Nanotoxicity in Systemic Circulation and Wound Healing - American

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Nanotoxicity in Systemic Circulation and Wound Healing Mandeep Singh Bakshi* Department of Natural and Applied Sciences, University of WisconsinGreen Bay, 2420 Nicolet Drive, Green Bay, Wisconsin 54311-7001, United States ABSTRACT: Nanotoxicity of nanomaterials is an important issue in view of their potential applications in systemic circulation and wound healing dressing. This account specifically deals with several characteristic features of different nanomaterials which induce hemolysis and how to make them hemocompatible. The shape, size, and surface functionalities of naked metallic as well as nonmetallic nanoparticles surfaces are responsible for the hemolysis. An appropriate coating of biocompatible molecules dramatically reduces hemolysis and promotes their ability as safe drug delivery vehicles. The use of coated nanomaterials in wound healing dressing opens several new strategies for rapid wound healing processes. Properly designed nanomaterials should be selected to minimize the nanotoxicity in the wound healing process. Future directions need new synthetic methods for engineered nanomaterials for their best use in nanomedicine and nanobiotechnology.

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CONTENTS

1. Introduction 2. Hemolysis 2.1. Nanosilica 2.1.1. Surface Silanol Groups of Silica 2.1.2. Porosity of Silica 2.1.3. Shape and Size Effect 2.1.4. MCM-41 and SBA-15 Silica 2.2. TiO2 NPs 2.2.1. Surface Functionalization 2.2.2. Comparison between TiO2 and SiO2 NPs 2.3. Semiconducting NPs 2.3.1. Quantum Dots 2.3.2. Cu2O NPs 3. Hemocompatibility 3.1. Protein and Bioactive Polymer Coated Au and Ag NPs 3.2. PEG and Lipid Coated Silica NPs 3.3. Polymer Coated Iron Oxide NPs and QDs 3.4. NPs Cell Internalization without Hemolysis 3.5. Polymeric NPs 4. Quantitative Analysis of Hemolysis: Raman Spectroscopy 5. Hemolysis in Wound healing 5.1. Curcumin NPs 5.2. Nanodiamonds 5.3. Ag NPs 6. Biocolloidal Nature of Nanomaterials in Biomedical Applications 7. Future Perspectives 7.1. Model Systems 7.2. Materials for Drug Carrying Abilities 7.3. Nanomaterials for Wound Healing Dressing 8. Concluding Remarks Author Information © 2017 American Chemical Society

Corresponding Author ORCID Notes Biography References

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1. INTRODUCTION Conventional medicine is a time-consuming, high cost, and low results oriented process. The usual way of medicine ingestion is associated with several side effects because a large amount of it never reaches the target. Hence, target drug delivery techniques are becoming increasingly important.1−3 They are rapid with little sample deterioration, require only the desired amount of the drug, and produce accurate results with little cost. Systemic circulation is the most convenient channel to achieve the target drug delivery up to the cellular level. However, it is equally important to follow how the target drug delivery tools interact with the components of systemic circulation.4−6 This account specifically focuses on the use of bionanomaterials as target drug delivery tools and how such nanomaterials interact with the blood cells. In other words, the focus is on the nanotoxicity toward blood cells and how to use such nanomaterials as target drug delivery vehicles in systemic circulation. Red blood cells primarily carry oxygen and collect carbon dioxide through hemoglobin. They have a lifespan of about 120 days. Hemolysis is the breakage of the blood cell membrane which causes the release of hemoglobin and other internal components into the surrounding fluid.7−9 It can be visually detected by the appearance of a pink to red tinge in the serum and is caused by a large number of medical conditions which include microbial infections, autoimmune and genetic disorders, and

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Received: March 9, 2017 Published: May 6, 2017 1253

DOI: 10.1021/acs.chemrestox.7b00068 Chem. Res. Toxicol. 2017, 30, 1253−1274

Chemical Research in Toxicology

Perspective

Figure 1. (a−c) Types of silanol groups that can exist on the amorphous silica surface. (d) Proposed reaction pathway for the generation of reactive oxygen species. Reproduced from ref 26. Copyright 2012 American Chemical Society.

essential component of blood cells. Apart from the red blood cells, white blood cells and platelets are also present in the blood plasma; however, our focus is primarily on the fate of the blood cells in terms of hemolysis when blood cells interact with different nanomaterials which are used as drug delivery vehicles in the systemic circulation or used as essential components of the wound healing process. Hemolysis of several different kinds of nanomaterials (both metallic as well as nonmetallic) has been discussed in terms of the shape, size, and surface chemical composition of NPs and their possible role as drug delivery vehicles in systemic circulation.

low solute concentration. Blood cells are prone to hemolysis when they come in contact with a nanoparticle (NP) surface since a free surface needs higher surface energy to interact.10−12 Metallic NPs such as Au10−12 and Ag13−16 have been found to cause significant hemolysis when they interact with the blood cell membrane. Several factors such as surface charge, functionality, shape, and size of the NPs influence hemolysis. However, properly coated NPs with the surface adsorbed species do not interact with the blood cell membrane and hence reduce the amount of hemolysis to a significant extent.10−12 Such NPs are considered to be the best suited vehicles for carrying an appropriate drug load to release in the systemic circulation.17 This perspective collects and discusses the synthesis and characteristic features of various kinds of possible nanomaterials which can be used as target drug delivery vehicles in the systemic circulation. In addition to their applications as drug delivery vehicles, the interactions of the bionanomaterials used in the wound healing processes have also been discussed to demonstrate another channel of possible nanotoxicity.18−22 In other words, one has to keep a balance between the applications of bionanomaterials in wound healing dressing as well as their toxic effects when they are allowed to directly interact with the blood cells in an open wound. Wound healing is a complex and dynamic process where broken cellular structures are restored in a stepwise time-consuming manner that involves inflammation, proliferation, and remodelling of the tissue layers. All of these processes are closely governed by the nature of the wound healing dressing in terms of its efficiency. Conventional dressing processes are considered to be outdated in comparison to those that involve the use of nanomaterials both from the reinforcement as well as antimicrobial properties. However, while achieving these goals, precautions should be taken as NPs embedded in the wound dressing are in direct contact with the blood cells and may induce significant hemolysis. Therefore, dose amount and nature of the NPs in terms of their surface properties are the important criteria to be considered in the wound healing process. Before starting with nanotoxicity, some preliminary understanding of the blood and its composition is necessary. Blood is a constantly circulating fluid which provides nutrition and involves oxygen exchange and the removal of waste from the body. The red color is provided by the red blood cells which are suspended in the form of biocolloids in a thick fluid known as plasma containing several blood proteins. Albumin is the main blood protein in plasma which regulates the osmotic pressure of blood cells. Hemoglobin, an iron-containing protein is an

2. HEMOLYSIS 2.1. Nanosilica. 2.1.1. Surface Silanol Groups of Silica. The synthesis and applications of mesoporous silica NPs are a rapidly growing field in nanotechnology.23−25 They are one of the most easily synthesized and economically viable nanomaterials. Silica NPs bear surface silanol groups which mainly exist in the form of tetrahedral arrangement.26 Hydrogen bonding among the surface terminated silanol groups may lead to the formation of other different arrangements known as vicinal, germinal, and isolated (Figure 1a).27,28 Since the silanol groups line a huge surface area of porous silica spheres, they are also associated with different forms of radicals (Figure 1b).29,30 The surface silanol groups can exist in the hydrolyzed and nonhydrolyzed forms and are the results of their methods of preparation. Aqueous phase synthesis, mainly followed by the Stöber synthesis,31 produces hydrolyzed silanol groups that upon annealing at elevated temperature leads to the nonhydrolyzed surface silanol groups (Figure 1c) because associated water molecules and hydrogen bonded silanols are removed upon annealing. It creates closed siloxane rings with high surface hydrophobicity. Thus, hydrolysis increases the total silanol concentration and decreases the number of isolated silanols. The surface silanol groups exhibit strong potential to interact with the blood cell membrane and induce hemolysis. Annealing treatment at elevated temperature reduces the amount of hydroxyl contents of silica spheres that results in the decrease in their cytotoxic effects, and hence, it reduces hemolysis while rehydration revokes the hazard potential of silica spheres.26 Thus, the surface silanol groups selectively promote the surface interactions with the blood cell membrane.32−35 They serve as hydrogen donors to quaternary and phosphate ester groups of phospholipid membrane components.36,37 The reactive oxygen species play a significant role in silica toxicity both for the hydrolyzed as well as for the nonhydrolyzed silica spheres.38 Blood cell membrane is 1254



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Figure 2. (i) Percentage of hemolysis of blood cells incubated with four sizes of silica sphere (SS) NPs at different concentrations ranging for 3 h. (b) Photographs of hemolysis of blood cells in the presence of four sizes of SS. (ii) Percentage of hemolysis of RBCs in the presence of five sizes of mesoporous NPs at different concentrations for 3 h. (b) Photographs of the hemolysis of blood cells incubated with four sizes of NPs. Reproduced from ref 32. Copyright 2010 American Chemical Society.

presence of surfactant,43 usually positively charged cetyltrimethylammonium bromide (CTAB). The size of nonporous NPs increases as the amounts of precursor tetraethyl orthosilicate (TEOS) and ammonium hydroxide are increased. As mentioned above, the smaller NPs have higher hemolytic activity than the larger particles which is due to the larger surface area per gram allowing a higher number of silanol groups to come in contact with the blood cells.44−46 Likewise, porous NPs also show size dependent hemolytic activity which is further related to the pore size (Figure 2).32 In comparison to nonporous NPs, porous NPs show relatively lower hemolysis due to the voids on the surface that reduce the silanol group’s contact with the cell membrane. Thus, porosity on the surface is the major factor that influences hemolysis.32 At the same time, porosity is required for carrying an appropriate drug load for a target delivery and hence an important aspect that provides the mesoporous namomaterials a better applicability in comparison to that of nonporous NPs. However, the pore stability of the mesoporous silica is supported by the presence of cationic surfactant CTAB which demonstrates cytotoxicity due to its highly ionic as well as surface active nature. For an appropriate use of mesoporous silica as drug carrying vehicles in the systemic circulation, CTAB has to be removed, which in turn results in the collapse of the porous structure. However, if

susceptible to oxidative damage. It leads to peroxidation of the membrane lipids, hemolysis, and alteration in activity of antioxidant enzymes catalase and superoxide dismutase.39 In addition, the ring strain (Figure 1d) results in preferential hemolytic cleavage of the three membered ring to form surface radicals that can further react with water, oxygen, or hydrogen peroxide to generate hydroxyl radicals.26 The amount of surface silanol groups is further related to the size and dose dependent hemolysis and quantifies the potential of toxicity. Silica particles of small different sizes such as 7−14, 20, and 50 nm are considered as highly toxic. The crystalline NPs of 5−15 nm are of medium toxicity, while hydrophobic silica NPs of 7−14 nm in size are usually of low toxic nature.40 The hemolytic activity and cytotoxicity of all silica NPs is significantly reduced in the presence of blood plasma which forms a corona layer over the surface of silica particles and inhibits their interactions with blood cell membrane. The lower toxicity of silica NPs in the presence of serum results in a higher agglomeration and lower cellular uptake.41,42 It reduces the hemolysis because of the “loss-of-function” of the silica surface activity associated with their surface silanol groups. 2.1.2. Porosity of Silica. Both nonporous as well as porous silica spheres induce hemolysis though they are synthesized by different methods. The former is mainly produced by the wellknown Stöber synthesis,31 while the latter is performed in the 1255



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Figure 3. TEM images of (A) Stöber SiO2 with an average diameter of 115 nm (referred to as Stöber), (B) mesoporous SiO2 with an average diameter of 120 nm (Meso S), (C) mesoporous silica nanorods with an aspect ratio 2 (AR2), (D) with an aspect ratio 4 (AR4), (E) with an aspect ratio 8 (AR8), and (F) high-resolution image of a single particle in B. Scale bars in A−E = 200 nm, and in F = 50 nm. (Right panel) Hemolysis assay on bare SiO2. (A) Relative rate of hemolysis in human blood cells upon incubation with nanoparticle suspension at incremental concentrations. Reproduced from ref 49. Copyright 2011 American Chemical Society.

Figure 4. (a) TEM images of MCM-41 (top) and SBA-15 (bottom). (b) Schematic illustration of the size- and surface dependent interaction with blood cell membrane. NP with radius r can be wrapped around or engulfed by the blood cell if the energy (Ei) released from the blood cell−NP interaction is greater than the energy (Eb) required for membrane bending. Reproduced from ref 50. Copyright 2011 American Chemical Society.

2.1.4. MCM-41 and SBA-15 Silica. Hemolytic activities of MCM-41 and SBA-15 silica are worth discussing since they are the conventional forms of silica known for the last several years.50−52 A significant difference is observed between the hemolytic activities of MCM-41 and SBA-15 silica. MCM-41 stands for Mobil Composition of Matter No. 41. It is a mesoporous material with hierarchical structures first developed by Mobil Oil Corporation for its applications as catalyst. SBA15, on the other hand, is named after a Santa Barbara Amorphous type material especially designed for its use as molecular sieves. Both materials have different synthetic methods but produce hexagonally ordered cylindrical nanopores of different dimensions which specifically depend on the nature of surfactant or micelle forming block copolymer used in the synthesis.53−56 SBA-15 possesses a larger pore size than MCM-41, which has thinner walls of the mesoporous channels, and hence, both are two-dimensional (2D) hexagonally ordered mesoporous materials. The large surface areas and pore volumes of these materials allow them to act as excellent carriers for a wide range of clinically important molecules, such as drugs,57−60 therapeutic proteins,61,62 antibiotics,63,64 and antibodies65 for biological marking and controlled drug delivery. In order to designate them as suitable materials for therapeutic purposes and with delivery through the systemic circulation, hemolytic analysis is an essential component of the procedure. MCM-41 NPs in the presence of blood cells tend to adsorb on the cell membrane with practically little alteration.50

mesoporous silica is aged in phosphate buffer solution, the degree of hemolysis is significantly reduced.32,47,48 2.1.3. Shape and Size Effect. Shape and size are the important factors of the silica NPs for their interactions with blood cells.49 On the basis of the size disparity, a blood cell is more than 100 times larger than a silica NP of about 50 nm in size. Thus, the shape and size of the silica NPs become important parameters and demonstrate marked effect on the degree of hemolysis (Figure 3)49 when NPs of different shapes and sizes interact with the highly flexible blood cell membrane. A dose amount of 100 μg/mL associated with different shapes of NPs does not significantly contribute toward hemolysis. However, significant hemolysis is observed when the amount of NPs exceeds this amount.49 High aspect ratio mesoporous SiO2 NPs demonstrate lower hemolytic activity than spherical or low aspect ratio NPs. Surface area and surface curvature of porous NPs influence hemolysis by affecting the magnitude of bending energy to wrap around the NPs.50 Large external surface area and small curvature render the hemolysis process thermodynamically favorable.50,32 It is further related to the surface density of the silanol groups which cause immediate cell membrane damage upon exposure. Surface modification from silanol to amine substituted NPs causes an increase in hemolysis with concentration. Increasing the surface charge beyond a certain threshold, which is considered to be >30 mV, shows enhanced interactions of NPs with blood cells and results in an increase in hemolysis.49 1256



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Figure 5. Erythrocyte sedimentation and agglutination under TiO2. (a) Erythrocyte + PBS, (b) erythrocyte + nano-TiO2 (100 μg/mL), (c) erythrocyte + nano-TiO2 (200 μg/mL), (d) erythrocyte + micro-TiO2 (100 μg/mL), and (e) erythrocyte + micro-TiO2 (200 μg/mL). Erythrocytes (b or c) are agglutinated. Ultrathin section of erythrocyte TEM analysis. Aggregated TiO2 NPs are found to be attached along the membrane of erythrocyte. Reprinted with permission from 75. Copyright 2008 Elsevier.

Figure 6. Photographs of control erythrocytes (a); erythrocytes treated at a concentration of 1 μg/mL (b), 10 μg/mL (c), 100 μg/mL (d), (magnification, 400×) of ammonium-terminated dendrimer coated TiO2 NPs. Hemolytic activity of the four hybrid materials. Reprinted from ref 79. Copyright 2015 American Chemical Society.

tion71−75 to understand their hemolytic behavior. They can enter into the biological systems through inhalation, ingestion, and even dermal penetration, and hence, they are subjected to permissible uses only. Once, in the biological system, they are found in the liver,76,77 kidney,76 and brain78 because of their transportation through systemic circulation. In the bloodstream, they show dramatic interactions with the blood cells whereupon they lead to significant erythrocyte sedimentation and hemolysis at an alarming rate that causes abnormal alterations in the shape and size of the cell membrane (Figure 5).75 Even coated TiO2 NPs used for different applications show considerable toxicity. Ammonium-terminated dendrimer coated TiO2 NPs easily undergo cell internalization and transcytosis across epithelial cells into blood and lymph circulation, and cause hemolysis with increasing concentration (Figure 6).79 Phosphorus dendrimers have a wide range of potential applications in medicinal chemistry80,81 and materials science.82 Their three-dimensional structures are particularly prone to interact with the biological systems.83 The presence of 1 and 10 μg/mL NPs in a cell suspension induces echinocytic transformation in the red blood cells with many small and evenly spaced thorny projections on the abnormal cell membrane. Higher concentrations cause cytoplasmic projections on the surface and the conversion of normal erythrocytes to echinocytes that eventually deform the cells and result in hemolysis. The percentage of hemolysis depends on the

The cell membrane maintains its normal biconcave shape (Figure 4a and b) during this event. In contrast, a large amount of SBA-15 NPs prefer to adsorb on to the cell membrane and induce strong local membrane deformation. It results in the NP’s cell internalization with shape transformation and a reduction in the ratio of surface area to volume which eventually leads to hemolysis. It is considered that cell membrane binding of the NPs is driven by the silanol-rich surface of NPs with the phosphatidylcholine-rich cell membrane36 as well as its bending to accommodate the rigid surface of NPs (Figure 4b).66−70 This association becomes energetically favorable when the amount of energy released from the binding of the NPs is overcome by the amount of free energy required to bend the membrane and adapt the NP’s surface accommodation. The former energy is associated with the external surface area,36 while the latter is proportional to the curvature or inversely proportional to the square of the radius (r) of the particle.66,67,70 The large surface area of SBA-15 NPs in comparison to that of MCM-41 NPs thus provides a greater binding energy for pulling the membrane to the particle surface, and hence, a lower bending energy is needed to wrap the larger NP in comparison to that for the smaller one.66 It makes the membrane wrapping and engulfment of SBA-15 NPs thermodynamically favorable. 2.2. TiO2 NPs. 2.2.1. Surface Functionalization. Recent applications of TiO2 NPs also require considerable atten1257



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2.3. Semiconducting NPs. 2.3.1. Quantum Dots. Fluorescent quantum dots (QDs) are well-known for their applications as biological markers and belong to a class of very useful nanomaterials for cellular imaging.92−94 Metallic QDs are even considered to be better fluorescent probes than the fluorescent dyes because of their enhanced quantum yield, tunable properties, longer lifetime, and colloidal behavior95 mainly required for the drug release vehicles in the systemic circulation. Despite several exciting applications of QDs, their widespread use in biological systems is under investigation in view of their prominent cytotoxic effects.96−100 Cell culture experiments demonstrate the potential design-dependent intracellular localization of QDs whereby they enter the liver and spleen following intravascular injection.96 They are retained within the biological system and hence pose long-term toxicity. As far as their hemolytic effect is concerned, only a few studies have been reported in the literature.100−105 Thioglycolic acid stabilized CdTe QDs when incubated with erythrocyte from 1 to 4 h at 37 °C cause an increase in the hemolysis rates from 4.6% to 19.4% and from 0.2% to 10.7% for glutathione CdTe/ ZnS core−shell QDs (Figure 8).101 Hemolysis also increases linearly with the increase in the amount of QDs, and it is more for the former rather than the latter. Thus, core−shell QDs demonstrate better biocompatibility, which is further related to the nature of nanostructured material composition and surface properties. Similar results are reported for the L-Cys capped PbS QDs.106 the degree of hemolysis for these QDs also increases with the increase in the amount. Although, hydrogen bonding between the coated NPs and cell membrane is one of the driving forces that induces the hemolysis,26,107−109 mercaptosuccinic acid coated QDs interact with the cell membrane through hydrogen bonding which does not depend on the size of the QDs and leads to the selfaggregation of blood cells without any serious destructive effects (Figure 8).110 It produces several grooves on the membrane111 which are caused by the membrane damage and perforations. Such grooves are the result of hydrogen bond formation between the free COO− groups at the surface of QDs and the lipid membrane. It allows the penetration of QDs among the gaps between the long biopolymer chains and their interactions with outer membrane proteins. Bigger red-emitting QDs show strong ability to form hydrogen bonds with lipids and induce strong conformational changes in lipids.110 They possess the ability to break the phosphate ester bond, which is responsible for the perforations in the lipid membrane. Once the perforations are created, it leads to the leakage of the hemoglobin and hence results in the hemolysis. 2.3.2. Cu 2O NPs. Copper oxide (Cu 2 O) NPs also demonstrate similar semiconducting properties especially as gas sensors and imaging contrast agents in biological systems and other biomedical related procedures where they are expected to be in frequent contact with blood cells.112−114 Their hemolytic activity has been tested by using fish blood.112 They show noticeable hemolysis when treated (160 μg/mL) with fish blood. A comparison between the NP treatment to whole blood and to only the blood cells in buffer demonstrates that whole blood possesses greater ability to reduce the extent of hemolysis in comparison to that of blood cells in buffer (Figure 9). It happens due to the instant adsorption of plasma proteins on the naked NP surface. Both serum albumen and fibrinogen are highly amphiphilic aqueous soluble proteins with inherent ability to adsorb on the naked NPs. It helps the NPs to screen their surface interactions with the cell membrane and

number of charges on the surface of the NPs and their electrostatic interactions with the blood cell membrane. Ammonium-terminated phosphorus dendrimers demonstrate strong interactions with both the hydrophobic part and the polar headgroup region of the phospholipid bilayer which decreases membrane fluidity.84 2.2.2. Comparison between TiO2 and SiO2 NPs. As both silica (SiO2) and titania (TiO2) NPs are the most commonly used materials in biological applications and other commercially available products, their comparative toxic effects need to be addressed. Apart from their colloidal nature, which is considered to be important as far as their drug carrying ability is concerned in the systemic circulation, it has been pointed out that their states of aggregation is an essential aspect in terms of cell internalization.85 All solution phase applications of NPs require their colloidal stability that allows a uniform distribution of NPs in the solution. Generally, smaller NPs produce more stable colloidal solutions in comparison to the larger particles. In the absence of stabilizing agent, even smaller NPs tend to aggregate. The initial state of the NPs, i.e., aggregated or nonaggregated, matters in the event of their interactions with the blood cell membrane. In comparison with the SiO2 NPs, TiO2 NPs tend to agglomerate more often both outside and inside the cell, while porous SiO2 agglomerates slightly more than nonporous SiO2. Hence, porous SiO2 more efficiently incorporated into cells than its nonporous counterparts of the same size.85 In this way, both surface chemistry and surface area influence the NP’s toxicity. A larger surface area results in more toxicity,86,87 in terms of cell-contactable surface area, cell-bound proteins, and cell-associated molecules. Nonporous SiO2 NPs cause the greatest percentage of hemolysis in comparison to that of nonporous TiO2 with practically little hemolytic effect (Figure 7). The difference in hemolytic activity between

Figure 7. Hemolysis after 3 h of exposure to varying concentrations of nonporous SiO2, porous SiO2, and nonporous TiO2 nanoparticles. Reproduced from ref 85. Copyright 2010 American Chemical Society.

nonporous SiO2 and nonporous TiO2 indicates that the material in contact with the cell plays a critical role in toxicity. Nonporous crystalline TiO2 NPs do not alter the cellular machinery that controls granule transport, docking, or fusion unlike nonporous SiO2 NPs.85 Thus, a varying biophysical response indicates that the mechanism of interaction between NPs and cells depends on the nature of material88,89 and accounts for the difference in surface chemistry mainly due to a difference in composition, surface species (hydroxyl groups of TiO290,91 and silanol of SiO2), surface atoms (Ti or Si), and their crystalline or amorphous natures. 1258



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Figure 8. TEM image of CdTe/ZnS QDs. Time (A) and concentration (B) dependences of hemolysis induced by thioglycolic acid stabilized CdTe and glutathione stabilized CdTe/ZnS QDs. Schematic of possible interaction of mercaptosuccinic acid-capped CdTe QDs with blood cell membrane. Schematic reproduced from ref 110. Copyright 2015 American Chemical Society. TEM image and graphs reprinted with permission from ref 101. Copyright 2010 Elsevier.

Figure 9. SEM image of Cu2O NPs. Pictures show the different hemolytic effects after exposure of blood cells in suspension or whole blood to 40 mg/mL Cu2O NPs. Right, dark-field light scattering images of the interaction between Cu2O NPs and blood cells. Many dispersed or aggregated Cu2O NPs are located on the blood cells or internalized by leukocytes after these blood cells were incubated with Cu2O NPs for 3 h. Reprinted with permission from ref 112. Copyright 2013 Springer.

suppress hemolysis is by coating NPs that reduce the interactions between naked surface and cell membrane. Serum albumen is considered to be the best choice because of its coexistence with the blood cells in plasma. Bovine serum albumen (BSA) coated NPs do not show any noticeable hemolysis,17 while other well-known model proteins such as cytochrome c (Cyc,c), lysozyme (Lys), and zein coated NPs result in hemolysis depending upon their degree of interactions with the cell membrane.10−12 A perfect coating of NP surface is usually achieved through a seeding process where the NP surface adsorbed protein leads to its unfolding that in turn attracts other solubilized folded protein through protein− protein interactions.17 In this way, several layers of protein are adsorbed on the NP surface thus completely passivating the free metallic surface. Initially, not all crystal planes of fcc geometry of Au or Ag are equally coated because of the surface preference of the adsorbed amphiphilic protein molecules. Unfolded BSA and zein prefer to adsorb on {100} or {110} crystal planes rather than the {111}. An efficient seeding process slowly blankets the whole NP and thereby suppresses its interactions with the cell membrane. We have observed that protein−protein or protein−bioactive polymer mixtures show even better hemocompatibility rather than the single protein component.11,116,117 A water-soluble protein is not that much surface active as much its protein−protein complexes between

hence reduce the degree of hemolysis. Microscopic analysis shows the presence of Cu2O NPs attached to the blood cell membrane and also present in the cytoplasm of leukocytes (Figure 9). Attached NPs scatter either blue or white light depending on the level of their aggregation. They are also efficiently engulfed by the phagocytes similar to when removing pathogens or foreign organisms from the physiological system. Though cetyltrimethylammonium bromide (CTAB)-coated gold nanorods are rapidly internalized by phagocytes,115 the presence of Cu2O NPs in the cytoplasm of leukocytes (Figure 9) demonstrates another efficient way of phagocytosis which is mainly driven by the adsorption of plasma serum proteins on the surface of Cu2O NPs.

3. HEMOCOMPATIBILITY 3.1. Protein and Bioactive Polymer Coated Au and Ag NPs. As we understand the mode of interactions of different kinds of NPs with blood cells and factors responsible for the hemolysis, it is equally important to understand how to produce hemocompatible nanomaterials for their appropriate use in the systemic circulation. Blood cell membrane mainly consists of lipids and proteins with a small amount of carbohydrates. Lipids and proteins possess high affinity to interact with the bare metallic surface resulting in its deformation and eventually disruption. The best way to 1259



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Figure 10. (a) Variation in the percentage hemolysis by Au NPs with different doses prepared over the entire mole fraction range of lysozyme + Cyc,c and (b) lysozyme + zein mixtures. (c) Snapshot of a DEAE and Peptide 2 complex on the surface of a gold slab. (red, O; blue, N; white, H; yellow, S; black, C). (d) Plots of hemolysis % versus wDEAE for 25 μg/mL (1), 50 μg/mL (2), and 100 μg/mL (3) Au NPs coated with DEAE− protein complex. (c, d) Reproduced from ref 11. Copyright 2015 American Chemical Society. (a, b) Reproduced from ref 116. Copyright 2014 American Chemical Society.

Figure 11. (Left panel) (A) Mesoporous silica NPs coated with phospholipids in contact with the blood cell membrane; significant deformation of the cell membrane, spiculation of the cell, and endocytosis of the particle are not observed. (B) Notice that while there is a slight curvature to the blood cell membrane in the area of the red circle, the overall cell morphology still resembles that of a healthy cell. (Right panel) (A) Mesoporous silica coated with only DPPC, in contact with a spiculated cell. (B) A clear bending of the RBC membrane is also observed at the corner of the particle (highlighted). Reproduced from ref 122. Copyright 2014 American Chemical Society.

the unlike proteins. Such complexes are usually produced to shield the hydrophobic domains from the aqueous phase and hence result in perfect amphiphilic structures most suited for the surface adsorption, that in turn induce negligible hemolysis. The latter is very well depicted by lysozyme−cytochrome and lysozyme−zein mixtures116 over the whole mixing range, while dextran−protein mixtures11 show in the dextran-rich region of the mixtures only (Figure 10). Apart from the protein coating, even conventional biocompatible polymers like poly(vinyl alcohol) and starch coated Ag, Au, and Pt NPs may act as hemocompatible.111 A comparative study indicates that

polymer coated Au and Pt NPs are hemocompatible, while Ag NPs are dose dependent. Exposure of blood cells to Ag NPs induces morphological echinocyte-like changes with numerous surface spikes. The biconcavity is lost, and the blood cells become swollen. Even significant hemagglutination takes place in the presence of starch coated Ag NPs, while poly(vinyl alcohol) coated Au and Pt do not show this. Hemolyzed blood cells show DNA damage due to toxic metabolic byproducts or free radicals generated by the membrane deformation in the event of interactions with NPs. 1260



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Figure 12. (a) Scanning electron micrographs of 200 nm polystyrene spheres attached to blood cells. (b) Representing the detachment of NPs from RBCs in tiny capillaries present in lung microvasculature. Reproduced from 129. Copyright 2013 American Chemical Society.

Figure 13. Scheme of hydrophobic QD encapsulation with poly(maleic anhydride-alt-1-octadecene)−Jeffamine M1000 polymer (QDs 1) and subsequent conjugation of the obtained QDs with Jeffamine M1000 (QDs 2) and Jeffamine ED-2003 (QDs 3) using ethyl-3-(3(dimethylamino)propyl)carbodiimide chemistry. Reproduced from ref 100. Copyright 2016 American Chemical Society.

3.2. PEG and Lipid Coated Silica NPs. Poly ethylene glycols (PEG) show a dramatic impedance in hemolysis when they appropriately coat the NP surface.118−121 The PEG modification on the surface of silica spheres does not alter the ordering of mesopores. Such a coating shows no hemolysis even after 3 h of blood incubation and at high nanoparticle doses (i.e., 1600 μg/mL). It demonstrates that the strong surface passivation by the PEG masks the surface silanol groups and serves as a protective layer. Thus, a simple surface modification strategy ensures the safety and use of PEG coated silica spheres in biomedical applications. It is also possible to make the silica NPs hemocompatible by coating them with a lipid bilayer which has little affinity to interact with the blood cell membrane and hence drastically reduce the hemolysis.122 NPs can be coated with two layer formation where the first one consists of mainly dipalmitoylphosphatidylcholine (DPPC) and the second outer one is composed of a mixture of dipalmitoylphosphatidylserine, DPPC, and cholesterol. It allows the mimicking of the coated layer of NPs to cholesterol, phosphatidylcholine, and phosphatidylethanolamine composition of the cell membrane. Such NPs are considered to be effective immunoadjuvants and carriers of drug delivery devices.123,124 Thus, lipid bilayer coating drastically reduces

the occurrence of hemolysis compared to that of uncoated particles where hemolysis is caused by the interactions between the negative surface charges of the silica NPs and the positively charged choline lipids that are the main components of the outer layer of blood cells. Because of the coating, a significantly less local deformation is noticed in comparison to that of uncoated ones (Figure 11). However, NPs in systemic circulation face removal from the mononuclear phagocytic system, which is a part of the immune system and possesses the ability to rapidly clear NPs from the system.125−128 In order to minimize the clearance, several strategies have been proposed.129 The use of PEG and poloxamer molecules adsorbed or linked to the NP surface demonstrates a dramatic decrease in the NP uptake by the immune system.130,131 Though it activates the immune system and decreases the efficacy, it allows an extended stay of the NPs in the bloodstream for their appropriate biofunctions as drug release vehicles. Alternatively, one can have the conjugation of self-recognition determinant to the surface of NPs,132 which can be carried out by electrostatic and hydrophobic interactions and do not induce hemolysis while attaching to the surface of blood cells (Figure 12). The attachment is reversible and hence provides the ability to transfer the drug load with ease. The rate 1261



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Figure 14. Cell internalization of coated Au NPs without hemolysis. TEM images of (A) PAEA-Au NPs attached onto microvilli, (B) endocytosis of PAEA-Au NPs, (C) endocytosis of PDHA-Au NPs, (D) endocytosis of PEG-Au NPs, (E) endocytosis of PAA-Au NPs, and (F) endocytosis of PNIPAM-Au NPs with zoomed-in views in the insets. All black scale bars represent 500 nm, and the arrows are used to indicate the 20 nm Au NPs. Reproduced from ref 139. Copyright 2011 American Chemical Society.

via passive or active diffusion processes involving both endocytosis and exocytosis.139−141 Because of the size limit for passive diffusion, most nanoscale entities enter the cells by endocytosis.142 The paracellular pathway allows molecules to pass through the tight junctions between the individual epithelial cells (Figure 14).139,143 It has been observed that the positively charged poly(2-aminoethylacrylamide) coated (PAEA) Au NPs prefer to attach to the microvilli of the Caco-2 cells (Figure 14A), while some are trapped inside the endocytic vesicles in the cytoplasm (Figure 14B). Cationic NPs are preferentially attracted to the negatively charged cell membrane,144 while the neutral, i.e., poly(2,3-hydroxypropylacrylamide) and poly(ethylene glycol) coated NPs show relatively lower presence inside Caco-2 cells (Figure 14C and D).145 The hydrophobic poly(N-isopropylacrylamide) (PNIPAM) NPs also show high levels of entrapment within large vesicles. Internalization of anionic poly(acrylic acid), (PAA), NPs is much less in comparison to that of cationic NPs and takes place through the caveolae-mediated process.146 Apart from this, a lower number of NPs passes through the monolayer when the size is large. Such internalization happens without the deformation of the blood cell membrane, usually leading to practically no detectable hemolysis. 3.5. Polymeric NPs. Neutral polymers are usually nontoxic in comparison to the charged polymers and hence considered to be the best choice for therapeutic agents. Hemocompatibility of biocompatible polymeric NPs is another exciting area of research where such NPs can be tested for their hemolytic assay.147 Cationic amphiphilic random methacrylate copolymers exhibit antimicrobial and hemolytic activities which are controlled by maintaining the amphiphilic balance between the amphiphilicity, i.e., cationic functionality, and hydrophobicity.148,149 The predominant hydrophobicity of such polymers is the dominant factor for hemolysis, and it depends on the molecular weight and mole fraction of alkyl side chains.150 Hemolysis is caused by the formation of nanosized pores in the cell membranes followed by colloid-osmosis. Homopolymers display little hemolysis, while some induce aggregation of blood cells or hemagglutination (Figure 15) with large clusters, which is concentration dependent. Increase in the cationic charge density increases the antimicrobial activity of cationic peptides due to their oppositely charged electrostatic interactions with the negatively charged bacterial cell wall. 151,152 Such

of the detachment of NPs from the blood cells is much faster than the rate of their clearance from the systematic circulation, and it depends on the size and location of the attachment to blood cells.129 This mechanism is attributed to the squeezing of blood cells through thin capillaries smaller in diameter than the blood cell mainly located in the pulmonary vasculature. Thus, the blood cell adsorbed NPs demonstrate about 5-fold higher lung accumulation in comparison to that of nonadsorbed NPs and allows the blood cell bound NPs to have longer lifetime in the systemic circulation than the free NPs and does not impede the morphology or functions of the blood cells. In this way, blood cells can perform their natural functions even when harboring the NPs. Such systems can provide new opportunities for therapeutic delivery without the occurrence of hemolysis and blood cell internalization. 3.3. Polymer Coated Iron Oxide NPs and QDs. Relatively few studies have been reported on the hemocompatibility of coated iron oxide NPs and QDs. Hemocompatibility of iron oxide NPs133,134 provides another useful tool for the diagnostic and therapeutic agents in oncology, drug delivery, molecular imaging, and even for hyperthermia treatment. This can be done by achieving dextran coating on iron oxide NPs. The presence of adsorbed dextran film reduces the interactions of iron oxide NPs with the cell membrane and hence prevents hemolysis. CuInS2 based QDs are the most studied heavy metal free NIR nanocrystals of I−III−VI2 type semiconductor QDs.100,135,136 In comparison to CdSe based QDs, CuInS2 based QDs have longer photoluminescence lifetime and can emit in the NIR region, which is an important aspect for in vivo imaging in biological systems. Therefore, they should be safe to incorporate in the biological system with the least cytotoxicity and appropriate hemocompatibility,137,138 as well as their stability against photooxidation. The best way to make them hemocompatible is to coat them with PEG derivitized polymers (Figure 13).100 Different polymer coatings do not differ as far as the red blood cell and platelet size distribution and hemolysis rate are concerned, and hence, they prove to be excellent fluorescent labels for in vivo applications due to their high quantum yield, photostability, and hemocompatibility. 3.4. NPs Cell Internalization without Hemolysis. Cell internalization of NPs can also happen without any occurrence of hemolysis when the size of the NP is so small that it faces little obstruction while passing through the epithelial barriers 1262



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interactions with nanometallic surfaces can be very well evaluated through Raman spectroscopic analysis, which is one of the most powerful tools for the quantitative analysis of blood in its liquid and dried states. It has already been used for the detection of diabetes,154,155 cancer screening,156−159 and cardiovascular and rheumatoid arthritis detections.160 Few studies161,162 have been reported in this direction where whole blood is used on Ag NPs. A thin layer of whole blood dried on Au nanostructured covering SiO2 substrates shows the Surface-Enhanced Raman Spectrum (SERS) mainly due to the proteins, lipoproteins, carbohydrates, and other small molecules found in blood plasma, and no cellular components of blood such as red blood cells, white blood cells, or platelets contribute to the SERS spectrum of whole blood excited at 785 nm.154 A comparison between the Raman spectra of whole human blood in the liquid and dried states compares the vibrational modes of oxygenated and deoxygenated hemoglobin only, and the most significant differences are due to the state of hemoglobin oxygenation. Raman scattering associated with oxygenated hemoglobin dominate the dried blood spectrum, and those of deoxygenated hemoglobin dominate the fresh liquid blood spectrum.163 However, when the SERS is conducted on the nanometallic Au surfaces, different strong vibrational transitions are observed at 490, 639, 895, 1134, 1362, 1569, and 1649 cm−1 in the SERS spectrum (Figure 16) which are practically absent in both the normal Raman spectra of whole blood. Reference154 can be followed for an appropriate assignment of these vibrational bands. This makes a contrasting difference between the SERS and the normal Raman analysis where the latter one is mainly due to the hemoglobin. Thus, for quantitative analysis, SERS is the better candidate where one can have appropriate information about the nature of interactions between the other components of blood apart from hemoglobin and the nanometallic surfaces and hence provides a better understanding of blood interactions with nanomaterials proposed to be used in the systemic circulation as drug release vehicles.

Figure 15. Hemagglutination induced by the homopolymer in different polymer concentrations of 0 (A), 250 (B), and 1000 μg/ mL (C) observed by optical microscopy. The scale bar represents 20 μm. Dose−response curves in hemolysis induced by the polymers and peptide melittin. Reproduced from ref 147. Copyright 2011 American Chemical Society.

interactions are considered to be of lower magnitude with the blood cells due to the presence of a lower number of anionic lipids on the membrane surface.153 Thus, manipulating the ratio of amphiphilicity due to cationic groups and hydrophobicity due to the side alkyl chains helps to optimize the hemocompatibility.

4. QUANTITATIVE ANALYSIS OF HEMOLYSIS: RAMAN SPECTROSCOPY Quantitative chemical analysis of human blood is required for a wide variety of diseases. A conventional way of determining the amount of hemolysis is by using the UV−visible measurements, which provide fairly good analysis of the amount of hemoglobin released by the blood cells upon hemolysis due to its absorption in the visible region. However, quantitative analysis on the basis of various other blood components and their

Figure 16. Normal Raman spectra excited at 785 nm of (a) liquid whole blood in a sealed cuvette and (b) dried whole blood sample are shown in the upper panel. Frequencies of liquid and dried blood samples corresponding to deoxy- and oxyhemoglobin, respectively, are shown in the lower panel. (Right panel) The 785 nm excited (b) SERS spectrum of fresh whole blood compared to (a) normal Raman spectrum of dried whole blood and (c) SERS spectrum of fresh plasma. The peak positions of the bands in the SERS spectrum of fresh whole blood are given in b. Reproduced from ref 154. Copyright 2012 American Chemical Society. 1263



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Figure 17. Systematic mechanism of the action of lactic acid and curcumin in the wound healing process. Reprinted with permission from ref 171. Copyright 2013 Elsevier.

alone.171 The combined activity of both releases the lactic acid and curcumin that dramatically increases the wound healing due to their inflammatory responses, accelerates re-epithelilization, and fresh tissue formation (Figure 17). They do not display cytotoxicity during the wound healing process. Their interactions with blood cells differ and depend on the type of curcumin nanoformulations. Usually, nanocomposites show greater toxicity and result in hemolysis in comparison to other curcumin nanoformulations, while PLGA-curcumin NPs show no sign of hemolysis and have much weaker interactions with blood proteins and blood cells. Instead, when dendrimercurcumin NPs are used, they interact with blood cells and induce a change in the morphology of blood cells that causes a loss of biconcavity of the blood cells. It happens due to the greater degree of penetration of such NPs through the blood cell membranes.175 Different studies176−178 have indicated that curcumin in fact prevents hemolysis, and its use as an ingredient in wound healing dressing is considered to be a much better option. Antioxidant properties of curcumin prevent the blood cells from oxidative damage that results in peroxidation of the membrane lipids and consequently causes hemolysis. When blood cells are treated with curcumin, they show a concentration dependent decrease in level of hemolysis.176 Similar results are obtained when chicken blood is treated with curcumin after inducing oxidative stress by using AAPH. Thus, curcumin significantly attenuates apoptosis and hemolysis in a time and dose dependent manner.177,178 5.2. Nanodiamonds. Among a wide variety of different NPs and QDs, nanodiamonds have attracted a lot of attention because of their effcient imaging and diagnosis,179,180 drug delivery,181−183 and gene therapy184,185 applications. They can be used as an insulin carrier for the wound healing process because it reduces the level of infection and facilitates healing. Insulin can be delivered through the use of nanodiamonds, and its release is triggered and controlled in the basic medium of an infected wound.184 Low concentrations of nanodiamonds are considered better for MTT activity, cell growth, and proliferation of normal human facial skin fibroblasts (Figure

5. HEMOLYSIS IN WOUND HEALING Blood clotting is a process that stops bleeding at the site of injury through a coagulation process which is known as blood clots. Blood platelets are the main components of this process and get activated when a blood vessel wall is damaged in order to prevent bleeding. Apart from the blood platelets, several blood proteins such as collagen and thrombin also participate in blood clotting. Applications of nanobiotechnology in the wound healing process have attracted a lot of attention in terms of its rapid healing in comparison to the usual slow and time-consuming conventional way.164−167 Two main factors are efficiently explored by using appropriate NPs in conjunction with wound dressing, i.e., proper aeration in the wound dressing process and antimicrobial response to speed up the healing process. In order to achieve this, NPs are used as hybrid materials in wound dressing where they directly come in contact with the blood cells from broken blood vessels and are subjected to interaction with blood cells. This may lead to additional hemolysis if an inappropriate concentration of NPs is used. Therefore, this aspect needs attention in terms of hemolysis induced by the NPs during the wound healing process, and precautions should be taken to minimize the hemolytic effects. Different kinds of NPs have been used in the wound dressing process, and most important among them are the curcumin,168−171 Ag NPs,172−174 and nanodiamonds in view of their known antimicrobial properties. 5.1. Curcumin NPs. Curcumin, 1,7-bis-{3-methoxy-4hydroxyphenyl}-1,6-heptadiene-3,5-dione, is an active ingredient of turmeric and is a potent anti-inflammatory and cancer preventative molecule. The wound healing process is significantly accelerated when it is treated with curcumin.171 Curcumin NPs are wound healing and antimicrobial agents. They accelerate the wound healing process through multiple biological mechanisms. However, curcumin−poly lactic-coglycolic acid (PLGA) hybrid NPs are considered to be better wound healing agents. Wound healing in a mouse model shows that PLGA-curcumin NPs cause an increase in the acceleration of wound healing compared to PLGA or curcumin NPs 1264



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Figure 18. Effects of a short-term exposure of FSF1 cells to nanodiamonds (ND) and SiO2 NPs in terms of growth and proliferation (A) and wound healing ability (B and C). Reprinted with permission from ref 186. Copyright 2016 Elsevier.

Figure 19. (1) FESEM images of (a) hydrogel and (b−d) hydrogel−Ag NPs with different magnification; (d) inset shows a TEM image of Ag NPs detached from the hydrogel−Ag NPs. Reproduced from ref 172. Copyright 2016 American Chemical Society. (2) (A) Photographs of chitosan dressing (CS), Ag NPs solution, and Ag NPs/chitosan dressing. (B) SEM images of CS (b1) and CS-Ag NPs (b2 and b3, white arrows in b3 indicate the Ag NPs). (C) TEM image and (D) EDX spectrum of AgNPs of CS-Ag0.2 dressing. Reproduced from ref 192. Copyright 2016 American Chemical Society. (3) Size dependent hemolytic activities of Ag NPs. (a) Photographs of blood cells after exposure to three sizes of Ag NPs for 2 h. (b) Percentage of hemolysis. Reproduced from ref 13. Copyright 2015 American Chemical Society.

nonspherical polyhedral shapes are more likely to induce hemolysis than the spherical shape. 5.3. Ag NPs. Keeping in view the antimicrobial properties of Ag NPs, they have been frequently used in the wound healing process.173,190,191 Their nanocomposites in antifouling zwitterionic hydrogels as wound healing dressing keep the environment moist and hence improve the wound healing process by preventing cellular dehydration (Figure 19(1)).172 The antifouling properties reduce the potential wound infections by minimizing bacterial growth. The dressing itself is hydrophilic, resistant to protein adsorption, bacterial adhesion, and cell attachment. It leads to an increase in the rate of wound healing because of the greater surface area provided by Ag NPs. This study172 was conducted on rats by dividing them into

18). No cell death occurs during the treatment of facial skin fibroblasts cells.186 Wound closure is accelerated by 75% when it is treated with nanodiamonds and hence results in the cell proliferation which contributes to wound healing. However, increased proliferation and accelerated wound healing are also prone to several pathophysiological events when a high dose of nanodiamonds is used, and this can lead to an increase in oxidative stress and DNA fragmentation.187,188 In relation to hemolysis, nanodiamonds change the kinetics of active oxygen generation, causing white cell destruction and erythrocyte hemolysis.189 Various mechanisms of the observed effects have been considered. Among them, the “shape and size” of the NPs are an important aspect for blood cell membrane damage, and 1265



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Figure 20. (a) Potential energy diagram of colloidal stability. (b) Unstable colloidal particles with predominate Vvan der Waals. (c) colloidal stabilization by an electrical double layer of ionic cloud, (b) of ionic surfactants, and (c) steric stabilization by biomacromolecules. (f) Incorporation of NPs in hydrogel matrix for wound healing dressing.

three groups; without dressing, with hydrogel, and with Ag NPs embedded in the hydrogel. The percentage of wound size reduction is maximum for Ag NP−hydrogel in view of its biocompatibility, antibacterial properties, and noncytotoxicity properties. Similarly, biocomposites of Ag NP-chitosan can be mold into hydrogels, membranes, and sponges which can act as suitable platforms for wound dressing with asymmetric wettability surfaces possessing excellent water absorbing as well as water repelling properties (Figure 19(2)).192 The purpose of using Ag NPs embedded in the chitosan sponge is to simply increase the antibacterial activity. By using stearic acid, it is possible to make one side of the chitosan sponge a hydrophobic surface that can resist bacterial infiltration and foreign particle adhesion properties, while the other hydrophilic surface induces the cell growth with faster results and lower levels of silver accumulation. Application of such a type of dressing allows the hydrophilic surface to be in contact with the wound so as to protect it from bacterial infection while the opposite hydrophobic surface keeps moisture entrapped. Practical use of this dressing indicates that it can completely heal the wound within 8 days. However, as far as the toxicity of Ag NPs is concerned, the amount of Ag NPs accumulated in blood, liver, kidney, and spleen is estimated. It is 0.01 μg/mL of silver found in the blood after 14 days. Instead of Ag NPs, another biocomposite of ZnO NPs-chitosan, castor oil for wound dressing, possesses similar properties where ZnO− chitosan specifically works against the Gram positive cells, and chitosan mainly acts as a hemostatic agent and stimulates healing.166 It binds with red blood cells, allowing rapid blood clotting, and also modulates the functions of inflammatory cells and subsequently encourages granulation and organization.193

Although Ag and ZnO nanocomposites work well in wound dressing and induce minimum hemolysis, Ag and ZnO NPs alone are known for their hemolytic activities. Therefore, in addition to the antimicrobial properties of Ag NPs, care must be taken while using the Ag NPs in wound dressing because of their significant toxic effects associated with cell membrane injury,13 DNA damage,194 inhalation, and cardiovascular system diseases.195,196 The size of Ag NPs is a critical factor that is the driving force of their interactions with blood cells. It also influences toxicity and uptake efficiency. Smaller Ag NPs induce greater hemolysis as compared to larger NPs (Figure 19(3)).13 The negatively charged silver surface makes it highly reactive and allows it to interact with the organic cations in the membrane of red blood cells.196 Similarly, ZnO NPs, though they may possess antimicrobial properties just like those of Ag NPs, they also induce dose dependent hemolysis.197

6. BIOCOLLOIDAL NATURE OF NANOMATERIALS IN BIOMEDICAL APPLICATIONS Applications of nanomaterials in systemic circulation as well as for wound dressing are closely associated with their biocolloidal nature. Blood is an aqueous solution of high viscosity which is forced through the systemic circulation by the forceful pumping mechanism of the heart. Thus, physiochemical properties of nanomaterials as biocolloids are the driving forces for their appropriate uses as drug delivery vehicles, i.e., while in the systemic circulation, nanomaterials must possess colloidal behavior so that their drug load carrying ability and photophysical properties are fully exploited. Colloidal behavior requires a delicate balance between the electrostatic repulsions and van der Waals forces of attraction operating between the 1266



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Figure 21. Schematic representation of coated (a) and mesoporous (b) NPs depicting the release of drug load. (c) Blood vessel carrying hemocompatible coated NPs in blood fluid as well as on blood cells for targeted delivery.

NPs, and it is given by the total potential VT = Velectrostatic + Vvan der Waals (Figure 20a). If the van der Waals forces predominate, they lead to coagulation among the NPs (Figure 20b), and hence, they cannot be used as drug delivery vehicles or biomarkers. In order to achieve colloidal suspension, NPs must overcome van der Waals forces of attraction. It can be done by creating an electrical double layer and/or steric stabilization. An electrical double layer is achieved when a NP is coated with polar molecules such as ionic surfactants198,199 that provide a net positive or negative charge to NPs (Figure 20c,d), whereas a coating of water-soluble neutral macromolecules such as polymers, proteins, or carbohydrates provides steric stabilization (Figure 20e).200−202 The latter is considered to be a better option in comparison to the former because the net charge on the NP surface triggers their interactions with the blood cell membrane that may result in hemolysis. In addition, neutral bioactive macromolecules such as PEG derivatives and serum albumin are known for their minimum hemolysis and are capable of completely passivating the NP surface. However, the stability of the colloidal suspension is further related to the size of the colloidal particles. Smaller NPs provide more stable colloidal suspensions rather than the bigger ones and hence allow greater surface area to carry a larger drug load. The smaller size also helps in fine-tuning the photophysical properties and hence provides a wide spectrum for their applicability in biological systems as biomarkers. Both drug carrying ability and spectroscopic behaviors can be appropriately quantified when the NPs exist in the monodisperse state, which is further related to their synthesis. In situ reaction conditions provide an opportunity for the neutral bioactive molecules to adsorb on the growing crystal planes of nucleating centers of crystalline NPs. That in turn controls the crystal growth to a desired shape and size, and achieves the required colloidal stability. Since most of the bioactive molecules are not good shape directing agents like surfactants, it is usually difficult to achieve a desired monodisperse morphology under in situ

reactions conditions. However, some bioactive macromolecules like phospholipids, BSA, and zein have demonstrated their excellent potential in achieving shape controlled morphologies just like those of conventional surfactants.203 Wherever an in situ synthesis of nanomaterials works, it produces fine coated NPs most appropriate for their applications in systemic circulation provided they induce minimum hemolysis. Otherwise, surfactant directed synthesis can be used to produce the desired morphologies of crystalline NPs that produce surfactant coated NPs204−206 which cannot be directly used in the systemic circulation unless another coating of hemocompatible molecules is used to fully passivate the surfactant coating. Thus, colloidal stability is an essential parameter for plentiful applications in systemic circulation. The biocolloidal nature of biocompatible nanomaterials207−209 is also an essential component for their applications in wound healing dressing where they have to be homogeneously mixed with the hydrogel network (Figure 20f). Only the monodisperse colloidal NP suspension can be appropriately and uniformly incorporated into the hydrogel in order to achieve a proper compatibility between the pore size and NPs dimensions. Several factors participate in this coexistence. For water-soluble NPs, it is the hydrophilicity of the hydrogel which favorably incorporates the colloidal NPs into the network structure due to different kinds of interactions. Biocompatible coated NPs can be much easily incorporated in the hydrogel network due to hydrogen bonding or site specific electrostatic interactions. Thus, uniform distribution of the colloidal NPs reinforces and provides maximum surface area to the wound healing dressing in terms of its hydration, aeration, and antimicrobial response.

7. FUTURE PERSPECTIVES 7.1. Model Systems. Recent advances indicate that the target drug delivery proposed through the systemic circulation is highly results oriented, cost-effective, and a rapid cure. 1267



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ing the NPs which accelerate the wound healing process where mostly naked NPs are used. Naked NPs favorably interact with blood cells and are known to induce hemolysis. In order to minimize hemolysis during the wound healing process, it is better to use the coated NPs by choosing biomolecules with their antimicrobial properties. Coated NPs are expected to incorporate in a much better manner in the three-dimensional network of the hydrogel rather than naked NPs. Coated molecules can act as binders to hydrogel cavities through the specific or nonspecific interactions that in turn allow a uniform distribution of NPs throughout the bulk phase. Such NPs can reinforce and support the hydrogel matrix in a much better manner than the naked NPs and simultaneously provide an effective antimicrobial environment with minimum hemolysis.

Nanomaterials are the ideal vehicles for target drug delivery. They can deliver only the required amount of the drug with maximum efficiency. All nanomaterials possess different levels of abilities to interact with blood cells and other components of the systemic circulation. Since blood is a complex fluid, result oriented applications need a proper understanding of interactions between the nanomaterials and the blood cells. Several characteristic features of nanomaterials govern their interactions with the blood cells which are the direct consequence of hemolysis. Among them, size, shape, and composition are the most prominent factors that significantly influence the degree of hemolysis. The best way to make them hemocompatible is to coat them with bioactive molecules which do not induce hemolysis (Figure 21). A majority of these species are bioactive macromolecules such as phospholipids, proteins, and polysaccharides. The coated nanomaterials thus produced can only be used as the best drug delivery vehicles if they are stable biocolloids in the aqueous bloodstream. Hence, their colloidal stability is another important parameter that has to be maintained throughout their journey in the bloodstream. Colloidal stabilization is best achieved by keeping the nanomaterial size as small as possible so that it has significant size disparity with the cells at the target site. Smaller size possesses a greater ability to carry a large drug load with a better distribution at the target site. The small size of nanomaterials may allow them to be easily cleared from the bloodstream by the immune system though it is not that clear how it happens. This can be prevented again by using hemocompatible biomolecules that would resist their clearance by the immune system and would increase their overall life span which may be helpful in contributing toward the booster dose. Thus, hemocompatibility and longer life spans are considered to be the most important factors for the applications of nanomaterials in the systemic circulation (Figure 21). 7.2. Materials for Drug Carrying Abilities. Among various nanomaterials, mesoporous NPs and QDs are highly promising nanomaterials. Mesoporous NPs are ideal carriers for a large drug load, while QDs are efficient fluorescent markers. Though several studies focused on various aspects of mesoporous nanomaterials in terms of their shape and size, crystalline or noncrystalline surface properties, and pore size, all mesoporous nanomaterials induce hemolysis of different scales. Coating them may reduce hemolysis significantly, but it may impede their drug loading ability. However, an appropriately designed hemocompatible pharmaceutical formulation that can be carried through the nanopore channels may be simply used with the uncoated mesoporous NPs. On the other hand, QDs can prove to be excellent drug carriers because of their small size and excellent photophysical properties, but little attention has been paid to such applications until now due to their highly cytotoxic nature. Appropriately coated hemocompatible QDs may prove to be excellent drug delivery vehicles and biomarkers in biological systems, and hence, new synthetic methods for the synthesis of hemocompatible QDs need to be designed. Thus, both mesoporous nanomaterials and QDs can prove to be excellent drug delivery vehicles in the systemic circulation. 7.3. Nanomaterials for Wound Healing Dressing. Most of the studies related to the applications of nanomaterials in the wound healing process are primarily related to their antimicrobial effects, and systematic detailed studies on the hemolytic behavior of nanomaterials in wound dressing are still lacking. The main emphasis in wound dressing is laid on the several compositional aspects of wound dressing by incorporat-

8. CONCLUDING REMARKS In summary, it is concluded that nanomaterials possess enormous potential in nanomedicine as drug delivery vehicles in the systemic circulation for rapid and fast cure of various critical illnesses. However, this exciting area needs more indepth analysis in terms of hemolysis that could be induced by various nanomaterials used as drug delivery vehicles. This account focuses on various characteristic features of different kinds of nanomaterials which may induce a high degree of hemolysis. The nature of the nanomaterials, their shape and size, and surface functionalities are the most prominent factors that drive the hemolysis. It is possible to minimize hemolysis by taking these factors into consideration while designing such materials for their possible applications in systemic circulation. Another aspect to make a nanomaterial hemocompatible is by coating it with appropriate biomolecules such as serum proteins or PEG which can synergistically exist with the blood cells. In addition, applications of nanomaterials in wound healing dressings as antimicrobial agents also induce hemolysis where they directly come in contact with the open blood vessels. Thus, instead of using naked nanomaterials, it is desirable to use hemocompatible nanomaterials as antimicrobial agents in wound dressings.

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AUTHOR INFORMATION

Corresponding Author

*Tel: 920-465-5169. E mail: [email protected]. ORCID

Mandeep Singh Bakshi: 0000-0003-1251-9590 Notes

The author declares no competing financial interest. Biography

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(15) Upadhyay, J., Kumar, A., Gogoi, B., and Buragohain, A. K. (2015) Antibacterial and Hemolysis Activity of Polypyrrole Nanotubes Decorated With Silver Nanoparticles by an in-Situ Reduction Process. Mater. Sci. Eng., C 54, 8−13. (16) Rujanapun, N., Aueviriyavit, S., Boonrungsiman, S., Rosena, A., Phummiratch, D., Riolueang, S., Chalaow, N., Viprakasit, V., and Maniratanachote, R. (2015) Human Primary Erythroid Cells As a More Sensitive Alternative in Vitro Hematological Model for Nanotoxicity Studies: Toxicological Effects of Silver Nanoparticles. Toxicol. In Vitro 29, 1982−1992. (17) Bakshi, M. S. (2011) Nanoshape Control Tendency of Phospholipids and Proteins: Protein Nanoparticle Composites, Seeding, Self-Aggregation, and Their Applications in Bionanotechnology and Nanotoxicology. J. Phys. Chem. C 115, 13947−13960. (18) Fontana, F., Mori, M., Riva, F., Makila, E., Liu, D., Salonen, J., Nicoletti, G., Hirvonen, J., Caramella, C., and Santos, H. l. A. (2016) Platelet Lysate-Modified Porous Silicon Microparticles for Enhanced Cell Proliferation in Wound Healing Applications. ACS Appl. Mater. Interfaces 8, 988−996. (19) Comfort, K. K., Maurer, E. I., Braydich-Stolle, L. K., and Hussain, S. M. (2011) Interference of Silver, Gold, and Iron Oxide Nanoparticles on Epidermal Growth Factor Signal Transduction in Epithelial Cells. ACS Nano 5, 10000−10008. (20) Pourali, P., and Yahyaei, B. (2016) Biological Production of Silver Nanoparticles by Soil Isolated Bacteria and Preliminary Study of Their Cytotoxicity and Cutaneous Wound Healing Efficiency in Rat. J. Trace Elem. Med. Biol. 34, 22−31. (21) Krausz, A. E., Adler, B. L., Cabral, V., Navati, M., Doerner, J., Charafeddine, R. A., Chandra, D., Liang, H., Gunther, L., Clendaniel, A., Harper, S., Friedman, J. M., Nosanchuk, J. D., and Friedman, A. J. (2015) Curcumin-Encapsulated Nanoparticles As Innovative Antimicrobial and Wound Healing Agent. Nanomedicine 11, 195−206. (22) Chowdhury, N. A., and Al Jumaily, A. M. (2016) Regenerated Cellulose/Polypyrrole/Silver Nanoparticles/Ionic Liquid Composite Films for Potential Wound Healing Applications. Wound Medicine 14, 16−18. (23) Asefa, T., and Tao, Z. (2012) Biocompatibility of Mesoporous Silica Nanoparticles. Chem. Res. Toxicol. 25, 2265−2284. (24) Naik, S. P., Elangovan, S. P., Okubo, T., and Sokolov, I. (2007) Morphology Control of Mesoporous Silica Particles. J. Phys. Chem. C 111, 11168−11173. (25) Yano, K. (2015) Hollow Metal-Incorporated Monodispersed Mesoporous Silica Spheres. Langmuir 31, 8774−8779. (26) Zhang, H., Dunphy, D. R., Jiang, X., Meng, H., Sun, B., Tarn, D., Xue, M., Wang, X., Lin, S., Ji, Z., Li, R., Garcia, F. L., Yang, J., Kirk, M. L., Xia, T., Zink, J. I., Nel, A., and Brinker, C. J. (2012) Processing Pathway Dependence of Amorphous Silica Nanoparticle Toxicity: Colloidal Vs Pyrolytic. J. Am. Chem. Soc. 134, 15790−15804. (27) Brinker, C. J., and Scherer, G. W. (1990) In Sol-Gel Science: The Physics and Chemistry of Sol-Gel Processing, Academic Press, San Diego, CA. (28) Iler, R. K. (1979) The Chemistry of Silica, John Wiley and Sons, New York. (29) Fubini, B., and Hubbard, A. (2003) Free Radical Biol. Med. 34, 1507−1516. (30) Schoonen, M. A. A., Cohn, C. A., Roemer, E., Laffers, R., Simon, S. R., and O’Riordan, T. (2006) Rev. Mineral. Geochem. 64, 179−221. (31) Stöber, W., Fink, A., and Bohn, E. (1968) Controlled Growth of Monodisperse Silica Spheres in the Micron Size Range. J. Colloid Interface Sci. 26, 62−69. (32) Lin, Y. S., and Haynes, C. L. (2010) Impacts of Mesoporous Silica Nanoparticle Size, Pore Ordering, and Pore Integrity on Hemolytic Activity. J. Am. Chem. Soc. 132, 4834−4842. (33) He, Q., Zhang, Z., Gao, Y., Shi, J., and Li, Y. (2009) Small 5, 2722−2729. (34) Diociaiuti, M., Bordi, F., Gataleta, L., Baldo, G., Crateri, P., and Paoletti, L. (1999) Environ. Res. 80, 197−207. (35) Razzaboni, B. L., and Bolsaitis, P. (1990) Environ. Health Perspect. 87, 337−341.

Dr. M. S. Bakshi is Assistant Professor in the Department of Chemistry, UWGB, Green Bay, WI, USA. He received his Ph.D. in Chemistry from Panjab University Chandigarh, India in 1991. He taught at the Department of Chemistry, Guru Nanak Dev University, Amritsar, India, from 1996 to 2008. He was a visiting professor at Science University of Tokyo and California State University, Northridge, and worked on collaborative research projects related to biocolloids and bionanomaterials. His work is in the field of nanotechnology, and his main focus is on bionanomaterials and their applications.

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