Bioceramics and Biocomposites E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
Provides comprehensive coverage of the research into and clinical uses of bioceramics and biocomposites Developments related to bioceramics and biocomposites appear to be one the most dynamic areas in the field of biomaterials, with multiple applications in tissue engineering and medical devices. This book covers the basic science and engineering of bioceramics and biocomposites for applications in dentistry and orthopedics, as well as the state-of-the-art aspects of biofabrication techniques, tissue engineering, remodeling, and regeneration of bone tissue. It also provides insight into the use of bionanomaterials to create new functionalities when interfaced with biological molecules or structures. Featuring contributions from leading experts in the field, Bioceramics and Biocomposites: From Research to Use in Clinical Practice offers complete coverage of everything from extending the concept of hemopoietic and stromal niches, to the evolution of bioceramic-based scaffolds. It looks at perspectives on and trends in bioceramics in endodontics, and discusses the influence of newer biomaterials use on the structuring of the clinician's attitude in dental practice or in orthopedic surgery. The book also covers such topics as biofabrication techniques for bioceramics and biocomposites; glass ceramics: calcium phosphate coatings; brain drug delivery bone substitutes; and much more. * Presents the biggest trends in bioceramics and biocomposites relating to medical devices and tissue engineering products * Systematically presents new information about bioceramics and biocomposites, developing diagnostics and improving treatments and their influence on the clinicians' approaches * Describes how to use these biomaterials to create new functionalities when interfaced with biological molecules or structures * Offers a range of applications in clinical practice, including bone tissue engineering, remodeling, and regeneration * Delineates essential requirements for resorbable bioceramics * Discusses clinical results obtained in dental and orthopedic applications Bioceramics and Biocomposites: From Research to Use in Clinical Practice is an excellent resource for biomaterials scientists and engineers, bioengineers, materials scientists, and engineers. It will also benefit mechanical engineers and biochemists who work with biomaterials scientists.
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Veröffentlichungsjahr: 2019
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Table of Contents
Cover
List of Contributors
1 Multifunctionalized Ferri‐liposomes for Hyperthermia Induced Glioma Targeting and Brain Drug Delivery
1.1 Introduction
1.2 Liposome
1.3 Experimental
1.4 Liposome Synthesis
References
2 Biofabrication Techniques for Ceramics and Composite Bone Scaffolds
2.1 Introduction
2.2 Scaffolds
2.3 Manufacturing Processes
2.4 Conclusion
References
3 Developments in Hydrogel‐based Scaffolds and Bioceramics for Bone Regeneration
3.1 Introduction
3.2 Directions in the Design of Hydrogels for Bone Regeneration
3.3 Ca/P Biomaterials for Bone Regeneration
3.4 Perspectives
Acknowledgments
References
4 Zirconia‐Based Composites for Biomedical Applications
4.1 Introduction
4.2 Inert Ceramics for Biomedical Applications: Monolithic Al
2
O
3
and ZrO
2
4.3 New Approach for Biomedical Grade Ceramics: Zirconia‐Based Composites
4.4 Conclusion
References
5 Bioceramics Derived from Marble and Sea Shells as Potential Bone Substitution Materials
5.1 Introduction
5.2 Biomimetic Approaches for Biomaterials Design
5.3 Biogenic Precursors for Hydroxyapatite
5.4 Synthesis Routes
5.5 Processing of Marble and Shells‐Derived Hydroxyapatite
5.6 Material Characterization
5.7
In vitro
Behavior
5.8 Degradation in Biological Environment
5.9
In vivo
Performance Evaluation
5.10 Conclusions
Acknowledgment
References
6 Bioglasses and Glass‐Ceramics in the Na
2
O–CaO–MgO–SiO
2
–P
2
O
5
–CaF
2
System
6.1 Introduction
6.2 General Technical Aspects
6.3 Design of Compositions
6.4 Materials and Methods
6.5 Structural Features of Glasses, Devitrification, and Materials' Properties
6.6
In vitro
Biomineralization Ability (SBF Tests and HA Formation)
6.7 Cell Culture Testing and Tissue Response
6.8 Animal Testing and Clinical Tests
6.9 Concluding Remarks
Acknowledgments
Bibliography
7 Electrical Functionalization and Fabrication of Nanostructured Hydroxyapatite Coatings
7.1 Introduction
7.2 Necessity and Prerequisites of Electrical Functionalization of Hydroxyapatite to Control Bone Cell Attachment
7.3 Computed Designing of Nanostructured Hydroxyapatite Electrical Potential (Structurally Depended Functionalization)
7.4 HA Clusters and Nanoparticles (NPs)
7.5 Fabrication of Nanostructured Hydroxyapatite Coatings
7.6 Biological Properties of the Electrically Functionalized Hydroxyapatite Coatings
7.7 Biocompatibility of Nanostructured and Electrically Functionalized Hydroxyapatite Coatings: Subcutaneous Model
7.8 General Conclusions
References
8 Bioactive Micro‐arc Calcium Phosphate Coatings on Nanostructured and Ultrafine‐Grained Bioinert Metals and Alloys
8.1 Bioinert Alloys in Nanostructured and Ultrafine‐Grained States and Bioactive Calcium Phosphate Coatings for Medical Applications
8.2 Production, Structure, and Mechanical Properties of Bioinert Alloys Based on Titanium and Niobium in Nanostructured and Ultrafine‐grained States
8.3 Micro‐Arc Oxidation Method for the Production of Bioactive Calcium Phosphate Coatings on the Surface of Bioinert Metals and Alloys
8.4 Hydrophilic Calcium Phosphate Coatings with Developed Surface Relief, Porous Morphology, and High Rate of Bioresorption
8.5 Wollastonite–Calcium Phosphate Coatings with Enhanced Strength Characteristic and High Biological Activity
8.6 Zn‐ or Cu‐incorporated Calcium Phosphate Coatings with Promising Antibacterial Properties
8.7 Biological Studies
In Vitro
of Wollastonite‐, Zinc‐, and Copper‐incorporated Calcium Phosphate Coatings on Titanium and Niobium Alloys
8.8 Development and Medical Applications of Dental Implants Based on Nanostructured Titanium with Calcium Phosphate Coating
8.9 Conclusions
Acknowledgments
References
9 Engineering of Bioceramics‐Based Scaffold and Its Clinical Applications in Dentistry
9.1 Introduction
References
10 Bioceramics in Endodontics
10.1 Introduction
10.2 Portland Cement
10.3 Mineral Trioxide Aggregate (MTA)
10.4 MTA Angelus
10.5 OrthoMTA
10.6 MTA Fillapex
10.7 MTA Plus
10.8 MTA Bio
10.9 MTA Sealer (MTAS)
10.10 E‐MTA
10.11 MM‐MTA
10.12 Fluoride Containing MTA Cements
10.13 Nano‐modified MTA
10.14 Light‐Cured MTA
10.15 Endocem MTA
10.16 Biodentine
10.17 BioAggregate
10.18 DiaRoot BioAggregate
10.19 EndoSequence Root Repair Material (ERRM)
10.20 iRoot BP
10.21 iRoot BP Plus
10.22 iRoot SP
10.23 iRoot FS
10.24 EndoSequence BC Sealer
10.25 Ceramicrete‐D
10.26 Generex A
10.27 Capasio
10.28 Geristore
10.29 Radiopaque Dicalcium Silicate Cement (RDSC)
10.30 Calcium‐enriched Mixture (CEM) Cement
10.31 Calcium Silicate
10.32 EndoBinder
10.33 Quick‐Set
10.34 Bioceramic Gutta‐percha
10.35 Bioactive Glasses
10.36 Cimento Endodontico Rapido (CER)
10.37 Endo‐CPM Sealer
10.38 ProRoot Endo Sealer
10.39 Concluding Remarks
References
11 Extending the Concept of Hemopoietic and Stromal Niches as an Approach to Regenerative Medicine
11.1 Introduction
11.2 Postulated Stage (a Hypothesis) of the Niche Concept
11.3 Morphofunctional Stage of the Niche Concept
11.4 Topographical Stage of the Niche Concept
11.5 Quantitative Stage of the Niche Concept
11.6 Bioengineering Stage of the Niche Concept
11.7 Concluding Remarks
References
12 Experimental and Pilot Clinical Study of Different Tissue‐Engineered Bone Grafts Based on Calcium Phosphate, Mesenchymal Stem Cells, and Adipose‐Derived Stromal Vascular Fraction
12.1 Introduction
12.2 Materials and Methods
12.3 Results
12.4 Discussion
Acknowledgments
References
13 Bone Substitutes in Orthopedic and Trauma Surgery
13.1 Introduction
13.2 Principles of Bone Grafting
13.3 Causes of Bone Defects in Orthopedic Surgery
13.4 Properties of Bone Substitutes
13.5 Types of Bone Substitutes
13.6 Choosing the Bone Graft
13.7 Demineralized Bone Matrix (DBM)
13.8 Bone Morphogenetic Proteins (BMPs)
13.9 Calcium Phosphate and HA
13.10 Bioactive Glasses
13.11 Polymers‐Based Bone Graft Substitutes
13.12 Bone Substitutes in Treating Bone Infections
13.13 Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Nutrient transportation pathways in the BBB.
Table 1.2 Major MDDSs based on CPPs combined with other drug carriers.
Chapter 2
Table 2.1 Hierarchical pore size distribution for an ideal scaffold.
Table 2.2 Materials commonly used to produce bioceramic composite scaffolds for ...
Table 2.3 Additive manufacturing processes classification according to the
Americ
...
Table 2.4 Main characteristics of the additive manufacturing processes for tissu...
Chapter 4
Table 4.1 Biomedical application of ceramics [1–4].
Table 4.2 Classification and examples of ceramics according to their
in vivo
beha...
Table 4.3 Characteristics of first‐, second‐, and third‐generation Al
2
O
3
and ISO...
Table 4.4 Typical physical and mechanical properties of load‐bearing ceramics fo...
Table 4.5 Core material for the all‐ceramic dental restorations shown in Figure ...
Chapter 5
Table 5.1 Biogenic precursors used for the synthesis of hydroxyapatite.
Table 5.2 Scaffold fabrication techniques.
Table 5.3 Mechanical properties of HAP products [1,11,16,17,111,124,125,127,128,...
Chapter 6
Table 6.1 Chemical compositions of experimental glasses.
Table 6.2 Density and linear shrinkage of compacts made of the glass powders G‐A...
Table 6.3 General assignments of Raman and IR bands.
Table 6.4 Properties of glass‐powder compacts of G‐1, G‐2, and G‐3 heat treated ...
Chapter 7
Table 7.1 EP and surface charge density of calcium phosphate coatings prepared b...
Table 7.2 The experimental parameters for Si‐HA coating and Ti substrate.
Table 7.3 Subcutaneous biocompatibility of nanostructured electrically functiona...
Chapter 8
Table 8.1 Mechanical properties of ultrafine‐grained titanium produced after var...
Table 8.2 Mechanical characteristics of titanium alloys in ultrafine‐grained and...
Table 8.3 The free surface energy of CaP coatings on Ti and Ti–40Nb.
Table 8.4 Elemental composition of W‐CaP coatings produced under the voltage of ...
Table 8.5 The free surface energy of W–CaP coatings on Ti and Ti–40Nb.
Table 8.6 Elemental composition in atomic percentage of Zn–CaP and Cu–CaP coatin...
Table 8.7 Free surface energy of Zn–CaP and Cu–CaP coatings on Ti and Ti–40Nb.
Table 8.8 Potassium ion concentration in intercellular fluids and percentage of ...
Table 8.9 Ion concentrations and ALP activity in intercellular fluids of HLPSCs ...
Table 8.10 Death indices of Jurkat T cells after 24 hours of cultivation with th...
Table 8.11 Osteocalcin concentrations (ng/ml) in supernatants of seven‐day adipo...
Chapter 9
Table 9.1 Calcium phosphate ceramics with corresponding chemical formula and Ca/...
Table 9.2 Summary of polymers used in combination with ceramics, categorized in ...
Chapter 10
Table 10.1 Radiopacifiers used in endodontic bioceramics.
Table 10.2 Clinical application of bioceramics in vital pulp therapy.
Table 10.3 Clinical application of bioceramics in nonvital teeth.
Chapter 12
Table 12.1 Patients and tissue‐engineered bone grafts characteristics.
Chapter 13
Table 13.1 Bone substitutes commercial names and main characteristics.
List of Illustrations
Chapter 1
Figure 1.1 Transportation pathways across the BBB.
Figure 1.2 Cellular components of the blood–brain barrier (cross‐section view).
Figure 1.3 Molecular components of endothelial tight junctions.
Figure 1.4 Schematic drawing of a liposome.
Figure 1.5 Mechanisms of drug release from TTSL and the LTSL.
Figure 1.6
In vitro
BBB model confirmation using (a) FITC‐Dextran and (b) TEER....
Figure 1.7 Comparison of essential junction proteins expressed by bEnd.3 cells ...
Figure 1.8 Material characterization. (a) Dynamic light scattering (DLS) data o...
Figure 1.9 DOX release over time: (a) DOX release data from different liposome ...
Figure 1.10 Permeability of the ferri‐liposomes across the BBB model. Data are ...
Chapter 2
Figure 2.1 Variation of bone elastic modulus and yield strain as a function of ...
Figure 2.2 Interactions between bone and the scaffold surface at different topo...
Figure 2.3 μCT image of a PCL‐HA scaffold.
Figure 2.4 Young's modulus versus strength for different materials.
Figure 2.5 Porous composite scaffold of different inner structure designs produ...
Figure 2.6 (A) Schematic representation of the rapid direct deposition of ceram...
Figure 2.7 Schematic representation of the robocasting process.
Figure 2.8 SEM micrographs of a TCP scaffold: (a) general view. (b)
XY
plane vi...
Figure 2.9 β‐TCP/collagen scaffold built through vat‐photopolymerization and ge...
Figure 2.10 Schematic diagrams of the scaffold and the proposed implantation.
Figure 2.11 (a) Mould built by vat‐photopolymerization and respective sintered ...
Figure 2.12 Stereo‐thermal‐lithography system.
Figure 2.13 EDS and SEM micrograph of PEGDMA/HA hydrogel scaffolds.
Figure 2.14 Composite scaffolds containing 50% of β‐TCP and 50% PDLLA.
Figure 2.15 Commercial β‐TCP implant (a) and PCL/TCP scaffolds built by SLS (b)...
Figure 2.16 SEM micrograph of sintered layer's surface with irradiated at 1200 ...
Figure 2.17 (a) Effect of degradation tests and cell culturing on the compressi...
Figure 2.18 Alamar blue assay for different scaffold compositions after 7, 14, ...
Figure 2.19 Morphology of SaOS‐2 cells cultured on different scaffolds for 7 da...
Figure 2.20 (a) SEM image of PLLA/CHA nanocomposite microspheres. (b) PLLA/CHA ...
Chapter 3
Figure 3.1 Hydrogels with properties controlled by the nature and length of the...
Figure 3.2 Hydrogel formation by (a) cross‐linking of macromolecules; (b) polym...
Figure 3.3 (a) Schematic representation of osteoblasts anchored on nanostructur...
Figure 3.4 (a) μ‐CT analysis of a rabbit femoral condyle grafted with β‐TCP gra...
Figure 3.5 A wedge for tibial osteotomy prepared with HA and β‐TCP by laser sin...
Figure 3.6 Preparation of blocks of β‐TCP by the polyurethane foam method. (a) ...
Figure 3.7 (a) SEM of a β‐TCP granule prepared with 25 g Ca/P powder in the slu...
Figure 3.8 (a) Influence of increasing the concentration of β‐TCP in the slurry...
Figure 3.9 Vector analysis of the stacks of β‐TCP granules illustrated in Figur...
Chapter 4
Figure 4.1 Grain size distribution as retrieved from Al
2
O
3
femoral heads belong...
Figure 4.2
Field emission scanning electron microscopy
(
FESEM
) micrograph of ...
Figure 4.3 Scheme of crack growth rate–stress intensity behavior and determinat...
Figure 4.4 Schematic representation of the microstructures of the main types of...
Figure 4.5 Schematic illustration of stress‐induced phase transformation toughe...
Figure 4.6 Schematic representation of how a partial transformation of
t
‐ZrO
2
g...
Figure 4.7 Scanning electron microscopy (SEM) micrograph of Al
2
O
3
–5 vol% ZrO
2
c...
Figure 4.8 Crack velocity versus stress intensity factor (
K
I
) for biomedical gr...
Figure 4.9 Aging kinetics (monoclinic fraction increase versus time at 134 °C, ...
Figure 4.10 (a) Monoclinic ZrO
2
profiles acquired by micro‐Raman spectroscopy o...
Figure 4.11
Atomic force microscopy
(
AFM
) images of (a) 3Y‐TZP, (b) ATZ, and ...
Figure 4.12 Aging behavior (a) and mean flexural strength (b) of 3Y‐TZP, ATZ, a...
Figure 4.13 Gas phase condensation of Al
2
O
3
/ZrO
2
hybrid nanoparticles prepared ...
Figure 4.14 SEM micrographs of ATZ‐sintered composites derived (a) by the gas c...
Figure 4.15 TEM micrograph of 12Ce‐TZP/30 vol% Al
2
O
3
sintered at 1500 °C for tw...
Figure 4.16 Fracture strength (a) and volume fraction of the monoclinic phase o...
Figure 4.17 Relation between fracture toughness and biaxial flexure strength fo...
Figure 4.18 Biaxial flexure strength (a) and m‐ZrO
2
content (b) of Ce‐TZP/Al
2
O
3
Figure 4.19
V
–
K
I
curves of Ce‐TZP/Al
2
O
3
nanocomposite as compared to those of m...
Figure 4.20 Strength–toughness relationships for Ce‐TZP (squares), Ce‐TZP/Al
2
O
3
Figure 4.21 TEM image (a) and chemical composition (at%) on the A, B, and C gra...
Figure 4.22 Crack propagation in (a) 12Ce‐TZP/30 vol% Al
2
O
3
(12Ce‐30A), (b) 12C...
Figure 4.23 (a) Synthesized porous ZrO
2
/HA scaffold with 91 ± 2.8% porosity. (b...
Figure 4.24 SEM images of adhered cells on scaffold. Three days after cell seed...
Chapter 5
Figure 5.1 Processing steps for hydroxyapatite synthesis by thermal decompositi...
Figure 5.2 Processing steps for hydroxyapatite synthesis by thermal decompositi...
Figure 5.3 Derived hydroxyapatite processed by cold pressing and scaffolding te...
Chapter 6
Figure 6.1 Thermal analysis (dilatometry top curves and DTA bottom curves) of G...
Figure 6.2 Akermanite predominantly forms at ≥700 °C (JCPDS card of akermanite‐...
Figure 6.3 Characteristic microstructure of G‐A1 glass‐ceramics after heat trea...
Figure 6.4 Weibull statistics of flexural strength (three‐point bending) of gla...
Figure 6.5 Microstructure of interfaces developed between G‐A1 glass‐ceramic (u...
Figure 6.6 Phase separation occurred in the investigated annealed bulk glasses ...
Figure 6.7 Raman spectra of the investigated glasses, obtained from the surface...
Figure 6.8 FT‐IR spectra of the investigated glasses. The spectrum of crystalli...
Figure 6.9 Thermal analysis of Al‐free glasses G‐1, G‐2, G‐3, and G‐1b, and the...
Figure 6.10 Evolution of the microstructure of the annealed bulk glass G‐1 afte...
Figure 6.11 X‐ray diffractograms of the glass‐powder compacts from the Al‐free ...
Figure 6.12 Typical microstructures of glass‐powder compacts made of the compos...
Figure 6.13 Calculated spectrum “(G‐1d)‐(G‐1e)” yielded by the mathematical sub...
Figure 6.14 Typical evolution of (a) pH (along with the curve for the 45S5 Biog...
Figure 6.15 Formation of Ca‐P precipitates and corrosion evidences at the surfa...
Figure 6.16 Evolution of Raman spectra obtained from the surface of the glass G...
Figure 6.17 Evolution of FT‐IR spectra of the glass G‐1a over increasing immers...
Figure 6.18 1 × 10
5
osteoblasts were plated in the presence of glass powders G‐...
Figure 6.19 Histopathological analysis in sections of bones after different tim...
Figure 6.20 X‐ray images before implantation (a) and (b) 2 and (c) 6 months aft...
Chapter 7
Figure 7.1 Double‐wall potentials curve for monoclinic and hexagonal phases. Th...
Figure 7.2 Hexagonal HA unit cell ordered structure. All OH groups are oriented...
Figure 7.3 Clusters of HA extracted from the hexagonal HA crystal model with 36...
Figure 7.4 Density of states (DOS) for pure HA hexagonal structure: (a) (upper ...
Figure 7.5 (a) a side view of the stoichiometric (001) and (101) slabs. Multipl...
Figure 7.6 (a)–(c) Three prototype HA surface structures. From these three mode...
Figure 7.7 The surface energies as a function of Ca
3
(PO
4
)
2
chemical potential i...
Figure 7.8 (a) Surface energy averaged over the entire chemical range plotted a...
Figure 7.9 (a) Block diagram of surface charge density measurement: 1, substrat...
Figure 7.10 Energy diagram for the emitting photoelectron.
Figure 7.11 Schematic diagram of the typical rf‐magnetron sputtering process.
Figure 7.12 The elemental composition of the calcium phosphate coating of 1.1 μ...
Figure 7.13 X‐ray diffraction pattern of an as‐deposited calcium phosphate coat...
Figure 7.14 The typical XRD‐patterns of as‐deposited Si‐HA coating.
Figure 7.15 TEM‐image of Si‐HA coating. Inset: ED‐pattern.
Figure 7.16 A typical HRTEM‐pattern (a) of the crystallites in Si‐HA coating (t...
Figure 7.17 Flow chart of the number of publications for the most studied metal...
Figure 7.18 Hardness (
H
) and Young's modulus (
E
) of rf‐magnetron HA coatings ve...
Figure 7.19 The loading–unloading (
P
–
h
) curves for Si‐HA coating and Ti substra...
Figure 7.20 Subcutaneous tissue state around the specimen with electrically fun...
Figure 7.21 Digital images of donor syngeneic bone marrow
in vitro
and tissue p...
Figure 7.22 Correlation of the tissue platelets (laminae) growth with
ϕ
in...
Figure 7.23 Histological sections of tissue laminae on the hydrogenated nanostr...
Figure 7.24 Histological sections of tissue platelets on the hydrogenated nanos...
Chapter 8
Figure 8.1 Optical images (a,c) and bright‐field TEM images of microstructure w...
Figure 8.2 Scheme of
abc‐
pressing and further rolling: 1, initial sample ...
Figure 8.3 Bright‐field TEM images of microstructure with microdiffraction patt...
Figure 8.4 Bright‐field TEM image (a) with microdiffraction pattern (b); dark‐f...
Figure 8.5 XRD patterns of Ti–40Nb after annealing (a) and after
abc
‐pressing w...
Figure 8.6 Tensile diagrams of Ti VT1‐0 (a) and Ti–40Nb (b) in ultrafine‐graine...
Figure 8.7 SEM images of the top (a–e) and cross‐sectional (f–h) CaP coatings o...
Figure 8.8 Plots of thickness (a, curves 1 and 2), roughness (a, curves 3 and 4...
Figure 8.9 XRD patterns of CaP coatings on Ti (a) and Ti–40Nb (b) deposited und...
Figure 8.10 IR spectra of CaP coatings on Ti deposited under different voltages...
Figure 8.11 Plots of Ca/P ratio for the CaP coatings on Ti (1) and Ti–40Nb (2) ...
Figure 8.12 Bright‐field TEM images with microdiffraction patterns for the part...
Figure 8.13 Plots of the glycerol and water contact angles with CaP coatings on...
Figure 8.14 SEM micrographs of W‐CaP coating on Ti (a–c) and Ti–40Nb (d–f) prod...
Figure 8.15 SEM images of cross‐sectional W‐CaP coating on Ti produced for five...
Figure 8.16 Plots of thickness (a,d), apparent density (b,e), and roughness (C,...
Figure 8.17 SEM micrograph (a) and distribution of elements (b–d) into the W–Ca...
Figure 8.18 XRD patterns of W–CaP coatings on Ti (a) and Ti–40Nb (b) deposited ...
Figure 8.19 SEM micrographs of cross‐sectional W–CaP coatings on Ti produced at...
Figure 8.20 Plots of thickness (a, curve 1), apparent density (a, curve 2), rou...
Figure 8.21 XRD patterns of W–CaP coatings on Ti produced under the voltage of ...
Figure 8.22 Plots of the glycerol (1, 2) and water (3, 4) contact angles with W...
Figure 8.23 SEM images (a,b,d,e) and XRD patterns (c,f) of Zn–CaP (a–c) and Cu–...
Figure 8.24 SEM images (a,b,d,e) and XRD patterns (c,f) of Zn–CaP (a–c) and Cu–...
Figure 8.25 Plots of thickness and roughness of Zn–CaP and Cu–CaP coatings on b...
Figure 8.26 IR spectra of CaP coatings on Ti (a) and Ti–40Nb (b) deposited unde...
Figure 8.27 Plots of glycerol and water contact angles with Zn–CaP and Cu–CaP c...
Figure 8.28 Phase‐contrast microscopy images of AMMSCs adhered to plastic wells...
Figure 8.29 TEM image of microstructure of nanostructured/ultrafine‐grained VT1...
Figure 8.30 Set of dental screw intraosseous implants with instruments and impl...
Chapter 9
Figure 9.1 Enabling technology applied in dentistry by making use of scaffold a...
Chapter 10
Figure 10.1 Healing of periradicular bone in case of root perforations, regardl...
Figure 10.2 Healing of periradicular bone in case of root perforations, in rege...
Figure 10.3Figure 10.3 (a) Resorption‐related perforation in right upper centra...
Chapter 11
Figure 11.1 A timeline representation of major points that extended our underst...
Figure 11.2 Schematic representation of niche dynamic reconstruction while bone...
Chapter 12
Figure 12.1 SEM images of TCP (a) and OCP (b) ceramic granules.
Figure 12.2 Rabbit parietal bone defects in different time points after implant...
Figure 12.3 Rabbit parietal bone defects in different time points after implant...
Figure 12.4 Proportions of newly formed bone tissue in the peripheral (a) and c...
Figure 12.5 Rabbit parietal bone defects in different time points after implant...
Figure 12.6 The mandible of Patient No. 1: (a) before treatment, (b) 4.5 months...
Figure 12.7 Patient No. 2: (a) access to the anterior lateral surface of the ma...
Figure 12.8 Patient No. 3: (a) CT 4.5 months after bone grafting, (b) CT after ...
Figure 12.9 The maxillary left sinus floor of Patient No. 3: (a) 4.5 months aft...
Figure 12.10 Newly formed bone tissue within the area of implanting tissue‐engi...
Figure 12.11 Non‐union in the mandible frontal region of Patient No. 4: (a) bef...
Chapter 13
Figure 13.1 Aseptic loosening of total hip prosthesis with bone defect (a) gene...
Figure 13.2 Clinical (a) and X‐ray aspect (b) IIIB open fracture‐dislocation of...
Figure 13.3 Tibial plateau fracture with depression – X‐ray and CT (a), intra‐o...
Figure 13.4 Posttraumatic pseudarthrosis multiply operated: X‐ray (a) shows enl...
Figure 13.5 Posttraumatic deformity (a) needing osteotomy with bone defect (b);...
Figure 13.6 Pelvic protrusion (a) with septic complication (b) followed by temp...
Figure 13.7 CT aspect of the calcaneal osteolysis – frontal (a), sagital (b), a...
Figure 13.8 Intraoperative aspect (a) and favorable outcome – radiological – sa...
Figure 13.9 Bilateral infected open calcaneal fracture‐preoperative X‐ray.
Figure 13.10 Postoperative bilateral result, with bone gap, contaminated with
S
...
Figure 13.11 Bioactive glass was used for grafting – optimal result with healin...
Guide
Cover
Table of Contents
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Bioceramics and Biocomposites
From Research to Clinical Practice
Edited by
Iulian Antoniac, PhD
University Politehnica of Bucharest
Copyright
Copyright © 2019 by The American Ceramic Society. All rights reserved.
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Title: Bioceramics and biocomposites : from research to clinical
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Description: First edition. | Hoboken, New Jersey : John Wiley & Sons, Inc.,
[2019] | Includes bibliographical references and index. |
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Subjects: | MESH: Biocompatible Materials | Ceramics | Tissue Engineering |
Bone and Bones
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List of Contributors
Simeon Agathopoulos
Materials Science and Engineering Department,
University of Ioannina,
Ioannina, Greece
Ika D. Ana
Department of Dental Biomedical Sciences,
Faculty of Dentistry,
Universitas Gadjah Mada,
Yogyakarta 55281, Indonesia
Maidaniuc Andreea
Department of Metallic Materials Science,
Physical Metallurgy,
Faculty of Material Science and Engineering,
Politehnica University of Bucharest,
Bucharest, Romania
Ilia Y. Bozo
Human Stem Cells Institute,
Moscow, Russia
A.I. Evdokimov Moscow State University of Medicine and Dentistry,
Moscow, Russia
A.I. Burnazyan Federal Medical and Biophysical Center,
Moscow, Russia
Vladimir Bystrov
Institute of Mathematical Problems of Biology,
Keldysh Institute of Applied Mathematics,
Russian Academy of Sciences,
142290, Pushchino, Russia
Anna Bystrova
Institute of Biomedical Engineering and Nanotechnologies,
Riga Technical University,
Riga, Latvia
Mocanu A. Cătălina
Department of Metallic Materials Science,
Physical Metallurgy,
Faculty of Material Science and Engineering,
Politehnica University of Bucharest,
Bucharest, Romania
Daniel Chappard
GEROM Groupe Etudes Remodelage Osseux et bioMatériaux – NextBone and SCIAM,
Service Commun d'Imagerie et Analyses Microscopiques,
Institut de Biologie en Santé,
CHU d'Angers,
Université d'Angers,
49933 Angers Cedex, France
Roman V. Deev
Human Stem Cells Institute,
Moscow, Russia
A.I. Burnazyan Federal Medical and Biophysical Center,
Moscow, Russia
Kazan (Volga region) Federal University,
Kazan, Russia
Yuri Dekhtyar
Institute of Biomedical Engineering and Nanotechnologies,
Riga Technical University,
Riga, Latvia
Petr S. Eremin
A.I. Burnazyan Federal Medical and Biophysical Center,
Moscow, Russia
Ilya I. Eremin
A.I. Burnazyan Federal Medical and Biophysical Center,
Moscow, Russia
Anna Eroshenko
Institute of Strength Physics and Materials Science SB RAS,
2/4 Akademicheskii prospekt, Tomsk, 634055 Russia
Miculescu Florin
Department of Metallic Materials Science,
Physical Metallurgy,
Faculty of Material Science and Engineering,
Politehnica University of Bucharest,
Bucharest, Romania
Stan E. George
Laboratory of Multifunctional Materials and Structures,
National Institute of Materials Physics,
Măgurele‐Bucharest, Romania
Irina M. Gheorghiu
Department of Endodontology,
“Carol Davila” University of Medicine and Pharmacy,
Bucharest, Romania
Vasily I. Grachev
X‐ray Diagnostics Laboratories “3D Lab”,
Moscow, Russia
Sri Hinduja
The University of Manchester,
School of Mechanical, Aerospace and Civil Engineering,
Manchester, United Kingdom
Boyang Huang
The University of Manchester,
School of Mechanical,
Aerospace and Civil Engineering,
Manchester,
United Kingdom
Alexandru A. Iliescu
Department of Oral Rehabilitation,
University of Medicine and Pharmacy of Craiova,
Craiova, Romania
Mihaela G. Iliescu
Department of Endodontology,
“Carol Davila” University of Medicine and Pharmacy,
Bucharest, Romania
Voicu S. Ioan
Department of Analytical Chemistry and Environmental Engineering,
Faculty of Applied Chemistry and Material Science,
Politehnica University of Bucharest,
Bucharest, Romania
Iulian Antoniac
Department of Metallic Materials Science,
Physical Metallurgy,
Faculty of Material Science and Engineering,
Politehnica University of Bucharest,
313 Splaiul Independentei, District 6, JA 104‐106 Building, 060042 Bucharest, Romania
Igor A. Khlusov
Department of Morphology and General Pathology,
Siberian State Medical University,
634050, Tomsk, Russia
National Research Tomsk Polytechnic University,
Research School of Chemistry & Applied Biomedical Sciences,
634050, Tomsk, Russia
Marina Yu. Khlusova
Department of Morphology and General Pathology,
Siberian State Medical University,
634050, Tomsk, Russia
National Research Tomsk Polytechnic University,
Research School of Chemistry & Applied Biomedical Sciences,
634050, Tomsk, Russia
Ekaterina Komarova
Institute of Strength Physics and Materials Science SB RAS,
2/4 Akademicheskii prospekt, Tomsk, 634055 Russia
Vladimir S. Komlev
A.A. Baikov Institute of Metallurgy and Materials Science,
Russian Academy of Sciences,
Moscow, Russia
Institute of Laser and Information Technologies,
Russian Academy of Sciences,
Moscow, Russia
Larisa Litvinova
Laboratory of Immunology and Cellular Biotechnology,
Immanuel Kant Baltic Federal University,
14 A. Nevskogo Street, 236041 Kaliningrad, Russia
Fengyuan Liu
The University of Manchester,
School of Mechanical, Aerospace and Civil Engineering,
Manchester, United Kingdom
Horia O. Manolea
Department of Oral Rehabilitation,
University of Medicine and Pharmacy of Craiova,
Craiova, Romania
Miculescu Marian
Department of Metallic Materials Science,
Physical Metallurgy,
Faculty of Material Science and Engineering,
Politehnica University of Bucharest,
Bucharest, Romania
Gujie Mi
Department of Chemical Engineering,
Northeastern University,
Boston, MA 02115, USA
Lupescu Olivera
Department of Orthopaedics,
Faculty of Medicine,
“Carol Davila” University of Medicine and Pharmacy of Bucharest,
37 Dionisie Lupu Street, District 2, 020021 Bucharest, Romania
Paola Palmero
Department of Applied Science and Technology,
INSTM R.U. PoliTO,
LINCE Laboratory,
Politecnico di Torino,
Corso Duca degli Abruzzi, 24, 10129 Torino, Italy
Paula Perlea
Department of Endodontology,
“Carol Davila” University of Medicine and Pharmacy,
Bucharest, Romania
Vladimir Pichugin
National Research Tomsk Polytechnic University,
Research School of Chemistry & Applied Biomedical Sciences,
634050, Tomsk, Russia
Konstantin Prosolov
National Research Tomsk Polytechnic University,
Research School of High‐Energy Physics,
634050, Tomsk, Russia
Institute of Strength Physics and Materials Science of SB RAS,
Russia
Andrey A. Pulin
A.I. Burnazyan Federal Medical and Biophysical Center,
Moscow, Russia
Sergey I. Rozhkov
A.I. Evdokimov Moscow State University of Medicine and Dentistry,
Moscow, Russia
Maria Sedelnikova
Institute of Strength Physics and Materials Science SB RAS,
2/4 Akademicheskii prospekt, Tomsk, 634055 Russia
Yurii Sharkeev
National Research Tomsk Polytechnic University,
Research School of High‐Energy Physics,
634050, Tomsk, Russia
Institute of Strength Physics and Materials Science of SB RAS,
Russia
Di Shi
Department of Chemical Engineering,
Northeastern University,
Boston, MA 02115, USA
Valeria Shupletsova
Laboratory of Immunology and Cellular Biotechnology,
Immanuel Kant Baltic Federal University,
14 A. Nevskogo Street, 236041 Kaliningrad, Russia
Paulo J. da Silva Bartolo
The University of Manchester,
School of Mechanical, Aerospace and Civil Engineering,
Manchester, United Kingdom
Izabela‐Cristina Stancu
APMG Advanced Polymer Materials Group,
Faculty of Applied Chemistry and Materials Science,
Faculty of Medical Engineering,
University Politehnica of Bucharest,
1–7 Gh Polizu Street, Sector 1, 011061 Bucharest, Romania
Evgeniy N. Toropov
A.I. Burnazyan Federal Medical and Biophysical Center,
Moscow, Russia
Gabriel Tulus
European Society of Endodontology,
Viersen, Germany
Dilshat U. Tulyaganov
Turin Polytechnic University in Tashkent,
Niyazova, Uzbekistan
Grigory A. Volozhin
A.I. Evdokimov Moscow State University of Medicine and Dentistry,
Moscow, Russia
Thomas J. Webster
Department of Chemical Engineering,
Northeastern University,
Boston, MA 02115, USA
Center of Excellence for Advanced Materials Research,
King Abdulaziz University,
Jeddah, Saudi Arabia
Vadim L. Zorin
Human Stem Cells Institute,
Moscow, Russia
A.I. Burnazyan Federal Medical and Biophysical Center,
Moscow, Russia
1Multifunctionalized Ferri‐liposomes for Hyperthermia Induced Glioma Targeting and Brain Drug Delivery
Di Shi1Gujie Mi1 and Thomas J. Webster1,2
1Department of Chemical Engineering, Northeastern University, Boston, MA, 02115, USA
2Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia
1.1 Introduction
1.1.1 Blood–brain Barrier
1.1.1.1 What is the Blood–brain Barrier (BBB)?
The discovery of the blood–brain barrier (BBB) traces back to more than 100 years ago [1,2]. However, it was not until the 1960s when electron microscopes became available in medical research that the endothelial cells and the actual BBB were observed and confirmed [3]. Compared to “ordinary” endothelial cells that line blood vessels in the rest of the body, endothelial cells in the brain microvessels exhibit highly extensive tight junctions and thus lower endocytosis or transcytosis activities more than peripheral endothelial cells [3,4]. Besides the existence of the tight junctions, the endothelial cells in the BBB are distinct from the peripheral endothelial cells by processing much fewer pinocytic vesicles, producing high electrical resistance for over 0.1 Ω m and the absence of fenestration [5]. In addition, what also makes them distinguishable from peripheral endothelial cells is that several cytoplasmic adaptors are enriched at the BBB [6].
Generally, there are three different transport systems for compounds to pass through the BBB. Nutrients (such as glucose and amino acids) are transported by transport proteins, while larger molecules including insulin and iron transferrin are carried by receptor‐mediated endocytosis or transcytosis [7]. The other transcytosis is called adsorptive‐mediated transcytosis, which helps albumin and other native plasma protein transportation by cationization [5,8]. While it is worth mentioning that since more than 98% of hydrophilic agents, including polar drugs, are blocked by tight junctions, most of the central nervous system (CNS) drugs penetrate the BBB using either transcellular lipophilic pathways or one of the transportation routes (Table 1.1 and Figure 1.1).
Table 1.1 Nutrient transportation pathways in the BBB.
Pathways
Paracellular or transcellular
Molecules being transported
Available for drug delivery
Hydrophilic pathway
Paracellular
Water‐soluble small molecules (water, ethanol)
No
Lipophilic pathway
Transcellular
Lipid‐soluble small molecules (caffeine)
Yes
Transport proteins
Transcellular
Glucose, amino acids, vitamins, fatty acids
Yes
Receptor‐mediated transcytosis
Transcellular
Insulin, tranferin
Yes
Adsorptive‐mediated transcytosis
Transcellular
Plasma proteins (albumin)
Yes
Figure 1.1 Transportation pathways across the BBB.
Source: Abbott et al. 2006 [9]. Adapted with permission of Springer Nature.
Together with these highly selective tight junctions and transcellular transportation pathways, the brain endothelial cells scrupulously regulate brain homeostasis and the microenvironment, and limit the penetration of a majority of the microorganisms and compounds including potentially toxic compounds that circulate in the blood [4,9].
1.1.1.2 The BBB Formation and Composition
The basic building blocks of the BBB are formed by endothelial cells surrounded by the basal lamina (not shown in Figure) and are attached by pericytes, astrocyte endfeet, and neurons (Figure 1.2) [10]. As seen from Figure 1.5, the basement membrane of capillaries in the BBB are ensheathed with astrocyte end‐feet and are attached by pericytes, which for larger blood vessels (such as arteries and veins), will be replaced by a continuous layer of smooth muscle [12]. It is a consensus that all of the components in the BBB are important for stability and daily functions and among them endothelial cells and astrocytes are the most important building blocks.
Figure 1.2 Cellular components of the blood–brain barrier (cross‐section view).
1.1.1.3 Endothelial Cell and Tight Junctions
Endothelial cells of the capillaries continuously envelop the inner surface of the blood vessel and act as the first wall facing the circulating blood in the brain. As mentioned previously, this active interface shows several unique features not only as an endothelium, such as highly controlled paracellular and transcellular pathways, but also shows a high value of transepithelial electrical resistance (TEER) of 1500–2000 Ω cm2 compared to less than 30 Ω cm2 in other tissues [13,14].
TEER is a typical and straightforward method being used to assess the tightness of the BBB both in vivo and in vitro, since the tightness of the BBB is correlated to the flux of all the ions that go through the membrane [15]. The experiment is carried out by applying a transepithelial current to the membrane and then test the membrane potential that is being generated, and finally translate the value into resistance (current, Ohm [Ω]) multiplied by the area (cm2) of the endothelial monolayer (expressed as Ω cm2). For instance, as for the in vitro model that will be discussed later, the surface area of the transmembrane is 0.32 cm2 for 24‐well plates and 1.1 cm2 for 12‐well plates. Therefore, if the resistance of the measurement is 100 Ω, it will be 32 Ω cm2 for the 24‐well plate and 110 Ω cm2 for the 12‐well plate [16]. Such a discussion is important for in vitro models on the blood barrier. Tight junctions and adherent junctions are the interconnectors of cerebral endothelial cells [17] (Figure 1.3). There are basically four important integral membrane proteins being expressed in the tight junctions and basically they can be all divided into two categories [18]: transmembrane proteins (including occludin, claudin, and junctional adhesion molecules [JAMs]) and cytoplasmic proteins (including zonula occludens). These tight junctional proteins together form the super restrictive paracellular pathways, which represents one of the hallmarks of the BBB phenotype, and are discussed in greater detail subsequently [19,20].
Figure 1.3 Molecular components of endothelial tight junctions.
Both tight junctions and adherens junctions are composed of transmembrane proteins and cytoplasmic proteins. The difference is that transmembrane proteins such as JAM will physically associate with their counterparts on the plasma membrane and form dimers, whereas cytoplasmic proteins will not only connect tight junctional/adherens junctional proteins and the actin cytoskeleton but are also involved in intracellular signaling [17].
1.1.1.4 Astrocytes
Astrocytes, also known as astroglia, ensheath more than 99% of the endothelium. They are one of the major subtypes of glial cells and play an important role for providing cellular links to neurons in the CNS (Figures 1.5 and 1.6). These star‐shaped glial cells have been shown to perform many functions, including structurally supporting the endothelial cells to form the BBB. Since they are able to carry out glycogenesis, astrocytes can provide neurons with glucose when glucose consumption rate is high or during glucose shortage periods [21]. They are also involved in the transmission of neuronal synapses and regulate ion concentrations of extracellular space [22]. Since they provide a connection between neurons and the vascular endothelium, they are able to deliver signals and thus regulate blood flow by controlling the contraction and dilation of the smooth muscles and/or pericytes that surround the blood vessels [23]. In addition, if the brain or spinal cord undergoes traumatic injury, astrocytes will then execute a scar repairing process and form glial scars to heal the wound by transforming into neurons [24,25]. Astrocytes are also suggested to be an important mediator and regulate endothelial functions during BBB formation and development. For example, they are believed to be involved in vascular growth by secreting vascular endothelial growth factors (VEGF). However, a recent study showed that these cells might not be involved in the initial generation of the BBB but only maintain and regulate the BBB after it is formed. Research carried out at the University of California, San Francisco, showed that astrocytes are not required to induce BBB formation initially [26], but to act as a regulator that maintains BBB function and response to neural diseases or after injury when necessary as mentioned [27].
1.1.1.5 Glioma
Usually appearing inside the brain, glioblastoma multiformes (GBMs) are one of the most common brain tumors that arise mainly from astrocytes, which are the star‐shaped glial cells that support the tissues of the brain. GBM, also known as Grade IV glioma, accounts for more than 50% of all astrocytomas and has been considered as the most aggressive tumors of the brain due to their highly malignant (cancerous) base on the rapid cell reproduce rate supported by the large network of blood vessels inside the brain [28]. Patients receiving this diagnosis are most likely having an average of 15 months or less to live, and even those who survived from first‐line therapy will usually face long‐term neurologically impairment or be debilitated [29,30]. In recent years, increasing evidence indicates that primary and secondary GBMs exhibit distinct disease entities and therefore probably involve different genetic pathways and mutations, despite the fact that they both behave in a clinically indistinguishable manner and share the similar survival rates. For primary GBM, epidermal growth factor receptor (EGFR) and loss of heterozygosity (LOH) are shown to be the major genes that are amplified during tumor formation, accompanied by phosphatase and tensin homolog (PTEN) mutation and deletion in a mouse double‐minute 2 (MDM2) gene [31,32].
The cause of the GBM still remains a mystery, and currently, there is no strategy to diagnose nor cure the tumor, but only palliative treatment including surgery, radiotherapy, and chemotherapy are available [33,34]. Moreover, since there is no clearly defined margin for those GBMs in most of the cases, they tend to invade locally and spread out along white matter quickly, causing multi‐GBM formation or multicentric gliomas on imaging studies [35]. Therefore, biological targeted therapy becomes a promising area of medicine with a purpose of specifically and efficiently targeting the tumor area without harming the normal brain. Strategies include altering the natural behavior of tumor cells, such as angiogenic pathways. Several genetic pathways in the brain, such as the relevant growth factor pathways in malignant glioma include platelet‐derived growth factor (PDGF), VEGF, and epidermal growth factor (EGF), are under investigation recently based on the fact that they will undergo mutation and increase survival of abnormal cells and blood supply to the tumor [36,37]. Take EGF as an example, EGFR has been found to overexpress in more than 60% of GBM, and it mainly acts through the tyrosine kinase (RTK) pathways [38].
1.1.2 New Strategies for Measuring Drug Transport Across the BBB
Since it is that fact that over 98% of small molecule drugs cannot penetrate through the BBB due to the presence of the tight junctions, not only the hydrophilic but also hydrophobic ones, the BBB becomes the fundamental barrier that prevents progress in the development of new therapeutics for brain diseases and/or radiopharmaceuticals for imaging the brain, and the prospect for neuropharmaceuticals has become a promising global pharmaceutical market. Traditional pharmacokinetic techniques for measuring pharmaceutical agent transport across the BBB in vivo, such as intravenous administration and tissue sampling, are more sensitive and represent the full physiological conditions [39]. However, these kinds of methods are yet to be more time‐consuming and based on trial and error. Compared to traditional methods, there are emerging types of in vitro BBB models that can rapidly assess the potential permeability of drugs and screening procedures such as active efflux and carrier‐mediated uptake. This method is more accessible and repeatable to discover the molecular transport mechanism of pharmaceutical agents across the BBB and have an advantage of evaluating systemic drugs more efficiently with much less time and labor [40]. Therefore, this in vitro BBB model is now often used for predicting and prescreening drug candidates for in vivo studies [41].
1.2 Liposome
1.2.1 Introduction
Being first described by Bangham and Horne in 1964 in Cambridge, liposomes are currently one of the most popular vehicles for drug delivery in the pharmaceutical area. A liposome is defined as an artificial‐prepared, spherical vesicle composed of amphiphilic phospholipids bilayer with an aqueous center (Figure 1.4) by disrupting biological membranes, the preparation of liposomes from natural nontoxic phospholipids and cholesterol can be simply conducted by sonication [42,43]. With hydrophilic groups facing outside, this self‐closed bilayer structure is formed due to the accumulation of lipids that interact with one another in a specific manner. The assembled liposome is then able to protect therapeutic molecules inside the core from aqueous environments and go through the cell membrane.
Figure 1.4 Schematic drawing of a liposome.
The size of liposomes can vary from ∼50 nm to several micrometers, and there are also some different types of liposomal vesicles according to their diameters. The major types include multilamellar vesicle (MLV) which is composed of several concentric bilayers and ranging from 500 to 5000 nm; small unilamellar vesicle (SUV) 100 nm in size and consisting of a single bilayer; and a large unilamellar vesicle (LUV) with sizes ranging from 200 to 800 nm [44].
According to a report in 2005 [44], the current marketed liposomal products used for cancer therapy include Doxil® (PEGylated liposomal formulation of doxorubicin [DOX] for cancer treatment), DaunoXome® (liposomal formulation of daunorubicin to treat AIDS‐related Kaposi's sarcoma and leukemia), and DepoCyt® (cytarabine to treat cancers of white blood cells such as acute myeloid leukemia) [45]. Drugs (such as DOX) that have severe side effects on normal tissues usually intend to choose liposomes and other nanocarriers to shield itself from undesirable release and increase the applicable dosage.
Other than commercialized products, researchers in the University of Shizuoka indicated that liposomes as drug carriers could be used for cancer anti‐neovascular therapy. Regarding this liposome‐drug combinational delivery, liposome‐encapsulated DOX significantly inhibited the VEGF‐induced mitogen‐activated protein kinase (MAPK) pathway and suppressed VEGF‐induced human umbilical vein endothelial cell (HUVEC) proliferation in vivo. Consequently, tumor growth and surviving time were significantly suppressed [46].
1.2.2 Functionalization of Liposomes
Liposomes have been studied for a long time according to their attractive biological properties such as biocompatibility, biodegradability, controllable release, and ability to carry both hydrophilic pharmaceutical agents inside the aqueous internal area and hydrophobic ones into the membrane as well as protect the pharmaceutical agents from the external environment without having undesirable side effects [47]. However, there are limitations on the other side. Compared to other delivery systems, the drawbacks of using liposomes as drug carriers include fast elimination from the blood, relatively low encapsulation efficacy, poor storage stability, and the capture of the liposomes by the cells in the liver before it reaches the target [44]. Therefore, a number of developments have been developed in order to solve these problems.
1.2.2.1 PEGylation
To increase liposome circulation time and stability, attention has been given to the surface modification approaches that form stealth liposomes and therefore protect liposomes from the external bioenvironment after administration and prolong their residence time [48,49]. One of the most popular approaches is, according to Yuta Yoshizawa's research in 2011, by conjugating polyethylene glycol (PEG) units to liposomalization drugs such as paclitaxel (PTX). The author compared PEGylated‐liposome (also known as “stealth” or sterically stabilized liposome) to a naked liposome and O/W emulsion and indicated that after intravenous injection, area under the concentration‐time curve (AUC) of the PEG‐liposome was almost four times higher than the uncoated liposome. Also, pharmacokinetics and the release rate of PEG‐liposome were much better than the emulsion and naked liposome. For the most important, it was confirmed that the PEG‐liposome formation would deliver larger amounts of drugs to the target area, in this case tumor tissue, in vivo, and hence it was suggested that PEG‐coated liposomes could be treated as a potential drug carrier in cancer chemotherapy [45].
In addition, besides efficacy, a previous study showed that there was a significant reduction of adverse effects on PEG‐liposome–encapsulated drug compared to other entrapped drugs. For instance, in a study in 2001, Gerald Batist et al. indicated that PEG‐liposome–encapsulated DOX increased the therapeutic index of DOX by decreasing irreversible cardiotoxicity [50]. Also, similar to Doxil, a study showed that PEGylated liposomes efficiently blocked its interaction with plasma proteins as well as mononuclear phagocytes and exhibited significantly prolonged system‐circulation time as a result.
1.2.2.2 Ligand‐mediated Liposome Targeting
On the other hand, since optimization of immunoliposomes properties remains a big concern, conjugating specific ligands such as monoclonal antibodies have been shown to be a promising way to selectively deliver liposomes to many targets. Mostly in cancer research, the optimization of immunoliposomes properties is an ongoing concern. For instance, as reported by Zhang et al. [51], PEGylated OX26 (monoclonal antibody to the rat transferrin receptor)‐immunoliposomes loaded with expression plasmids of gene encoding tyrosine hydroxylase (TH) showed promising results in a rat model for Parkinson's disease. Puja Sapra, and Theresa M. Allen also demonstrated that antibody‐involved liposomes (such as anti‐CD19‐targeted liposomes) were able to be internalized into human B‐lymphoma (Namalwa) cells rapidly and achieved a much more enhanced therapeutic efficacy [52]. Moreover, due to the fact that folate receptors (FR) are usually overexpressed in a range of tumor cells, delivering folate‐modified liposomes has been assessed by different groups as a promising approach. For example, oligonucleotide (ON)‐encapsulated in folate‐targeted liposomes to FR‐positive tumor cells have been recently evaluated both in vitro and in vivo by Leamon et al., and revealed that the functionalized liposome delivered about twofold more oligonucleotides to the livers of nude mice than nontargeted formulations [53]. FR‐targeted liposomes have also been demonstrated to have great capability in delivering DOX both in vitro and in vivo, and havealso indicated being able to inhibit multidrug‐resistant tumor cells [54].
Similar to folate‐targeted liposome, transferrin (Tf)‐mediated liposome targeting is another approach that has been investigated for tumor targeting, since the transferring receptor (TfR) is frequently overexpressed on the surface of many tumor cells. As a result, TfR antibodies become one of the most popular ligands for liposomes to target tumor cells [55]. Studies show that Tf‐modified DOX‐liposomes exhibit increased binding efficiency and selectively cytotoxicity toward C6 glioma cells [56] and Tf/anti TfR antibodies also display an enhanced gene delivery ability to endothelial cells with cationic liposomes as carriers [57,58].
1.2.2.3 Cell‐penetrating Peptide (CPP) Modification
Different from most of the peptides, cell‐penetrating peptides (CPPs) are a class of short peptides, typically around 5–30 amino acids that can cross the cellular membrane. There are basically two main types of CPP: one is the polypeptide motifs that are derived from natural proteins that exhibit penetrating functions (such as TAT) [59], VP22[60], Antp [61], gH625 [62,63], etc.; and the other type is artificially synthesized polypeptides that are being designed based on the structure of naturally derived CPPs, such as mTAT(C‐5H‐TAT‐5H‐C) [64]. Based on its ability to facilitate cellular uptake and accessibility by incorporating functional motifs [65,66], CPP has been used as a vector for delivering various cargos such as chemical molecules, siRNA [67], contrast (imaging) agents, and proteins both in vitro and in vivo [68,69]. The discovery of CPP can be traced back to 1988, when Frankel and Pabo [70], together with Green and Loewenstein [71], reported that the viral trans‐activator of transcription protein (TAT) encoded by HIV‐1 was able to cross biological membranes and dramatically enhance viral transcription efficiency [72]. Currently, the amino acid sequence of the protein transduction domain of TAT has been narrowed down to YGRKKRRQRRR (amino acids 47–57), in which the arginine and lysine‐rich motif GRKKR was found to be the nuclear localization sequences (NLSs) responsible for nuclear localization and thus mediates further translocation of TAT into the nucleus [73–75].
Within the last several decades, more than hundreds of CPPs have been discovered, but the application of those CPPs in biomedical and clinical research has been retained due to their nonspecific targeting and weak stability [76]. Other than adding, replacing, or other methods to modify amino acid sequences of CPP itself to enhance its integrity, it draws people's attention that CPP is also able to combine with other drug carriers and hence integrate with various characteristics associated with different drug‐deliver techniques for developing innovative multifunctional drug delivery systems (MDDS). Major MDDSs based on CPPs combined with other drug carriers include CPP‐liposome, CPP‐polymers, and CPP‐nanoparticles (such as magnetic nanoparticles and nanogold Table 1.2).
Table 1.2 Major MDDSs based on CPPs combined with other drug carriers.
Drug carriers
CPPs
Purpose
References
Liposome
R
8
Deliver siRNA into cells and gene silencing
[77]
Gh
625
Anti‐cancer drug delivery
[78]
Polymers
PEI
TAT
Gene delivery
[79]
CBA‐DAH
TAT
Increase the delivery of siRNA to cardiomyocytes
[80]
PNVA‐
co
‐AA
D‐R
8
Mucosal vaccine deliver
[81]
Nanoparticles
PEI‐MNP
G
3
R
6
‐TAT
Gene transfer
[82]
Gold
TAT
For intracellular localization studies
[
83
,
84
]
Nanomicelle
TAT
Anti‐cancer drug delivery
[85]
Others
Cholesterol
G
3
R
6
‐TAT
Antimicrobial application
[86]
Dendrimer
TAT
Deliver oligonucleotide into cells
[87]
PEI, polyethylenimine; CBA‐DAH, cystamine bisacrylamide‐diaminohexane; PNVA‐co‐AA, poly(N‐vinylacetamide)‐co‐acrylic acid; PEI‐MNP, polyethylenimine coated magnetic nanoparticles.
Among all the MDDS, the CPP‐liposome is one of the most utilized systems due to its ability to be manipulated in many different ways and its good biocompatibility. CPP coupled liposomes, especially sterically stabilized liposomes, are under investigation by many researchers. For example Yun‐Long Tseng et al. indicated that, compared to the control peptide group, both penetratin (PEN) and TAT displayed improved translocation ability of liposomes and the more peptides attached onto the liposomal surface, the better the translocation effect would show, and the peptide number could be as few as five to enhance intracellular delivery of liposomes [88]. Moreover, an arginine‐rich‐peptide conjugated liposome was evaluated by Soon Sik Kwon et al. for its ability to deliver an antioxidant, Polygonum aviculare L. extract transdermally. Results indicated that CPP‐liposomes presented improved cellular uptake activity and skin permeability compared to antioxidant agents only [89]. In addition to intracellular drug delivery, CPP‐conjugated liposome also plays an important role in siRNA translocation. In this case, CPP‐liposomes entrapped with nona‐arginine (R9) and NF‐κB decoy oligodeoxynucleotides have been evaluated for their intracellular uptake efficiency as well as anti‐glioma ability in vitro[90]. Results showed that the CPP‐liposomes were successfully and effectively taken up by U87MG glioblastoma cells and facilitated tumor cell death.
1.2.3 Physiologically Modified Liposomes
1.2.3.1 PH‐sensitive Liposome
Since the 1970s, pH‐sensitive drug delivery system (DDS) in biomedical treatments have been extensively investigated [91]. A majority of the early work was to propose a kind of PSL formed with pH‐responsive phospholipids, such as dioleylphosphoethanolamine (DOPE), which contains unsaturated acyl chains that destabilize the liposomes at low pH spots and release the encapsuled drug/DNA as a result [92,93]. To achieve the localized release of the liposome content, PSL consisting of DOPE was demonstrated to be endocytosed and fused with the endovascular membrane due to the low pH inside the endosome and released its contents into the cytoplasm as a result [94]. Selvam et al. indicated that anionic polyelectrolyte (PE) containing immuno‐PSL showed successful release of antisense oligonucleotides (ONs) and suppressed by 85% HIV‐1 replication in vitro, which was much higher than the control group [95]. Furthermore, in the in vivo evaluation, liposomes consisting of DOPE and oleic acid was indicated as an efficient and stable immune‐PSL with the addition of cholesterol [96]. In other cases, the PH value around the tumor tissue was not much lower than normal tissue and usually around a pH of 6.5 [97]. In this scenario, fusogenic lipids are therefore introduced and DOPE together with cholesteryl hemisuccinate (CHEMS) have become a popular combination for synthesizing fusogenic PSL for endosomal/lysosomal escape [98]. CHEMS is a kind of acidic cholesterol ester which undergoes self‐assembly and forms bilayers under high or neutral pH [99]. In slightly acidic pH values, CHEMS with the inverted conical shape and a large headgroup will lose its original shape and lead to membrane destabilization due to the disruption of ionized headgroup [100]. Consequently, the cargos (such as anticancer drugs and genes) will then be released under mild acidic pH.
1.2.3.2 Thermosensitive Liposomes
Thermosensitive liposomes (TSLs) are another stimuli‐triggered localized drug delivery strategy that has been frequently explored for cancer and antimicrobial therapies. First introduced in 1978, when Yatvin et al. formulated a kind of liposome that released a hydrophilic antibiotic neomycin in vitro at specific temperatures and inhibited bacteria protein synthesis [101]. This kind of liposome with its ability to release hydrophilic drugs when the temperature increased to a few degrees higher than physiological temperature was then known as a traditional thermosensitive liposome (TTSL
