Cardiac Tissue Engineering on the Nanoscale - ACS Publications

Review Cite This: ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Cardiac Tissue Engineering on the Nanoscale Ranjith Kumar Kankala,†,‡,§ Kai Zhu,†,⊥,|| Xiao-Ning Sun,*,⊥,|| Chen-Guang Liu,‡ Shi-Bin Wang,‡,§ and Ai-Zheng Chen*,‡,§ ‡

Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, P. R. China Fujian Provincial Key Laboratory of Biochemical Technology, Xiamen 361021, P. R. China ⊥ Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China || Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, P. R. China §

ABSTRACT: In recent years, the fabrication of smart materials at an arbitrary gauge has attracted enormous interest from researchers in the tissue engineering (TE) field. This potential tool has been utilized for the generation of various biomimetic/bioinspired structures to repair and improve the performance of the injured tissues. Cardiac TE is one of them that offers immense benefits in treating various cardiovascular diseases, such as myocardial infarction (MI). Currently, various nanoparticles have been utilized alone or by incorporating them in hydrogels or other biomimetic scaffolds to mimic the morphological and electrophysiological characteristics of native cardiac tissue for a better regenerative outcome. Herein, we aim to give a brief overview, which provides an emphasis and discussion of the latest reports on these innovative nanoconstructs intended for cardiac TE. Finally, we summarize the existing challenges and prospects of the cardiac TE field. KEYWORDS: biomaterials, hydrogels, myocardial infarction, nanoparticles, tissue regeneration

1. INTRODUCTION Recently, nanotechnology has attracted increasing interest from researchers in various fields for designing smart materials that have better performance.1 This interdisciplinary field involves the engineering of materials at the molecular scale (approximately in the 1−100 nm size regime in at least one dimension)1 and has been applied widely in many areas such as electronics, biomedical fields, and others.2,3 The resultant ultrasmall components (1−100 nm) exhibit a wide variety of tunable physicochemical properties, such as electronic (interplay between charge transfer), magnetic, mechanical (potential superplasticity, high strength, toughness, and ductility), and optical (refractive indices, color, photoactive effects), among others.3−8 More often, the aforementioned desired properties of nanomaterials could exist either in the intermediate or final form of the designed construct.9 In recent years, tremendous progress has been evidenced by advancements in developing innovative biomaterials using various methods of nanotechnology.8,10 Furthermore, these versatile materials have been utilized for a better understanding of the molecular mechanisms that are relevant to the nanobiointerface, i.e., binding interactions between cell receptors/ligands of the extracellular matrix (ECM) and engineered nanomaterials.5,10−12 Cardiovascular diseases (CVDs) are the most burdensome health concerns that are caused due to various reasons, including health factors (blood pressure, high amounts of low-density cholesterol, glucose imbalance) and health © XXXX American Chemical Society

behaviors (lack of physical activity, improper diet control, energy imbalance).13−15 Myocardial infarction (MI), commonly known as heart attack, is one of the most lethal conditions of CVDs13,16 and results from the sudden restriction of blood flow in coronary arteries to the myocardium, which leads to the dysfunction or death of cardiomyocytes.14,16 The inability of myocardium to regenerate after infarction has led researchers toward the development of various therapeutic strategies.17,18 In this way, new treatment modalities, including stem cell-based therapy for paracrine factor delivery and engineered preparations of cardiac tissue, have been aimed at guiding cardiomyocyte growth, differentiation, and tissue organization.19−21 The concept of cell-based therapy to increase the cardiomyocyte population was first developed in the early 90s.22 Since then, various cell types that include skeletal myoblasts, and stem cells such as endothelial progenitor cells (EPCs), hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs), have been immensely utilized for cardiac repair. These cells have been shown to act through an upsurge in tissue perfusion, reduction in infarct size, and improvement in cardiac function.23 Furthermore, other cell types such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), have also been successfully explored for the cardiogenic differentiation.24,25 In addition to the cardiomyoReceived: December 12, 2017 Accepted: February 2, 2018 Published: February 2, 2018 A

DOI: 10.1021/acsbiomaterials.7b00913 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

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ACS Biomaterials Science & Engineering

Figure 1. Schematic illustration of the important classes of nanoparticle-based formulations for cardiac TE. Abbreviations: CNTs, carbon nanotubes; GNPs, gold nanoparticles; GNRs, gold nanorods; GO, graphene oxide; IONPs, iron oxide nanoparticles; MSNs, mesoporous silica nanoparticles; PCs, polymeric carriers.

In recent years, significant progress has been evidenced by advancements of TE in recreating the bioinspired microenvironment of cardiac tissues for repairing damaged myocardium.19,20,28,38 During the preparation of biomimetic tissues, the anatomy of the environment at an arbitrary gauge is considered from the macroscale (at the organ level), to the microscale (at the cellular and tissue level) and the nanoscale (the molecular level), which plays a crucial role in tissue maturation and significant functional improvement.11 Despite the significant advancements in the TE, macro- as well as microsized scaffolds still face challenges, such as inadequate cell migration into the scaffolds, limited electrical coupling at the gap junctions between adjacent cells, and inability to mimic the highly organized, complex architecture of the native myocardium.14,39,40 In this scenario, the ascertained curbs of components at the microscale and above have led the engineers and chemical biologists in search of new approaches and technologies for fabricating nanosized components to improve the performance of 3D biomimetic tissues.40 Their unique structure enables the rapid propagation of action potentials in the cardiomyocytes and active synchronous contractions in the engineered tissues.40 In addition to action potential propagation, these nanostructures guide the cardiomyocyte for its growth and differentiation during the regeneration process, and further improvements can be made by altering their intrinsic molecular properties.9,40 Despite several reviews published on the potential of TE, very few focused on utilizing this innovative technology in treating CVDs.16,19,40−45 Here, we present an overview to recapitulate the effect and importance of the nanostructured components on cardiomyocyte behavior and tissue formation. Then, we give an emphasis and discussion on various nanomaterials, such as carbon-based nanomaterials (carbon nanotubes (CNTs) and graphene oxide (GO)), gold nanoparticles (GNPs), iron oxide nanoparticles (IONPs), mesoporous silica nanoparticles (MSNs), and polymeric carriers (PCs), applied alone or in combination with polymeric scaffolds or injectable materials in cardiac tissue regeneration

cyte regeneration, it is important to discuss regarding the other cell types that are responsible for coronary vascularization. The cell types include vascular endothelial cells (ECs) and smooth muscle cells (SMCs), which are accountable for the formation of inner lining and wall of blood vessels, respectively. These cell types play a crucial role in developing a new network of vascular tissues that supply nutrients and oxygen to the myocardium leading to vessel anastomosis with the host vasculature for proper functioning of the heart.26,27 These promising strategies have unlocked the potential of the cells and their three-dimensional (3D) functional microenvironment to recreate tissue that mimics the native myocardium.14 Tissue engineering (TE) has garnered significant attention due to the upsurge of the demand for organ replacement therapies and a shortage of donated organs.28−30 Conceptually, the malfunctioning or damaged tissues or organs will be replaced by artificial biological substitutes to improve or restore the function. This field has already shown a great promise in treating various ailments such as cancer, diabetes, cardiovascular conditions, osteoarthritis, skin burns, and various traumatic injuries.31 This field integrates various disciplines such as biology, chemistry, engineering, and material science, among others, for the preparation of functional tissue substitutes while considering various biochemical as well as physiochemical factors.29,32 In the past few decades, tremendous progress has been evidenced by advancements in various techniques for generating highly organized and functional 3D constructs since the native tissues exhibit a 3D complex architecture that is composed of ECM, different cell types, and various signaling cues.33,34 More often, the cells or biochemical cues are embedded into the biomimetic tissue substitutes, including nano/micro-fibrous biocompatible scaffolds, photo-cross-linkable hydrogels, and 3D biodegradable porous scaffolds.9,33,35−37 The use of these scaffolds with the desired architecture often constitutes an important prerequisite of TE to repair or improve control over the microenvironment for tissue growth.19,33 B


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Figure 2. Schematic illustration representing the different approaches of cardiac TE (hydrogels, fibrous scaffolds, and biomimetic constructs via LbL assembly method) and the internalization of nanocarriers into the cardiomyocyte. Abbreviations: LbL, layer-by-layer; TE, tissue engineering.

space with a high surface area of intimacy for the organization and growth of cells during tissue regeneration.9,19 In addition, other factors are considered, such as hydrophobicity, feature size, the radius of curvature, charge, and coatings, which dictate the regeneration capacity of the formulation.19,53 Several approaches have been explored to alter the physicochemical properties of nanomaterials for better performances.14,19,30,32,33,36,40,42,51,54 More often, the surface of the nanoparticles is functionalized with the organic linkers for the immobilization of biochemical signals (i.e., ligands).42 In addition, these versatile organic linkers improve the hydrophobicity/charge of the nanomaterials and enhance the interactions between the nanoparticles and the cardiomyocytes. For example, CNTs possess better control over the degree of surface functionalization and endow immobilized active groups for cell-adhesion requirements in the ECM by improving the receptor−ligand interactions and modulation of the microenvironment.9,42,52,54 Moreover, the organization of nanomaterials for cell/drug delivery significantly alters the regeneration process through nanoparticle-cardiomyocyte interactions. The arrangement of the regenerative constituents can be achieved better through various approaches such as nanoparticleentrenched hydrogels, nanofibrous scaffolds, and LbL assembly of nanocomplexes. 2.1. Hydrogels. Hydrogels are typically formed by gelation of polymer chains via different cross-linking methods, and they are widely used in many areas, including regenerative medicine, drug delivery, soft electronics, and actuators.9,55−57 The waterrich nature of hydrogels makes them accelerate electrical signals by enhancing the cellular excitability of both cardiomyocytes and neurons, which endorses the cell differentiation and their long-term survival.9,11,12,58 In one case, Davis et al. prepared an injectable formulation of self-assembling peptides, which created a nanofibrous environment within the myocardium by recruiting vascular ECs and promoting their survival and organization.59 In addition, they improved cardiac function by prolonged delivery of insulin-like growth factor-1 (IGF-1), a cardiomyocyte growth and differentiation factor in the myocardium, for more than 28 days.60 Despite the significant regeneration capacity of self-assembled hydrogels, these cell-laden constructs still lack proper electrical

(Figure 1). In addition, we discuss various methodologies of the fabrication of nanoparticles, highlighting their advantages as well as constraints of processing.

2. IMPORTANCE OF NANOSTRUCTURED COMPONENTS In the native heart, the Purkinje fibers or subendocardial branches exert conductivity through propagating electrical communication between adjacent cells.34 During MI, the engineered cardiac tissues (ECTs) are utilized to retain the electrical conductivity of the cardiac tissue. However, the current ECTs lack the anticipated levels of electrical conductivity.34 Indeed, the integration of nanotechnology with ECT offers enormous potential and opportunities for the functional improvement and structural restoration of cardiac tissues. In fact, the microenvironment of native tissues is highly organized, with abundant nanofibrous elements such as collagen, elastin, and others, which significantly guide the cell behavior.9,11 In addition, preceding reports on biomimetic scaffolds have indicated that cardiomyocytes respond profoundly to the 3D topology of encapsulated nanoparticles.11,19,32 Moreover, the intrinsic molecular properties of nanoparticles alter the spatiotemporal arrangement of their extracellular cues.11,14,40,46 Various nanosized biomimetic structures have been utilized for the tissue regeneration process through cell/drug delivery, such as electrospun scaffolds, selfassembling peptides, peptide amphiphiles, and layer-by-layer (LbL) complexes (Figure 2).9,11,14,19 Other nanostructured components, such as CNTs, GO, GNPs, IONPs, MSNs, and PCs, are also utilized, which are of particular interest for improving the electrical conductivity and delivery of cardioprotective drugs.33,35−37,42,44,46−52 Indeed, the encapsulation of nanomaterials within the biomimetic tissue construct is highly advantageous due to their high surface-to-volume ratio, malleability, tunable sizes, and shapes with a desired 3D pattern and provides a convenient way to regulate the biochemical as well as mechanical cues in the cardiac microenvironment.23,24 Furthermore, these materials make themselves acquiescent to adsorbing the proteinaceous constituents in the ECM and provide an appropriate 3D C


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long-term survival of cells. Together, these multilayered hierarchical nanoassemblies with excellent conductive properties mimic the electrophysiological environment of the native heart.40 In addition to various scaffolds and nanoconstructs used in cardiac TE, some other key elements need to be considered carefully during engineering the cardiac tissue constructs. In this context, we highlight the fundamental concepts that should be taken into account, in addition to the poor regeneration ability of cardiomyocytes. The first key consideration is that the alignment of cardiomyocytes and their arrangement into tissue bundles characterized by spontaneous and synchronous contraction further intricate the development of biorelevant cardiac tissues.26 However, the strategy of organizing the cardiomyocytes into biological tissue bundles should be explored for elucidating their performance efficiency. Second, the generation of dense cardiac tissue constructs apparently requires the vascular networks to supply nutrients and oxygen, remove waste products and carbon dioxide, and eventually promote the vessel anastomosis with the host vasculature.26 Therefore, it should be noted that the vascularized networks are one of the important features of ECTs for their efficient clinical performance. Third, while constructing ECTs, the nanosized materials intended for the delivery of cardioprotective agents or sensitizing the surface of cardiomyocyte for cell−cell coupling or enhancement of synchronous contractions, are required to be efficiently internalized by cardiomyocytes to promote the cellular functions.19,32,51 In addition, the interactions between the cardiomyocyte surface and intrinsic molecular structure of encapsulated nanoparticles play a crucial role in cardiomyocyte activation and alter the spatiotemporal arrangement of their extracellular cues.11,19,51 Moreover, the interfacing allows changes in the scaffold morphology and results in the proliferation of cells, differentiation and eventually maturation into a cardiac lineage.52,69−71 Though, tremendous progress in the past decade has been evidenced by the advancements in developing various nanoconstructs for ECTs; it is worth mentioning an innovative strategy of producing versatile nanoparticles that are modified with “do-not-eat-me” peptide on their surface.72,73 These surface-modified peptides offer numerous benefits, including improvement of their biocompatibility, cell targeting ability, and ease of internalization. Although these cell-membrane fragments-coated biomimetic nanoparticles have shown potential in delivering drugs and other biomedical applications, deep analyses of these surface engineered innovative constructs on cardiac TE remain to be explored.72,73

conductivity in a few cases. To overcome this limitation, electroactive nanoparticles such as CNTs have been incorporated during cell culturing and cell sheet preparation to accelerate the electrical conductivity of the hydrogel construct. In addition, these electrically active biomaterials simulate the electrophysiological environment of the native myocardium and play a crucial role in the performance efficacy of the bionic devices (i.e., cardiac pacemakers).19,33,61,62 2.2. Fibrous Scaffolds. In general, polymeric fibrous structures have been considered as substitutes for soft tissues, because of their ability to mimic the 3D architecture of the ECM.63,64 More often, the fibrous structures fabricated by various processes are grafted into the defective site of the myocardium to facilitate the proliferation and differentiation of delivered cells into a cardiac lineage.65 The ideal characteristics of fibrous scaffolds include tunable size, biocompatibility, biodegradability, and cell philicity.66 The electrospun fibrous scaffolds from naturally derived precursors are highly suitable candidates to generate desirable cardiac ECM, such as collagen, fibrin, and pericardium.9 The major advantage of these fibrous scaffolds is that they preferentially adsorb human serum proteins and improve the molecular interactions between the cells and scaffolds, which effectively facilitate cardiomyocyte growth and differentiation.9,65 In addition, the immobilization of inorganic nanoparticles on the surface of polymeric fibrous scaffolds enhances the differentiation status and the functional parameters of the cells.66 The only minor disadvantage is that traditional polymers can be prone to degradation in the acidic environment and result in undesirable toxic substances, which usually obstruct the precise assessment of therapeutic outcomes.9 The formation of an efficient scaffold utterly depends on a few critical parameters, such as the diameter and pore dimension of the obtained electrospun fibers, which play crucial roles in cell/drug delivery in situ. The optimum diameter and pore size of typical electrospun fibrous scaffolds are ≤100 and 5 nm, respectively. Moreover, preceding reports have indicated that the delivery pattern could be improved by altering the dimensions of the fibrous structures to enhance the regenerative outcome.9 2.3. LbL Structures. LbL processing involves the alternate and consecutive adsorption of oppositely charged polyelectrolytes for the generation of multilayered nanofilms (5 to 1000 nm).33,67 Various substituents can be deposited on solid surfaces during the LbL assembly, including organic molecules, polymers, cells, natural proteins, inorganic clusters, and colloids.33,67,68 The LbL processing of nanoencapsulation holds several advantageous over other approaches, such as the ease of tuning and control over physical attributes such as swelling and permeability.9 In a typical LbL assembly technique, the controlled processing of components results in dense and highly organized 3D cardiac tissue constructs, in which nanostructured thin films along with the desired cell lineage can be subsequently deposited on the surface.33 However, the arrangement pattern of cells utterly depends on the type of cells and location of implantation.9 The major advantage of LbL processing over other approaches is that the physicochemical properties of the multilayered films can be well-regulated to ensure the behavior of ECM.33 In addition, this method of processing created a scope for the recreation of the electrically active ECM-like nanosized films through the encapsulation of nanoconstructs.33 The conductive nanoparticles incorporated between the layers promote the attachment, viability, growth, differentiation, and

3. PREPARATION STRATEGIES OF NANOMATERIALS Broadly speaking, the methods were classified into two major classes, a bottom-up and a top-down approach, based on the method of processing.74 The bottom-up method miniaturizes the material components to the atomic level, and they were further assembled to yield nanosized constructs, for example, colloidal dispersions. At the other end, the top-down method generates nanoparticles from the larger initial structures under externally controlled processing conditions. The most commonly used top-down methods include milling and etching, among others.74 The bottom-up approach is more advantageous over the top-down approach because it has a better chance of fabricating nanostructures with homogeneous chemical composition, fewer defects, and better ordering of molecules.74 In general, the appropriate method is selected D


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Figure 3. Schematic illustration of various types of fabrication methods that have been predominantly used for the production of nanoparticles.

based on the requirements, including the form (colloids, fibers, clusters, tubes, rods) and dimension of the nanomaterial (0, 1, 2, and 3D), particle size and quantity.74 Here, we briefly discuss the most commonly used synthetic processes that involve nanoparticle formation (Figure 3). 3.1. Electrospinning Method. Electrospinning is one of the most convenient and widely chosen techniques for fabricating nanofibrous structures with novel architectures and desired functionalities.40 The resultant fibrous architecture can be patterned either in the random or aligned form by using coaxial or side-by-side spinnerets, which prominently influence the cell orientation and functional attributes. This platform has a potentially high impact compared to the other multistep contemporary methods in the preparation of nanomaterials because it is a one-step process that is safe and cost-effective.42 Moreover, the desired architecture of the nanoconstructs can be obtained by optimizing the processing parameters such as the voltage, feed rate, tip-to-collector distance, and other processing conditions, such as humidity, to fine-tune the morphology, size, and charge of the scaffolds.30 Recently, this strategy has been applied to the fabrication of CNTs by applying electric charge.42 3.2. Phase Separation Approach. The phase separation process precipitates nanoparticles with the desired particle size distribution and morphology in two ways.75 One of them is liquid-based precipitation, which enables the growth of nanoparticles via diffusion or the Ostwald ripening method.75 The desired morphology of the particles could be obtained by optimizing the concentration of the substrate and temperature during the synthesis. More often, surfactants or electrolytes are added to avoid undesirable agglomerates in the end product. However, it results in the contaminated interfaces and surfaces of nanoparticles.76 The other approach of phase separation is the gas-based method, which results in uniform-sized particles with the intrinsic merit of generating a clean interface and surfaces.76,77 The particle formation in a typical gas-based approach involves a series of steps. Initially, the nucleus is formed via a chemical reaction, which is then followed by the

agglomeration of molecules and eventually their coalescence, which yields the nanostructures.76,78 The minor disadvantage of this process is that it results in the formation of hard agglomerates due to high processing temperatures.78 However, the oversized agglomerates can be subsequently separated and pulverized into uniform-sized small particles. 3.3. Template-Based Method. In a template-based synthetic process, nanoparticles are fabricated by depositing the desired materials of interest in the channel arrays of nanoporous templates.5 Various particle fabrication strategies that are based on the template-based method include chemical polymerization, chemical vapor deposition, electrochemical and electroless depositions, and sol−gel deposition. In general, track-etching membranes and porous alumina have been used as templates to prepare the nanosized fibrils, rods, and tubules of carbons, conductive polymers, metals, semiconductors, and other solid matter.5 For example, CNTs and MSNs are the most promising nanocomposites of TE that are synthesized using this method.79,80 3.4. Self-Assembly Method. Self-assembly is another important process of nanoparticle fabrication that results in the formation of fine particles by the spontaneous rearrangement of pre-existing components.81 The arrangement of molecules can be caused by a range of physical mechanisms that involve direct interactions between the molecules and/or indirect interactions through the influence of the environment.82 The desired atoms or molecules for arrangement are assembled into a definite pattern by minimizing the Gibbs free energy and by maximizing the attractive forces among themselves.81 The self-assembly that results in supramolecular architectures involves distinctive molecular interactions, such as intermolecular forces and Hamaker interaction forces, which are considered to be advantages to the components and result in desired selfassembled nanoaggregates.83 3.5. Sonochemical Process. Recently, the sonochemical process has emerged as one of the most efficient fabrication methods for producing nanoparticles with desired morphology and particle size distribution. This method is operated by E


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ACS Biomaterials Science & Engineering Table 1. Various Nanoconstructs Used in Cardiac TE nanoconstructs CNTs

materials

a

size

outcome

MWCNTs

20−30 nm

SWCNTs/PNIPAAm

2 nm in diameter and 5−30 μm in length

GelMA

∼5 nm thickness

SWCNTs/Gelatin-chitosan

1 nm in diameter, 0.1−4 μm in length

MWCNTs/alginate SWCNTs/Gelatin MWCNTs/PNIPAAm PGS, gelatin, GelMA MWCNTs/PELA

10−50 nm in diameter and 1−25 μm in length 30 ± 15 nm in diameter and 5−20 μm in length 10−20 nm in dia., 10−20 μm in length

GO

PLL, GelMA

GNPs/GNRs/ GNTs

GNPs/AV, PCL, SF, vitamin B-12 GNTs/PU, castor oil

∼16−20 nm

GNPs/PCL

∼10 nm

GNPs/polyaniline GNPs/chitosan

∼20 nm 7.2 nm

GNPs, native omentum GNRs/GelMA

4, 10 nm ∼4 nm

GNPs/collagen

∼30−60 nm

magnetite (Fe3O4), TMAG, DLPC, DOPE Fe2O3, DMSA

∼10 nm

IONPs

iron(III) acetylacetonate, DSPE-mPEG, DSPE-PEGNH2 magnetite (Fe3O4)

MSNs

PCs

7.9 ± 0.8 nm

22 nm ∼10 nm

ferric chloride, ferrous chloride, alginate ferric chloride, ferrous chloride, PVDF TEOS, PAH TEOS

IONPs, 5−20 nm; alginate scaffolds, 776 ± 416 nm ∼200 nm

CMC, stearic acid, homing peptide TAT, DNA

∼250 nm 480 ± 18.2 nm

PLGA

156 ± 9 nm

MAA, (PEG)EEMA, TRIM

30 ± 10 nm

PBAE

∼200 nm

∼175 nm 94.9 ± 8.3 nm

reference

these nanotubes instructed the physiological growth and functionally mature syncytia of cardiomyocytes SWCNTs in PNIPAAm improved the adhesion of scaffolds to the cells aligned-CNTs in biocompatible hydrogels exhibited excellent anisotropic electrical conductivity, bioactuation, and cardiac differentiation these scaffolds as electrical nanobridges between the cardiomyocytes resulted in the enhancement of electrical coupling functionalized MWCNTs enhanced the adhesion and proliferation of cardiomyocytes these conductive nanomaterials improved the implant integration and cardiac function interpenetrating nanomaterials improved the cell sheet engineering

52,69

these scaffolds exhibited the superior mechanical properties with enhanced cardiomyocyte beating properties these scaffolds modulated the electrical conductivity and improved the cardiac regeneration GOs improved the cardiomyocyte organization, maturation, and cell−cell electrical coupling these nanoparticles efficiently guided the differentiation of MSCs

63

GNPs improved the cell communication through electrical stimulation Addition of GNPs to the scaffolds resulted in the formation of elongated and aligned cardiac tissues GNPs regulated the lineage of MSCs for efficient regeneration these scaffolds enhanced the cardiomyogenic differentiation of MSCs GNPs exhibited superior cardiomyocyte function GNRs in the hydrogels promoted the electrical conductivity and mechanical stiffness of the hydrogel matrix metallized collagen improved the mechanical properties of ECMlike biomimetic tissues MCL-based cardiac tissue rings exhibited a spontaneous contraction and were electrically excitable DMSA-modified IONPs increased the hydrophobicity and reduced the intracellular ROS levels in cardiomyocytes for their proliferation IONPs improved the cellular cross-talk between MSCs and H9C2 cells to progress the therapeutic efficacy

106

MCLs cocultured with ADRC sheets efficiently promoted the angiogenesis at the infarcted site magnetite stimulated the cells for vasculogenesis and angiogenesis

114

manoparticles encapsulated in the polymeric fibers for noninvasive MRI and endogenous neovascularization 5-Aza in MSNs efficiently induced stem cell differentiation AA in MSNs induced differentiation of human ESCs to cardiomyocytes a spatiotemporal cardiomyocyte targeted polymeric nanoconstructs efficiently delivered carvedilol to regress cardiac hypertrophy the baculovirus-incorporated hybrid nanoplexus efficiently transduced hASCs coenzyme Q10 in PLGA nanoparticles reduced MI through its antioxidant effect. nanoparticles rebounded with the MMP-9 to generate ECM-like geometry VEGF delivery up-regulated the cellular therapy

38

89

36,37,39

35

91

97

98

101

33

66

110

71 108

109 86

111

112

113

51

115

50 116

46

87

15

64

117

a

Abbreviations: diameter (dia), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-mPEG), 1,2distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG-NH2), 2,3-dimercaptosuccinic acid (DMSA), adipose-derived regenerative cells (ADRC), aloe vera (AV), ascorbic acid (AA), carbon nanotubes (CNTs), carboxymethyl chitosan (CMC), deoxyribonucleic acid (DNA), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidyl-ethanolamine (DOPE), embryonic stem cells (ESCs), extracellular matrix (ECM), gelatin methacrylate (GelMA), gold nanoparticles (GNPs), gold nanorods (GNRs), gold nanotubes (GNTs), graphene oxide (GO), human adipose tissue-derived stem cells (hASCs), iron oxide nanoparticles (IONPs), magnetic resonance imaging (MRI), magnetite cationic liposomes (MCLs), mesenchymal stem cells (MSCs), mesoporous silica nanoparticles (MSNs), methacrylic acid (MAA), matrix metalloproteinase (MMP-9), multiwalled CNTs (MWCNTs), myocardial infarction (MI), N-(α-trimethylammonioacetyl)-didodecyl-D-glutamate chloride (TMAG), poly(β-amino esters) (PBAE), poly(allylamine hydrochloride) (PAH), poly(ethylene glycol)-poly(D,L-lactide) copolymers F


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ACS Biomaterials Science & Engineering Table 1. continued

(PELA), poly(ethylene glycol) ethyl ether methacrylate ((PEG)EEMA), polycaprolactone (PCL), poly-L-lysine (PLL), poly(lactide-co-glycolide) (PLGA); poly(glycerol sebacate) (PGS), Poly(N-isopropylacrylamide) (PNIPAAm), polymeric carriers (PCs), polyurethane (PU), polyvinylidene fluoride (PVDF), reactive oxygen species (ROS), silk fibroin (SF), single-walled CNTs (SWCNTs), tetraaniline (TA), tetraethylorthosilicate (TEOS), transactivating transcriptional activator (TAT), trimethylolpropane trimethacrylate (TRIM), vascular endothelial growth factor (VEGF).

applying ultrasound radiation (20 kHz to 100 MHz) and temperature for acoustic cavitation.84 Indeed, this method has been used to prepare various types of nanoconstructs such as metal nanoparticles, colloids, and alloys, among others, which are of particular interest in various applications including biomedicine.85

CNTs and their functionalized derivatives have been utilized as ideal materials for regenerative medicine due to their attractive properties, such as high mechanical resistance and elasticity, significant electrical as well as thermal conductivity, and biocompatibility.42,69,70,88,91 Other essential features of CNTs include excellent near-infrared (NIR) absorptivity as well as a thermoresponsive property (especially FWCNTs)90 and the adsorption of extracellular and serum proteins to improve their interaction with cells. 42 More often, CNTs are incorporated into polymeric scaffolds for the structural and functional restoration of ECTs (Table 1).89 Polymers from natural (alginate, chitosan, gelatin) and synthetic (poly-L-lactide (PLLA), polycarbonate-urethane (PCU), polycaprolactone (PCL), polyethylene glycol (PEG), poly(N-isopropylacrylamide) (PNIPAAm), poly(lactide-co-glycolide) (PLGA), poly(glycerol sebacate) (PGS), polystyrene (PS), and polyurethane (PU)) origin are preferred as templates to promote tissue growth efficiently (Table 1).42,93,94 These nanoparticles improve the mechanical properties of polymeric scaffolds such as tensile and compressive moduli and substantially reduce their degradation rate in vivo.42 In addition, CNTs interact with cardiomyocytes splendidly and promote electrical conductivity. Moreover, the interfacing between the CNT and cardiomyocyte allows for changes in the scaffold morphology and results in the proliferation of cells, differentiation and eventually maturation into a cardiac lineage.52,69,70 However, it should be noted that the size and the orientation of CNTs in the scaffolds play crucial roles in dictating cardiomyocyte growth.42 In recent times, remarkable progress has been observed in the development of various types of scaffolds that utilize CNTs after the first report on the evaluation of their cytocompatibility.49 Garibaldi et al. explored the in vitro cytocompatibility of highly purified SWCNTs with cardiomyocytes for the first time (i.e., rat heart cell line (H9c2 cells)).49 In another study, carbon nanofibers, also known as stacked-up CNTs, integrated with PLGA have achieved exceptional conductivity as well as cytocompatibility.95 These studies have demonstrated that the CNTs are nontoxic and safe to explore the biological effects in vivo. However, a mild toxicity of CNTs to cardiomyocytes has been reported in a few studies. For example, Maria et al. reported that SWCNTs have mildly affected the structure and impulse conduction characteristics of myofibril through the generation of reactive oxygen species (ROS) in the patterned growth strands of cardiomyocytes.96 To overcome this limitation, CNTs are preferably incorporated into implantable devices such as polymeric scaffolds or hydrogels to enhance their impulse conduction with minimal or no foreign body immune responses.42,70 The ultimate goal of a cardiac TE strategy is the recreation of functional myocardium along with an effective propagation of electric potential among the cardiomyocytes.35 However, this goal is quite intricate to accomplish due to the poor regeneration potential of cardiomyocytes in ECTs because the in vitro regeneration ability of cells was successful but failed to replicate in vivo and eventually led to apoptosis.89 Several studies have been devoted to addressing this critical issue by utilizing CNT-dispersed polymeric composites for the pro-

4. NANOPARTICLES FOR CARDIAC TE In recent years, ECTs have garnered increasing interest of researchers in the healthcare field because they increase the regeneration capacity of myocardium through various methods such as allocating the cells and delivering cardioprotective drugs.33,35−37,42,44,46−52 Although polymeric scaffolds as biomimetic tissues obtained from various processing methods have shown significant potential in the regeneration of cardiac tissue, the propagation of electrical signals within the construct is still inadequate due to lack of innate conductivity.42 To overcome this limitation, the electroconductive nanomaterials are integrated with the ECTs, which can successfully augment interactions with the host matrix and eventually promote electrical conductivity.52,69 Among the various types of nanomaterials available, inorganic-based nanoparticles have garnered the significant interest of researchers because of their attractive properties such as ease of synthesis, innate conductivity, nanofibrous organization that mimics the native heart, ability to integrate with the host scaffold and augment the cellular excitability by establishing the interactions with the cardiomyocytes and neurons, biocompatibility, and biodegradability.33,36,42,44,51,69,86 Moreover, these conductive nanoparticles efficiently promote the viability, reorganization, differentiation, cell elongation and regeneration of cardiomyocytes.14,35,36,40,42,48,52 In addition to inorganic nanoparticles, a few organic polymer-based nanoparticles are utilized in cardiac TE for the efficient conveyance of the cardioprotective drugs.15,46,87 As depicted in Table 1, various types of nanoparticles have been incorporated into polymeric substrates for the fabrication of functional ECTs to improve the adequate functional maturation progress and mimic the morphological as well as electrophysiological features of the native heart.54 4.1. Carbon-Based Nanomaterials. 4.1.1. CNTs. CNTs are seamless hollow cylinders of graphene that can be either open-ended or capped.88 Based on their geometry, CNTs are classified into three categories: single-walled CNTs (SWCNTs),89 few-walled CNTs (FWCNTs),90 and multiwalled CNTs (MWCNTs).42,91 SWCNTs are composed of a single graphene layer wrapped into a concentric cylinder, whose diameter ranges from 0.8 to 2 nm.42 On the other hand, the FWCNTs/MWCNTs consist of several coaxial cylinders with an outer diameter in the range of 2−100 nm.92 Indeed, CNTs are highly advantageous over other nanomaterials due to their high surface area and ease of synthesis as well as surface functionalization.91 These attractive properties of CNTs offer a way to fine-tune their mechanical as well as biological properties to alter their metabolic fate and performance in vivo.91 G


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Figure 4. Examples of CNTs-incorporated polymeric constructs for cardiac TE. (a) SEM image showing the rough structure of SWCNT-dispersed PNIPAAm hydrogels (scale bar, 50 μm). Reproduced with permission from ref 89. Copyright 2014 Elsevier. (b) SEM image showing that the SWCNTs were well-dispersed in gelatin hydrogels (scale bar, 400 nm). Reproduced with permission from ref 97. Copyright 2014 Nature Publishing Group. (c) TEM sagittal section illustrating that the continuous layer of MWCNTs interacting with the cell membrane for promoting the cardiomyocyte growth. Reproduced with permission from ref 69. Copyright 2012 American Chemical Society. (d) SEM image showing a detail of MWCNTs adherent to cardiomyocyte and their ability to instruct the physiological growth of the cardiomyocyte. Reproduced with permission from ref 52. Copyright 2013 American Chemical Society. (e) SEM images of (i) vertically aligned CNT forests (width, 460 μm; height, 300 μm); (ii, iii) magnified parts of the CNT forest surface; and (iv) HRTEM image of individual MWCNTs isolated from the CNT forest. Reproduced with permission from ref 37. Copyright 2015 John Wiley & Sons. (f) TEM image of GelMA-coated CNTs. Reproduced with permission from ref 36. Copyright 2013 American Chemical Society. (g) SEM image of dielectrophoretically aligned CNTs showing highly aligned CNTs between indium tin oxide (ITO) electrode bands. Reproduced with permission from ref 39. Copyright 2016 Elsevier. (h) (i) SEM image and (ii) a representative TEM image showing the un-cross-linked CNT-dispersed PGS: gelatin scaffolds. Reproduced with permission from ref 63. Copyright 2014 Elsevier.

gression of ECTs.89,98,99 For example, electroactive cardiac patches were prepared by dispersing the CNTs in PLLA scaffolds.93 These composites, when cocultured with MSCs, resulted in cell elongation and reorientation with increased communication between the cells. In another study, Yoon et al. fabricated the 3D structures of CNT-PCL scaffolds for cardiac TE.94 Herewith, the CNT alignment strengthened the polymeric chains and resulted in the enhancement of crystallinity of the PCL matrix. Moreover, Xing et al. prepared SWCNTs-incorporated PNIPAAm hydrogels (Figure 4a) for the intramyocardial delivery of brown adipose-derived stem cells to improve their efficacy during myocardial repair.89 Furthermore, the SWCNTs-embedded gelatin hydrogels (Figure 4b) were constructed to provide a cardiac microenvironment that possesses electrochemical-associated proteins. 97 In addition to the inhibition of pathological deterioration, these scaffolds held significant therapeutic potential in repairing the myocardium by promoting cardiomyocyte proliferation, adhesion, migration, and differentiation.89,97,98,100 More often, the research on cardiac TE has been focused on cardiomyogenesis and effective propagation of electric potential among the cardiomyocytes. Further effort has also been made

in improving the growth of cardiomyocytes (Figure 4c, d).52,69 Moreover, Zhang et al. fabricated electrospun CNT fibers by tuning the electrical conductivity as well as the inner structure, which promoted cardiomyocyte elongation and synchronous beating.101 CNTs resulted in the formation of conductive networks and accelerated the electrical communication between cardiomyocytes. In addition, these nanoconstructs efficiently promoted the cell viability, induced cell elongation by increasing the levels of various muscle proteins (sarcomeric α-actinin and cardiac Troponin I (cTnI)) and promoted synchronous beating of cardiomyocytes.101 In addition to cardiomyogenesis, control over the electrical conductivity of the biomimetic tissue is considered during the design of ECTs, which significantly enhances the regenerative outcome in cardiac TE.35,52 To regulate the electrical conductivity of ECTs, researchers must overcome the hindrance of ECTs during the transfer of electrical signals between the cardiomyocytes.37 In one case, Khademhosseini et al. fabricated CNTs-embedded PEG hydrogel-based scaffolds to control the actuation behavior of the myocardium and its electrical conductivity for a better therapeutic outcome.37 These ECTs have significantly altered the excitation thresholds and achieved better control over the beating frequency of H


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Figure 5. Fabrication of PLL-coated GO thin films and multilayered cell sheets by the LbL assembly technique. (a) Schematic illustration of the multilayered tissue constructs fabricated via LbL cell seeding and deposition of PLL-coated GO thin films. (b) Images captured by a mini-microscope during adhesion and spread of 3T3 fibroblasts after they were seeded on 5% GelMA, CNT-GelMA (1.0 mg/mL), and GO-GelMA (1.0 mg/mL) hydrogel substrates. (c) Fluorescence images of 3T3 fibroblasts after 2 days of culture. F-actin and cell nuclei were labeled with green and blue fluorescent dyes, respectively. (d) Cell size (i.e., area per cell) was generated by quantitative analysis of the fluorescence images. (e) Compressive modulus of pure GelMA, CNT-GelMA, and GO-GelMA under compression at a fully swollen state varied significantly with the CNT concentration (*p < 0.05 and **p < 0.001). Reproduced with permission from ref 33. Copyright 2014 John Wiley & Sons.

have been utilized for repairing various cardiac-related defects, such as atrial and ventricular septal defect, right ventricular outflow tract for Tetralogy of Fallot, and other cardiac defects, to overcome the risk of cardiac arrhythmia.35 In addition to tissue repair and regeneration, CNTs-based cardiac TE scaffolds have been utilized for the inhibition of blood clotting in coronary vessels, which is one of the noticeable reasons for cardiac arrest during postoperative implantable surgeries. For example, CNTs impregnated in PU scaffolds efficiently inhibited the key factors of clotting (tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)) through different mechanisms.102 4.1.2. GO. GO is another promising class of carbon-based nanomaterials that has attracted enormous interest for the fabrication of biomimetic tissues due to its attractive properties such as high conductivity, toughness, high stability and low toxicity.7,103,104 Indeed, the structural features of graphene mimic the highly organized 3D architecture of cardiac ECM.33 In addition, it significantly interferes with living cells and efficiently accelerates the electrical conductivity of cells.104 For example, Khademhosseini and co-workers have designed an

biohybrid actuators in both parallel and perpendicular directions relative to the alignment of the CNTs (Figure 4e). In another approach, CNTs were incorporated into the photocross-linkable gelatin methacrylate (GelMA) hydrogels (Figure 4f), which resulted in the spontaneous synchronous beating with improved cardiac cell adhesion, cell−cell coupling, organization, mechanical integrity, and electrical activity.36 Remarkable effort has been devoted by researchers in improving the mechanical robustness of ECTs by incorporating CNTs into various polymeric scaffolds, such as PGS-gelatin electrospun nanofibrous material, and gelatin-chitosan hydrogels.36,39,62,63,100 The nanoparticles dispersed in the polymeric architecture provide robust mechanical integrity to the scaffolds and substantially improve the mechanical properties of the composite polymeric scaffolds, such as the tensile and compressive moduli, which substantially reduce their degradation rate in vivo.39,42,90 In addition, these hybrid scaffolds act as electrical nanobridges between the cardiomyocytes, in which they provide enhanced electrical properties through electrical coupling and synchronous beating, for efficient cardiomyocyte function (Figure 4g, h).39,63 Moreover, these flexible scaffolds I


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Figure 6. Gold-based composites for cardiac TE. (a) Environmental SEM (ESEM) image of GNPs-deposited fibrous scaffold of decellularized omental matrices (Scale bar: 100 nm). Reproduced with permission from ref 109. Copyright 2014 American Chemical Society. (b) ESEM image of an electrospun coiled fiber embedded with GNPs. Reproduced with permission from ref 110. Copyright 2014 Royal Society of Chemistry. (c) Backscattered SEM image of the GNPs-dispersed chitosan scaffold (Scale bar: 30 μm). Reproduced with permission from ref 108. Copyright 2016 Elsevier. (d) Dark-field image of human MSCs internalized with GNPs. Image was captured after incubating the cells with GNPs for 24 h. Reproduced with permission from ref 71. Copyright 2016 Elsevier. (e) TEM image of GNPs-blended nanofibers (dia, diameter). Reproduced with permission from ref 66. Copyright 2015 Elsevier. (f) TEM micrograph showing GNRs embedded within a thin layer of GelMA-GNR hybrid. Reproduced with permission from ref 86. Copyright 2016 Elsevier.

pristine patches (ECTs devoid of GNPs). In addition, engineered cardiomyocytes within these patches have shown better elongation, massive striation and organized connexin 43 (CX-43) electrical coupling proteins in the gap junctions of cardiomyocytes.109 In another study, GNPs were encapsulated in the coiled electrospun PCL fibers, which resemble the perimysial fibers of the native heart (Figure 6b).110 These nanofibrous scaffolds allowed the cardiomyocytes to extend (i.e., relaxation) and contract efficiently by propagating the electrical signals between the adjacent cardiomyocytes through an intense contraction force, high contraction rate, and low excitation threshold.110 Moreover, GNPs induced the rapid elongation of cardiac tissues with superior function compared to that of the pristine PCL fibers. In another study, Aghdami et al. designed the GNPs-dispersed injectable hydrogels using thermosensitive and conductive porous chitosan to mimic the electromechanical properties of the myocardium (Figure 6c).108 These biodegradable hydrogels significantly improved the performance of electrical conductivity and the regeneration behavior of the cardiomyocytes. The manipulation of electro-actuated GNPs both intra- as well as extra-cellular has guided the cardiomyogenic differentiation of human MSCs after successful internalization (Figure 6d), which opened a new paradigm in cardiac TE to recreate the electro-active microenvironment of the heart.71 In one case, Venugopal et al. synthesized GNPs-embedded fibrous architecture using a mixture of PCL, vitamin B-12, aloe vera (AV) and silk fibroin (SF) for stem cell differentiation (Figure 6e).66 These supplements have replenished the microenvironment by altering the cardiomyocyte morphology. Moreover, the cocultured cardiomyocytes and MSCs interacted through paracrine and autocrine signaling during myocardial regeneration.66 In another case, ultraviolet-cross-linkable gold nanorods (GNRs) were encapsulated in GelMA hydrogels (Figure 6f), which promoted the electrical conductivity and increased the mechanical stiffness of the scaffold.86 Moreover, GNRs in

innovative approach that demonstrates the construction of multilayered cell sheets and poly-L-lysine (PLL)-coated GO thin films by the LbL assembly technique, which were arranged alternately on a reduced GO-GelMA hybrid hydrogel.33 These alternatively deposited layers resulted in the formation of a dense interlayer-connected cardiac tissue-like construct (Figure 5a). Moreover, GO enhanced the electrical conductivity and mechanical properties of GelMA, which indicates the provision of high-fidelity tissue models with improved biological activity, mechanical integrity, ease of handling, and retrievability of engineered tissue for drug screening and cardiac tissue-related development.105 In addition, this multilayered architecture has improved the cardiac cell organization, maturation, and cell− cell electrical coupling, to resemble complex native tissues. Furthermore, these two-dimensional (2D) GO nanoplatelets significantly promoted cell adhesion and spreading, compared to that of the one-dimensional (1D) CNTs as well as pristine GelMA hydrogels (Figure 5b−e). Moreover, the authors claim that these GO-based scaffolds allow the researcher to quickly analyze and ensure the adhesion and formation of a stable cell layer.33 4.2. GNPs. In recent years, the design of smart materials using gold-based composites has attracted increasing interest due to their desired properties of efficient propagation of impulses in the cardiomyocytes and an effective organization of cells.48,66,106 More often, the gold-based composites in diverse forms are favorably used in cardiac TE such as spheres, rods, tubes, and wires.48,107,108 Similar to CNTs, the gold nanoparticles are utilized to enrich the 3D architecture of ECTs by accelerating the electrical wave propagation and improving the mechanical integrity of the polymeric scaffolds, which substantially results in the efficacious regeneration ability of biomimetic tissues (Table 1).48 In one case, Dvir et al. fabricated GNPs-embedded decellularized-functional tissue matrix for treating MI (Figure 6a).109 These hybrid patches have exhibited superior function compared to that of the J


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Figure 7. Examples of IONPs-based biomimetic constructs for cardiac TE. (a) Bright-field photographs illustrating the construction of adiposederived regenerative cells (ADRC) sheets on an ultralow attachment plate by combining the Magnetite-TE technology and ECM precursorembedding systems. (b) Bright-field microscopic photograph of hematoxylin and eosin stained cross sections of ADRC sheets. (c) TUNEL assay elucidating that positive apoptotic cells were virtually absent at 24 h after the sheet construction. Reproduced with permission from ref 114. Copyright 2014 Elsevier. (d) Schematic representation of IONPs-coated PEG. (e) TEM images of (i) IONPs and (ii) IONPs uptaken by cardiomyoblast H9C2 cells (rhodamine B isothiocyanate (RITC)). IONPs are marked with white arrows. Reproduced with permission from ref 51. Copyright 2015 American Chemical Society. (f) Synthesis of USPIO-labeled PVDF pellets (top) and fibers (middle) containing 0, 0.05. and 0.2% (w/w) of IONPs. Visualization of the labeled fibers in T2-weighted MRI is shown in the bottom panels (scale bar, 5 mm). (g) 3D rendering of a labeled graft elucidated by MR characterization. (h) Photograph of a TEVG after 14 days of bioreactor cultivation. Reproduced with permission from ref 38. Copyright 2015 Elsevier.

the scaffolds enhanced the synchronous tissue-level beating of cardiomyocytes. Other polymeric substrates, such as bovine serum albumin (BSA) and poly(vinyl alcohol) (PVA), have also been used in the generation of ECTs due to their potential in cardiac repair.66,107 4.3. IONPs. IONPs, often referred to as magnetic substances, are widely used as contrast agents and have an ability to alter the cardiac microenvironment.51 Various studies have explored the underlying effects of iron in ECTs, such as vasculogenesis, angiogenesis, and magnetic-responsive stimulation, leading to cardiomyocyte actuation and crosstalk improvement between the cells, among other properties (Table 1).51,112,113,115,118 More often, the adipose-derived autologous stem cells are preferred to demonstrate the regenerative ability of IONPs. In one case, Murohara et al. prepared multilayered adipose-derived stem cell sheets (approximately 10−15 layers) that were cocultured with magnetic nanoparticles-incorporated

liposomes (Figure 7a) to promote angiogenesis and systolic function in the infarcted heart through the upregulation of messenger ribonucleic acid (mRNA) expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF).114 These reticular-patterned sheets (Figure 7b) resulted in no signs of apoptosis (Figure 7c) after the initiation of the sheet construction, and the transplanted stem cell sheets were then protected against adverse cardiac remodeling following MI. In addition, MSCs were utilized to evaluate the effects of magnetic species in repairing the injured myocardium. However, a few critical factors of MSCs should be considered, such as electrophysiological phenotype development and its paracrine action, which played a crucial role in determining the therapeutic efficacy of magnetic species. In another case, Choi et al. developed an innovative IONPsmediated TE platform (Figure 7d, e (i)) to evaluate the repairing potential of MSCs.51 IONPs were internalized well K


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Figure 8. MSNs for the differentiation of stem cells to cardiomyocytes. (a) Schematic summarizing the synthesis of fluorescein isothiocyanate (FITC)-MSNs (FMSNs) and the plausible mechanism of the drug delivery process in inducing P19 cell differentiation (APTES- 3aminopropyl)triethoxysilane, PAH-poly(allylamine hydrochloride)). (b) Fluorescence image of P19 cells treated with FMSNs + 5-azacytidine (5Aza) + PAH for 6 h. (c) 5-Aza-delivered by FMSNs in P19 cells up-regulated the expression of differentiation genes and cardiac marker genes at various treatments, phosphate-buffered saline (PBS, as a blank), FMSNs, 5-Aza, and FMSNs + 5-Aza + PAH for 6 days and subjected to Western blot analysis using antibodies against Forkhead Box (FOX) A2, SOX (SRY-Box)17, GATA binding protein (GATA) 4, and myocardin genes. Antiactin was used as a loading control. Reproduced with permission from ref 50. Copyright 2016 Royal Society of Chemistry. (d) Fluorescence images of human ESCs treated with TMSNs (i) TRITC signal assigned in orange and (ii) overlaid with bright field image of ESCs. (e) TMSN-AA nanoplex induced the differentiation of human ESCs toward cardiomyocytes (Human ES cells were treated with PBS, TMSNs, AA. and TMSN-AA for 14 days and subjected to Western blot analysis using antibodies against myocardial marker genes cTnI and FLK-1. Antiactin was used as a loading control). Reproduced with permission from re 116. Copyright 2015 Elsevier.

the bioinspired vascular grafts with IONPs could be a promising approach (Figure 7h). 4.4. MSNs. In recent years, MSNs have gained immense interest from researchers in TE due to their attractive physicochemical features, such as well-defined structure, tunable morphology, high surface area and drug loading ability, biocompatibility, biodegradability, tunable pores, colloidal stability, and high dispersity.50,116,119−121 In particular, the unique mesoporous structure with an extensive functionalizable surface provides enormous scope for the immobilization of various desired molecules of interest.119 These versatile nanocontainers functionalized with the organic moieties have been utilized for various applications, such as controlled drug delivery, molecular recognition, and sensing.79,121 In one way, MSNs are one of the most efficient carriers used for the delivery of cardioprotective drugs, and these carriers have drawn tremendous attention in cellular engineering and stem cell therapy because of their high drug loading capacity, and biocompatibility.50 ESCs are promising cell resources for regenerative medicine because they have the great potential to differentiate into various types of cells in the body. Despite their success in TE, ESCs in a few instances resulted in a very low efficiency of

(Figure 7e(ii)) and concomitantly augmented the expression of a gap junction protein, CX-43, which favored the gap junctional communication/crosstalk between the cardiomyoblasts H9C2 cells when cocultured with MSCs. Moreover, IONPs in MSCs have induced the formation of electrophysiological cardiac biomarkers and a cardiac repair-favorable paracrine profile, which indicates the enormous potential of conventional MSCs in repairing cardiac tissues.51 Recently, magnetic materials have attracted increasing attention toward TE-assisted magnetic resonance imaging (MRI) because of their attractive properties, such as noninvasive nature, assessment of implant localization, high efficiency, maturation, acceptance, and remodeling.51,113,118 In addition, the tremendous growth in the past decade has evidenced the advancements in generating IONP-based ECTs. The use of these composites can often avoid the application of additional contrast agents. For example, Lammers et al. fabricated noninvasive imageable TE vascular grafts (TEVG) by incorporating ultrasmall superparamagnetic iron oxide (USPIO) nanoconstructs into polyvinylidene fluoride (PVDF)-based textile fibers (Figure 7f).38 These biocompatible and functional grafts were sensitively detected using T1-, T2-, and T2*-weighted MRI (Figure 7f, g), which demonstrates that L


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Figure 9. Functionalized polymer scaffolds for cardiac TE. (a) The design of the ECM-like structure of the microfabricated polymeric systems: simplified geometric scheme of a single cell of the structure with dimensions. (b) Schematic illustration displaying the hypothetical arrangement of cardiomyocytes within the cells; (c) Superposition of the designed ECM-like structure on the native cardiac tissue. (d) SEM images demonstrating the morphological analysis of the particle-loaded system, (i) after the MMP-9/MIP nanoparticles deposition and (ii) after stability tests in PBS solution for 3 days. Reproduced with permission from ref 64. Copyright 2011 Springer. (e) Immunofluorescence images demonstrating the cardiomyocyte specificity of FITC-labeled carboxymethyl chitosan (CMC)-peptide in neonatal cardiomyocytes (NCMs). (i) 4′,6-Diamidino-2phenylindole (DAPI), (ii) FITC, (iii) counter-stained with a sarcomeric α-actinin antibody, and (iv) merged image (scale bar = 20 μm, magnification = 40×). Reproduced with permission from ref 46. Copyright 2015 Elsevier.

demonstrates the significant potential of MSNs in delivering various cardioprotective agents.116 4.5. PCs. In general, polymer-based carriers are predominantly utilized to transport the drug molecules for adjunctive/ synergistic therapy that involves multiple drugs and clinical interventions to promote angiogenesis and substantially myocardial regeneration.46,117 Here, we present the most interesting reports on PCs that have been utilized in TE and regenerative medicine (Table 1). In one case, an efficient gene delivery system was prepared using recombinant baculovirus complexed with cell-penetrating transactivator of transcription (TAT) peptide/DNA nanoparticles (Bac-NP) to modify the angiopoietin-1 (Ang1)-expressing human adipose tissue-derived stem cells for myocardial therapy. 87 These genetically engineered nanoconjugates have shown a large cell retention effect, increased the capillary density and significantly reduced the infarct sizes. In addition, Maria et al. developed the PLGA particles that carried VEGF and coenzyme Q10 and were intended for oral administration to overcome the hypoxia and stress conditions during myocardial angiogenesis.15 In another approach, Cristallini et al. prepared multifunctional polymeric 3D scaffolds by using the innovative molecular imprinting (MIP) process that supports cardiomyocyte adhesion and proliferation (Figure 9a−c).64 Indeed, this biodegradable,

differentiation, which limited their application in cardiac TE.50,116 To overcome this limitation, ESCs were engineered by delivering cardioprotective drugs/inducers using the MSNbased delivery platform to induce/regulate their differentiation to cardiomyocytes (Table 1).50,116 For example, Lu et al. designed mobil composition of matter (MCM)-41-type MSNs (Figure 8a), which efficiently monitored the transfection of ESCs in situ after successful internalization (Figure 8b).50 5azacytidine (5-Aza) was successfully loaded into the pores of MSNs, and these nanocontainers were then coated with poly(allylamine hydrochloride) (PAH), which resulted in the pH-sensitive release of 5-Aza at pH-5.0 (inside the cell). The released drug molecules selectively induced the differentiation of ESCs (P19 cells) to cardiomyocytes. Further, the differentiation was confirmed by the resultant changes in the histone modifications on the regulatory regions of differentiation genes and cardiac marker genes (Figure 8c).50 In another study, Ren et al. investigated the potential of ascorbic acid (AA)-loaded tetramethylrhodamine (TRITC)-conjugated MSNs (TMSNs) (Figure 8d) in repairing the myocardium damage.116 These drug-loaded nanoconjugates have significantly induced the differentiation of ESCs compared to that of the AA treatment alone. Moreover, they up-regulated the myocardial marker genes, cTnI and fetal liver kinase 1 (FLK-1) (Figure 8e), which M


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and efficient methods for engineering various scaffolds for cardiac TE. Recently, there has been increasing attention in the development of electronic interfaces with tissues, which would be utilized to record the electrical activities of various tissues.124 In addition, these devices monitor whole organs such as the heart and brain.40,124 Although in its infancy, the development of efficient nanoelectronics is anticipated for the regulation of cardiac tissue growth.

microfabricated 3D architecture was composed of a three coblock polymer blend, namely, δ-valerolactone, PEG, and gelatin, with normal functional integrity replicating the ECM of cardiac tissue, which was further modified with molecularly imprinted nanoparticles (Figure 9d). These 3D polymeric scaffolds specifically detected the matrix metalloproteinase (MMP-9) and prevented the expansion of left ventricular remodeling in post-MI, which is a detrimental effect of infarction.64 Despite the significant advantages of stem cell-based therapy in treating ischemic disease, the lower survival rate of stem cells in vivo has remained a major challenge.122 To overcome this limitation, Langer and colleagues have developed a nonviral, gene therapy based on biodegradable poly(β-amino esters) (PBAE) nanoparticles to modify the human umbilical vein endothelial cells (HUVECs) with VEGF for the treatment of ischemic disease.117 The VEGF released from PBAE nanoparticles has efficiently transfected the HUVECs and subsequently improved their viability by upregulating the survival factors, which led to enhanced angiogenesis and ischemic limb salvage. Moreover, other promising approaches for the improvement of cell survival in vivo include autologous bioengineered cardiac grafts, in which cardiomyocytes were cocultured with nanofibrous PCL meshes for the replacement of infarcted myocardium.17 Moreover, PCs have also been utilized for the improvement of the electrical conductivity of ECTs. For example, homogeneous electronically conductive double network (HEDN) hydrogels were prepared by incorporating rigid, hydrophobic poly(thiophene-3-acetic acid) (PTAA) in photocross-linking GelMA using a one-step preparation method.123 Furthermore, the electrical conductivity of these hydrogels was confirmed in brown adipose-derived stem cells, which demonstrates that these biocompatible nanoconstructs were ideal enough in propagating the electric potential.123 In another approach, Xing et al. prepared a cardiac tissue patch that mimicked the structural and functional attributes of native myocardium.45 This cryogel-based patch was prepared by using conductive polypyrrole nanoparticles, GelMA, and poly(ethylene glycol) diacrylate (PEGDA) with a dopamine crosslinker, in which the uniformly distributed nanoparticles and the coordination interactions between the dopamine and nanoparticles significantly provided superelastic properties to the cardiac patch. In addition, the patch resulted in sharp synchronous contractions through the upregulation of α-actinin and CX-43. Currently, most of the cardiac TE strategies using different nanocarriers are intended for the recreation of biomimetic scaffolds to promote adhesion, growth, expansion, differentiation of cardiomyocytes and accelerating the electrical conductivity between the cells. However, it is also essential to achieve control over the microenvironment for cardiac tissue growth. In one case, Sarker et al. prepared a nanopolymer vector system to regress the cardiac hypertrophy abating bystander effect by successfully targeting the hypertrophied cardiomyocyte using stearic acid-modified carboxymethyl chitosan (CMC) (Figure 9e).46 This vector system carried high payloads of carvedilol/siRNA and resulted in the knockdown of causal genes, such as atrial natriuretic factor (ANF), β-myosin heavy chain (β-MHC), and others, for the management of myocardial physiology. This study demonstrated that the biodegradable polymeric systems provide safe

5. NANOTOXICITY ON CARDIAC HEALTH In addition to therapeutic efficacy, the toxicity evaluation of pharmaceutical products is an essential feature that needs to be addressed to translate them from bench to the clinics. In general, the toxicity has widely been defined as the amount of substance that induces adverse biological responses and damage cells, tissues or organs, thus leading to sickness or death.125,126 The tremendous progress in the past few decades has been evidenced by the advancements of various methods in developing nanoconstructs and their associated products that could become future medical devices for various biomedical applications. Moreover, it should be noted that the biological behavior of nanoparticles is significantly different compared to their bulk counterparts’ which depends on various physicochemical attributes such as size, surface area, shape, chemical composition, surface chemistry, surface charge, aggregation state, and lattice structure, among others.1,3 In addition, the nanotoxicity depends on the interaction between nanoparticles and biological membranes. 4 Thus, it is an important prerequisite to exploring the toxicity issues of such devices. Due to concerns over the safety hazards of nanomaterials for biomedical applications, there has been a drastic upsurge in the research that predominantly focused on human safety for clinical applications.125,126 Preceding reports indicated that carbon-based nanoconstructs (e.g., CNTs) used in cardiac TE had exhibited exceptional cytocompatibility in vitro.49,95 Differently, a recent study has reported that the fibrous forms of these materials have shown mild toxicity leading to proliferation inhibition and eventually cell death.95,96 To overcome this limitation, stackedup CNTs are integrated with the polymeric scaffolds or hydrogels to enhance the impulse conduction in cardiomyocytes with minimal or no foreign body immune responses.42,70 Similarly, the other nanomaterials used in cardiac TE either alone or in combination with the polymeric scaffolds have also shown excellent biocompatibility and promoted the cardiomyocyte growth and differentiation.33,36,37,50,64 In an attempt to elucidate this fact, very recently, an observational investigation of nanomaterials first-in-man (NANOM-FIM) long-term clinical outcome trial has demonstrated that no signs of cytotoxicity or clinical complications were observed in the group of patients who underwent the clinical intervention of bioengineered silica-gold nanoparticles-dispersed on-artery patch.127 These clinical follow-up trials for atheroprotective management have shown a lower risk of cardiovascular death with no cases of target lesions in the nanoparticle-treated groups.128 On the other hand, the authors also demonstrated that iron-bearing silica-gold composites have some limitations in their clinical advancement due to pronounced toxicity.127 It should be noted that the dosage of material plays a crucial role in the nanotoxicity evaluation. In a few cases, even the suitable dose metric for toxicity assessment is not appropriate without considering the physicochemical attributes of nanoparticles, N


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therapeutics. These versatile delivery systems also actively drive the cardiac differentiation as well as regeneration, and improvement of electrical conductivity.31,34 Moreover, these versatile delivery systems play an important role in postsurgical procedures for healing the heart-related ailments. In this framework, various biodegradable polymeric carriers and inorganic nanomaterials such as MSNs, have been utilized for the delivery of growth factors (such as VEGF) and cardioprotective drugs (such as carvedilol, 5-Aza) with higher clinical efficacy.46,50 On the other hand, these formulated carriers for delivering bioactive molecules also improve the mechanical properties or impart diverse functionalities.47 It should be noted that the spatiotemporal control over the release of these drugs and bioactive molecules from nanocontainers will efficiently drive the function of the biomimetic scaffolds.31 More often, the nanocarriers intended for controlled drug release are engineered such that they aim to deliver the bioactive molecules over an extended period and maintain the effective concentration of biomolecules at the desired site.31 These multifunctional nanoparticle-based delivery systems are administered through various systemic routes of administration. However, the delivery of cardioprotective agents through the intramyocardial route seems to be the ideal and highly suggested route of administration to achieve the localized delivery with minimal side effects.47 Together, these versatile delivery systems aim to heal the heart-related ailments and efficiently drive the biomimetic scaffolds toward cardiac regeneration.

which may drive them to severe agglomeration and result in toxicity. We believe that nanomaterials have significantly contributed to our health care system concerning the scientific advances, however, in-depth analyses on the evaluation of nanotoxicity yet remain to be performed.

6. MISCELLANEOUS STRATEGIES 6.1. 3D Bioprinting. In recent times, bioprinting has emerged as the most promising technology for fabrication of biomimetic tissue models through controlled deposition of cells and other biomaterials in a spatially defined manner.27,129 Conceptually, these geometrically defined structures in 3D orientation significantly improve the physiological relevance through architectural mimicry of native tissues and organs.26 In addition, this technique surpasses the limitations associated with the traditional scaffold-based methods, including reproducibility issues, oversimplified structures, and limited control over the tissue microenvironment.26 Although the 3D printing technique was developed decades ago, very recently, it has gained the attention of researchers for fabrication of biomimetic tissue models. The most common approaches of bioprinting include extrusion-based printing, inkjet printing, laser-assisted printing, and stereolithography.34,129,130 In this context, various 3D components such as cardiac tissues, valves, and vascular networks have been developed by different 3D bioprintingbased approaches.34 During the fabrication of tissue constructs, this bioprinting strategy not only allows the direct encapsulation of cells and other bioactive molecules but also enables the vascularization of the engineered tissue constructs, providing the versatility in producing vascularized cardiac organoids.26,129 In addition, this microfabrication strategy is usually biocompatible and provides a platform for personalized drug screening to alleviate the druginduced cardiovascular toxicity or advance the treatment efficacy of cardioprotective drugs. For example, Khademhosseini and Zhang and colleagues have prepared the 3D microfibrous scaffolds for engineering the endothelialized myocardium26 and perfusable vascular constructs using the specially designed cell-laden blend bioink to create highly organized 3D vascular networks that promote the transport of nutrients, oxygen, and waste products.27 in addition, this platform enables the testing of nanomedicine regarding the interactions between the endothelium and nanoparticles. Together, these large-sized engineered tissue constructs produced by advanced bioprinting technology will significantly find a potential way in organ transplantation and repair. Furthermore, they developed GNRsincorporated GelMA-based bioink to improve the function of ECTs through enhanced cell adhesion via cell-to-cell coupling and promoted the synchronized contraction of the bioprinted constructs.48 In another study, Yoon et al. prepared the 3D printed structures of CNT-PCL scaffolds for cardiac TE.94 In this framework, the alignment of CNTs have strengthened the polymeric chains and resulted in the enhancement of crystallinity of the polymeric matrix. Hence, the application of bioprinting for cardiac TE results in the overall 3D architectures with better control over the tissue microenvironment, and it is also evident from the above-mentioned studies that the embedded nanomaterials with desired properties significantly improve the function of these engineered tissues. 6.2. Cardiac Drug Delivery. In addition to generating 3D biomimetic structures for spatial arrangement of tissues, much research has been dedicated in engineering numerous multifunctional drug delivery vehicles for potential cardiac

7. CONCLUSIONS AND FUTURE TRENDS In summary, this reviewed data indicated that nanotechnology has high potential to improve the functionality of biomaterials in TE. Furthermore, nanoparticles such as carbon-based materials, GNPs, MSNs, IONPs, and PCs fabricated in different biomimetic architectures, focusing hydrogels, fibrous scaffolds and LbL structures have been reviewed. In addition, we gave a brief overview of the synthetic methods for producing nanoparticles and insights on other miscellaneous strategies such as 3D bioprinting and cardiac drug delivery. Despite their significant progress in the advancement of biomimetic scaffolds, inorganic nanoparticles still face several challenges in clinical safety, such as biocompatibility and toxicity issues. Further studies are required to address these critical issues before their clinical translation. Recently, steps have been taken to address the issues associated with the nanotoxicity on cardiac health by developing new nanoparticle formulations with cardioprotective properties such as cellmembrane fragment/peptide-coated biomimetic nanoparticles and exosomes. Exosomes are the resultant nanosized lipid products of multivesicular bodies secreted by many cells, including stem cells, via an exotic pathway.72 These innovative vesicles are the most appealing candidates for cell-free treatment strategy and offer attractive properties such as cellspecific targeting, transport and deliver a large cargo of therapeutic proteins and nucleic acids to ischemic myocardium, the source of cardiovascular biomarkers and nonimmunogenic means of manipulating the heart.72 In addition, stem cell transplantation-based theranostic procedure has enormous potential in cardiac repair, where stem cells predominantly act through widely accepted paracrine effect. Moreover, stem cell-derived exosomes that are increasingly recognized as mediator factors since microRNAs and proteins could also promote cardiac repair.131 These therapeutic approaches may O


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(7) Chen, Y.; Tan, C.; Zhang, H.; Wang, L. Two-dimensional graphene analogues for biomedical applications. Chem. Soc. Rev. 2015, 44 (9), 2681−2701. (8) Kankala, R. K.; Tsai, P.-Y.; Kuthati, Y.; Wei, P.-R.; Liu, C.-L.; Lee, C.-H. Overcoming multidrug resistance through co-delivery of ROSgenerating nano-machinery in cancer therapeutics. J. Mater. Chem. B 2017, 5 (7), 1507−1517. (9) Wan, A. C. A.; Ying, J. Y. Nanomaterials for in situ cell delivery and tissue regeneration. Adv. Drug Delivery Rev. 2010, 62 (7), 731− 740. (10) Tang, H.; Zheng, Y.; Chen, Y. Materials Chemistry of Nanoultrasonic Biomedicine. Adv. Mater. 2017, 29 (10), 1604105. (11) Toh, Y.-C.; Ng, S.; Khong, Y. M.; Zhang, X.; Zhu, Y.; Lin, P.-C.; Te, C.-M.; Sun, W.; Yu, H. Cellular responses to a nanofibrous environment. Nano Today 2006, 1 (3), 34−43. (12) Zhang, L.; Webster, T. J. Nanotechnology and nanomaterials: Promises for improved tissue regeneration. Nano Today 2009, 4 (1), 66−80. (13) Mozaffarian, D.; Benjamin, E. J.; Go, A. S.; Arnett, D. K.; Blaha, M. J.; Cushman, M.; Das, S. R.; de Ferranti, S.; Després, J.-P.; Fullerton, H. J.; Howard, V. J.; Huffman, M. D.; Isasi, C. R.; Jiménez, M. C.; Judd, S. E.; Kissela, B. M.; Lichtman, J. H.; Lisabeth, L. D.; Liu, S.; Mackey, R. H.; Magid, D. J.; McGuire, D. K.; Mohler, E. R.; Moy, C. S.; Muntner, P.; Mussolino, M. E.; Nasir, K.; Neumar, R. W.; Nichol, G.; Palaniappan, L.; Pandey, D. K.; Reeves, M. J.; Rodriguez, C. J.; Rosamond, W.; Sorlie, P. D.; Stein, J.; Towfighi, A.; Turan, T. N.; Virani, S. S.; Woo, D.; Yeh, R. W.; Turner, M. B. Heart Disease and Stroke Statistics2016 Update. Circulation 2016, 133 (4), 447−454. (14) Chan, V.; Raman, R.; Cvetkovic, C.; Bashir, R. Enabling Microscale and Nanoscale Approaches for Bioengineered Cardiac Tissue. ACS Nano 2013, 7 (3), 1830−1837. (15) Simón-Yarza, T.; Tamayo, E.; Benavides, C.; Lana, H.; Formiga, F. R.; Grama, C. N.; Ortiz-de-Solorzano, C.; Kumar, M. N. V. R.; Prosper, F.; Blanco-Prieto, M. J. Functional benefits of PLGA particulates carrying VEGF and CoQ10 in an animal of myocardial ischemia. Int. J. Pharm. 2013, 454 (2), 784−790. (16) Amezcua, R.; Shirolkar, A.; Fraze, C.; Stout, D. Nanomaterials for Cardiac Myocyte Tissue Engineering. Nanomaterials 2016, 6 (7), 133. (17) Shin, M.; Ishii, O.; Sueda, T.; Vacanti, J. P. Contractile cardiac grafts using a novel nanofibrous mesh. Biomaterials 2004, 25 (17), 3717−23. (18) Engel, F. B.; Hauck, L.; Cardoso, M. C.; Leonhardt, H.; Dietz, R.; von Harsdorf, R. A mammalian myocardial cell-free system to study cell cycle reentry in terminally differentiated cardiomyocytes. Circ. Res. 1999, 85 (3), 294−301. (19) Bouten, C. V. C.; Dankers, P. Y. W.; Driessen-Mol, A.; Pedron, S.; Brizard, A. M. A.; Baaijens, F. P. T. Substrates for cardiovascular tissue engineering. Adv. Drug Delivery Rev. 2011, 63 (4−5), 221−241. (20) Webber, M. J.; Han, X.; Prasanna Murthy, S. N.; Rajangam, K.; Stupp, S. I.; Lomasney, J. W. Capturing the stem cell paracrine effect using heparin-presenting nanofibres to treat cardiovascular diseases. J. Tissue Eng. Regener. Med. 2010, 4 (8), 600−10. (21) Zhu, K.; Li, J.; Wang, Y.; Lai, H.; Wang, C. NanoparticlesAssisted Stem Cell Therapy for Ischemic Heart Disease. Stem Cells Int. 2016, 2016, 1384658. (22) Kaur, S.; Rishiraj, U., Nanotechnology and Cardiovascular Tissue Engineering. In Stem-Cell Nanoengineering; John Wiley & Sons: New York, 2015; pp 285−297. (23) Orlic, D.; Kajstura, J.; Chimenti, S.; Jakoniuk, I.; Anderson, S. M.; Li, B.; Pickel, J.; McKay, R.; Nadal-Ginard, B.; Bodine, D. M.; Leri, A.; Anversa, P. Bone marrow cells regenerate infarcted myocardium. Nature 2001, 410 (6829), 701−5. (24) Freund, C.; Mummery, C. L. Prospects for pluripotent stem cellderived cardiomyocytes in cardiac cell therapy and as disease models. J. Cell. Biochem. 2009, 107 (4), 592−9. (25) Beltrami, A. P.; Barlucchi, L.; Torella, D.; Baker, M.; Limana, F.; Chimenti, S.; Kasahara, H.; Rota, M.; Musso, E.; Urbanek, K.; Leri, A.; Kajstura, J.; Nadal-Ginard, B.; Anversa, P. Adult cardiac stem cells are

explore a new frontier at the nanoscale, which will undoubtedly advance the search for innovative strategies of cardioprotection. The complexity of the architecture and an intricate structural organization of myocardium demand careful engineering of the nanoparticle-incorporated scaffolds for improving their therapeutic efficacy. In addition, gene/drug delivery along with the engineered cardiac patches for treating MI and the nanodelivery systems that promote stem cell treatment would be the most promising strategies for effective treatment of CVDs. We envision that the anticipated progress in the design of the scaffolds along with systematic investigations in vivo exploring the nanotoxicity and, in addition, addressing the challenges in scalability and reproducibility will eventually bring them from bench to clinical practice. In addition, we believe that the nanoelectronic devices could be integrated with the tissue substitutes intended for cardiac TE to record the function of the transplanted patches and report the secretion of bioactive molecules, such as proteins in ECM.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel./fax: +86 592 616 2326 (A.Z.C.). *E-mail: [email protected] (X.-N.S.). ORCID

Ranjith Kumar Kankala: 0000-0003-4081-9179 Ai-Zheng Chen: 0000-0002-5840-3406 Author Contributions †

R.K.K. and K.Z. contributed equally to this work

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS R.K.K., A.Z.C., and S. B. Wang acknowledges financial support from National Natural Science Foundation of China (U1605225, 31570974 and 31470927), Huaqiao University (Project 16BS803), Public Science and Technology Research Funds Projects of Ocean (201505029), and Promotion Program for Young and Middle-aged Teacher in Science and Technology Research of Huaqiao University (ZQN-PY107). K.Z. acknowledges National Natural Science Foundation of China (81771971), “Chen Guang” project funded by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (14CG06), and Shanghai Pujiang Program (17PJ1401500 and 14PJD008).

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REFERENCES

(1) Farokhzad, O. C.; Langer, R. Impact of Nanotechnology on Drug Delivery. ACS Nano 2009, 3 (1), 16−20. (2) Riehemann, K.; Schneider, S. W.; Luger, T. A.; Godin, B.; Ferrari, M.; Fuchs, H. Nanomedicine–challenge and perspectives. Angew. Chem., Int. Ed. 2009, 48 (5), 872−97. (3) Farokhzad, O. C.; Langer, R. Nanomedicine: Developing smarter therapeutic and diagnostic modalities. Adv. Drug Delivery Rev. 2006, 58 (14), 1456−1459. (4) Sun, T.; Zhang, Y. S.; Pang, B.; Hyun, D. C.; Yang, M.; Xia, Y. Engineered nanoparticles for drug delivery in cancer therapy. Angew. Chem., Int. Ed. 2014, 53 (46), 12320−12364. (5) Huczko, A. Template-based synthesis of nanomaterials. Appl. Phys. A: Mater. Sci. Process. 2000, 70 (4), 365−376. (6) Qian, X.; Han, X.; Chen, Y. Insights into the unique functionality of inorganic micro/nanoparticles for versatile ultrasound theranostics. Biomaterials 2017, 142, 13−30. P


Review

ACS Biomaterials Science & Engineering multipotent and support myocardial regeneration. Cell 2003, 114 (6), 763−76. (26) Zhang, Y. S.; Arneri, A.; Bersini, S.; Shin, S.-R.; Zhu, K.; GoliMalekabadi, Z.; Aleman, J.; Colosi, C.; Busignani, F.; Dell’Erba, V.; Bishop, C.; Shupe, T.; Demarchi, D.; Moretti, M.; Rasponi, M.; Dokmeci, M. R.; Atala, A.; Khademhosseini, A. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials 2016, 110, 45−59. (27) Jia, W.; Gungor-Ozkerim, P. S.; Zhang, Y. S.; Yue, K.; Zhu, K.; Liu, W.; Pi, Q.; Byambaa, B.; Dokmeci, M. R.; Shin, S. R.; Khademhosseini, A. Direct 3D bioprinting of perfusable vascular constructs using a blend bioink. Biomaterials 2016, 106, 58−68. (28) Khademhosseini, A.; Langer, R. Microengineered hydrogels for tissue engineering. Biomaterials 2007, 28 (34), 5087−5092. (29) Kankala, R. K.; Zhang, Y. S.; Wang, S.-B.; Lee, C.-H.; Chen, A.Z. Supercritical Fluid Technology: An Emphasis on Drug Delivery and Related Biomedical Applications. Adv. Healthcare Mater. 2017, 6, 1700433. (30) Perán, M.; García, M.; Lopez-Ruiz, E.; Jiménez, G.; Marchal, J. How Can Nanotechnology Help to Repair the Body? Advances in Cardiac, Skin, Bone, Cartilage and Nerve Tissue Regeneration. Materials 2013, 6 (4), 1333. (31) Leijten, J.; Rouwkema, J.; Zhang, Y. S.; Nasajpour, A.; Dokmeci, M. R.; Khademhosseini, A. Advancing Tissue Engineering: A Tale of Nano-, Micro-, and Macroscale Integration. Small 2016, 12 (16), 2130−45. (32) Isenberg, B. C.; Wong, J. Y. Building structure into engineered tissues. Mater. Today 2006, 9 (12), 54−60. (33) Shin, S. R.; Aghaei-Ghareh-Bolagh, B.; Gao, X.; Nikkhah, M.; Jung, S. M.; Dolatshahi-Pirouz, A.; Kim, S. B.; Kim, S. M.; Dokmeci, M. R.; Tang, X.; Khademhosseini, A. Layer-by-Layer Assembly of 3D Tissue Constructs with Functionalized Graphene. Adv. Funct. Mater. 2014, 24 (39), 6136−6144. (34) Kankala, R. K.; Zhu, K.; Li, J.; Wang, C. S.; Wang, S. B.; Chen, A. Z. Fabrication of arbitrary 3D components in cardiac surgery: from macro-, micro- to nanoscale. Biofabrication 2017, 9 (3), 032002. (35) Pok, S.; Vitale, F.; Eichmann, S. L.; Benavides, O. M.; Pasquali, M.; Jacot, J. G. Biocompatible Carbon Nanotube−Chitosan Scaffold Matching the Electrical Conductivity of the Heart. ACS Nano 2014, 8 (10), 9822−9832. (36) Shin, S. R.; Jung, S. M.; Zalabany, M.; Kim, K.; Zorlutuna, P.; Kim, S. b.; Nikkhah, M.; Khabiry, M.; Azize, M.; Kong, J.; Wan, K.-t.; Palacios, T.; Dokmeci, M. R.; Bae, H.; Tang, X.; Khademhosseini, A. Carbon-Nanotube-Embedded Hydrogel Sheets for Engineering Cardiac Constructs and Bioactuators. ACS Nano 2013, 7 (3), 2369− 2380. (37) Shin, S. R.; Shin, C.; Memic, A.; Shadmehr, S.; Miscuglio, M.; Jung, H. Y.; Jung, S. M.; Bae, H.; Khademhosseini, A.; Tang, X.; Dokmeci, M. R. Aligned Carbon Nanotube−Based Flexible Gel Substrates for Engineering Biohybrid Tissue Actuators. Adv. Funct. Mater. 2015, 25 (28), 4486−4495. (38) Mertens, M. E.; Koch, S.; Schuster, P.; Wehner, J.; Wu, Z.; Gremse, F.; Schulz, V.; Rongen, L.; Wolf, F.; Frese, J.; Gesché, V. N.; van Zandvoort, M.; Mela, P.; Jockenhoevel, S.; Kiessling, F.; Lammers, T. USPIO-labeled textile materials for non-invasive MR imaging of tissue-engineered vascular grafts. Biomaterials 2015, 39, 155−163. (39) Ahadian, S.; Yamada, S.; Ramón-Azcón, J.; Estili, M.; Liang, X.; Nakajima, K.; Shiku, H.; Khademhosseini, A.; Matsue, T. Hybrid hydrogel-aligned carbon nanotube scaffolds to enhance cardiac differentiation of embryoid bodies. Acta Biomater. 2016, 31, 134−143. (40) Fleischer, S.; Dvir, T. Tissue engineering on the nanoscale: lessons from the heart. Curr. Opin. Biotechnol. 2013, 24 (4), 664−671. (41) Campbell, T. A.; Ivanova, O. S. 3D printing of multifunctional nanocomposites. Nano Today 2013, 8 (2), 119−120. (42) Hopley, E. L.; Salmasi, S.; Kalaskar, D. M.; Seifalian, A. M. Carbon nanotubes leading the way forward in new generation 3D tissue engineering. Biotechnol. Adv. 2014, 32 (5), 1000−1014.

(43) Dvir, T.; Timko, B. P.; Kohane, D. S.; Langer, R. Nanotechnological strategies for engineering complex tissues. Nat. Nanotechnol. 2011, 6 (1), 13−22. (44) Kharaziha, M.; Memic, A.; Akbari, M.; Brafman, D. A.; Nikkhah, M. Nano-Enabled Approaches for Stem Cell-Based Cardiac Tissue Engineering. Adv. Healthcare Mater. 2016, 5 (13), 1533−53. (45) Wang, L.; Jiang, J.; Hua, W.; Darabi, A.; Song, X.; Song, C.; Zhong, W.; Xing, M. M. Q.; Qiu, X. Mussel-Inspired Conductive Cryogel as Cardiac Tissue Patch to Repair Myocardial Infarction by Migration of Conductive Nanoparticles. Adv. Funct. Mater. 2016, 26 (24), 4293−4305. (46) Rana, S.; Datta, K.; Reddy, T. L.; Chatterjee, E.; Sen, P.; PalBhadra, M.; Bhadra, U.; Pramanik, A.; Pramanik, P.; Chawla-Sarkar, M.; Sarkar, S. A spatio-temporal cardiomyocyte targeted vector system for efficient delivery of therapeutic payloads to regress cardiac hypertrophy abating bystander effect. J. Controlled Release 2015, 200, 167−178. (47) Han, J.; Park, J.; Kim, B.-S. Integration of mesenchymal stem cells with nanobiomaterials for the repair of myocardial infarction. Adv. Drug Delivery Rev. 2015, 95, 15−28. (48) Zhu, K.; Shin, S. R.; van Kempen, T.; Li, Y.-C.; Ponraj, V.; Nasajpour, A.; Mandla, S.; Hu, N.; Liu, X.; Leijten, J.; Lin, Y.-D.; Hussain, M. A.; Zhang, Y. S.; Tamayol, A.; Khademhosseini, A. Gold Nanocomposite Bioink for Printing 3D Cardiac Constructs. Adv. Funct. Mater. 2017, 27 (12), 1605352. (49) Garibaldi, S.; Brunelli, C.; Bavastrello, V.; Ghigliotti, G.; Nicolini, C. Carbon nanotube biocompatibility with cardiac muscle cells. Nanotechnology 2006, 17 (2), 391. (50) Cheng, J.; Ding, Q.; Wang, J.; Deng, L.; Yang, L.; Tao, L.; Lei, H.; Lu, S. 5-Azacytidine delivered by mesoporous silica nanoparticles regulates the differentiation of P19 cells into cardiomyocytes. Nanoscale 2016, 8 (4), 2011−2021. (51) Han, J.; Kim, B.; Shin, J.-Y.; Ryu, S.; Noh, M.; Woo, J.; Park, J.S.; Lee, Y.; Lee, N.; Hyeon, T.; Choi, D.; Kim, B.-S. Iron Oxide Nanoparticle-Mediated Development of Cellular Gap Junction Crosstalk to Improve Mesenchymal Stem Cells’ Therapeutic Efficacy for Myocardial Infarction. ACS Nano 2015, 9 (3), 2805−2819. (52) Martinelli, V.; Cellot, G.; Toma, F. M.; Long, C. S.; Caldwell, J. H.; Zentilin, L.; Giacca, M.; Turco, A.; Prato, M.; Ballerini, L.; Mestroni, L. Carbon Nanotubes Instruct Physiological Growth and Functionally Mature Syncytia: Nongenetic Engineering of Cardiac Myocytes. ACS Nano 2013, 7 (7), 5746−5756. (53) Mattson, M. P.; Haddon, R. C.; Rao, A. M. Molecular functionalization of carbon nanotubes and use as substrates for neuronal growth. J. Mol. Neurosci. 2000, 14 (3), 175−182. (54) Bosi, S.; Ballerini, L.; Prato, M., Carbon Nanotubes in Tissue Engineering. In Making and Exploiting Fullerenes, Graphene, and Carbon Nanotubes; Marcaccio, M., Paolucci, F., Eds.; Springer: Berlin, 2014; pp 181−204. (55) Lu, H. D.; Soranno, D. E.; Rodell, C. B.; Kim, I. L.; Burdick, J. A. Secondary Photocrosslinking of Injectable Shear-Thinning Dock-andLock Hydrogels. Adv. Healthcare Mater. 2013, 2 (7), 1028−1036. (56) Zhang, Y. S.; Khademhosseini, A. Advances in engineering hydrogels. Science 2017, 356 (6337), eaaf3627. (57) Hartgerink, J. D.; Beniash, E.; Stupp, S. I. Self-Assembly and Mineralization of Peptide-Amphiphile Nanofibers. Science 2001, 294 (5547), 1684−1688. (58) Purcell, B. P.; Elser, J. A.; Mu, A.; Margulies, K. B.; Burdick, J. A. Synergistic effects of SDF-1alpha chemokine and hyaluronic acid release from degradable hydrogels on directing bone marrow derived cell homing to the myocardium. Biomaterials 2012, 33 (31), 7849−57. (59) Davis, M. E.; Motion, J. P.; Narmoneva, D. A.; Takahashi, T.; Hakuno, D.; Kamm, R. D.; Zhang, S.; Lee, R. T. Injectable selfassembling peptide nanofibers create intramyocardial microenvironments for endothelial cells. Circulation 2005, 111 (4), 442−450. (60) Davis, M. E.; Hsieh, P. C.; Takahashi, T.; Song, Q.; Zhang, S.; Kamm, R. D.; Grodzinsky, A. J.; Anversa, P.; Lee, R. T. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with Q


Review


(81) Whitesides, G. M.; Kriebel, J. K.; Love, J. C. Molecular engineering of surfaces using self-assembled monolayers. Sci. Prog. 2005, 88 (1), 17−48. (82) Yang, S.; Yan, Y.; Huang, J.; Petukhov, A. V.; Kroon-Batenburg, L. M. J.; Drechsler, M.; Zhou, C.; Tu, M.; Granick, S.; Jiang, L. Giant capsids from lattice self-assembly of cyclodextrin complexes. Nat. Commun. 2017, 8, 15856. (83) Wetterskog, E.; Agthe, M.; Mayence, A.; Grins, J.; Wang, D.; Rana, S.; Ahniyaz, A.; Salazar-Alvarez, G.; Bergstrom, L. Precise control over shape and size of iron oxide nanocrystals suitable for assembly into ordered particle arrays. Sci. Technol. Adv. Mater. 2014, 15 (5), 055010. (84) Okitsu, K.; Ashokkumar, M.; Grieser, F. Sonochemical Synthesis of Gold Nanoparticles: Effects of Ultrasound Frequency. J. Phys. Chem. B 2005, 109 (44), 20673−20675. (85) Chen, M.; Xing, Y. Polymer-Mediated Synthesis of Highly Dispersed Pt Nanoparticles on Carbon Black. Langmuir 2005, 21 (20), 9334−9338. (86) Navaei, A.; Saini, H.; Christenson, W.; Sullivan, R. T.; Ros, R.; Nikkhah, M. Gold nanorod-incorporated gelatin-based conductive hydrogels for engineering cardiac tissue constructs. Acta Biomater. 2016, 41, 133−146. (87) Paul, A.; Nayan, M.; Khan, A. A.; Shum-Tim, D.; Prakash, S. Angiopoietin-1-expressing adipose stem cells genetically modified with baculovirus nanocomplex: investigation in rat heart with acute infarction. Int. J. Nanomed. 2012, 7, 663−682. (88) Popov, V. N. Carbon nanotubes: properties and application. Mater. Sci. Eng., R 2004, 43 (3), 61−102. (89) Li, X.; Zhou, J.; Liu, Z.; Chen, J.; Lü, S.; Sun, H.; Li, J.; Lin, Q.; Yang, B.; Duan, C.; Xing, M.; Wang, C. A PNIPAAm-based thermosensitive hydrogel containing SWCNTs for stem cell transplantation in myocardial repair. Biomaterials 2014, 35 (22), 5679− 5688. (90) Zeng, Y.; Lu, J. Q. Optothermally Responsive Nanocomposite Generating Mechanical Forces for Cells Enabled by Few-Walled Carbon Nanotubes. ACS Nano 2014, 8 (11), 11695−11706. (91) Joddar, B.; Garcia, E.; Casas, A.; Stewart, C. M. Development of functionalized multi-walled carbon-nanotube-based alginate hydrogels for enabling biomimetic technologies. Sci. Rep. 2016, 6, 32456. (92) Journet, C.; Maser, W. K.; Bernier, P.; Loiseau, A.; de la Chapelle, M. L.; Lefrant, S.; Deniard, P.; Lee, R.; Fischer, J. E. Largescale production of single-walled carbon nanotubes by the electric-arc technique. Nature 1997, 388, 756. (93) Mooney, E.; Mackle, J. N.; Blond, D. J. P.; O’Cearbhaill, E.; Shaw, G.; Blau, W. J.; Barry, F. P.; Barron, V.; Murphy, J. M. The electrical stimulation of carbon nanotubes to provide a cardiomimetic cue to MSCs. Biomaterials 2012, 33 (26), 6132−6139. (94) Ho, C. M.; Mishra, A.; Lin, P. T.; Ng, S. H.; Yeong, W. Y.; Kim, Y. J.; Yoon, Y. J. 3D Printed Polycaprolactone Carbon Nanotube Composite Scaffolds for Cardiac Tissue Engineering. Macromol. Biosci. 2017, 17 (4), 1600250. (95) Stout, D. A.; Basu, B.; Webster, T. J. Poly(lactic−co-glycolic acid): Carbon nanofiber composites for myocardial tissue engineering applications. Acta Biomater. 2011, 7 (8), 3101−3112. (96) Helfenstein, M.; Miragoli, M.; Rohr, S.; Müller, L.; Wick, P.; Mohr, M.; Gehr, P.; Rothen-Rutishauser, B. Effects of combustionderived ultrafine particles and manufactured nanoparticles on heart cells in vitro. Toxicology 2008, 253 (1−3), 70−78. (97) Zhou, J.; Chen, J.; Sun, H.; Qiu, X.; Mou, Y.; Liu, Z.; Zhao, Y.; Li, X.; Han, Y.; Duan, C.; Tang, R.; Wang, C.; Zhong, W.; Liu, J.; Luo, Y.; Mengqiu Xing, M.; Wang, C. Engineering the heart: evaluation of conductive nanomaterials for improving implant integration and cardiac function. Sci. Rep. 2015, 4, 3733. (98) Chen, Y.-S.; Tsou, P.-C.; Lo, J.-M.; Tsai, H.-C.; Wang, Y.-Z.; Hsiue, G.-H. Poly(N-isopropylacrylamide) hydrogels with interpenetrating multiwalled carbon nanotubes for cell sheet engineering. Biomaterials 2013, 34 (30), 7328−7334.

biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (21), 8155−60. (61) Kichula, E. T.; Wang, H.; Dorsey, S. M.; Szczesny, S. E.; Elliott, D. M.; Burdick, J. A.; Wenk, J. F. Experimental and Computational Investigation of Altered Mechanical Properties in Myocardium after Hydrogel Injection. Ann. Biomed. Eng. 2014, 42 (7), 1546−1556. (62) Rosales, A. M.; Vega, S. L.; DelRio, F. W.; Burdick, J. A.; Anseth, K. S. Hydrogels with Reversible Mechanics to Probe Dynamic Cell Microenvironments. Angew. Chem., Int. Ed. 2017, 56 (40), 12132− 12136. (63) Kharaziha, M.; Shin, S. R.; Nikkhah, M.; Topkaya, S. N.; Masoumi, N.; Annabi, N.; Dokmeci, M. R.; Khademhosseini, A. Tough and flexible CNT−polymeric hybrid scaffolds for engineering cardiac constructs. Biomaterials 2014, 35 (26), 7346−7354. (64) Cristallini, C.; Gagliardi, M.; Barbani, N.; Giannessi, D.; Guerra, G. D. Novel biodegradable, biomimetic and functionalised polymer scaffolds to prevent expansion of post-infarct left ventricular remodelling. J. Mater. Sci.: Mater. Med. 2012, 23 (1), 205−216. (65) Fleischer, S.; Feiner, R.; Shapira, A.; Ji, J.; Sui, X.; Daniel Wagner, H.; Dvir, T. Spring-like fibers for cardiac tissue engineering. Biomaterials 2013, 34 (34), 8599−8606. (66) Sridhar, S.; Venugopal, J. R.; Sridhar, R.; Ramakrishna, S. Cardiogenic differentiation of mesenchymal stem cells with gold nanoparticle loaded functionalized nanofibers. Colloids Surf., B 2015, 134, 346−354. (67) Decher, G. Fuzzy Nanoassemblies: Toward Layered Polymeric Multicomposites. Science 1997, 277 (5330), 1232−1237. (68) Ai, H.; Jones, S. A.; Lvov, Y. M. Biomedical applications of electrostatic layer-by-layer nano-assembly of polymers, enzymes, and nanoparticles. Cell Biochem. Biophys. 2003, 39 (1), 23. (69) Martinelli, V.; Cellot, G.; Toma, F. M.; Long, C. S.; Caldwell, J. H.; Zentilin, L.; Giacca, M.; Turco, A.; Prato, M.; Ballerini, L.; Mestroni, L. Carbon Nanotubes Promote Growth and Spontaneous Electrical Activity in Cultured Cardiac Myocytes. Nano Lett. 2012, 12 (4), 1831−1838. (70) Martinelli, V.; Cellot, G.; Fabbro, A.; Bosi, S.; Mestroni, L.; Ballerini, L. Improving cardiac myocytes performance by carbon nanotubes platforms. Front. Physiol. 2013, 4, 239. (71) Thrivikraman, G.; Madras, G.; Basu, B. Electrically driven intracellular and extracellular nanomanipulators evoke neurogenic/ cardiomyogenic differentiation in human mesenchymal stem cells. Biomaterials 2016, 77, 26−43. (72) Yellon, D. M.; Davidson, S. M. Exosomes. Circ. Res. 2014, 114 (2), 325−332. (73) Villa, C. H.; Pan, D. C.; Zaitsev, S.; Cines, D. B.; Siegel, D. L.; Muzykantov, V. R. Delivery of drugs bound to erythrocytes: new avenues for an old intravascular carrier. Ther. Delivery 2015, 6 (7), 795−826. (74) Kulkarni, S. K., Synthesis of NanomaterialsI (Physical Methods). In Nanotechnology: Principles and Practices; Springer International Publishing: Cham, Switzerland, 2015; pp 55−76. (75) Takai, C.; Tamura, A.; Fuji, M. Synthesis of a silver nanoparticle network induced by a micro-phase separation. Adv. Powder Technol. 2014, 25 (2), 621−624. (76) Xu, Y. H.; Wang, J. P. Direct Gas-Phase Synthesis of Heterostructured Nanoparticles through Phase Separation and Surface Segregation. Adv. Mater. 2008, 20 (5), 994−999. (77) Gröschel, M.; Körmer, R.; Walther, M.; Leugering, G.; Peukert, W. Process control strategies for the gas phase synthesis of silicon nanoparticles. Chem. Eng. Sci. 2012, 73 (Suppl. C), 181−194. (78) Luo, N.; Jing, H. W.; Ma, Z. G.; Liu, W.; Zhang, L.; Sun, G. Synthesis of polymorphic titanium oxide nanoparticles by a rapid gasphase chemical reaction. Mendeleev Commun. 2016, 26 (2), 157−159. (79) Lee, C.-H.; Lin, T.-S.; Mou, C.-Y. Mesoporous materials for encapsulating enzymes. Nano Today 2009, 4 (2), 165−179. (80) Wu, S. H.; Mou, C. Y.; Lin, H. P. Synthesis of mesoporous silica nanoparticles. Chem. Soc. Rev. 2013, 42 (9), 3862−75. R


Review

ACS Biomaterials Science & Engineering (99) Kim, M. S.; Hansgen, A. R.; Wink, O.; Quaife, R. A.; Carroll, J. D. Rapid prototyping: a new tool in understanding and treating structural heart disease. Circulation 2008, 117 (18), 2388−94. (100) Vozzi, F.; Cabiati, M.; Gemma, F.; Montemurro, F.; De Maria, C.; Vozzi, G.; Domenici, C.; Del Ry, S. Gelatin and carbon-based nanotubes scaffold for cardiac tissue engineering: A preliminary study. Vasc. Pharmacol. 2015, 75, 44−45. (101) Liu, Y.; Lu, J.; Xu, G.; Wei, J.; Zhang, Z.; Li, X. Tuning the conductivity and inner structure of electrospun fibers to promote cardiomyocyte elongation and synchronous beating. Mater. Sci. Eng., C 2016, 69, 865−874. (102) Meng, J.; Han, Z.; Kong, H.; Qi, X.; Wang, C.; Xie, S.; Xu, H. Electrospun aligned nanofibrous composite of MWCNT/polyurethane to enhance vascular endothelium cells proliferation and function. J. Biomed. Mater. Res., Part A 2010, 95A (1), 312−320. (103) Compton, O. C.; Nguyen, S. T. Graphene oxide, highly reduced graphene oxide, and graphene: versatile building blocks for carbon-based materials. Small 2010, 6 (6), 711−723. (104) Thompson, B. C.; Murray, E.; Wallace, G. G. Graphite Oxide to Graphene. Biomaterials to Bionics. Adv. Mater. 2015, 27 (46), 7563−82. (105) Shin, S. R.; Zihlmann, C.; Akbari, M.; Assawes, P.; Cheung, L.; Zhang, K.; Manoharan, V.; Zhang, Y. S.; Yuksekkaya, M.; Wan, K. T.; Nikkhah, M.; Dokmeci, M. R.; Tang, X. S.; Khademhosseini, A. Reduced Graphene Oxide-GelMA Hybrid Hydrogels as Scaffolds for Cardiac Tissue Engineering. Small 2016, 12 (27), 3677−89. (106) Ganji, Y.; Li, Q.; Quabius, E. S.; Böttner, M.; Selhuber-Unkel, C.; Kasra, M. Cardiomyocyte behavior on biodegradable polyurethane/gold nanocomposite scaffolds under electrical stimulation. Mater. Sci. Eng., C 2016, 59, 10−18. (107) Ravichandran, R.; Sridhar, R.; Venugopal, J. R.; Sundarrajan, S.; Mukherjee, S.; Ramakrishna, S. Gold nanoparticle loaded hybrid nanofibers for cardiogenic differentiation of stem cells for infarcted myocardium regeneration. Macromol. Biosci. 2014, 14 (4), 515−25. (108) Baei, P.; Jalili-Firoozinezhad, S.; Rajabi-Zeleti, S.; TafazzoliShadpour, M.; Baharvand, H.; Aghdami, N. Electrically conductive gold nanoparticle-chitosan thermosensitive hydrogels for cardiac tissue engineering. Mater. Sci. Eng., C 2016, 63, 131−141. (109) Shevach, M.; Fleischer, S.; Shapira, A.; Dvir, T. Gold Nanoparticle-Decellularized Matrix Hybrids for Cardiac Tissue Engineering. Nano Lett. 2014, 14 (10), 5792−5796. (110) Fleischer, S.; Shevach, M.; Feiner, R.; Dvir, T. Coiled fiber scaffolds embedded with gold nanoparticles improve the performance of engineered cardiac tissues. Nanoscale 2014, 6 (16), 9410−9414. (111) Orza, A. I.; Mihu, C.; Soritau, O.; Diudea, M.; Florea, A.; Matei, H.; Balici, S.; Mudalige, T.; Kanarpardy, G. K.; Biris, A. S. Multistructural biomimetic substrates for controlled cellular differentiation. Nanotechnology 2014, 25 (6), 065102. (112) Akiyama, H.; Ito, A.; Sato, M.; Kawabe, Y.; Kamihira, M. Construction of cardiac tissue rings using a magnetic tissue fabrication technique. Int. J. Mol. Sci. 2010, 11 (8), 2910−20. (113) Mou, Y.; Zhou, J.; Xiong, F.; Li, H.; Sun, H.; Han, Y.; Gu, N.; Wang, C. Effects of 2,3-dimercaptosuccinic acid modified Fe2O3 nanoparticles on microstructure and biological activity of cardiomyocytes. RSC Adv. 2015, 5 (25), 19493−19501. (114) Ishii, M.; Shibata, R.; Shimizu, Y.; Yamamoto, T.; Kondo, K.; Inoue, Y.; Ouchi, N.; Tanigawa, T.; Kanemura, N.; Ito, A.; Honda, H.; Murohara, T. Multilayered adipose-derived regenerative cell sheets created by a novel magnetite tissue engineering method for myocardial infarction. Int. J. Cardiol. 2014, 175 (3), 545−553. (115) Sapir, Y.; Cohen, S.; Friedman, G.; Polyak, B. The promotion of in vitro vessel-like organization of endothelial cells in magnetically responsive alginate scaffolds. Biomaterials 2012, 33 (16), 4100−4109. (116) Ren, M.; Han, Z.; Li, J.; Feng, G.; Ouyang, S. Ascorbic acid delivered by mesoporous silica nanoparticles induces the differentiation of human embryonic stem cells into cardiomyocytes. Mater. Sci. Eng., C 2015, 56, 348−355. (117) Cho, S.-W.; Yang, F.; Son, S. M.; Park, H.-J.; Green, J. J.; Bogatyrev, S.; Mei, Y.; Park, S.; Langer, R.; Anderson, D. G.

Therapeutic angiogenesis using genetically engineered human endothelial cells. J. Controlled Release 2012, 160 (3), 515−524. (118) Sapir, Y.; Polyak, B.; Cohen, S. Cardiac tissue engineering in magnetically actuated scaffolds. Nanotechnology 2014, 25 (1), 014009. (119) Lee, C.-H.; Cheng, S.-H.; Huang, I. P.; Souris, J. S.; Yang, C.-S.; Mou, C.-Y.; Lo, L.-W. Intracellular pH-Responsive Mesoporous Silica Nanoparticles for the Controlled Release of Anticancer Chemotherapeutics. Angew. Chem., Int. Ed. 2010, 49 (44), 8214−8219. (120) Zhu, K.; Wu, M.; Lai, H.; Guo, C.; Li, J.; Wang, Y.; Chen, Y.; Wang, C.; Shi, J. Nanoparticle-enhanced generation of gene-transfected mesenchymal stem cells for in vivo cardiac repair. Biomaterials 2016, 74, 188−199. (121) Kankala, R. K.; Liu, C.-G.; Chen, A.-Z.; Wang, S.-B.; Xu, P.-Y.; Mende, L. K.; Liu, C.-L.; Lee, C.-H.; Hu, Y.-F. Overcoming Multidrug Resistance through the Synergistic Effects of Hierarchical pHSensitive, ROS-Generating Nanoreactors. ACS Biomater. Sci. Eng. 2017, 3 (10), 2431−2442. (122) Zhu, K.; Lai, H.; Guo, C.; Li, J.; Wang, Y.; Wang, L.; Wang, C. Nanovector-based prolyl hydroxylase domain 2 silencing system enhances the efficiency of stem cell transplantation for infarcted myocardium repair. Int. J. Nanomed. 2014, 9, 5203. (123) Yang, B.; Yao, F.; Hao, T.; Fang, W.; Ye, L.; Zhang, Y.; Wang, Y.; Li, J.; Wang, C. Development of Electrically Conductive DoubleNetwork Hydrogels via One-Step Facile Strategy for Cardiac Tissue Engineering. Adv. Healthcare Mater. 2016, 5 (4), 474−488. (124) Cohen-Karni, T.; Langer, R.; Kohane, D. S. The smartest materials: the future of nanoelectronics in medicine. ACS Nano 2012, 6 (8), 6541−5. (125) Stern, S. T.; McNeil, S. E. Nanotechnology Safety Concerns Revisited. Toxicol. Sci. 2008, 101 (1), 4−21. (126) Zhang, Y.; Chen, X.; Zhao, B.; Wu, H.; Yuan, L.; Zhang, H.; Dai, W.; He, B.; Xing, G.; Zhang, Q.; Wang, X. Biosafety study and mechanism comparison on two types of silica with different nanostructures. Toxicol. Res. 2017, 6 (4), 487−498. (127) Kharlamov, A. N.; Feinstein, J. A.; Cramer, J. A.; Boothroyd, J. A.; Shishkina, E. V.; Shur, V. Plasmonic photothermal therapy of atherosclerosis with nanoparticles: long-term outcomes and safety in NANOM-FIM trial. Future Cardiol. 2017, 13 (4), 345−363. (128) Kharlamov, A. N.; Tyurnina, A. E.; Veselova, V. S.; Kovtun, O. P.; Shur, V. Y.; Gabinsky, J. L. Silica-gold nanoparticles for atheroprotective management of plaques: results of the NANOMFIM trial. Nanoscale 2015, 7 (17), 8003−8015. (129) Liu, W.; Zhang, Y. S.; Heinrich, M. A.; De Ferrari, F.; Jang, H. L.; Bakht, S. M.; Alvarez, M. M.; Yang, J.; Li, Y. C.; Trujillo-de Santiago, G.; Miri, A. K.; Zhu, K.; Khoshakhlagh, P.; Prakash, G.; Cheng, H.; Guan, X.; Zhong, Z.; Ju, J.; Zhu, G. H.; Jin, X.; Shin, S. R.; Dokmeci, M. R.; Khademhosseini, A. Bioprinting: Rapid Continuous Multimaterial Extrusion Bioprinting. Adv. Mater. 2017, 29 (3), DOI: 10.1002/adma.201770016. (130) Zhang, Y. S.; Duchamp, M.; Oklu, R.; Ellisen, L. W.; Langer, R.; Khademhosseini, A. Bioprinting the Cancer Microenvironment. ACS Biomater. Sci. Eng. 2016, 2 (10), 1710−1721. (131) Xiao, J.; Pan, Y.; Li, X. H.; Yang, X. Y.; Feng, Y. L.; Tan, H. H.; Jiang, L.; Feng, J.; Yu, X. Y. Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4. Cell Death Dis. 2016, 7 (6), e2277.

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