be used for various biomedical applications [32]. The release of photosensitive materials under hypoxic conditions is an example of a nanosystem designed to respond to various stimuli at different conditions [33]. Tailored DNA-based assemblies could perform as smart drug delivery vehicles with multifunctions, such as cancer therapy, prodrug medication, and enzyme replacement [34].

      Biodegradable nanosystems are advantageous only when they degrade after releasing the drugs at the target site [30,34–36]. Cyclodextrins have been efficient as biodegradable drug delivery systems [35]. DNA nanoclews with self-degradation property as shown in Fig. 1.3 has been recently reported by Sun et al. [36], where NCl/Au-NCa complexes with doxorubicin which could self-degrade on releasing the drug at acidic pH (Fig. 1.3A). The complex could be internalized by the cancer cell; the small drug molecules released inside the cell on degradation of the complex could reach the DNA as shown in Fig. 1.3B, thus triggering effective killing of cancer cells.

      Fig. 1.3 (A) The main components of the cocoon-like self-degradable DNA nanoclew, consisting of DOX/FA-NCl/NCa, and acid-triggered DOX release. (B) Schematic illustration of efficient delivery of DOX by DOX/FA-NCl/NCa to the nuclei for cancer therapy. Reproduced with permission from W. Sun, T. Jiang, L. Yue, M. Reiff, R. Mo, Z. Gu, Cocoon-like self-degradable DNA nanoclew for anticancer drug delivery, J. Am. Chem. Soc. 136 (2014) 14722–14725. http://pubs.acs.org/doi/full/10.1021/ja5088024. Copyright 2014 American Chemical Society.

      1.4 Versatality to the Target Site

      Drug delivery vehicles are expected to carry the drug to the target site inside any living system. The mode or the route of delivery of the drug could be any one of the following:

      •Intravenous—circulation through the blood

      •Inhalation—circulation through the respiratory system

      •Oral—circulation through the digestive system

      •Transdermal—local application through the skin

      Each of the above routes of administration of the drug is specific to its target. Except for diseases originating from the digestive track and respiratory system, intravenous is the most preferred route for drug delivery systems, wherever blood circulation is available. When drug alone is injected through the blood circulation, the chance of accumulating the preferred quantity of drug in the target site is very less. Also, the injected drugs can affect the normal metabolism of noninfected cells and tissues. Hence, a drug delivery vehicle which can carry the drug safely to the target site and can release the drug in a controlled manner is required.

      In the case of cancer targeting, the ability of the nanosystems to accumulate and subsequently increase the availability of drug in tumor cells can be attributed to the enhanced permeability retention (EPR) effect [37] of tumor cells to macromolecules because of the high-blood supply available for the increased metabolism of tumor cells and reduced venous return.

      Porous and large nanocarriers can be retained in the lungs for weeks as they can escape the lung-surface macrophages and drugs conjugated with these nanoparticles could be progressively released for curing respiratory diseases [38]. Optimization of the dosage of combination drugs need to be focused before further clinical trials [39,40].

      Mucoadhesive behavior is required for oral, dermal, and ocular drug delivery [40,41]. Colloidal nanocarrier systems have been increasingly exploited for dermal drug delivery as they offer increased efficiency in targeted delivery, reduced irritation, and facilitate the formulation of poorly water-soluble lipophilic compounds [42]. Phospholipids form biodegradable and safe nanoemulsions which are highly suitable for topical delivery or penetration through the skin [22,23]. Mucoadhesive nanosystems such as liposomes, niosomes, dendrimers, and polymeric and lipid nanostructures have also proved efficient in topical vaginal delivery and therapy for the treatment of fungal and bacterial infections [40].

      Targeting brain cancer is more complex. Brain cancer exhibits distinct characteristic features at each stage of cancer growth—the blood-brain tumor barrier (BBTB) formed between the blood-brain barrier (BBB) and the tumor presents another hindrance to targeting when the tumor progresses. The systematic drug delivery involves complete targeting which includes BBB, BBTB, EPR effect, variant tumor cells, and tumor stem cells [43].

      For the treatment of diabetes, the pulsatile system of insulin secretion in response to the glucose level is a sought after system [44]. Indomethacin-loaded PLGA self-assembling nanosystems could be retained in the synovial fluid and were found efficient in the treatment of arthritic joints [45]. Nanoenabled drug delivery systems with interpolymeric blend could improve the bioavailability and therapeutic efficiency of Levopoda against Parkinson’s disease [46]. Multifunctional nanosystems designed for simultaneous diagnosis, tumor targeting, radio-frequency-controlled drug release, and photodynamic therapy of tumor is also recently reported to be beneficial as an antimalarial target [47].

      Cationic pullulan complexed with DNA could be used for liver cell targeting [48]. Sorbitan monooleate (Span180)-based nanoparticles with cationized pullulan and lipoplex (lipid-polymer nanoplex) were capable of safe delivery of siRNA for human stem cell differentiation and regeneration [49]. Functionalized metallic nanoparticles, polymers, and liposomes could target the mitochondria and address dysfunctions such as DNA mutation and oxidative stress, and hence could be used in the treatment of diseases such as Alzheimer’s and diabetes [50].

      1.5 Perspectives

      For complete development of any system, a multidimensional approach is required in research. This not only involves the development of new materials, but also standardizing the testing procedure. Since the advent of nanomaterials, there are a lot of new materials and new nanosystems being identified and reported frequently. But lack of guidelines in testing is a hindrance, and it stops these nanosystems from further clinical trials. Very few standard test procedures have been developed till date, because of variations in the physical characteristics of various nanoparticles reported and because of the limited number of reports published with uniform results specific to each nanoparticle.

      To reduce the low drug-loading issue of nanocarriers, drug self-delivery nanosystems are under development where novel pure nanodrugs could be used, but they are still in infancy and require carriers to transport the drugs to the target site safely [51]. Similarly, nanocolloid formation of hydrophobic drugs also requires more research to prove its potency [52]. Self-assembled magnetic nanoclusters, peptide-based nanostructures, and micelles are widely researched [27,53,54]. Tuning of the existing nanosystems for new targets could prove to be cost effective than developing new nanosystems, as explored by Marques et al. for antimalarial drug delivery [55].

      For diseases that cannot be cured by drugs and phototherapy, gene therapy is very promising. But the limitation is safe delivery of the small nucleic acids to the target site, which is done by the nanosystems. Although most of the disadvantages of nanoparticles such as insufficient biodistribution, rapid plasma clearance, and cellular toxicity are solved by selecting appropriate nanosystems, a combination of viral vectors could be preferred for increasing the transfection efficiency for effective gene delivery [56,57].

      Exploring the possibility of increasing the bioavailability of naturally identified drugs such as curcumin with various nanosystems is rapidly progressing, and future prospects will be to focus on more clinical trials with already explored nanosystems.

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      Chapter 2

      Blood compatibility of nanomaterials

      John L. Brash    McMaster University, Hamilton, ON, Canada

      Abstract

      Nanoparticles and other nanomaterials are increasingly used as drug carriers for targeted delivery. When administered intravenously they interact with the blood in a variety of ways that are detrimental to the delivery function, including protein adsorption, platelet activation, coagulation, complement activation, and hemolysis. Research on the blood compatibility of macro-materials for the construction of medical devices such as vascular grafts and stents has been intensive and extensive over many years; yet problems in particular coagulation-thrombosis remain unsolved. Work on nanomaterials is less extensive and the problems are at once somewhat different and somewhat the same for the two scales. The main issue for nanomaterials, typically nanoparticles, is the rapid formation of a protein coating or corona, which masks the surface of the particles, nullifying the specific function for which they were designed, and priming them for premature elimination. In this chapter, the literature on blood compatibility on both scales is reviewed. In the case of nanomaterials, emphasis is placed on the protein corona, its composition, and methods to suppress its formation.

      Keywords

      Nanoparticle; Blood; Compatibility; Protein; Corona; Suppression; Resistance; Coagulation

      Chapter Outline

      2.1Introduction

      2.2Blood Compatibility: Background

      2.3Macro-Materials

      2.4Nanomaterials

      2.4.1Platelet Adhesion/Aggregation, Plasma Coagulation, Complement Activation, Hemolysis

      2.4.2Protein Adsorption: The Corona

      Acknowledgments

      References

      Acknowledgments

      The financial support of the Natural Sciences and Engineering Research Council of Canada (NSERC) is acknowledged. The author acknowledges the many students and colleagues who have contributed to his research on blood compatibility over many years. He is also thankful to his colleagues in the Macromolecules and Biointerfaces Laboratory at Soochow University, Suzhou, China, for their excellent collaboration on fibrinolytic materials.

      2.1 Introduction

      Blood compatibility of materials as a field of study (or perhaps, rather, as a set of problems requiring a solution) has a substantial history going back several decades. A large body of research exists most of which is in relation to medical devices used in contact with blood either inside or outside the body. Many such devices are currently used in clinical practice despite blood compatibility problems related to the materials of construction. Well-known examples include vascular grafts, prosthetic heart valves, intravascular stents, cardiopulmonary bypass systems, and simpler devices such as intravascular catheters. With respect to scale, the materials used in these devices may be described as macro, in contrast to the nano scale materials which are the focus of this volume. Due to their relatively short history, blood compatibility research on nanomaterials is much less extensive. The problems are at once somewhat different and somewhat the same for the two scales, but in any event give rise to severe limitations in both cases. In this chapter, a brief background on blood compatibility issues relevant to both scales is first presented. This is followed by a discussion of the blood compatibility of macro-materials serving as a jumping-off point for a more detailed discussion on nanomaterials.

      2.2 Blood Compatibility: Background

      Problems encountered in blood-material contact in macro-systems include platelet consumption and activation, complement activation, immune and inflammatory responses, bacterial infection, and plasma protein loss and denaturation. Neointimal hyperplasia, leading to restenosis, is often encountered in stenting. Material mineralization leading to loss of mechanical properties, particularly loss of elasticity of polymeric materials, is also problematic for chronically implanted devices. Tissue-based prosthetic heart valves are especially vulnerable in this regard. Loss of material properties due to biodegradation is similarly a longer-term limitation. However, blood clotting and thrombus formation (and thromboembolization in the case of implants) remain the most serious problems in the development of macroscale blood contacting devices, problems that are as yet unsolved. These phenomena cause, for example, the occlusion of vascular grafts of diameter less than about 6 mm [1], the blockage of catheters [2,3], and the failure of heart assist devices [4]. The main focus of research in this area has, therefore, been on elucidating the mechanisms of thrombogenesis on artificial (as opposed to vascular) surfaces and developing methods for prevention thereof. This research has continued over many years and has been reviewed thoroughly [5–7]. The reader is referred to these publications for details.

      The major responses of blood to contact with foreign materials are as follows:

      Protein adsorption: This is widely accepted as the first significant event in blood-material interactions, with complete surface coverage occurring in seconds [8]. The adsorbed layer primes the surface for subsequent events, notably the activation of coagulation and the adhesion and activation of platelets leading to thrombus formation. The adsorbed protein layers are discussed in detail under Section 2.4.2.

      Platelet activation: Platelets are nonnucleated blood cells present at a concentration of 150–450 × 10⁶/mL in normal blood. They are discoid particles of size on the order of 3 μm. Their physiologic raison d’être is their role in hemostasis, that is, the arrest of bleeding following injury to blood vessels. Hemostasis is achieved by the adhesion of platelets to subendothelial structures, notably collagen fibers, followed by aggregation to form the so-called hemostatic plug. Fibrin formed by simultaneous activation of plasma coagulation stabilizes the platelet plug which also contains trapped red cells. Thrombosis is the other, pathologic, face of hemostasis. It is essentially the same process, but is initiated by atherosclerotic lesions on the surface of diseased blood vessels. Thrombosis is also initiated by the contact of blood with foreign materials, that is, all materials other than the normal vascular endothelium.

      Thrombosis on foreign surfaces and the role of platelets therein have been studied extensively in the context of macro-materials and medical devices. As discussed briefly below antiplatelet strategies have been a major part of research aimed at preventing thrombosis on macro-materials. Thrombosis may occur as a result of the introduction of nanomaterials into the bloodstream and nanoparticle clumping mediated by adherent platelets is also possible. However, only a few platelet-related investigations have been carried out.

      Coagulation: It should be emphasized that, other than the normal vascular endothelium, no surface is known that does not trigger coagulation in contact with blood. The mechanisms of plasma coagulation are well established [9]. Traditional descriptions are given in terms of the intrinsic and extrinsic pathways, also known as the contact factor and tissue factor pathways, respectively. The intrinsic pathway, involving only agents that are present in the blood, is the more relevant of the two to coagulation on foreign surfaces. These two pathways converge to a single common pathway, leading ultimately to fibrin (clot) formation. The pivotal reaction is the formation of the enzyme thrombin, which then catalyzes the conversion of fibrinogen to fibrin. Thrombin is also a potent activator of platelets through interactions with platelet-thrombin receptors [10]. Generally speaking, negatively charged surfaces such as glass and clay minerals (e.g., kaolin) have been considered as strong activators of the intrinsic pathway. However differences among surfaces are only a matter of degree. Modification of standard materials (notably polymers, the most common material category used for blood contact) with anticoagulants such as heparin [11], heparin variants [12], and hirudin [13] has been shown to improve performance somewhat, but patients with stents, heart valves, etc., irrespective of the blood contacting material, are generally given anticoagulants systemically.

      Complement activation: The complement system is a part of the innate immune system, which enhances the clearance of pathogens and cellular debris from the body. It consists of a number of plasma proteins (designated C1, C2, …) and cell membrane proteins that interact via complex activation pathways, referred to as classical, alternative, and lectin, to produce C3 convertases that cleave the complement protein C3 to give activation fragments C3a and C3b. The pathways are complex [14] and lead ultimately to assembly of the so-called membrane attack complex C5b-9 (MAC) which kills or damages the pathogen.

      Complement is relevant to blood-material contact in that complement proteins, some of which are abundant (e.g., C3, plasma concentration 1.2 mg/mL), may be adsorbed leading to complement activation, similar to activation on the surface of a pathogen. In the early days of hemodialysis, for example, this was manifest as leukopenia due to complement activation on the dialyzer membrane and sequestration of leukocytes in the lungs. This problem was largely overcome upon the realization that the C3 cleavage component C3b attaches to surfaces via reaction with hydroxyl or amino groups so that dialysis membranes rich in these groups, for example, cellulose-based membranes, should be avoided [15]. Nonetheless, some activation can still occur and indeed activation does occur on most if not all artificial materials. In the case of particles, including nanoparticles, adsorption of complement proteins, in addition to activating complement, may cause opsonization and premature elimination of the particles from the circulation via phagocytosis by cells of the reticuloendothelial system.

      Hemolysis: Hemolysis is the rupture of red blood cells and the release of free hemoglobin into the blood. It can occur as a result of osmotic shock and, more relevant to this discussion, as a result of physical shock on contact with blood, especially flowing blood, with foreign materials. Hemolysis occurs in all blood-material contact situations though most often to a small, inconsequential, extent. If significant, hemolysis can reduce the red cell concentration to unacceptable levels; in addition free hemoglobin in the blood is highly toxic in a number of ways, in particular to the kidneys [16].

      Investigations of blood compatibility of materials, whether on the macroscale or nanoscale, are generally concerned with these five effects, or some subset thereof.

      2.3 Macro-materials

      A number of approaches have been pursued for the design of blood-compatible macro-materials, some of which are relevant to nanomaterials. These may be grouped under three general headings [6]:

      (1)Surface passivation[6]: The objective here is to inhibit the attachment of proteins and cells to the surface. Most of the work has been on proteins, since cells interact with the already-adsorbed proteins, not the bare surface. The objective then becomes to develop surfaces that are protein resistant, that is, that adsorb quantities in the range below a few ng/cm², that is, less than 1% of full monolayer coverage. Surfaces satisfying these criteria based on the data from experiments in simple media have been developed as discussed below. It should be noted that surface passivation is used extensively to modify the blood interactions of nanomaterials and many of the methods described in the following paragraphs have been used to passivate nanomaterials as well. (see Section 2.4.2)

      Two general approaches have been followed for surface passivation: (1) incorporation of hydrophilic polymers including polyethylene oxide/polyethylene glycol (PEO/PEG), polyvinylpyrrolidone (PVP) [17], poly(hydroxyethyl methacrylate) (PHEMA) [18], poly(dimethylaminoethyl methacrylate) (PDMAEMA) [19], and polysaccharides such as dextran [20]; (2) surface modification with zwitterionic polymers such as poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) [21], poly(carboxybetaine acrylamide) (PCBAA) [22,23], poly(carboxybetaine methacrylate) (PCBMA) [24], and poly(sulfobetaine methacrylate) (PSBMA) [24].

      Important variables for the protein resistance of polymer-grafted surfaces are the graft molecular weight and surface graft density, the latter being generally regarded as the more important of the two. Resistance has been found, in general, to increase with graft MW up to a few thousands, and then to level off [25]. Graft density may be described in terms of brush and mushroom configurations, brushes being graft layers where the chain density is high and the chains must stretch toward their fully extended conformation, mushrooms where the density is low enough that the chains can adopt their larger footprint random coil conformation. Protein resistance is generally greater at high chain density, though an intermediate or optimum density has been reported for some systems [26]. Many reports have emphasized the role of hydration and water structure in protein resistance, and as a general rule adsorption has been found to decrease with increasing surface hydrophilicity [27]. Of the hydrophilic polymers shown to be protein resistant, PEO/PEG is the most extensively investigated and is widely regarded as the gold standard.

      Zwitterionic polymers as agents for protein resistance have gained much attention in recent years. Ishihara et al. have shown PMPC to be strongly protein resistant when end tethered to solid surfaces [28,29]. They have suggested that the water associated with these surfaces is highly mobile and exchanges rapidly with bulk water, thereby weakening the interactions with proteins [30]. Extensive work on polymeric carboxy-, sulfo-, and phosphobetaines has been carried out by Jiang et al. [22–24,31,32]. Some of these materials have shown exceptionally low protein adsorption; for example, one carboxybetaine polymer surface was found to adsorb ~ 1 ng/cm² (total protein) from undiluted human plasma. The protein resistance of these materials has been attributed to water layers bound via electrostatic interactions and to the exact balance between the positive and negative charges in the zwitterion [33].

      (2)Incorporation and/or release of bioactive agents: This approach has been used mainly to prevent coagulation and thrombosis. Bioactive agents include anticoagulants such as heparin and hirudin, antiplatelet agents such as nitric oxide (NO), and thrombolytic agents, such as tissue plasminogen activator (t-PA) and plasmin [6].

      Heparin is used routinely in the clinic as a systemic anticoagulant and is by far the most extensively investigated anticoagulant for surface modification. It is a naturally occurring glycosaminoglycan (GAG) with a high density of negative charge (sulfates and sulfonates); it acts mainly by catalyzing the inhibition of thrombin (generated by the coagulation pathways) by endogenous antithrombin [34]. The heparin molecule is regenerated in this interaction and so is ideal as a surface modifier since, in principle, the bioactivity of the surface is conserved over many catalytic cycles. Many methods have been proposed for the surface attachment of heparin [6] including electrostatic and covalent bonding methods, and some commercially developed materials, notably the CBAS surface of Carmeda, are now in clinical use [11,35,36].

      Antiplatelet functionality is also required for thromboresistance. An example of agents used for surface modification in this regard is prostaglandin E1 (PGE1) which inhibits platelet activity by increasing cyclic AMP through augmented activity of adenylate cyclase. PTFE and Dacron grafts with covalently immobilized PGE1 showed greatly reduced platelet adhesion in whole blood in vitro compared with controls [37]. A more recent line of investigation involves the release of NO. NO has several beneficial functions in the cardiovascular system such as vasodilation, antiplatelet activation/aggregation, antiinflammation, antibacterial, and proangiogenesis [38,39]. It is released from the endothelium of healthy blood vessels by the action of nitric oxide synthase (NOS) on arginine. NO is of interest in the field of blood-compatible materials as an antithrombotic agent due to its inhibitory effect on platelets. Two general approaches have been followed based, respectively, on N-diazeniumdiolates [40] and S-nitrosothiols [41] as NO release agents. The recent review of Naghavi et al. [42] gives a comprehensive account of work on NO-releasing materials.

      An alternative approach to the problem of coagulation/thrombosis is to destroy the thrombus rather than prevent its formation, which thus far has proved difficult if not impossible. The destruction approach exploits the body’s fibrinolytic system which breaks down hemostatic plugs (similar in composition to thrombi) when they are no longer needed. Fibrinolysis occurs via the conversion of the circulating zymogen plasminogen to the enzyme plasmin which breaks down fibrin into small fragments termed fibrin degradation products (FDP) [43]. Plasminogen conversion is achieved through the action of plasminogen activators, in particular tissue-type plasminogen activator (t-PA) released from the damaged endothelium. t-PA in blood has a half-life of only ~ 5 min and is inactivated by endogenous plasminogen activator inhibitor-1 (PAI-1). It is largely protected from PAI-1 when bound to fibrin.

      Attempts to adapt this mechanism for the design of fibrinolytic surfaces are of two types: mimicry of the physiological mechanism, and incorporation and release of t-PA into the blood. Research in this area has been reviewed by Li et al. [44]. An example of the mimicry approach is the work of Brash et al who exploited the well-known affinity of plasminogen and t-PA for C-terminal lysine residues in fibrin. From this it is expected that a lysine-rich surface would provide a good substrate for the capture of endogenous plasminogen and t-PA from blood; the interaction of these two molecules on the surface should then lead to plasmin formation and fibrinolysis. Various lysine-modified surfaces were developed and were shown to bind plasminogen extensively from the plasma and to lyse fibrin in their vicinity when treated with t-PA [45–48]. A disadvantage of this approach is the requirement to provide an exogenous source of t-PA for the activation of the adsorbed plasminogen since adsorption from plasma (t-PA concentration ~ 10 ng/mL) is inadequate.

      An example of the release of t-PA for fibrinolysis on a blood contacting material is provided by the work of Park et al. They developed a t-PA-loaded porous poly(l-glutamic acid)/PEG hydrogel which could lyse fibrin clot by releasing t-PA [49]. Wu et al. developed a polycation-modified polyurethane on which t-PA was loaded at high pH. When released at lower pH in contact with plasma, the t-PA was shown to generate plasmin and lyse fibrin [50]. Recently, a t-PA-releasing concept based on a unique protein-displacement triggering mechanism was reported, taking advantage of the fact that plasminogen has higher affinity than t-PA for surface-bound ε-lysine [51]. This concept was implemented using a lysine-modified polyurethane fibrous mat. t-PA was loaded via specific interaction with lysine residues and was displaced from the surface (released) by plasminogen when in contact with plasma

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