Nanobiomaterials E-Book
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- Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
- Kategorie: Fachliteratur
- Sprache: Englisch
Written by an international team of editors and contributors from renowned universities and institutes, this book addresses the latest research in the field of nanobiomaterials, covering nanotechnologies for their fabrication, developments in biomedical applications, and the challenges of biosafety in clinic uses.
Clearly structured, the volume defines the scope and classification of the field, resulting in a broad overview from fundamental principles to current technological advances, and from materials synthesis to biomedical applications along with future trends.
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Veröffentlichungsjahr: 2017
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Table of Contents
Cover
Title Page
Copyright
Preface
Part I: Introduction
Chapter 1: Nanobiomaterials: State of the Art
1.1 Introduction
1.2 Nanobiomaterials for Tissue Engineering Applications
1.3 Nanobiomaterials for Drug Delivery Applications
1.4 Nanobiomaterials for Imaging and Biosensing Applications
1.5 Conclusions and Perspectives
References
Part II: Classification of Nanobiomaterials
Chapter 2: Metallic Nanobiomaterials
2.1 Introduction
2.2 Conventional to Ultrafine-Grained Materials – A Novel Transformation
2.3 Severe Plastic Deformation (SPD)
2.4 Mechanical Behavior of Metallic Nanobiomaterials
2.5 Corrosion
2.6 Wear
2.7 Biocompatibility of Metallic Nanobiomaterials
2.8 Biomedical Application of Metallic Nanobiomaterials
2.9 Future Aspects
References
Chapter 3: Polymeric Nanobiomaterials
3.1 Introduction
3.2 Types of Polymeric Nanobiomaterials
3.3 Polymeric Nanofibers
3.4 Polymeric Nanofibers to Provide Microenvironmental Cues
3.5 Biological Relevance of Polymeric Nanofibers
3.6 Recent Trends in Polymeric Nanofibers
3.7 Applications of Nanofibers in Regenerative Medicine
3.8 Concluding Remarks
Acknowledgment
References
Chapter 4: Carbon-Based Nanobiomaterials
4.1 Introduction
4.2 Tissue Engineering
4.3 Gene and Drug Delivery
4.4 Biosensing
4.5 Biomedical Imaging
4.6 Conclusions
References
Part III: Nanotechnology-Based Approaches in Biomaterials Fabrications
Chapter 5: Molecular Self-Assembly for Nanobiomaterial Fabrication
5.1 Introduction
5.2 Self-Assembling Peptides
5.3 Nano-Drug Carriers
5.4 Inorganic Nanobiomaterials
5.5 Perspectives
Acknowledgments
References
Chapter 6: Electrospraying and Electrospinning for Nanobiomaterial Fabrication
6.1 Introduction
6.2 What is Electrospinning?
6.3 Key Considerations in Electrospinning
6.4 The Application of Electrospun Materials in Biomedicine
6.5 Future Directions
References
Chapter 7: Layer-by-Layer Technique: From Capsule Assembly to Application in Biological Domains
7.1 Definition of Layer-by-Layer (LbL) Assembly
7.2 Stabilizing Interactions between LbL Films
7.3 Emerged Technologies Employed for LbL Assembly
7.4 Typical Methods for the Assembly of LbL Particles/Capsules
7.5 Application of LbL Capsules in Biological Environment
7.6 LbL Capsules as a Therapeutic Delivery Platform: Cargo Loading and Release
7.7 The Effect of Physicochemical Properties of LbL Capsules on Cellular Interactions
7.8 Conclusion and Outlook
References
Chapter 8: Nanopatterning Techniques
8.1 Introduction
8.2 Types of Nanopatterning Techniques
8.3 Nano-biopatterning
8.4 Chemical Patterning
8.5 Topographical Patterning
8.6 Combinatorial Patterning
8.7 3D Patterning
8.8 Factors Influencing Nanopatterning
8.9 Concluding Remarks
References
Chapter 9: Surface Modification of Metallic Implants with Nanotubular Arrays via Electrochemical Anodization
9.1 Introduction
9.2 Fabrication of Nanotubular Arrays on Metals via Electrochemical Anodization
9.3 Biocompatibility of Metals with Nanotubular Surfaces
9.4 Conclusion
References
Part IV: Nanobiomaterials in Biomedical Applications: Diagnosis, Imaging, and Therapy
Chapter 10: Nonconventional Biosensors Based on Nanomembrane Materials
10.1 Introduction
10.2 Soft Electronics
10.3 Injectable Electronics
10.4 Biodegradable Electronics
10.5 Conclusions
References
Chapter 11: Nanobiomaterials for Molecular Imaging
11.1 Introduction
11.2 Conclusion
References
Chapter 12: Engineering Nanobiomaterials for Improved Tissue Regeneration
12.1 Introduction
12.2 Extracellular Microenvironment: Role of Nanotopography
12.3 Type of Nanobiomaterials for Tissue Engineering
12.4 Applications of Nanobiomaterials to Tissue Regeneration
12.5 Conclusions and Future Perspectives
References
Chapter 13: Nanobiomaterials for Cancer Therapy
13.1 Introduction
13.2 Cancer Pathophysiology
13.3 Types of Cancer Treatment and Related NBMs
13.4 Current NBMs in Cancer Therapy
13.5 Conclusions
References
Chapter 14: Chemical Synthesis and Biomedical Applications of Iron Oxide Nanoparticles
14.1 Introduction
14.2 Chemical Synthesis of IONP (Fe
3
O
4
) NPs
14.3 Biomedical Applications of IONPs
14.4 Conclusion and Perspective
References
Chapter 15: Gold Nanoparticles and Their Bioapplications
15.1 Introduction
15.2 The Preparation of Various AuNPs
15.3 Optical Bioimaging Based on AuNPs
15.4 AuNPs for Theranostic Integration Platforms
15.5 Conclusions and Perspectives
References
Chapter 16: Silicon-Based Nanoparticles for Drug Delivery
16.1 Introduction
16.2 Porous Silicon Nanoparticles
16.3 Silicon Nanocrystals (Silicon Quantum Dots)
16.4 Porous Silica Nanoparticles
16.5 Conclusions
References
Chapter 17: Dendritic-Polymer-Based Nanomaterials for Cancer Diagnosis and Therapy
17.1 Introduction
17.2 Dendritic-Polymer-Based Nanomaterials for Cancer Diagnosis
17.3 Dendrimers as Drug Carriers for Cancer Therapy
17.4 Dendritic Polymers for Theranostics
17.5 Conclusion and Prospects
References
Part V: Biosafety and Clinical Translation of Nanobiomaterials
Chapter 18: Biosafety of Carbon-Based Nanoparticles and Nanocomposites
18.1 Introduction
18.2 Evaluation of Biosafety of Carbon-Based NMs
18.3 Carbon Nanotubes
18.4 Graphene and Its Derivatives
18.5 Carbon-Based NCs
18.6 Summary and Outlook
Acknowledgment
References
Chapter 19: Clinical Translation and Safety Regulation of Nanobiomaterials
19.1 Introduction
19.2 Key Examples of Nanobiomaterials in Clinical Applications
19.3 Safety of Nanobiomaterials
19.4 Prospective Future of Nanobiomaterials
References
Index
End User License Agreement
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Guide
Cover
Table of Contents
Preface
Part I: Introduction
Begin Reading
List of Illustrations
Chapter 1: Nanobiomaterials: State of the Art
Figure 1.1 3D nanofibrous scaffolds fabricated by electrospinning for vascular tissue engineering application. (a) Optical microscope micrograph of aligned P(LLA-CL) nanofibrous scaffold; (b) and (c) SEM micrographs showing the cell–matrix adhesion between the SMCs and the aligned P(LLA-CL) nanofibrous scaffold; Laser scanning confocal microscopy (LSCM) micrographs of immunostained a-actin filaments in SMCs after 1 day of culture, (d) on aligned nanofibrous scaffold, (e) on aligned nanofibrous scaffold, overlay image on the aligned fiber, and (f) on TCPS. (With permission from Xu
et al
. 2004 [49], Elsevier.) Currently, nanobiomaterials have been fabricated into 2D and 3D scaffolds for vascular tissue engineering applications, indicating enormous promise to promote the efficiency of vascular stents or grafts for tissue regeneration.
Figure 1.2 Schematic graphs of injured nerve regeneration in the central and peripheral nervous systems. (a) Central nervous system recovery process with glial scar tissue formation and (b) peripheral nervous system recovery process involving the activity of Schwann cells, macrophages, and monocytes.
Figure 1.3 Hierarchical structural organization of bone.
Chapter 2: Metallic Nanobiomaterials
Figure 2.1 Flowchart depicting the comparison of CG and UFG/NC materials.
Figure 2.2 Schematic showing the (a) ECAP, (b) HPT, and (c) ARB processes.
Chapter 3: Polymeric Nanobiomaterials
Figure 3.1 Schematic representation of the electrospinning setup.
Figure 3.2 Immobilization of fibronectin on PCL nanofibers through the coating process.
Figure 3.3 Nanotopography regulates ESC self-renewal. (a, b) Polymethylglutarimide (PMGI) nanofibrous surfaces serve as a cellular scaffold for maintaining self-renewal of mouse ESCs without murine embryonic fibroblasts (MEFs). (a) Bright field (top) and fluorescence images (middle) of R1-Oct4-EGFP mouse ESCs cultured on nanofibers at three different densities (i.e., low, medium, and high) and controls. Bottom panels show the density of PMGI nanofibers doped with Rhodamine 6G for visualization. (b) The number of colonies within 5 mm
2
after culturing for 3 days on various substrates. Data are presented as mean ± SD of three independent experiments (*
p
< 0.001, **
p
< 0.01,
n
> 3).
Figure 3.4 A representative heparin-/fibrin-based delivery system (HBDS)/nanofiber scaffold with 11 alternating layers of aligned electrospun PLGA nanofiber mats separated by HBDS containing 1 × 10
6
ADSCs is shown. (a–d) Micrograph showing the HBDS/nanofiber scaffold
in vitro
; the PLGA was labeled with fluorescein isothiocyanate (FITC) (green), the HBDS was labeled with Alexa Fluor 546 (red), and the ASC nuclei were labeled with Hoescht 33258 (blue) (scale bar = 200 lm). (b, inset) Scanning electron microscopy (SEM) image of the scaffold showing PLGA nanofiber alignment. (e) Micrograph showing the HBDS/nanofiber scaffold
in vivo
9 days after implantation in a tendon repair. Eleven alternating layers of PLGA and HBDS can be seen (i.e., six layers of PLGA and five layers of fibrin); the PLGA was labeled with FITC (green) (scale bar = 100 lm). (f) A schematic of the layered scaffold is shown.
Figure 3.5 Nanofibers with dexamethasone concentration gradient induce mouse bone-marrow-derived MSC differentiation. (a) Fluorescent images of MSC attachment and proliferation grown on dexamethasone gradient nanofibers. (b) Schematic diagram of MSC-specific differentiation induced by substrate (i). Alkaline phosphatase (osteocyte) and red-oil (adipocyte) staining images of MSC growth on nanofibers with dexamethasone concentration gradient (ii). Differentiation proportion of MSCs induced by substrate with different dexamethasone concentrations (iii).
Chapter 4: Carbon-Based Nanobiomaterials
Figure 4.1 Level of neuronal survival on (a) IrOx–graphene and (b) platinum.
Figure 4.2 Immunostaining of human MSCs on glass substrates, SWCNT, and oxygen-plasma-treated SWCNT (O-SWCNT) cultured with normal culture medium and human MSCs cultured on a glass slide with osteogenic-induced medium. Scale bars show 100 µm. (a) Bright-field pictures, (b) immunostaining of osteocalcin (OCN) at day 12 of culture, (c) gene expression of CBFA1, OCN, and ALP for human MSCs on the substrates at days 7 and 14 of culture (
n
= 5). The results show the enhanced osteogenic differentiation of human MSCs on O-SWCNT and SWCNT without any differentiation-inducing factors.
Figure 4.3 Selected biomedical applications of CNTs and graphene: (a) A schematic CNT-based electrochemical biosensor, (b) thermal pictures of mice after photothermal treatment with CNTs (top) and without treatment (bottom), (c) intratumoral injection of PEG–SWCNT complex to a mouse with tumor and its NIR photothermal treatment.
Chapter 5: Molecular Self-Assembly for Nanobiomaterial Fabrication
Figure 5.1 Peptide nanostructures. (a) Nanofiber formed from amphiphilic peptides that are composed of a hydrophobic alkyl tail, a short peptide sequence capable of forming intermolecular hydrogen bonding, a charged head, and a bioactive epitope. (With permission from Hartgerink
et al
. 2001 [81], The American Association for the Advancement of Science.) (b) Nanofiber formed from ionic self-complementary peptide. (With permission from Zhang 2003 [94], Nature Publishing Group.) (c) Nanotubes formed from cyclic peptides. (With permission from Fernandez-Lopez
et al
. 2001 [62], Nature Publishing Group.) (d) Nanotube and nanovesicle formed from amphiphilic peptides.
Figure 5.2 Schematic examples of nano-drug carriers, including nanocrystal, liposome, polymeric micelle, protein-based nanoparticle (NP), polymeric dendrimer, carbon nanotube, and polymer–drug conjugate.
Figure 5.3 Scheme of graphite forms. Graphene is a 2D carbon material. It can be wrapped up to form 0D fullerene, rolled up to form 1D carbon nanotubes, and stacked to form 3D graphite.
Chapter 7: Layer-by-Layer Technique: From Capsule Assembly to Application in Biological Domains
Figure 7.1 Schematic overview of LbL assembly. Diverse substrates (e.g., particles, fibers, membranes, surfaces) and layer materials (e.g., DNA, polymer, lipids, proteins, and nanoparticles) could be employed for the fabrication of multilayer (nano)film through LbL assembly.
Figure 7.2 LbL assembly of multilayer films on both planar and nonplanar substrates (i.e., particulate) using different stabilizing interactions. Interactions clockwise from top left: (a) electrostatic; (b) hydrogen bonding; (c) covalent bonding; (d) DNA hybridization; (e) stereocomplexation; (f) metal–ligand coordination; (g) hydrophobic; (h) host–guest; (i) halogen bonding; and (j) charge-transfer interactions (M. Van Koeverden (2015), personal communication).
Figure 7.3 Five major LbL assembly technologies. (a) Immersive assembly; (b) spin assembly; (c) spray assembly; (d) electromagnetic assembly; and (e) fluidic assembly.
Figure 7.4 Three major methods used for the preparation of multilayered particles. (a) Centrifugation; (b) microfluidics; and (c) eletrophoresis [13].
Chapter 8: Nanopatterning Techniques
Figure 8.1 Schematic representation of different types of nanopatterning techniques.
Figure 8.2 C 1s (A) and F 1s (B) XPS spectra of the SAMs prepared from the assembly solutions with different PFA fraction. (a–e) Pure OEG, 25% PFA, 50% PFA, 75% PFA, and pure PFA.
Figure 8.3 The morphology of MSCs on different −OH/−CH
3
mixed SAMs after 12 h of culture was examined by laser scanning confocal microscopy. Cells were fixed and stained for F-actin with AlexaFluor488 phalloidin (green). Cell nuclei were counterstained with DAPI (blue). (a) −OH; (b) −OH/−CH
3
(9/1 v/v); (c) −OH/−CH
3
(7/3 v/v); (d) −OH/−CH
3
(5/5 v/v); (e) −OH/−CH
3
(3/7 v/v); (f) −CH
3
.
Figure 8.4 Schematic representation of alignment of silane-based SAM on substrate: (a) an originally inert surface is unable to house any further surface modification without prior activation; (b) by depositing a layer of Si/SiO
x
onto the ceramic surface, this additional activation becomes possible; (c) the SAM itself is applied through the addition of a solution holding the desired molecules in such a way that a surface attachment is only possible in one specific direction; (d) after the reaction, the solution is retracted and an originally inert surface has been chemically activated and is capable of housing further molecules of various kinds [31].
Figure 8.5 Immunofluorescence staining of hESCs with neural and glial markers. (a, d) hESCs were immunolabeled for DAPI, Tuj1, and HuC/D. (b, e) hESCs were immunolabeled for DAPI,Tuj1, and MAP2. (c, f) hESCs were immunolabeled for DAPI, Tuj1, and Glial fibrillary acidic protein (GFAP). hESCs cultured for 5 days (a–c) and 10 days (d–f) on the 350-nm ridge/groove pattern arrays.
Figure 8.6 Schematic of the major steps involved in NIL.
Figure 8.7 Representing the R2P and R2R system for the lithography process.
Figure 8.8 Schematic illustration of the effects of stiffness of matrix and organization of cell-adhesive ligands on stem cells. (a) Matrix stiffness effect. The strong mechanical feedback from a stiff hydrogel leads to more activation of FA complexes and stronger cell tension. The corresponding inside-outside-in sensing leads to more osteogenesis. (b) RGD nanospacing effect. While focal adhesions are well formed on patterns of a small nanospacing, cells could not form cross-linked actin bundles above the critical adhesion nanospacing (around 70 nm). The large RGD nanospacing favors osteogenesis. The interesting RGD nanospacing effect implies an unknown outside-in signaling pathway.
Chapter 10: Nonconventional Biosensors Based on Nanomembrane Materials
Figure 10.1
Soft electronics
. (a) Schematic illustration of the transfer printing process. Membrane materials on a donor substrate are released by etching the intermediate sacrificial layer (certain points of the membranes are anchored on the substrate to prevent drifting during the etching process if necessary). A stamp is laminated on the donor substrate to pick up the membranes via a quick motion. To retrieve the nanomembranes, the stamp is pressed against a receiver substrate. By slowly peeling the stamp away, nanomembranes can be released on the target substrates (adhesive layer is applied on the receiver substrate if necessary).
Figure 10.2
Injectable electronics
. (a) Injectable micro-needle integrated with electronics with the blue (450 nm) μ-ILEDs being lighted.
Figure 10.3
Biodegradable electronics
. (a) Transfer printing process for biodegradable electronics. Si nanomembrane is first transfer printed onto Si/PMMA/D-PI substrate, followed by patterned deposition of dielectric and metallic materials. A top D-PI layer is deposited as a supporting layer for transfer printing. Both the top and the bottom D-PI layers are patterned into a mesh structure, and the device is released through PMMA undercut in acetone. PDMS stamp is used to pick up the device, followed by the etching of the bottom D-PI layer. The device is then retrieved on the PLGA substrate followed by a final etching of the top D-PI layer.
Chapter 11: Nanobiomaterials for Molecular Imaging
Figure 11.1 Structure of reporter nanomolecule system. Transmission electron microscope (TEM) images of (a) iron oxide nanoparticle with a very monodisperse distribution [24]. Selective area electron diffraction (SAED) image of (b) iron oxide nanoparticles [24], (c) gadolinium oxide nanoparticles [25], (d) CdS quantum dots [26] and gold nanoparticles [27]. Microbubble visualized by light microscopy (Scale bar equals 10 mm) [28]. (g) MRI relaxation behavior of Gadolinium oxide nanoparticles, (h) K-edge of gold nanoparticle showing x-ray attenuation [29], (i) fluorescent dependence on the size of quantum dots [30] and (j) absorption characteristics of organic semiconductor.
Figure 11.2 Common chemical structures used for coating nanoparticles, functionalizing nanoparticles, and chelating metals used as imaging reporters. Cyclodextran is far more the most common coating materials. It comprises polysaccharide made of glucose molecule. Polyethylene glycol, polyvinyl pyrrolidone, poly lactide and polycaprolactone, and polyvinyl alcohol are most common organic materials used for designing nanoparticles with considerably long blood circulation. Silicon oxide is considered an amorphous mesoporous coating with good biological tolerance. Liposomes are molecular assemblies composed of amphiphilic lipid chain such as dipalmitoylphosphatidylcholine (DPPC), and such assemblies resemble cells in the circulatory system. Carbodiimide, melamide, and biotin are common linker molecules used in molecular imaging, to link targeting ligands to the nanoparticles. Metal chelators such as DOTA, NOTA, and DTPA are low-molecular-weight materials which can chelate reporter molecules like gadolinium, iron, and other metals.
Figure 11.3 (a) Gadolinium-based polymeric nanoparticle exhibiting blood-pool property using MRI [55]. (b) cRGD-functionalized SPIOs imaging using MRI [56] (c) SPIOs labeled with Cu64 for PET imaging [57]. Herceptin-antibody-based molecular imaging data is shown using (d) MRI imaging of Her2 receptor [58] (e) near-infrared (NIR) QD imaging of Her2 binding in tumor [59] and (f) ultrasound using Her-Ab-mircobubbles [60].
Graph 11.1 Binding affinity, (a) concentration-dependent binding of nanoparticles on to Herceptin (cell surface receptor) expressing breast cancer cells. Circles (dark) coated nanorods (white) uncoated nanorods. Square (dark) coated nanospheres (white) uncoated nanospheres. (b) Particle binding “area under the curve” values for different nanoparticles with and without traztuzumab coating [84].
Chapter 12: Engineering Nanobiomaterials for Improved Tissue Regeneration
Figure 12.1 An illustration of a tissue-engineered nanobiomaterial scaffold for tissue regeneration.
Figure 12.2 A range of nanobiomaterials emerging for tissue regeneration (e.g., nerves, bone, and heart).
Figure 12.3 Applications of nanobiomaterials to tissue regeneration (e.g., nerves (A), bone (B), and heart (C)). (A) High-magnification confocal microscopy images taken from the cultured neurons on (a) the parallel-aligned and (b) the cross-linked CNT patterned substrate, and (c) the plain polystyrene substrates, respectively, after a 5-day culture. The solid black lines in parts a and b are the CNTs. (With permission from Fan
et al
. 2012 [73], American Chemical Society.) (B) Autologous-engineered bone transplantation. (a) Radiography of rabbit tibia before and after creation of cortical bone defect. Arrowhead indicates empty defect. (b) Magnified radiographs of rabbit tibia defects 6 weeks after transplantation of Gelfoam (control) and autologous bone from the bone bioreactor in the contralateral tibia. (c) H&E-stained sections of the defect site 6 weeks after transplantation of autologous bone. Arrowhead points to the integration between transplanted bone and cortical bone of the tibia. Ct, cortical bone. (With permission from Stevens
et al
. 2005 [74], National Academy of Sciences.) (C) Application of CNT–GelMA hydrogels to heart regeneration. (a) Schematic diagram illustrating the isolated heart conduction systems showing the heart muscle with Purkinje fiber networks on the surface of the heart muscle fibers. (b) SEM images show porous surfaces of a 1 mg ml
−1
CNT–GelMA thin film with nanofibrous networks across and inside a porous structure. (c) Phenotype of cardiac cells on CNT–GelMA hydrogels. (With permission from Shin
et al
. 2013 [57], American Chemical Society.)
Chapter 13: Nanobiomaterials for Cancer Therapy
Figure 13.1 Tumor angiogenesis and enhanced permeability and retention (EPR) effect. (A) Different stages and key events during angiogenic switch of tumor: tumors usually start to grow as avascular nodules (dormant stage) until a steady-state level of apoptosing and proliferating cells is reached. The process of angiogenic switch is required to guarantee the exponential tumor growth. It starts with perivascular detachment and vessel dilation, followed by sprouting of angiogenic, formulation and maturation of new vessel, then the perivascular cell recruiting. As long as tumor grows, the blood vessel formation will continue, providing essential nutrients and oxygen for the tumor.
Figure 13.2 Major treatment options of cancer therapy in the clinic and recent studies: (a) surgery (With permission from [36], by the authors © 2015.); (b) radiotherapy (With permission from [37], by the authors © 2013.); (c) chemotherapy (Reproduced from [38].); (d) photodynamic therapy (With permission from [39], by the authors © 2011.); (e) gene therapy (With permission from [40], by the authors © 2014.); and (f) immunotherapy [41]. (Andy Dean/Getty Images.).
Figure 13.3 Examples of NBM-based nanovectors applied in cancer therapy: (a) polymeric NPs (With permission from Tao
et al
. 2015 70, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.); (b) liposomes (Reproduced from [71], CC-SA-3.0/ Dennis Barten.); (c) QDs, which usually have a CdSe core (With permission from Bae
et al
. 2013 [72], American Chemical Society.); (d) gold NPs; (e) magnetic NPs (MNPs), usually iron oxide; (f) upconverting nanophosphors (UCNPs, With permission from Yang
et al
. 2012 [73], WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.); (g) nanotubes (Reproduced from [74], CC-AS-3.0/Michael Ströck.); and (h) micelles (With permission from Pasquali [75], Nature Publishing Group.).
Chapter 14: Chemical Synthesis and Biomedical Applications of Iron Oxide Nanoparticles
Figure 14.1 Transmission electron microscopy (TEM) image of spherical Fe
3
O
4
nanoparticles synthesized by (a) co-precipitation method. (With permission from Hui
et al
. 2008 [19], American Chemical Society.) (b) Microemulsion. (With permission from Chin and Yaacob 2007 [20], Elsevier B.V.) (c) Polyol method. (With permission from Cai and Wan 2007 [21], Elsevier Inc.)
Figure 14.2 TEM image of (a) octahedral Fe
3
O
4
nanoparticles obtained at a high temperature in the mixture of tetracosane and oleylamine. (With permission from Zhang
et al
. 2009 [27], American Chemical Society.) (b) Spherical Fe
3
O
4
nanoparticles synthesized by Sun. (With permission from Sun and Zeng 2002 [28], American Chemical Society.) (c) Spherical Fe
3
O
4
nanoparticles synthesized using oleylamine as both reducing agent and stabilizer. (With permission from Xu
et al
. 2009 [29], Royal Society of Chemistry.)
Figure 14.3 TEM image of (a) spherical Fe
3
O
4
nanoparticles synthesized at 140 °C for 6 h without using the surfactants. (With permission from Wang
et al
. 2003 [33], Elsevier Science Ltd.) (b) Spherical Fe
3
O
4
nanoparticles with diameter of 27 nm in the presence of a surfactant, sodium bis(2-ethylhexyl)sulfosuccinate (AOT). (With permission from Zheng
et al
. 2006 [34], Elsevier Ltd.)
Figure 14.4 (a)
T
2
-weighted spin echo MR images of IONPs and SHP15 at different concentrations; (b)
T
2
-weighted MR images of a mouse before and after injection of casein-coated iron oxide nanoparticles (CNIOs) at a dosage of 2.5 mg Fe/kg per mouse body weight.
Figure 14.5 A schematic illustration showing the composition of a multifunctional nanoparticle-polyethylene glycol (MFNP-PEG) and the concept of
in vivo
imaging-guided magnetically targeted photothermal therapy. The magnetic field around the tumor region induces local tumor accumulation of multifunctional nanoparticles (MFNPs).
Figure 14.6 (a) Schematic illustration of drug delivery system based on hollow iron oxide NPs. (b) confocal laser scanning microscopy (CLSM) visualization of free drug and drug-loaded iron oxide NP uptake by resistant (OVCAR8-ADR) cells. Drug DOX is in red and cancer cell nuclei are stained blue (4′,6-diamidino-2-phenylindole).
Figure 14.7 (a–c) Targeting and magnetic manipulation of Ab-Zn-MNPs. (a,b) Ab-Zn-MNPs selectively bind to the specific cell-surface Tie2 receptors. (c) In the presence of an external magnetic field, the Ab-Zn-MNPs are magnetized to form nanoparticle aggregates, which then induce the clustering of receptors to trigger intracellular signaling. (d) Tie2-receptor-bound nanoparticles before and after application of the magnetic field.
Chapter 15: Gold Nanoparticles and Their Bioapplications
Figure 15.1 (a) Schematic illustration of APMNs composed of metal cores and amphiphilic BCP coronas, and the assembly structures. (b) Representative TEM image of vesicular assemblies of PS-34-Au-5. (c) SEM and (d) TEM images of vesicular assemblies of PS-34-Au-40.
Figure 15.2 (a) Schematic illustration of the amphiphilic AuNP coated with Raman reporter BGLA, mixed polymer brushes of hydrophilic PEG and pH-sensitive hydrophobic PMMAVP grafts, and the drug-loaded plasmonic vesicle tagged with HER2 antibody for cancer cell targeting. (b) The cellular binding, uptake, and intraorganelle disruption of the SERS-encoded pH-sensitive plasmonic vesicles.
Figure 15.3 (a–e) TEM images, (f) one- and two-photon excitation fluorescence enhancement factors, and (g) fluorescence lifetime decay of AuNR/SiO
2
-T790 with different silica shell thickness (13, 20, 28, 34, 42 nm) in DMF solutions (scale bar is 20 nm). The two-photon excitation (TPE) efficiency enhancement, estimated from the ratio of TPEF enhancement factor to quantum yield enhancement factor, is also plotted in (f). IRF in (g) is the instrument response function.
Chapter 16: Silicon-Based Nanoparticles for Drug Delivery
Figure 16.1 Synthesis of porous silicon nanoparticles. (a) Schematic description of the electrochemical etching synthesis of porous silicon, followed by sonication. (With permission from Sailor and Wu 2009 [11], WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) (b) Scanning electron microscopy (SEM) image of a porous silicon sample made through photolithography. (With permission from Jiang
et al
. 2015 [20], Nature Publishing Group.) (c) Transmission electron microscopy (TEM) image of a typical porous silicon nanoparticle sample synthesized by electrochemical etching. (d) Size control of porous silicon nanoparticles by creating samples with low porosity–high porosity periodical superstructures. The
X
-axis of the plot corresponds to the thickness of the low-porosity layer, while the
Y
-axis stands for the hydrodynamic diameter of the final nanoparticles. The blue squares represent samples with 50 nm of high-porosity layer, and the red solid circle is a control sample that does not have the low porosity–high porosity periodical superstructure. (With permission from Qin
et al
. 2014 [21], WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.).
Figure 16.2 (a) Plot of porosity against etching current density for porous silicon formed in a 25% HF electrolyte by using a heavily p-type doped silicon wafer as anode. (b) Plot of porosity against HF concentration for porous silicon formed on a heavily p-type doped silicon wafer anode by applying various etching current densities. (With permission from Herino
et al
. 1987 [22], The Electrochemical Society.) Plane view SEM images of porous silicon formed on a 0.05 Ω cm n-type doped silicon wafer in an ethanolic KOH electrolyte by applying 50 mA cm
−2
etching current for (c) 2 min and (d) 8 min. (With permission from Tinsley-Brown
et al
. 2000 [23], WILEY-VCH Verlag Berlin GmbH, Fed. Rep. of Germany.) Cross-section SEM images of porous silicon formed on a (e) 0.005 Ω cm p-type doped wafer and (f) 0.05 Ω cm n-type doped wafer. (With permission from Canham 1990 [18], AIP Publishing LLC.) Schemes showing surface termination for (g) as-synthesized porous silicon and porous silicon that are treated with (h) oxidation and (g) hydrosilylation.
Figure 16.3 (a) PEG-coated porous silicon nanoparticle dispersion emitting red fluorescence upon excitation by a UV lamp. (b) UV–vis absorption and photoluminescence (PL) spectra of PEG-coated porous silicon nanoparticles, showing absorption in the UV-blue range and emission in the red and near-infrared range. The excitation wavelength used for PL spectroscopy is 370 nm. (c) PL decay data of PEG-coated porous silicon nanoparticles. (d) The live mouse used in the
in vivo
imaging study. (e) Fluorescence signal distribution pattern acquired in the continuous-wave imaging, showing signal from both porous silicon nanoparticles and tissue autofluorescence. (f) Fluorescence signal distribution pattern acquired in the time-gated imaging, showing fluorescence signal mostly from porous silicon nanoparticles. (With permission from Gu
et al
. 2013 [28], Nature Publishing Group.)
Figure 16.4 Schematic descriptions of (a) covalent binding, (b) physical adsorbing, and (c) oxidation-induced physical trapping mechanisms for loading drugs into porous silicon nanoparticles.
Figure 16.5 Various pathways of drug-loaded porous silicon nanoparticles that are administered intravenously to an animal body.
Figure 16.6 Schematic descriptions of (a) solid-state and (b) gas-state synthesis of silicon nanocrystals. (With permission from Mangolini and Kortshagen 2007 [44], WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Figure 16.7 (a) Scheme showing a thermal or UV-irradiation-initiated hydrosilylation between terminal alkenes and hydride-terminated silicon nanocrystals. (b) Representative FTIR spectrum proving the success of hydrosilylation. (With permission from Hessel
et al
. 2010 [5], WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) (c) Scheme showing room temperature hydrosilylation with bifunctional alkenes. (d) Representative FTIR spectrum proving the success of room temperature hydrosilylation. (With permission from Yu
et al
. 2013 [3], American Chemical Society.) (e) Scheme showing thiolation between hydride-terminated silicon nanocrystals and alkyl thiols. (f) XPS S 2p spectra of thiolate-capped 2.5- and 5.0-nm silicon nanocrystals, showing size-dependent S 2p binding energies of thiolate-capped silicon nanocrystals that are clearly different from the binding energy of free thiols. (With permission from Yu
et al
. 2015 [45], American Chemical Society.)
Figure 16.8 TEM images of monodisperse (a) 2.5-nm (With permission from Yu
et al
. 2013 [47], WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) and (b) 6.1-nm diameter dodecene-capped silicon nanocrystals that self-assemble into ordered structures. (With permission from Yu
et al
. 2013 [48], American Chemical Society.) (c) Representative normalized photoluminescence spectra of dodecene-capped silicon nanocrystals with various average diameters. (d) High-resolution transmission electron microscopy image of dodecene-capped silicon nanocrystals on a lacey carbon substrate that shows both crystalline silicon cores and amorphous capping ligand layers. (Yixuan Yu at The University of Texas at Austin.) (e) Representative normalized XRD patterns of dodecanethiol-capped silicon nanocrystals with various average diameters, showing diffraction peaks indexed to diamond cubic silicon structure and peak broadness corresponding to the nanocrystal average diameter. (With permission from Yu
et al
. 2015 [45], American Chemical Society.)
Figure 16.9 (a) Scheme showing drug molecules covalently attached to a silicon nanocrystal. (b) Scheme showing drug molecules loaded into the hydrophobic region of an amphiphilic-shell-coated silicon nanocrystal. (c) Scheme showing silicon nanocrystals and drugs are co-incorporated into the hydrophobic core of a surfactant micelle, in which silicon nanocrystals are used as fluorescent tags to track the drug delivery.
Figure 16.10 Energy diagram of silicon nanocrystals showing the possible routes of harvesting excitation energy for fluorescence imaging, photothermal therapy, and photodynamic therapy. Silicon nanocrystals could be excited by absorbing one blue or UV photon (1PA) or by absorbing two red or near-infrared photons (two-photon absorption, TPA).
Figure 16.11 Porous silica nanoparticle formation mechanism: (a) silica precursor casting on the preformed liquid crystal templates; and (b) self-assembly mediated by the template–silica precursor interactions. (With permission from Hoffmann
et al
. 2006 [65], WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Figure 16.12 Possible mechanisms of “gated” drug releasing from porous silica nanoparticles. (a) Chemical stimuli irreversibly remove the particles or molecules that block the pores and induce drug release. (b) Optical stimuli reversibly introduce conformational changes for photoswitchable molecules, switch porous silica nanoparticle between “on” and “off” states for drug releasing, leading to programmable drug releasing profile.
Chapter 17: Dendritic-Polymer-Based Nanomaterials for Cancer Diagnosis and Therapy
Figure 17.1 (a) Synthetic illustration and structures of peptide CLT1-targeted nanoglobular contrast agents; (b, c) contrast-to-noise ratio (CNR) of blood in the heart and the tumor with G2, G3, and peptide-targeted G2(P-G2) and G3(P-G3) nanoglobular MRI contrast agents administrated at 0.03 mmol Gd kg
−1
in nu/nu female nude mice, respectively (
*
P
< 0.05); (d) biodistribution profiles (
n
= 3) of gadolinium content in major organs and tissues for G2, G3, and peptide-targeted G2(P-G2) and G3(P-G3) nanoglobular MRI contrast agents at 48 h after administration (
*
P
< 0.05).
Figure 17.2 Structures and illustration of (a) dendron–DOX conjugate and (b) its nanoparticle. (c) The nanoparticles were confirmed via TEM. (d)
In vivo
anticancer studies showed the polymeric nanoparticles demonstrated significant enhanced anticancer efficacy compared to free drug DOX (DOX) and saline in the breast tumor model (
n
= 7).
Figure 17.3 Schematic illustration of the structure of copoly(EOEOVE-
block
-ODVE) and PAMAM-dendrimer-based liposome with temperature-controlled drug release feature and DOTA-Gd MRI imaging probes.
Chapter 19: Clinical Translation and Safety Regulation of Nanobiomaterials
Figure 19.1 Schematic representation of different mechanisms by which nanocarriers can deliver drugs to tumors. Passive tissue targeting is achieved by extravasation of nanoparticles through increased permeability of the tumor vasculature and ineffective lymphatic drainage (EPR effect). Active cellular targeting (inset) can be achieved by functionalizing the surface of nanoparticles with cell-specific ligands.
Figure 19.2 Examples of nanocarriers for targeting cancer. (a) Types of delivery agents are possible but the main components typically include a nanocarrier, a targeting moiety, and a cargo (chemotherapeutic drugs, pDNA, microRNA, and proteins) and the carriers including polymer, inorganic, metal, dendrimers, and some other particulate carriers. (b) Schematic diagram of the drug conjugation and entrapment processes. The cargos could be bound to the nanocarrier, or they could be entrapped inside the nanocarrier.
Figure 19.3 Higher magnification of the mineralized collagen fibrils. Inset is the selected area electron diffraction pattern of the mineralized collagen fibrils. The asterisk is the center of the area and the diameter of the area is about 200 nm.
Figure 19.4 The tissue-specific extravasation of nanomaterials. (a) The hepatic sinusoidal endothelial cells possess open fenestraes sized 100–200 nm for nanomaterials diffusion, and smaller particles (10–20 nm) are removed from blood via rapid liver uptake. (b) In sinusoidal spleen (as in rat and humans), blood flows through the discontinuous capillary into the splenic venous system. Nondeformable entities sized above 200 nm may be cleared from blood by splenic filtration. (c) The capillary fenestraes in the glomeruli have size between 10 and 100 nm, but the basal lamina can block the penetration of particles larger than 5 nm. (d) The endothelia of lung, muscle, and bone capillaries are generally characterized by a continuous morphology that allows only small particles sized below 3 nm to cross the interendothelial cell slits. (e) The blood concentration of PEG-SWCNTs versus time following intravenous administration to mice. (f) The translocation to the secondary target organs and the intertissue redistribution of nanoceria via blood circulation.
List of Tables
Chapter 2: Metallic Nanobiomaterials
Table 2.1 Grain size and hardness comparison between conventional and metallic nanobiomaterials
Table 2.2 Composition of physiological solution
Table 2.3 Published studies of cell interactions with titanium metallic nanobiomaterials [31]
Chapter 8: Nanopatterning Techniques
Table 8.1 Progress of nanotopographical patterning
Chapter 11: Nanobiomaterials for Molecular Imaging
Table 11.1 Molecular imaging modalities and corresponding reporter molecules
Table 11.2 Few well-studied molecular targets and their corresponding ligands
Chapter 14: Chemical Synthesis and Biomedical Applications of Iron Oxide Nanoparticles
Table 14.1 Summary comparison of the synthetic methods [40, 41]
Table 14.2 Characteristics of superparamagnetic iron oxide (SPIO) agent: commercial or under clinical investigation [53]
Chapter 18: Biosafety of Carbon-Based Nanoparticles and Nanocomposites
Table 18.1 Methods for evaluation of
in vitro
cytotoxicity.
Table 18.2 Summary of studies on the
in vitro
biosafety of CNTs to date.
Table 18.3 Summary of studies on the
in vivo
biosafety of CNTs to date.
Table 18.4 Summary of studies on the
in vitro
biosafety of graphene and its derivatives to date.
Table 18.5 Summary of studies on the
in vivo
biosafety of graphene and its derivatives to date.
Chapter 19: Clinical Translation and Safety Regulation of Nanobiomaterials
Table 19.1 List of liposomal nanobiomaterials in clinical applications and trials
Table 19.2 List of metal and inorganic nanobiomaterials in clinical applications
Nanobiomaterials
Classification, Fabrication and Biomedical Applications
Edited by XiuMei Wang, Murugan Ramalingam, Xiangdong Kong, and Lingyun Zhao
Editors
Prof. XiuMei Wang
Tsinghua University
School of Materials Science and Engineering
Yifu Technology & Science Building
100084 Beijing
China
Dr. Murugan Ramalingam
Christian Medical College Campus
Centre for Stem Cell Research
IDA Scudder Road
632002 Vellore
Tamil Nadu
India
Tohuku University
WPI-Advanced Institute for Materials Research
Sendai 980-8577
Japan
Prof. Xiangdong Kong
Zhejiang Sci-Tech University
College of Materials and Textiles
No. 2 Road, Xiasha,
310018 Hangzhou
China
Prof. Lingyun Zhao
Tsinghua University
School of Materials Science and Engineering
Yifu Technology & Science Building
100084 Beijing
China
Cover credit: gettyimages: enot-poloskun
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Preface
Over the past decade, the integration of advances in materials and life sciences with cutting-edge nanotechnologies has driven biomaterials science into the “nano era.” A new term, nanobiomaterials which describes biomaterials with the constituent or surface feature sized between 1 and 100 nm, but usually 1–100 nm in at least one dimension, has emerged and caused great attention, either in research or industry. Because of their unique nano effects and characteristics, nanobiomaterials possess extraordinarily unique structures and properties. Therefore, nanobiomaterials have blossomed into one of the most important branches in biomaterials, which show great promise in biomedical applications, such as regenerative medicine, cancer therapy, molecular imaging and theranostics, diagnostics, and drug delivery. In the next decade, the applications of nanobiomaterials in the biomedical area will definitely get major breakthroughs and even create more fantastic modern medical techniques.
This book, Nanobiomaterials: Classification, Fabrication, and Biomedical Applications, aims to address state-of-the-art research progresses in the field of nanobiomaterials. The main topics include nanotechnologies for nanobiomaterials fabrication, developments in biomedical applications, and the challenges of biosafety in clinical applications. The book defines the scope and classification of the field of nanobiomaterials and compiles a broad spectrum from fundamental principles to current technological advances, from materials synthesis to biomedical applications along with future prospects.
The book consists of a collection of invited chapters contributed by leading researchers around the world. Chapter 1 firstly defines the scope of nanobiomaterials and reviews the current status and future perspectives. Then, multiple classes of nanobiomaterials are presented. Next, five typical nanotechnology-based approaches exemplify the methods and ideas in biomaterials fabrications. More than that, the book provides a detailed overview of the biomedical applications of nanobiomaterials ranging from tissue regeneration to molecular diagnosis, imaging, and therapy. Finally, it also highlights the biosafety issues associated with nanobiomaterials, including the biocompatibility and regulation for clinical translation.
Currently, the field of nanobiomaterials is in a rapidly developing period with fast-moving changes every day. The development of novel nanobiomaterials depends on the advanced nanotechnologies and biotechnologies, and vice versa. The strategies for designing and synthesizing nanobiomaterials introduced in this book are not only suitable for biomedical applications but also for other applications such as microelectron, new energy, and environment science. Therefore, the main target audiences are researchers and other professionals working in the fields of, but not limited to, materials science and engineering, biomaterials, life sciences, biomedical devices, medicine, and nano-science. And, the book might be useful for graduate students who could also be our audience.
Beijing, November 2016
Xiumei WangMurugan RamalingamLingyun ZhaoXiangdong Kong
Part IIntroduction
Chapter 1Nanobiomaterials: State of the Art
Jing Wang1, Huihua Li2, Lingling Tian3 and Seeram Ramakrishna3,4
1Donghua University, College of Chemistry and Chemical Engineering and Biotechnology, 2999 North Renmin Road, Shanghai, 201620, China
2Jinan University, College of Science and Engineering, Department of Material Science and Engineering, Biomaterial Research Laboratory, 601 Huangpu Road, Guangzhou, 510632, China
3National University of Singapore, Center for Nanofibers and Nanotechnology, Department of Mechanical Engineering, 2 Engineering Drive 3, Singapore, 117576, Singapore
4Jinan University, Guangdong-Hongkong-Macau Institute of CNS Regeneration (GHMICR), 601 Huangpu Road, Guangzhou, 510632, China
1.1 Introduction
Nanoscience and nanotechnology, an interdisciplinary research activity that deals with sub-nanometer to several hundred nanometer materials, has been developing explosively worldwide in the past decade. Biomaterial is the material used for diagnosis or treatment of disease, evaluation, repair, or replacement of any tissue, organ, or function of the body [1]. Nanobiomaterial – the combination of nanotechnology and biomaterials – has provided great opportunities to improve the preclusion, diagnosis, and treatment of various diseases. Nanobiomaterial, traditionally defined as a special category of biomaterials with constituent or surface sizes not more than 100 nm [2], is a new class of extraordinary materials with unique structures and properties such as mechanical, optical, and electrical compared to bulk traditional materials with microscopic or macroscopic structures. It has been broadly applied in a wide range of biological and biomedical applications such as tissue engineering, drug delivery, imaging and biosensor, and so on. These nanobiomaterials include nanoparticles, nanotubes, nanofibers, and so on.
Although nanobiomaterials have been applied to many aspects of biomedical fields, the accurate interface interaction between cells/tissues and materials is not completely clear. The safety and toxicity of nanobiomaterials have caused extensive concern at both occupational and research levels. Biocompatibility is an essential issue that requires evaluation for a nanobiomaterial under consideration for clinical application. Currently, researches on nanobiomaterials have entered a more comprehensive and systematic stage. The researchers are seeking further understanding of the mechanism behind the biological response to biomaterials and better design of such materials.
The absolute efficiency of nanobiomaterials on the human body has not been confirmed completely and the full benefit of nanobiomaterials cannot be evaluated precisely at this stage. Therefore, it is meaningful to review the current state of the art regarding the application of nanobiomaterials. This chapter provides a discussion on prospective applications of nanobiomaterials in different biomedical fields covering tissue engineering, drug delivery, imaging, and so on. In addition, an overview of the unique properties of nanoscale materials, the assessment of biocompatibility and toxicity, and the future development is also presented.
1.1.1 Properties of Nanobiomaterials
Nanomaterials refer to those materials with constituent components or surface sizes within 1–100 nm in at least one dimension [3], and the definition has been extended to several hundred nanometers today. Nanomaterials possess numerous novel and significantly changed properties, such as mechanical, electrical, magnetic, optical, and others [4], compared to those traditional materials in the micron or larger scales. Firstly, nanomaterials have much larger specific surface area than their conventional forms, which is beneficial to greater biochemical reaction. Secondly, the mechanical properties such as yield strength and ductility are enhanced because of the many mechanisms hinging on their chemistry such as grain boundary sliding and short-range diffusion healing. Thirdly, the nanostructure can lead to novel optical, electrical, and magnetic properties for materials due to the quantum effects playing a prior role in determining the properties and characteristics in nanoscale. In addition, the homogeneousness and purity in ingredient and structure are improved due to reaction or mixture at the molecular and atomic levels. These novel and unique properties enable nanomaterials to be suitable candidates for applications in electronics, medicine, and other fields. Specifically, nanobiomaterials possess some important properties provided by nanoscale structures. First, the chemical properties and structure are similar to the native tissues with nanometer hierarchical components. For example, the collagen fibers and nanosized hydroxyapatite (HA) can mimic the components of bone tissue. Second, researchers can easily identify, handle, and mediate biocomponents because of the comparable size of nanoscale materials to biomolecules and bio-microstructures. At last, it is possible to modify the surface properties of nanostructured materials through advanced techniques [5].
1.1.2 Interaction between Nanobiomaterials and Biological System
The nanometer-scaled functional elements in the biological system determine that the interaction between nanobiomaterials and the biological system is at the molecular level [6], and the understanding of the interactions between them is of great importance. For example, embryonic and adult stem cell behavior can be controlled by modifying the material surface with intrinsic signals (e.g., growth factors and signaling molecules) if the interaction between a particular nanobiomaterial and stem cells could be understood [5, 7]. Up to now, details of the reaction at the interface between nanobiomaterials and biological systems (e.g., cells, blood, and tissues) have not been completely understood. Given the current knowledge, the interaction between cells and biomaterials surface at the cellular and molecular level can be described as the interaction between the binding sites on the surface of the cell membrane and nanobiomaterials. In the physical environment, the interaction between cells and biomaterials is actually the molecular recognition between the receptors on the cell membrane and the ligand on the biomaterials surface, followed by a series of biological specific and nonspecific interactions. The previous researches showed that a sequence of events occur at the interface between biomaterials and cells [8, 9]. Firstly, the proteins in blood and tissue fluids are adsorbed onto the nanomaterial surface and protein desorption also usually occurs in the meantime. Then the tissue cells and/or immunocytes come close to the biomaterials. Next, the matrix proteins released from the biomaterial and specific proteins are adsorbed selectively. Eventually, the cells adhere to the surface of biomaterials and commencement of subsequent cell functions (the proliferation, migration, differentiation, and phagocytosis) occurs. These are a series of host responses toward the nanobiomaterials. Correspondingly, there is also a sequence of material responses to the host such as material decomposition that exists at the interface between cells and nanobiomaterials [9]. These events truly reflect the cytocompatibility and inflammatory/immune host responses that eventually determine the efficiency and safety of nanobiomaterials, which are vital for the successful design and application of nanobiomaterials. Thus, the deep understanding of the interaction between nanobiomaterial surface and cells is the key to clinical application of nanobiomaterials.
The response between cells/tissues and biomaterials can be altered or controlled by the surface properties of materials [3, 10, 11], such as topography, surface chemistry, charge, and energetics, which are closely related to cell or tissue responses [3, 10–16], due to the fact that cells/tissues can recognize the surface properties and synthesis nature of nanobiomaterials both in vitro and in vivo. Surface modification of biomaterials can make specific recognition sites for cellular and molecular responses, which has been widely applied in modulating cell and tissue responses by nanobiomaterials both in vitro and in vivo.
1.1.3 Biocompatibility and Toxicity of Nanobiomaterials
Nanobiomaterials have been applied to tissue engineering applications, and the researches demonstrated that nanobiomaterials can enter the body through different ways [17]. There is a well-developed system called the immune system in the human body which can protect it from invading organisms such as bacteria, viruses, and other parasites. The nanomaterial implanted into the body may be identified as foreign matter and consumed by immune cells. The pathway and route of biomaterial-like particles into the human body rest with the size, even at the nano-level. The agglomeration of nanobiomaterials is one of the vital factors that can affect their toxicity [18]. A research showed that the aggregation of nanoparticles can be problematic and even cancer may be induced because of the shape of nanomaterials [19]. The biocompatibility and toxicity of nanostructured biomaterials are important issues that require investigation for clinical development. For example, the nanoparticles used to deliver drugs to targeted cells can normally traverse the cell membranes and be uptaken by the cells. Moreover, many implants undergo biodegradation in vivo. The effect of degradation on the cells and tissues in the physiological environment should be investigated [20]. The toxicity of nanobiomaterials is mostly dependent on the materials. In addition, the toxicity levels of a nanobiomaterial can also be affected by surface modification and functionalization. The evaluations of biocompatibility and toxicity of the nanobiomaterials are indispensable.
Presently, a series of in vitro and in vivo researches have been launched on the biocompatibility and toxicity of nanobiomaterials. As for the in vitro investigations, the influence of nanobiomaterials on cell morphology and cellular functions including proliferation, differentiation, and mineralization will be studied by microscopy and the gene/protein expressions with various biochemical analyses. The negative effects of nanobiomaterials in vivo usually include oxidative stress, inflammation, granulomas, and fibrosis. In order to see if nanobiomaterials trigger severe inflammation reaction and cause significant effects on the normal functions of the surrounding tissues or main organs, the materials are implanted into the animal body, and further histological, histopathological, and immunohistochemical studies are conducted [20]. Although there are existing methods to assess the biocompatibility and toxicity of the nanobiomaterials, they are nowhere near enough. Further researches such as deeper analytical approaches to animal experiments and much more convincing mechanisms on this issue are necessarily needed. For example, it has been shown that the toxic effects of carbon nanobiomaterials partially depend on the aspect ratio [21], but the actual toxicity levels of carbon nanotubes (CNTs) is still a debatable issue. It is necessary to improve the current measurement accuracy of biocompatibility and toxicity, and it is essential to establish more appropriate methods to evaluate the long-term safety of nanobiomaterials both in vitro and in vivo. Most importantly, it is urgent to find more effective methods to improve the biocompatibility and reduce the cytotoxicity of nanobiomaterials.
1.2 Nanobiomaterials for Tissue Engineering Applications
Tissue engineering, with the goal of developing or identifying appropriate biomaterials able to facilitate the desired cell behaviors and tissue functions, is promising to restore partial or even full functionality once a defect has occurred in tissues or organs [22]. The fine structure of nanobiomaterials, allowing direct mechanical interactions with cell surface receptors and cellular components and providing guidance for cells, usually serves as a microenvironment in which rich extracellular matrices (ECMs) and various cell types reside for tissue regeneration application [23]. Nanobiomaterials have been used in a wide range of tissue engineering applications in various basic structural units, such as nanoparticles, nanofibers, nanotubes, and nanofilms, to fulfill the specific requirements of different biological substitutes that repair or replace malfunctioning tissues and organs with separate physiological functions [24], which are reviewed in this section.
1.2.1 Vascular Tissue Engineering
There are three distinct layer structures in native blood vessels. The inner layer is composed of an endothelial cell layer with an anticoagulant function, the middle layer is composed of smooth muscle cells (SMCs) embedded in a three-dimensional ECM, and the outer adventitial layer is connective tissue composed of fibroblast cells. There are nanostructured collagen and elastin in ECM. Some studies found that cells of vascular tissues indeed can interact with nanomolecules in vivo [25–28]. There is an urgent requirement for an appropriate approach to replace vascular tissues that have been damaged or lost due to injury or disease. Currently, the therapy for damaged vessels involves replacement of the vessels with autografts or allografts or artificial vascular grafts with a structure similar to that of the native blood vessel [29]. However, due to the formation of thrombus and compliance incongruity, most synthetic materials used in vascular grafts have been indicated to be prone to clot and fail, and do not function well in the long term [30, 31]. Numerous methods have been used to fabricate artificial blood vessels with structures and functions similar to that of the native ones [32–35]. The vascular tissue engineering approach is used to overcome the defects of traditional vascular substitutes, particularly referring to small-diameter (≤6 mm) vascular grafts. Nanomaterials have been used to mimic these actual nanostructures in vascular tissues. Various nanobiomaterials have been designed, fabricated, and modified to promote and control the function of vascular endothelial cells and SMCs and to overcome associated problems such as inflammation and thrombosis [24].
The desired vascular graft should have good mechanical property, which enables it to resist long-term blood pressure [36, 37]. Nanofibers, nanopatterns, and nanostructured materials have been fabricated to increase the mechanical strength of vascular grafts [38]. Besides, good biocompatibility is an important consideration for the design of vascular grafts, which requires that these constructs possess structures similar to that of native blood vessels and natural ECM [39]. A number of recent studies have indicated that nanomaterials are able to increase vascular cell (especially endothelial and SMCs) function such as the adhesion, proliferation, and synthesis of related collagen and elastin [40–44]. Choudhary et al. reported that the nanostructured surface on Ti greatly promoted the adhesion and proliferation of vascular endothelial cells compared to conventional Ti. It was also found that endothelial cells showed greater competitive functions than that of SMCs on the nanostructured Ti surface, which indicated that vascular endothelial cell functions were improved over that of vascular SMCs. Therefore, the endothelialization on nanostructured stents may be increased and vascular restenosis can be limited [41]. Miller et al. created poly(lactic-co-glycolic-acid) (PLGA) vascular grafts [43, 45, 46] with nanometer surface features that stimulated proliferation of both vascular endothelial cells and SMCs compared to the conventional PLGA scaffold [45]. It also proved that the PLGA scaffold with nanostructure improved adsorption of fibronectin and vitronectin from serum compared to the conventional PLGA scaffold [46]. Hence, the nanostructured PLGA can lead to greater vascular cell response. In addition, the influence of PLGA with different nanometer surface features (500, 200, 100 nm) on vascular responses was studied. It showed that the vascular cell response was promoted by PLGA with 200-nm surface features and there was greater fibronectin interconnectivity than with smooth PLGA and PLGA with 500-nm surface structures [43].
Apart from nanoscaled surface l structures, 3D nanofibrous scaffolds have been fabricated for vascular tissue engineering application via electrospinning [47, 48]. Xu et al. fabricated poly(l-lactide-co-ϵ-caprolactone) P(LLA-CL) scaffolds with diameter of 400–800 nm by electrospinning [49], and they found that the adhesion and proliferation of vascular endothelial cells and human SMCs were both supported by these nanofibrous scaffolds that could mimic the nanoscaled dimensions of native ECM (Figure 1.1). Cells cultured on nanofibrous scaffolds could preserve their phenotype and then be integrated with nanofibers to form 3D ECM. Hashi et al. fabricated poly-l-lactic acid (PLLA) nanofibrous scaffolds [50] for culturing vascular SMCs and mesenchymal stem cells (MSCs) for 2 days, suggesting that cells had a cellular organization like that of native blood vessel. In addition, the nanofibrous grafts were also implanted in the carotid artery of rats for up to 60 days, and results showed that the nanofibrous scaffold combined with MSCs possessed antithrombotic and anti-immune functions. The nanofibrous structure enhanced recruitment of vascular cells in vivo and promoted the organization of a layered structured similar to that of the native blood vessel. In
