Metallic nanosystems in hard tissue implants

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Metallic nanosystems in hard tissue implants

13

Oana Fufa˘ 1,2, Ecaterina Andronescu1,4, Alexandru Mihai Grumezescu1,4 3 ˘ and Drago¸s Radulescu 1

Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Bucharest, Romania 2Lasers Department, National Institute for Lasers, Plasma & Radiation Physics, Bucharest, Romania 3Department of Orthopedics and Traumatology, Bucharest University Hospital, Bucharest, Romania 4Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

13.1 INTRODUCTION The histological features related to osseous tissue indicate a particular category of connective tissue, made out of three significant structural and functional basic components. The organic component of bone tissue mainly consists of type I collagen (.90%) and noncollagenous proteins—such as albumins, glycoproteins (osteonectin, thrombospondin), sialoproteins (osteopontin), glycosaminoglycans, and proteoglycans (Saladin, 2007; Holick et al., 2003; Henrikson et al., 1997). The inorganic component of the bone tissue mainly consists of crystallized hydroxyapatite (HAp) (calcium phosphate salt) and lesser amounts of various mineral complexes (due to the presence of carbonate, phosphate, hydroxyl, sulfate, fluoride, magnesium, sodium, and potassium ions) (Holick et al., 2003; Ranga, 1970a). Thanks to its specific organic
inorganic compositional structure, bone tissue can be considered a composite, where the protein (polymeric) matrix provides the favorable environment for bony mineralization and variable flexible behavior, while the mineral (ceramic) filler provides suitable mechanical properties. The mesenchymal-originating bone cells provide the proper adjustment of the human body’s hard tissue physiology—osteoblasts (immature bone cells that provide specific synthesis of proteins and mucopolysaccharides required in bone formation and mineral metabolism), osteocytes (adult bone cells with reduced synthetic activity that provide bone nutrients through the specific lacunaecanaliculi structure), and osteoclasts (mature bone cells that provide controlled erosion and physiological maintenance, restoration, and remodeling of bone tissue) (Ranga, 1970a; Currey, 2002; Papilian, 2006).

Nanobiomaterials in Hard Tissue Engineering. DOI: http://dx.doi.org/10.1016/B978-0-323-42862-0.00013-4 © 2016 Elsevier Inc. All rights reserved.

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In terms of microstructural architectonics, physiological evolution, and functional activity, there are two main specific components of bones, namely the cortical (compact) bone and the trabecular (spongy) bone. The compact bone tissue has a specific homogeneous, solid and dense microstructure, with close-packed osseous lamellae that define structural and functional cavities (lacunae) and ducts (lacunae-radiating canaliculi and longitudinal Haversian and transversal Volkmann’s canals that provide the bone tissue’s blood and nerve supply) (Ranga, 1970b; Currey, 2002; Kini and Nandeesh, 2012). The spongy bone tissue has a porous microstructure thanks to the specific honeycomb-like structural disposal of trabeculae (size-reduced bony lamellae as peculiar plates and spicules), that enclose small cavities for bone marrow hosting (Ranga, 1970a; Papilian, 2006; Kini and Nandeesh, 2012). Given its specific complex composition and physiological variety, the osseous tissue performs distinct functions in the human body, such as: (i) structural support (thus providing the basic hard framework for the human body’s requirements); (ii) protective role (organizing the required protective frameworks for body organs); (iii) locomotor function (the skeleton provides the regions for muscle origin and insertion and encourages the suitable function of human motor systems necessary for movement); (iv) mineral storage (the osseous tissue represents a reusable and renewable mineral source for the body); and (v) blood cell formation (most formation processes occur within marrow cavities of certain bones—sternum, ribs, long bones) (Saladin, 2007; Henrikson et al., 1997; Currey, 2002; Papilian, 2006; Ranga, 1970b). As we have already stated in the previous paragraph, the physiological relevance regarding the proper development, growth, and activity of bone tissue is essential for the human body’s movement and internal processes, but it is also noteworthy to mention that this specific connective tissue is prone to various diseases. The human genetics and individual variables (such as age, gender, personal and family medical history, residency, and workplace) and the etiologic diversity are clinically relevant factors responsible for the occurrence and the variety of bone disorders. Thus, the specific classification of musculoskeletal disorders seems a laborious and sustained process for health professionals, but a brief classification of skeletal diseases follows. (i) Bone fractures are acute or chronic trauma injuries caused by external large forces or repetitive strains, determined by a direct (shock action) or indirect (flexure, torsion, compressive, or avulsion action) mechanism of external harmful stress, accompanied by severe local pain, frequent local deformity, significant bleeding, and functional disability (Antonescu and Cristea, 1999; Imhof and El-Khourky, 2005; Kaye and Dalinka, 2005; Snell, 2007; Hasler and Hefti, 2007). (ii) Due to multitudinous genetic abnormalities occurring during the fetus development process, various local (three groups of dysostoses) and systemic (33 groups of osteochondrodysplasias) skeletal defects with noticeable dysfunction have been reported as distinctive diagnostic clues for complex syndromes inflicted by bone congenital disorders

13.1 Introduction

(Weiner, 2004; Wilson and Cheung, 2005; Wilson and Brunner, 2007). (iii) Degenerative disorders are painful, neurologically radiating and often neurologically affecting conditions related to aging patients, consisting of complex anomalies of osseous minerals and protein metabolism that affect the bone tissue (osteoporosis, spinal disk degeneration) and the articular cartilage (osteoarthritis) (Popescu, 1999; Antonescu and Stoica, 1999; Weihaupt and McCall, 2005; Valle et al., 2005). (iv) Inflammatory disorders of the bone—so-called osteomyelitis— are painful, swelling, and dysfunctional conditions that can affect the bone marrow (infectious osteomyelitis as a result of infection with Gram-positive and Gram-negative bacteria, fungi, and parasites via the bloodstream) and the bone tissue (exogenous osteomyelitis due to posttraumatic and postoperative microbial colonization) (St˘anculescu, 1999a; Jevtic and Pullicino, 2005; Forrester and Kilcoyne, 2005; Wilson, 2005). (v) Bone tumors are rare, severe, damaging disorders, asymptomatic in the early stage, that consist of solid tumor masses with specific malignant (osteosarcoma, parostal sarcoma, periosteal sarcoma, soft tissue sarcoma) or benign (osteoma, osteoid osteoma, osteoblastoma, histiocytoma, desmoplastic fibroma) cellular proliferation (St˘anculescu, 1999b; Sundaram and Vanel, 2005; Hefti and Jundt, 2007). The irremediable damage to the structural and functional integrity of the bone has been a concern for humanity since ancient times and still represents a significant research direction for today’s healthcare professionals. The first historical clue related to hard tissue restoration and replacement showed traumatic and low-success interventional techniques, while the sustained progress reported in medical practice and technologies led to the development of innovative surgical techniques with an improved prognosis. Given the permanent interest in increasing the patient’s life quality, several interventional approaches have been successfully recommended for structural and functional regeneration of severely damaged bone tissue, such as (i) autograft—immunological nonreactive tissue transplant from different anatomic regions of the same individual body, (ii) isograft—immunological nonreactive tissue transplant between two genetically identical individuals of the same species, (iii) allograft—moderate immunological reactive tissue transplant between two genetically different individuals of the same species, and (iv) heterograft or xenograft—high immunological reactive tissue transplant between individuals of different species. In order to overcome the major drawbacks of the aforementioned therapeutic approaches—such as reduced bioavailability, immune reactions, potential postoperative complications, postgrafting syndromes, and graft rejection—the scientific research activity aimed toward the improvement and innovative development of synthetic-based materials for orthopedic implants that can provide bone tissue restoration, replacement, or regeneration. The evolution of such nonviable complex systems requires the knowledge of different but complementary fields such as life science, material engineering, regenerative medicine, and modern healthcare practice, in order to provide the best orthopedic material choice for bone therapeutic strategy.

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13.2 CONVENTIONAL THERAPEUTIC APPROACHES IN HARD TISSUE IMPLANTS Mankind’s perpetual concern towards improving medical practice, as well as the tremendous progress lately reported in novel technologies, has enabled the promotion of genuine biomaterials, which represent any nondrug substances (solid, liquid, or gel substances), natural-derived (plant-derived, animal-tissue-derived, human-tissue-derived), synthetic origin (metals, ceramics, polymers, or composites), or hybrid substances that have been engineered to properly interact with living systems (alone or as part of a complex system), in order to precisely lead any therapeutic or diagnostic procedure (Nandi and Biswas, 2013; Kulinets, 2015; Chen and Thouas, 2015). In order to use these specific materials for potential orthopedic applications, there are some distinct requirements that have to be fulfilled, such as: (i) biocompatibility; (ii) mechanical properties; (iii) physical, chemical, and biological properties; and (iv) particular osteoconductive, osteoinductive, and osteogenic properties (Kulinets, 2015; Bose and Bandhyopadhya, 2013). The biocompatibility of bone implant materials represents a specific complex feature that expresses the nonharmful effects of the designed material to the living host, and covers various aspects related to the host
implant interactions (which tags the concerned material as toxic, bioinert, bioactive, or bioresorbable) and implant
host interactions (which evaluate the immunogenic, thrombogenic, cytotoxic, carcinogenic, or mutagenic potential of the concerned material) (Kulinets, 2015; Chen and Thouas, 2015; Bose and Bandhyopadhya, 2013; Thasneem and Sharma, 2013; Dang et al., 2014). In order to design and fabricate the convenient biomaterial for orthopedic applications, it is mandatory to accurately assess the mechanical requirements of physiological osseous tissue (depending on the anatomical region) and to anticipate the mechanical behavior of the concerned implantable system (stiffness, hardness, wear resistance, compressive strength, tensile strength, torsion strength, flexural strength, shear strength, yield strength, mechanical shock resistance, fracture toughness, fatigue failure, viscoelasticity, creep, ductility, plasticity, resilience), thus providing the bone implant’s future performance (Kulinets, 2015; Currey, 1998; Keaveney, 1998; Roeder, 2013). When the physical and chemical properties of materials are considered for bone implants, it is necessary to address the bulk physical (microstructure, phases and phase transitions, homogeneity or heterogeneity, density, porosity, crystalline or amorphous nature, particle size and morphology) and chemical (chemical composition, chemical stability, atomic and molecular bonding, atomic structures) specific features (Kulinets, 2015; Bose and Bandhyopadhya 2013; Kumar, 2013; Mani, 2015). Also, given the final potential application of these materials, it is crucial to properly consider the surface’s physical properties (absorption, permeability, topography, wettability) and chemical properties (chemical reactivity, corrosion, specific internal surface area, surface energy, surface tension) (Kulinets, 2015; Mani, 2015; Nouri and Wen, 2015; Holmes and

13.2 Conventional Therapeutic Approaches in Hard Tissue Implants

Tabrizian, 2015). The biological properties of osseous implantable materials represent the specific behavior of such systems in biological-simulated and biological environments—such as physicochemical and pathophysiological interactions—in order to accurately evaluate their subsequent therapeutic potential (Nandi and Biswas, 2013; Bose and Bandhyopadhya, 2013; Thasneem and Sharma, 2013).

13.2.1 METALLIC HARD TISSUE IMPLANTS Given their versatile process ability and specific physicochemical and distinctive mechanical properties, metallic materials (metals and metallic alloys) have been extensively used in restoration or replacement of damaged osseous tissue and also have been investigated and improved in terms of biocompatible features, providing thus suitable biomaterials for long-term performance orthopedic implants. As will be revealed in the following paragraphs, various metallic materials provide proper requirements for bone-implantable prostheses. Thanks to its peculiar protective chromium oxide layer that is spontaneously developed in oxygen atmosphere for more than 12% Cr content, stainless steel (SS) proved a peculiar anticorrosive behavior in physiological environments, having been thus used in various bone therapeutic approaches for a long time (Ivanova et al., 2014; Kurgan, 2014). Furthermore, specific mechanical properties (hardness, wear resistance, compressive strength, tensile strength, yield strength, elongation) (Kurgan, 2014; Dehsorkhi et al., 2014; Yetim and Yazici, 2014; Oshkour et al., 2015), versatile manufacturing, physicochemical features (density, thermal and electrical behavior, wettability, physical and chemical stability) (Oshkour et al., 2015; Hatada et al., 2014; Naghibi et al., 2014; Pourhashem and Afsharn, 2014; Horodek et al., 2015), low price requirements, and biocompatible characteristics (due to alloying elements and impurities) (Ivanova et al., 2014; Sutha et al., 2013; Lee et al., 2014; Pang et al., 2015; Chaves de Andrade Afonso et al., 2015) strongly recommend such materials for temporary orthopedic devices and permanent hard tissue implants. SS-based orthopedic implants exhibited durable therapeutic success in the case of medical-graded austenitic 304 SS (weight percentage chemical composition: C , 0.05, Cr 18.00
18.90, Ni 8.80
9.20, Si 0.80
1.00, Mn 1.60
2.00, S , 0.02, P , 0.02, and Fe balance) and 316L SS (weight percentage chemical composition: C , 0.03, Cr 16.00
18.50, Ni 10.00
14.00, Si , 1.00, Mn , 2.00, S , 0.03, P , 0.045, Mo 2.00
3.00, and Fe balance). Cobalt
chromium alloys are also extensively used for orthopedic implants, thanks to their specific properties, such as improved biocompatibility (compared to the previously discussed SS-based biomaterials), hardness, wear resistance, fracture toughness, fatigue strength, wettability, and good corrosion resistance against various corrosive mechanisms (Chen and Thouas, 2015; Ivanova et al., 2014; Lindahl et al., 2015; Zhang et al., 2015d). Several metallic elements have been considered as alloying agents for Co-Cr alloys (in order to improve their structural and functional properties), but given the specific bony tissue therapeutic direction of such materials only two compositional structures displayed superior

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properties and long-term performance: Co-Cr-Mo alloys (Yamanaka et al., 2014a; Mitsunobu et al., 2014; Zhang et al., 2015a; Barucca et al., 2015) and Co-Cr-W alloys (Yamanaka et al., 2014b, 2014c, 2015). Superior mechanical properties (wear resistance, compressive strength, tensile strength, torsion strength, flexural strength, fatigue failure) (Li et al., 2015a; Wang et al., 2015c), ease process ability, physiochemical behavior (suitable density and porosity, excellent corrosion resistance) (Benea et al., 2014; Mure¸san, 2014), and enhanced biocompatibility (as a consequence of titanium oxide native coating) (Tejero et al., 2014; Anitua et al., 2015; Gasik et al., 2015) are specific features of Ti-based materials (pure titanium and titanium alloys) with potential therapeutic perspectives in bone implants. Considering the chemical versatility of this valuable metal, various chemical elements have been intensively investigated and evaluated as pure Ti alloying or contaminating elements, in order to develop novel titanium-based orthopedic biomaterials, such as Ti-xAl-yV (Wu et al., 2015; Bolzoni et al., 2014; Li et al., 2015d; Ren et al., 2014), Ti-xAl-yNb (Łyczkowska et al., 2014; Rafieerad et al., 2015; Ashida et al., 2015), Ti-xNb (Byeon et al., 2015; Zhao et al., 2015a; Santos de Oliveira et al., 2015), Ti-xNbyZr (Jeong et al., 2014; Ozan et al., 2015; Inaekyan et al., 2015), Ti-xNb-yTa (Ren et al., 2014; Kim et al., 2014a), Ti-xTa-yZr (Bolzoni et al., 2014; Kim et al., 2014b, 2014c), Ti-xTa-yNb-zZr (Stenlund et al., 2015), Ti-xNb-yMo-zZr-tSn (Wang et al., 2014b; Wan et al., 2015), Ti-xMo-yZr (Nespeque Correa et al., 2015; Akita et al., 2015), Ti-xMo (Hsu et al., 2015; Chung et al., 2015; Neac¸su et al., 2015), and Ti-xFe-yTa (Haghighi et al., 2015).

13.2.2 CERAMIC HARD TISSUE IMPLANTS Considering their compositional versatility and specific workable properties, researchers and healthcare professionals point toward ceramic materials as potential candidates for bone prosthetic therapy. There are various parameters that have to be considered when a ceramic material is designed to be used for orthopedic applications, such as chemical composition, compositional phases (phase and grain origin, size and shape of grain), intimate structure (crystalline or amorphous, structural imperfections), density and porosity, morphology and topography, process ability (ceramic powder, ceramic coating, ceramic fiber, or ceramic solid specimen), physiological behavior, and the potential local or systemic effects of the material in the human host. Thanks to their peculiar elemental composition—which significantly imitates that of natural bone apatites—calcium-phosphate ceramics possess an important position in hard tissue restoration and replacement. For such specific applications the acknowledged properties of these biomaterials are considered: biomimetic composition, modifiable density and porosity, bulk and surface morphology, tolerated mechanical properties, excellent chemical stability and biocompatibility, optional biodegradable, osteoconductive and osteoinductive specific features (Samavedi et al., 2013; Rey et al., 2014; Garcı´a-Gareta et al., 2015). Promising

13.3 Unconventional Therapeutic Approaches in Hard Tissue Implants

and lasting results have been acquired by using the insoluble lab-synthesized HAp that provides the required elemental composition (Ca21 and P1 ions), versatility in terms of synthesis and processing, structural features (crystallinity, grain dimension and shape, porosity, surface topography), physical and chemical properties (wear resistance, compressive and tensile strength, chemical stability) and biological behavior (bioinertness or bioactivity, biomineralization and biodegradation, osseous cells adhesion, proliferation and new bone formation potential) (Zhou et al., 2015a; Nga et al., 2015; Liu et al., 2015; Qi et al., 2015). Thereby, the use of HAp in bone implants seems to represent one of the most attractive and successful therapeutic strategies. Another ceramic biomaterial successfully used in bone implants is aluminum oxide (Al2O3), which recently showed up in this complex prosthesis area thanks to its specific attractive mechanical properties (superior to that of calcium-phosphate ceramics). It is also worth mentioning the specific features of this fascinating ceramic that recommend it for such significant applications: physical properties (pure crystalline phases, controllable and stable microstructure, thermal stability, low friction interactions, and self-polishing features) (Bal and Rahaman, 2011; Yoon et al., 2008; Sellappan et al., 2015), chemical properties (chemical stability, strong anticorrosive behavior) (Piconi et al., 2014), manufacturing aspects (various synthesis methods can successfully be used to produce dense or porous alumina bone-like materials), mechanical behavior (excellent compressive and tensile strength, good torsion and flexural strength, improved fracture toughness, extraordinary wear resistance, and fatigue failure) (Affatato et al., 2012; Yoo et al., 2013; Kawano et al., 2013; Lee et al., 2013), and remarkable biocompatibility (Soh et al., 2015; Song et al., 2013; Pedimonte et al., 2014; Wittenbrink et al., 2015). Excellent mechanical properties assigned to oxide-stabilized (Y2O3, CaO, MgO, CeO, La2O3) zirconium dioxide—such as hardness, tensile strength, flexural strength, fracture toughness, and wear resistance—strongly draw the attention of medical professionals towards potential ZrO2-based orthopedic implants (Piconi et al., 2014; Alao and Yin, 2014; Camposilvan et al., 2015). The physicochemical-specific features (tunable microstructure, thermal stability, optical properties, physical and chemical stability, remarkable corrosion resistance, versatile surface chemistry) and biological behavior (current research reports formidable results in terms of noncytotoxicity, noncarcinogenicity, and nonmutagenicity) shown by zirconia-based materials, depict the ideal candidate for long-term performance bone implants (Maia et al., 2012; Gremillard et al., 2013; Hsu et al., 2014; Yilmaz et al., 2015).

13.3 UNCONVENTIONAL THERAPEUTIC APPROACHES IN HARD TISSUE IMPLANTS The structural and functional versatility displayed by pristine metallic and ceramic biomaterials provides suitable groundwork for hard tissue implants, in terms of specific physicochemical, mechanical, and biocompatible features. However, it is

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necessary to mention that these pure inorganic materials also possess distinctive problems when it comes to biomedical applications, such as (i) metallic ion release, (ii) potential immune reactions, (iii) potential postoperative side effects, (iv) natural bone resorption and osteolysis, and (v) potential implant failure (due to inappropriate mechanical features, improper surgical strategy, potential intraoperative microbial contamination) (Piconi et al., 2014; Sirova, 2014; Agarwal and Garcı´a, 2015). In order to overcome these drawbacks, researchers and healthcare professionals turned their attention towards novel engineered biomaterials for bone implants, considering thus not only the bioinertness and bioactivity of such distinctive materials, but also the osteoconductive activity (the ability of biomaterials to support adhesion and proliferation of bone cells), osteoinductive activity (the ability of biomaterials to promote osteoprogenitor cells into specific functional cells), and osteogenic potential (the peculiar property of advanced biomaterials to contribute to new bone formation, in terms of mineralization, cellular growth, differentiation, adhesion and proliferation, angiogenesis, and even nerve regeneration) (Samavedi et al., 2013; Agarwal and Garcı´a, 2015; Khan et al., 2012; Wu et al., 2014). The development of unconventional materials for bone prosthesis requires extensive knowledge (considering the principles of life science, material engineering, regenerative medicine, and modern healthcare practice) and suitable technologies (considering the basis of tremendous interdisciplinary nanotechnology). The amazing outcome lately reported in nanotechnologies provides the possibility to design novel biomaterials (composite and hybrid nanomaterials, synthetic tissues, and organs) as well as to modify the conventional ones (nanocoatings and nanoparticles), in order to engineer customized bone implants with a specific personalized therapeutic strategy and long-standing performances.

13.3.1 COMPOSITE AND TISSUE-ENGINEERED IMPLANTS Given the intrinsic composite structure of natural bone, the current trend in improving and producing biomaterials for hard tissue restoration, replacement, and regeneration aims towards a biomimetic strategy (i.e. imitating the compositional, structural, functional, and physiological behavior of natural osseous tissue), where the pristine inorganic (metals and ceramics) and organic (polymers) materials are genuinely used to develop exclusive compounds that provide suitable physical, chemical, mechanical, and biological properties for such specific and effective applications. As mentioned above, it is mandatory to consider interdisciplinary fundamentals and interdisciplinary professional cooperation in order to provide enhanced and personalized therapy for minor and severe bone damage. For orthopedic applications, various metallic, ceramic, and polymeric materials have been intensely investigated, medically graded, clinically and commercially used, but the assessment of long-time behavior in patients revealed significant imperfections for any of these. Thereby, a wide variety of composite materials has been engineered and successfully evaluated for this specific purpose

13.3 Unconventional Therapeutic Approaches in Hard Tissue Implants

as dense or porous materials or as coatings: (i) metallic
ceramic composites (TiZrO2 (Huang et al., 2013; Kaluðerovi´c et al., 2014; Ormanci et al., 2014), TiAl2O3 (Ormanci et al., 2014; Sakka et al., 2014; Wang et al., 2015a), and Ti-HAp (Khanna et al., 2015; B˘ail˘a, 2014) biomaterials proved enhanced properties compared to pure metallic or ceramic compounds); (ii) ceramic
ceramic composites (ZrO2-Al2O3 (Omran et al., 2015; Valle´e et al., 2014; Spies et al., 2015), ZrO2HAp (Ngashangua et al., 2015; An et al., 2012; Shojaee and Afshar 2015), ZrO2ceramic glass (Drdlik et al., 2015), Al2O3-HAp (Tallia et al., 2014; Ghazanfari and Zamanian, 2014; Radha et al., 2015), Al2O3-CaSiO3 (Shirazi et al., 2014; Bainon and Vitale-Brovarone, 2015)); and (iii) ceramic
polymeric composites. For the last mentioned composite category, various natural or synthetic organic materials have been used to produce novel bone-like composites, including alginate (Cattalini et al., 2013; Kim et al., 2015), cellulose (Eftekhari et al., 2014; Kim et al., 2014; Park et al., 2015), chitosan (Pon-On et al., 2014; Shavandi et al., 2015; Serra et al., 2015), collagen (Xia et al., 2013; Basha et al., 2015; Quinlan et al., 2015; Linh et al., 2015), fibrin (Rao et al., 2014; Xuan et al., 2014), gelatin (Islam et al., 2015; Fu et al., 2015), hyaluronic acid (Huh et al., 2015; Cui et al., 2015), keratin (Saravanan et al., 2013; T˘anase et al., 2014; Zhao et al., 2015b), polyhydroxyalkanoates—(PHAs) (Yang et al., 2014; Zhang et al., 2015c; Gredes et al., 2015), polycaprolactone—(PCL) (Ni et al., 2014; Fereshteh et al., 2015a, 2015b), poly(ethylene glycol)—(PEG) (Yang et al., 2013; Wang et al., 2015b), polylactide—(PLA) (Zhou et al., 2012; Persson et al., 2014; Lin et al., 2014), polyglycolide (PGA) (Cao and Kuboyama, 2010; Wang et al., 2014a), poly(lactic-co-glycolic) acid—(PLGA) (Buschmann et al., 2012; Qian et al., 2014; Lin et al., 2015; Naik et al., 2015), polyurethane—(PU) (Pon-On et al., 2014; Tetteh et al., 2014; Li et al., 2015c), polyvinyl alcohol—(PVA) (Maheshwari et al., 2014; Douglas et al., 2014), and silk fibroin (Oliveira Barud et al., 2015; Ribeiro et al., 2015; Jin et al., 2012). Furthermore, the last class of composites—the so-called third-generation biomaterials—brings in novel alternatives for orthopedic implants, by considering the structural and functional specific features of such smart materials and the tremendous potential to combine them with biologically active molecules (proteins, specific extracellular matrix molecules, growth factors, drugs) and living cells (tissue-derived osteoblasts, adult stem cells, mesenchymal stem cells (MSCs), embryonic stem cells, induced pluripotent stem cells), in order to develop tissueengineered implants that provide personalized therapeutic strategies, autograftlike behavior, and long-term performances (Garcı´a-Gareta et al., 2015; Sirova, 2014; Amini et al., 2012; Liu et al., 2013; Rana et al., 2015).

13.3.2 METALLIC NANOSYSTEMS IN HARD TISSUE IMPLANTS The tremendous expansion of nanotechnologies provides unprecedented possibilities to design nanosized metal-based systems, that possess particular and genuine properties (in terms of structure, morphology, physics, chemistry, and specific

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functionality) and enable proper physiological interactions, thanks to their specific high surface/volume ratio (Cabral et al., 2014; Schro¨fel et al., 2014; Edmundson et al., 2014). The use of noble metal (silver and gold) nanoparticles and metallic oxide nanostructures in current medical practice is familiar to healthcare professionals, but it still represents an attractive and challenging research direction due to specific features and potential use of such metal-based structures (antimicrobial therapy, biosensing, bioimaging, drug delivery, molecule and gene delivery, tissue engineering, and antitumor therapy). Therefore, metallic nanostructures represent ideal candidates for various biomedical applications, including the development of improved bone implants—as we propose to highlight in the following paragraphs. Given the acknowledged microbial activity of silver and the current progress recorded in novel technologies, plenty of research studies have reported the successful use of silver nanoparticles (AgNPs) in producing novel biomaterials for bone implants. In order to use such multifunctional inorganic nanosystems in osseous tissue implants, the biocompatibility and osteogenic potential of AgNPs was investigated by Pauksch et al. (2014). Silver nanosized particles stabilized with polyoxyethylene glycerol trioleate (PGT) and polyoxyethylene sorbitan monolaurate (Tween 20) were commercially procured for this experimental work. The hydrodynamic diameter of the particles was investigated in deionized water, MSCs medium, and osteoblast medium, the obtained data being collected after 24 h (5, 5
10, and 5
10 nm), respectively, 7 days (10, 5
10, 100 nm) after inoculation. For rational AgNP amounts, the in vitro assays reported no toxic effects after 24 h treatment against MSCs and osteoblast cell cultures, while reduced cellular viability and modified morphology data were detected for both cases at 21 days after particle inoculation. Also, superior cellular uptake and no morphological modifications against cellular-specific structures were reported in MSCs and osteoblast experiments for 7 days incubation. For both cell types the reports have shown a noticeable detection of osteogenetic markers, so the overall data emphasized the potential of AgNPs to be used in novel therapeutic strategies for bone diseases. Saravanan et al. (2011) successfully developed a novel chitosan, nanosized HAp (,200 nm) and AgNPs (80
120 nm) biomaterial for bone implants, by controlled reduction of aqueous silver nitrate solution within an intimate network of lyophilized polymeric-ceramic scaffold. The synthesized macroporous materials showed reduced degradation in lysozyme-containing media and noncytotoxic potential against Wister-rat-derived osteoprogenitor cells. Also, the presence of AgNPs conferred antibacterial activity to this biomaterial—as it was experimentally assayed against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) strains—which can significantly minimize potential postoperative complications and implant failure. Polyethylene glycol methyl ether methacrylate (PEGMEM) and 2-dimethylamino ethyl methacrylate (DEM) were used by Gonza´lez-Sa´nchez et al. (2015) to produce a gel that was further mixed with N,N0 -methylenebis(acrylamide)

13.3 Unconventional Therapeutic Approaches in Hard Tissue Implants

(BIS) and ammonium persulfate (APS) to form a hydrogel, which was dialyzed in AgNP solution (prepared by chemical reduction of AgNO3 with sodium citrate). Subsequently, the hydrogel was placed into a plastic tube with a connection to calcium and phosphate sources, in order to produce a biomineralized methacrylate material with encapsulated AgNPs for bone substitution. Thus, spherical metallic particles with 60
80 nm mean size were synthesized and successfully entrapped into the polymeric network, whose rheological properties were not influenced by the presence of AgNPs. The in vitro biological activity of the material showed excellent antibacterial potential against a Staphylococcus epidermidis strain and lower—but significant—activity against a methicillin-resistant S. aureus strain. Also, the cytotoxicity studies performed against MC3T3 osteoblast cells revealed nonharmful activity of the designed material, thus confirming the multifunctional potential of this tentative biomaterial for bone graft therapy. The influence of silver nanosized particles in osseous substitutes was also studied for pristine ceramic scaffolds, as was reported by Zhou et al. (2015b). By using the microsyringe extrusion method the authors used needle-like commercial HAp to produce a porous scaffold that was presintered at 400  C for 30 min, sintered at 1200  C for another 30 min and further immersed into a solution of AgNPs (which was obtained by a facile chemical route of silver nitrate with hydrazine hydrate as the reducing agent and oleic acid as the stabilizing agent). Pure and crystalline spherical AgNPs with 4.62 6 1.40 nm average size were homogeneously dispersed within the macroporous inorganic scaffold. The in vitro antibacterial assay was performed against E. coli and showed significant bacteriostatic activity of this biomaterial, thus revealing its potential use as a low-risk infection bone implant. A similar study was performed by Piccirillo et al. (2015), who successfully developed a marine-derived HAp material modified with nanosized silver. Cod fish bones were mechanically processed and mixed with AgNO3 solution, then dried and calcined at 650  C to produce the final powders with different Ag:HAp molar ratios. The experimental structural and elemental analysis showed the presence of silver within this new material, whereas the release profile highlighted reduced silver ions release from the modified marine HAp. In order to evaluate the antimicrobial potential of such materials, in vitro assays were performed against E. coli and methicillin-resistant S. aureus bacterial strains for the lowest Ag-containing calcium phosphate (Ag:HAp molar ratios of 1:1 and 1:2). The resulting data showed a strong bacterial biofilm inactivation rate for Gramnegative bacteria (up to 99.23% after 2 h contact) and significant bacterial biofilm inactivation rate for Gram-positive bacteria (up to 91% after 8 h contact), which confirmed the potential use of these materials for bacteria-resistant orthopedic prostheses. Besides the encapsulation of silver nanoparticles into composite scaffolds for novel and superior biomaterials used in bone substitution, various research studies aimed toward functional improvement of current materials by using silver in surface modification strategies. Erakovi´c et al. (2014) successfully reported the

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deposition of Ag-doped HAp coatings on commercially pure Ti plates modified by anodization-produced TiO2 nanotubes, by using the pulsed laser deposition technique. Spherical and submicron (150
1500 nm) particulate layers with reduced thickness (1.64 6 0.1 μm) and significant roughness were thus produced and biologically evaluated. The in vitro cytological assay performed against a HEp2 cell line showed nontoxic effects of the tested material, by reporting a normal cellular cycle (with no influence for cellular viability), whereas the in vitro antifungal activity was assessed against Candida albicans (the examined material caused complete colonial dissolution) and Aspergillus niger (the examined material caused 99.73% colonial regression) strains. Another research study, performed by Guo et al. (2014), reported the formation of highly ordered and organized TiO2 nanotubes (180 nm diameter and 2500 nm length) by pure Ti anodization and further modification with AgNPs (produced by UV irradiation of Ti-based substrate soaked into silver nitrate aqueous solution). Nanometric silver particles (with mean size of 30
70 nm) were thus produced on the edges, inner and outer walls of TiO2 nanotubes and reduced Ag1 release profiles were reported for simulated body fluid (SBF) immersion assay, for up to 2 weeks. Furthermore, compared to a bare TiO2 tubular coating (that showed 20% antibacterial rate) the silver-based coating showed significant antimicrobial activity against E. coli and S. aureus pathogenic strains (100% antibacterial rate in the first 4 days, followed by a slight decline down to 90% bactericide efficiency). A recent study performed by Jia et al. (2015) revealed the possibility of immobilizing AgNPs within a Ti6Al4V-based porous metallic scaffold obtained by complex processing with electron beam melting and micro-arc oxidation. The so-produced scaffold was subsequently immersed in silver nitrate solution and the synthesis of homogeneous sphere-like morphology and reduced dimension (B50 nm) AgNPs was feasible by using ultraviolet light radiation. The metallic nanoparticles were homogeneously entrapped in the metallic scaffold’s intimate network and the obtained structure was further in vitro assessed for cellular compatibility against human osteosarcoma MG63 cell line. As reported by the authors, the designed material provided a suitable environment for cellular growth, intercellular confluence, and specific bone tissue extracellular matrix formation. Thereby, the porous Ti-based scaffold with immobilized AgNPs proved an advantageous choice for potential orthopedic applications. Massa et al. (2014) reported enhanced activity of commercial medical-graded Ti6Al4V alloy through a surface modification process with AgNPs-loaded silica thin layer. A metallic suspension was produced by using starch both as a reducing agent for AgNO3 solution and as a stabilizing agent for the synthesized silver nanoparticles and the obtained suspension was afterwards mixed with tetraethyl orthosilicate (TEOS) solution. The Ti-based substrates were immersed into the resulting mixture, dried and calcined in order to form a nanostructured coating by induced evaporation of composite sol
gel. Thus, 8-nm mean size AgNPs were

13.3 Unconventional Therapeutic Approaches in Hard Tissue Implants

synthesized and homogeneously dispersed within highly ordered silica nanoporous structure (4-nm pore average dimension). As reported in a previous research study, the titanium alloy coated with nanoporous silica layer promotes cellular adhesion and stimulates stem cells differentiation, thus enhancing the properties of Ti6Al4V metallic implants (Inzunza et al., 2013). The experimental in vitro assays performed against an Aggregatibacter actinomycetemcomitans Gramnegative strain showed significant bactericidal potential of the designed material both on planktonic bacteria and bacterial biofilm. Thus, the development of silica
AgNP composite coatings for Ti-based implants extends the functional properties of such biomaterial beyond superior osseointegration properties, in terms of reduced periprosthetic infection potential. Gold nanoparticles (AuNPs) have also been intensively investigated for potential engineered bone-grafting materials thanks to their variant specific features. For such distinctive applications it is mandatory to firstly evaluate the compatibility and potential side effects that may occur during AuNP
osteogenic cell interactions. Different concentrations of gelatin solution were used by Suarasan et al. (2015) to reduce HAuCl4 aqueous solution, in order to produce one-step gelatin-functionalized gold nanoparticles. In the case of reduced gelatin concentrations (,1%) AuNPs with triangular and spherical morphologies were simultaneously produced (the amount of triangle-like particles decreased with higher concentrations of gelatin). When using higher gelatin concentrations (between 1% and 5%) only spherical nanosized particles were reported. Sphere-shaped and monodispersed AuNPs with specific 18 6 3.5 nm mean size that were obtained with 1.5% gelatin concentration were further investigated in this study. The concerned particles showed excellent stability in simulated physiological conditions and cellular medium. The in vitro assays performed against osteoblast cultures showed significant internalization of the synthesized AuNPs, no toxic effects against osteoblast cells and—as was reported—the increasing concentrations of inoculated particles promoted excellent cellular viability, superior osteoblast proliferation, and potential osteogenic activity. Thanks to their specific features, the so-produced AuNPs proved suitable physicochemical properties and functional behavior for potential modern bone therapies (specific diagnostic tools, targeted drug delivery, and osseous tissue-regenerative therapy). The research study performed by Zhang et al. (2014) considered the uptake and cellular compatibility assays of AuNPs (20- and 40-nm metallic particles synthesized by chemical reduction of chloroauric acid with citrate) in primary osteoblasts (isolated from NIH mice calvarias). The in vitro evaluation reported nonharmful activity of AuNPs against osteoblasts, but significant cellular proliferation and mineralization (with noticeable enhanced activity assigned to 20-nm metallic nanoparticles). The presence of AuNPs in cellular cultures promoted the osteoblast expression of specific extracellular matrix compounds, such as bone morphogenetic protein (BMP-2), runt-related transcription factor 2 (Runx-2), osteocalcin (OCN), and type 1 collagen (Col-1), thus the potential bone therapy being highlighted by using gold nanosized particles.

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Another study related to potential inorganic nanoparticle
living cell interactions was performed by Li et al. (2015b), who experimentally examined the influence of different charged AuNPs on human mesenchymal stem cells (hMSCs) osteogenesis. A one-step synthetic method was used to produce amine (
NH2) functionalized AuNPs, while a two-step synthetic method was used to produce hydroxyl (
OH) and carboxyl (
COOH) functional groups onto the surface of gold particles. The potential effects of the obtained AuNPs (with specific dimensional range lower than 25 nm, in either of the experimental versions) were investigated against hMSC cultures (with specific osteogenic medium) and the reported data mentioned nondamaging effects for cell viability, but also a preferential cellular uptake of the positively charged AuNP-NH2. The extracellular matrix mineralization was also evaluated after long-term interactions (up to 21 days) and the results reported enhanced osteogenic mineralization for the AuNPCOOH experiment. Such significant results can contribute to the proper development of gold-based novel nanostructured biomaterials for bone implants. Also, the influence of AuNP dimensional features was investigated on adipose-derived stem cell (ADSC) osteogenesis by Ko et al. (2015). The authors reported the successful synthesis of spherical and nanosized gold particles by using the citrate reduction of HAuCl4 and various stabilizing agents, in order to produce 15-, 30-, 50-, 75-, and 100-nm mean sized gold nanoparticles that were further used alongside ADSCs to seed the plates containing osteogenic culture media. The in vitro assays showed high cellular viability up to 7 days for all experimental trials (even higher than the control examination, consisting of untreated cellular culture) and significant cellular uptake in the case of 50-nmsized AuNPs. Also, after 21 days of treatment, the same nanoparticles and the 30-nm-sized AuNPs were discovered to encourage the highest levels of alkaline phosphatase (corresponding to the most representative differentiation of ADSCs into osteoblasts) and the highest amount of calcium deposition. Specific bone extracellular expressed molecules were experimentally identified in all specimens—Runx-2, OCN, Col-1, and bone sialoprotein—but the highest levels were reported for the 30- and 50-nm AuNPs, thus fortifying the previous results regarding the effectiveness of such gold nanoparticles in ADSC osteogenesis. Farghali et al. (2015) successfully developed a nanobiocomposite material consisting of chitosan and gold nanoparticles for improved bioactivity of titanium orthopedic implants. Thus, a homogeneous mixture of chitosan solution and AuNPs (spherical nanosized particles obtained through chemical reduction of hydrogen tetrachloroaurate) was electrodeposited on commercially pure Ti plates and further immersed in glutaraldehyde cross-linker, in order to form a uniform and smooth coating (as was experimentally reported). The corrosion behavior of the modified Ti was investigated by performing electrochemical studies in Hank’s solution and the results showed superior stability and improved corrosion resistance compared to bare titanium (where pitting corrosive mechanism was observed after only 4 days of immersion). The in vitro antimicrobial assay performed against a S. aureus bacterial strain revealed excellent antibacterial activity

13.3 Unconventional Therapeutic Approaches in Hard Tissue Implants

of the composite-coated Ti plates (compared to bare Ti, chitosan-coated Ti, and AuNP-coated Ti). So, the developed chitosan-AuNP nanobiocomposite material showed tremendous potential for enhanced Ti-based orthopedic implants, in terms of lasting anticorrosive performance and periprosthetic infection prevention. The study performed by Jayalekshmi and Sharma (2015) recently reported the development of a novel promising biomaterial for osseous regeneration and therapy, consisting of AuNPs, bioglass, and two natural polymers. Herein, AuNPs were mixed with hydrolyzed TEOS, disodium hydrogen phosphate and calcium nitrate tetrahydrate in order to produce a powdery specimen that was further calcined, sintered, and finally powdered. The obtained material was dispersed into a chitosan
gelatin polymeric mixture with subsequent glutaraldehyde addition and the final composite was lyophilized, in order to produce polymeric encapsulation of AuNP
bioglass structures. Highly porous gold
bioglass nanosized aggregates were formed within the polymeric matrix. A favorable degradation profile was reported for this material during phosphate-buffered saline (PBS) evaluation. Also, physiological pH values reported after long-term immersion in PBS and specific protein adsorption (albumin and fibrinogen) predicted the potential biocompatibility of such material. The biological activity of the composite was evaluated for bare and doxorubicin (DOX)-loaded materials during the in vitro assays, performed against G6 glioma cell cultures. Nontoxic effects were reported for ceramic
polymeric composite and DOX-loaded composite, while the results were significantly changed when the presence of AuNPs within the composite was considered, such that the cell viability significantly decreased during the experiment, as a result of controlled drug release profile provided by the obtained AuNP-encapsulated composite. Thus, the produced nanobiocomposite can successfully provide bone regeneration (by filling the osseous defects and postoperative voids) and control targeted drug therapy (in terms of anti-inflammatory and antitumor local treatment). Except for pristine metallic nanoparticles, various metallic oxide nanosized structures have been successfully reported for bone implant engineering and improvement strategies. HAp and sodium-silicate glass were used to experimentally produce a bioactive highly porous composite in which 9-nm mean sized magnetite (Fe3O4) was successfully encapsulated, in order to produce biogenic magnetic biomaterial with potential use in drug delivery of therapeutic substances (Kuda et al., 2009). Also, considering the peculiar behavior of Fe3O4 and the acknowledged bioactivity assigned to titanium dioxide, magnetite nanoparticles (with diameters lower than 10 nm) were successfully coated with TiO2 (with average thickness about 20 nm), in order to synthesize core-shell particles (Zhu et al., 2014). As was experimentally reported, crystalline structures with magnetic properties were thus produced and specific minimal toxic effects were shown during the in vitro assays performed against 293T (human embryonic kidney), BMDCs (bone-marrowderived dendritic cells), and Raw 264.7 (mouse leukemic monocyte macrophage) cell lines. Furthermore, reduced hemolytic activity was reported, as well as

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significant cellular uptake and specific gene expression of dendritic cells (antigen-presenting cells that were found to crucially regulate the immune response in cancer). Thus, the designed metallic nanosystem revealed optimal requirements for the development of intravenous therapeutic adjuvant systems with promising potential in bone tumor clinical management. Bone-derived HAp and shrimp shell-derived chitosan were used to produce a composite scaffold that further served for in situ precipitation of nanosized and irregular-shaped magnetite (mean size B23.5 nm) and maghemite (mean size B55.2 nm) particles (Heidari et al., 2015). Homogeneous and quite dense biomaterial with specific magnetic properties was thus obtained with potential biomedical applications including osseous tissue engineering and drug delivery, and potential local antitumor treatment. Complex materials consisting of high porous alumina with dispersed titanium dioxide and maghemite nanosized particles were also produced by the freezecasting method and investigated for potential orthopedic applications. As was reported, the presence of Fe2O3 inorganic structures provided the experimental synthesis of a dense material (compared to pure TiO2-Al2O3 sample in which dendritic-shaped porosity was noticed) with an enhanced crack propagation mechanism (Silva et al., 2015). Thanks to its nanosize-dependent peculiar properties, zinc oxide has been intensely explored for improving biomaterials for use in bone tissue therapeutic strategies. A composite chlorapatite-ZnO powder for potential orthopedic applications was successfully produced by Nasiri-Tabrizi and Fahami (2014) using a ball-milling mechanical synthetic method against a mixture consisting of CaO, P2O5, CaCl2, and hydrothermally presynthesized ZnO nanoparticles, followed by calcination. Rod-shaped pure and crystalline inorganic particles were obtained thanks to hydrothermal synthesis, while high purity and crystalline cluster-like nanostructures (average size less than 100 nm) with ellipsoidal and polygonal shapes were reported in the case of chlorapatite-ZnO composite. A homogeneous and uniform layer of highly oriented and organized ZnO hexagonal nanorods (mean cross-section size of B25 nm) was successfully formed onto Si wafer substrates by using the hydrothermal synthesis by Cheng et al. (2013). Further, the sol
gel synthesis was used to produce a continuous HAp coating on the ZnO-modified substrates. The presence of inorganic nanoarray in the obtained composite material caused a highly hydrophobic behavior (after dark light storage), as well as a highly hydrophilic behavior (after ultraviolet light irradiation), thus emphasizing the tremendous potential of ZnO-based material for use in controllable wettability bioactive materials. Favorable results for reduced and sustained Zn21 ion release were reported after long-term tris-buffered solution immersion. Also, improved protein adsorption was observed for both hydrophobic (bovine serum albumin) and hydrophilic (lysozyme) molecules after UV treatment. Thus, the designed composite coating exhibited promising results for potential cellular adhesion, proliferation, and osteogenesis, in order to provide improved biomaterials for bone regeneration.

13.3 Unconventional Therapeutic Approaches in Hard Tissue Implants

Electrophoretic deposition was successfully used by Cordero-Arias et al. (2015) to experimentally produce alginate-based coatings containing ZnO nanoparticles, in order to improve the biocompatibility of 316L SS medical-graded materials. Homogeneous and continuous microsized layers of alginate-ZnO nanoparticles and alginate-bioglass-ZnO nanoparticles were thus produced onto the metallic surface. The electrochemical behavior studies showed enhanced longterm anticorrosive behavior of both experimental coatings, but significant relevant results reported for the alginate-ZnO coating (due to bioglass dissolution). As expected, only the alginate-bioglass-ZnO nanoparticle composite coating promoted the in vitro formation of HAp structures, after SBF immersion. The bactericide activity of the obtained coatings was also investigated during in vitro assays performed against E. coli bacterial strains, and the reported result showed significant antibacterial potential of the bionanocomposite coatings. The current study revealed the enormous potential of ZnO nanoparticles to successfully improve the physicochemical and functional properties of ceramic
polymer composites intended to be used for osseous tissue therapeutic applications. Tetra needle-shaped ZnO nanoparticles (T-ZnOw) were successfully used as a reinforcing agent within forsterite (Mg2SiO4)—bioglass scaffolds to improve the mechanical features of the oxide-based composite (Shuai et al., 2015). As was reported, interconnected porous structures were fabricated and the homogeneous dispersion of ZnO nanosized particles significantly affected the mechanical behavior of the composite scaffold in terms of improved compressive strength and fracture toughness (the addition of inorganic nanoparticles encouraged the transgranular fracture mechanism, to the detriment of intergranular fracture mechanism specific for the native composite). The biocompatibility of the ZnO particles entrapped within the composite was in vitro evaluated against a human osteosarcoma MG63 cell line, and the reported result revealed no harmful effects against the cells and promising cellular behavior in terms of improved adhesion and proliferation. The designed material proved to have suitable mechanical properties and biological behavior, so potential use in bone restorative and regenerative biomaterials is present without a doubt. The improved biocompatibility owned by Ti-based material (thanks to their native titanium oxide protective coating) and the tremendous material processing genuine techniques promoted by nanotechnology extended the possibilities to produce novel surface layers based on nanostructured TiO2. The influence of a specific diameter assigned to anodization-produced TiO2 nanotubes onto commercially pure Ti was investigated on osteoblast cell response by Zhang et al. (2015b). Highly voltage anodization performed at 60, 90, 120, 150, and 180 V encouraged the formation of homogeneously grown and highly ordered TiO2 nanotubes onto the substrate, with steady diameters corresponding to the applied voltage of 150, 260, 360, 470, and 570 nm. The experimental work reported single-walled nanotubes for anodization voltage lower than 120 V, double-walled nanotubes for higher voltage values, and even heterogeneity of the TiO2 array for voltage higher than 180 V, but all the obtained nanostructures showed hydrophilic

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features. The in vitro assays were performed against mouse-derived MC3T3-E1 osteoblast cells. All the TiO2 nanoarrays showed nontoxic effects against cellular cultures (in terms of excellent cellular viability, proliferation, morphology, and osteogenic potential). However, a specific behavior was distinguished: the 470nm TiO2 nanotubes encouraged the best cellular proliferation, while the 150-nm inorganic nanostructures induced the highest concentration levels of alkaline phosphatase. An electrospinning technique was successfully used to produced TiO2 nanofibers onto commercially pure titanium plates that were subsequently subjected to a pyrolysis process. As Dumitriu et al. (2014) reported, a porous multilayer of highly oriented inorganic filaments was longitudinally produced onto the Ti substrate and the reported diameter of the TiO2 fibers was between 10 and 100 nm (depending on synthesis conditions). The biological activity of the modified Ti plates was tested against the osteoblast-like MG63 cell line and the reported data showed high viability of the cells, with specific cellular adhesion and growth and noticeable osteogenic potential.

13.4 CONCLUSIONS When considering bone replacement, restoration, and regeneration strategies, it is mandatory to take into account the physicochemical, mechanical, and biocompatibility properties of the concerned materials, but also the individual human healthcare needs. Given the intrinsic complexity of natural bone and the multitude of pathological conditions specific to osseous tissue, personalized treatment is sought out nowadays by medical professionals. The current progress in nanotechnology made this possible, so various therapeutic strategies for bone prosthesis are medically used or still under intense research activity. For this specific application, pristine metallic, ceramic, and polymeric materials represented the best choice for a long time, but some drawbacks were reported for each of these. Therefore, the immediate demand to develop novel biomaterials or to enhance the existing ones for damaged bone treatment was indisputable. The biomimetic engineering of such compounds requires complex and interdisciplinary knowledge but it now represents the gold standard in personalized healthcare practice. Thus, the unconventional therapeutic strategies can be successfully used to provide superior biomaterials for osseous tissue implants, in terms of biocompatibility, bioactivity, osseointegration, reduced infection potential, targeted and controlled therapeutic delivery systems, and local antitumor treatment. Such specific requirements are successfully provided by metallic nanosystems, either pure metallic nanoparticles or metallic oxide-based nanostructured systems. In the light of current research and development employed in such advanced and complex materials, a new path is being paved for medical practitioners worldwide and, thus, a possible new and elegant future for our health is just within our grasp.

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