Biomaterials for craniofacial tissue engineering and regenerative dentistry

Biomaterials for craniofacial tissue engineering and regenerative dentistry

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Sukumaran Anil1, Elna Paul Chalisserry2, Seung Yun Nam2,3 and Jayachandran Venkatesan4 1 Department of Dentistry, Hamad Medical Corporation, Doha, Qatar, 2Interdisciplinary Program of Marine-Biomedical, Electrical and Mechanical Engineering, Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, South Korea, 3Department of Biomedical Engineering, Pukyong National University, Busan, South Korea, 4Yenepoya Research Centre, Yenepoya University, Mangalore, India

Chapter Outline 24.1 Introduction

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24.1.1 Scaffolds for bone tissue engineering 645 24.1.2 Functions and features of scaffolds 646 24.1.3 Classification of biomaterials 646

24.2 Natural biomaterials 24.2.1 24.2.2 24.2.3 24.2.4 24.2.5 24.2.6 24.2.7 24.2.8

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Collagen 647 Fibrin 648 Alginate 649 Silk 650 Hyaluronate 651 Chitosan 651 Agarose 653 Elastin 653

24.3 Synthetic biomaterials

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24.3.1 Polyethyleneglycol 654 24.3.2 Poly-e-caprolactone 654 24.3.3 Polyglycolic acid 655

24.4 Bioceramics 655 24.4.1 24.4.2 24.4.3 24.4.4

Tricalcium phosphate 655 Hydroxyapatite 656 Tricalcium phosphate/hydroxyapatite biphasic ceramics (biphasic calcium phosphate) 657 Bioactive glasses 657

24.5 Metals 658 24.5.1 Biodegradable metal scaffolds 658 24.5.2 Titanium 659 24.5.3 Zirconia 660

Advanced Dental Biomaterials. DOI: https://doi.org/10.1016/B978-0-08-102476-8.00025-6 Copyright © 2019 Elsevier Ltd. All rights reserved.

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24.6 Bioactive restorative materials

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24.6.1 Mineral trioxide aggregate 661 24.6.2 Biodentine 662

24.7 Three-dimensional printed scaffolds 24.8 Conclusion 664 References 664

24.1

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Introduction

The craniofacial skeleton is complex and serves important functional demands. Regeneration of craniofacial structures requires a sound understanding of complex developmental processes, physiology, and the remodeling characteristics (Tevlin et al., 2014). Regenerative tissue engineering deals with generating a biologic substitute capable of sustaining itself and integrating with functional native tissue from living cells and biocompatible scaffolds. Cells, scaffolds, and growth-stimulating signals are generally referred to as the tissue engineering triad, the key components of engineered tissues (Chan and Leong, 2008). Scaffolds serve as space-holders, provide a temporary support structure for the tissue that they are intended to replace, create a substrate for cells to attach, grow, proliferate, migrate, and differentiate. They also serve as a delivery vehicle for cells and facilitate their retention and distribution in the region where new tissue growth is desired (Hsu et al., 2013). Biomaterials are generally used as biocompatible scaffold systems that allow for the migration, proliferation, and differentiation of either resident or externally delivered cells, which are used to promote new bone formation. A wide variety of biomaterials have been used for craniofacial bone augmentation. An ideal scaffold should be biocompatible, biodegradable, and their degradation rates should match the healing rate of new tissues (Keane and Badylak, 2014; Jafari et al., 2017). The various factors that contribute to tissue response by the scaffolds are shape and size of the implant, chemical reactivity, the mechanism rate and byproducts of degradation, and ability of the material to promote cell material interactions (Schulte et al., 2000). Biodegradable and nonbiodegradable materials have been utilized in bone tissue engineering. These materials should be chosen based on their in vivo degradation rates with the idea that as the scaffold is degraded it should gradually be replaced by newly formed tissue. When the biomaterials are implanted in the body, cell biomaterial interactions depend on the surface characteristics of biomaterials such as chemical, topological, and macro microarchitectured conditions. Naturally derived and synthetic scaffold materials have been used to exploit the regenerative capacities of host tissues or transplanted cells. Scaffolds are defined as three-dimensional porous solid biomaterials designed to perform some or all of the following functions: (1) promote cell biomaterial interactions, cell adhesion, and extra cellular matrix (ECM) deposition; (2) permit sufficient transport of gases, nutrients, and regulatory factors to allow cell survival, proliferation, and

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differentiation; (3) biodegrade at a controllable rate that approximates the rate of tissue regeneration under the culture conditions of interest; and (4) provoke a minimal degree of inflammation or toxicity in vivo. The tissue engineered construct for cartilage and bone repair and replacement poses a number of specific requirements on scaffold materials including biocompatibility, osteoconduction or induction, temporary mechanical support, controlled degradation, and adequate interstitial fluid flow (Elisseeff et al., 2005). Polymeric biomaterial scaffolds provide the structural support for cell attachment and subsequent tissue development. The best scaffold for an engineered tissue should imitate the (ECM) of the target tissue in its native state. Nevertheless, the multiple functions, the complex composition, and the dynamic nature of ECM in native tissues make it difficult to mimic exactly (Giannitelli et al., 2014). Bone grafts are selected based on its characteristics such as osteoinductiveness, osteoconductiveness, mechanical stability, quality of transplantable bone, and preservation techniques. Osteoconductive grafts function as a scaffold for native bone cells and stimulate progenitor cells to differentiate into osteoblasts. The application of bone grafts is based on three biological drivers: the utilization of a bone graft that will bring new bone-forming cells into the defect, the ability of the scaffold to induce bone formation, and the presence of factors that may induce osteoblastic proliferation and differentiation.

24.1.1 Scaffolds for bone tissue engineering Bone tissue engineering utilizes scaffolds to deliver biofactors including cells, genes, and proteins to generate bone, blood vessel formation and maturation into the construct. The desirable characteristics of a scaffold for bone tissue engineering should be three primary functions to ensure successful treatment of bone defects (Arvidson et al., 2011). 1. Provide the correct anatomic geometry to define and maintain the space for tissue regeneration. 2. Provide temporary mechanical load bearing within the tissue defect. 3. Enhance the regenerative capability of the chosen bio factor; a balance to a regenerative capacity.

Achieving stiffness and strength equivalent to bone tissue requires minimally porous scaffolds, whereas the enhanced delivery of biofactors requires highly connected porous scaffolds that allow cell migration, vascularization, and connective tissue formation within scaffolds. The scaffold should fully integrate into the surrounding bone providing the initial three-dimensional (3D) structure which can allow the cells to adhere, proliferate, differentiate, and lay down extracellular matrix. A good scaffold is biocompatible, biodegradable, and porous for it to be used for construction of a biological tissue. This means that even the breakdown products of the scaffold should be nontoxic to the body. It should also be resorbable to allow the growing bone to take its place gradually and it should have porous 3D structures to accommodate implanted cells.

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The scaffold for bone regeneration should accelerate osteoinductivity and increase cell migration, proliferation, and release growth factors. Immune-potent activity by such scaffolds is acceptable. Scaffold should have strong water uptake and water-binding capacity as well as water delivery characteristics in order to absorb the inflammatory mediators and cellular elements in its architecture, preserve them, and slowly deliver the beneficial growth factors and proinflammatory mediators in order to provide an optimum environment during different stages of bone healing (Moshiri and Oryan, 2012). Scaffold should have the capability to align the callus and establish the continuity in the defect area. Assembling the growth factors to tissue-engineered scaffolds results in enhanced healing capability of the injured area (Oryan et al., 2013).

24.1.2 Functions and features of scaffolds 1. Architecture: Scaffolds should provide void volume for vascularization, new tissue formation, and remodeling so as to facilitate host tissue integration upon implantation. 2. Cyto and tissue compatibility: Scaffolds should provide support for either extraneously introduced or endogenous cells to attach, grow, and differentiate during both in vitro culture and in vivo implantation. 3. Bioactivity: Scaffolds may interact with the cellular components of the engineered tissues actively to facilitate and regulate their activities. 4. Mechanical property: Scaffolds provide mechanical and shape stability to the tissue defect. The intrinsic mechanical properties of the biomaterials used for scaffolding or their postprocessing properties should match that of the host tissue.

24.1.3 Classification of biomaterials A scaffold material must adequately reproduce the physical and chemical properties of natural bone in order to promote the attachment, proliferation, and differentiation of both seeded osteoprogenitor cells and surrounding recipient tissues. The 3D structure of a scaffold is of critical importance for the adequate bone development and for the cellular interactions (Kale et al., 2000). An overwhelming variety of substances are employed by researchers seeking to generate a scaffolding material that possesses all the desired traits of an ideal scaffold. Three individual groups of biomaterials—ceramics, synthetic polymers, and natural polymers—are used in the fabrication of scaffolds for tissue engineering. There has been widespread use of ceramic scaffolds, such as hydroxyapatite (HA) and tricalcium phosphate (TCP), for bone regeneration applications. Ceramic scaffolds are typically characterized by high mechanical stiffness, very low elasticity, and a hard-brittle surface. From a bone perspective, they exhibit excellent biocompatibility due to their chemical and structural similarity to the mineral phase of native bone. The interactions of osteogenic cells with ceramics are important for bone regeneration as ceramics are known to enhance osteoblast differentiation and proliferation (Ambrosio et al., 2001).

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Biomaterials can be classified broadly as natural biomaterials or synthetic biomaterials. Natural biomaterials can further be classified as protein-based biomaterials and polysaccharide-based biomaterials. G

G

Protein-based biomaterials include collagen, fibrin, and silk. Polysaccharide-based biomaterials include chitosan (CS), alginate, and hyaluronan.

Synthetic biomaterials include polymer-based biomaterials, peptide-based biomaterials, and ceramic-based biomaterials. G

G

G

G

Polymer-based biomaterials include PLGA and polyethyleneglycol (PEG). Peptide-based biomaterials include short amino acids and self-assembling peptides. Ceramic-based biomaterials include bioactive glass and hydroxyapatite. Composite biomaterials.

Biomaterials used in tissue engineering and regeneration can be classified based on their original sources into different categories: G

G

G

G

Human-derived biomaterials such as human acellular dermal matrix; Animal-derived biomaterials including processed bovine bone materials and porcinebased collagen membranes; Other natural biomaterials such as polysaccharide-based biomaterials (cellulose, chitin/ CS); Synthetic biomaterials such as polymers, composites, and ceramic-based dental biomaterials.

24.2

Natural biomaterials

24.2.1 Collagen Collagen is one of the two major components of the bone, making up 89% of the organic matrix and 32% of the volumetric composition of bone (Kang et al., 2013). Because of the biomimetic properties, collagen-based biomaterials are the most highly investigated for bone regeneration (Stoppel et al., 2015; Glowacki and Mizuno, 2008). Collagen provides strength and structural stability to tissues in the body, such as the skin, blood vessels, tendon, cartilage, and bone. Native collagen and denatured collagen (gelatin), alone or in combination with other natural and synthetic polymeric fibers as well as ceramics, have been assessed for their inherent scaffold characteristics (Kruger et al., 2013). Collagen biomaterial has poor mechanical properties and swells readily when implanted in vivo due to its high hydrophilicity. Therefore collagen is commonly modified, cross-linked, or mixed with other components (polymers or ceramics) in order to tailor the physicochemical and mechanical properties of the scaffold to the requirements of the final application. Collagen is used mainly used in the forms such as injectable hydrogels, membranes and films, sponges and scaffolds, and micro nanospheres (Ferreira et al., 2012). The cross-linked collagen scaffolds can

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exhibit minimal inflammatory as well as encapsulation responses and nonfibrotic cellular growth (Ahmed et al., 2008). The major advantages of using collagen of natural origin are its profusion, low index of immunological reaction, and its capacity to form fibers from soluble preparations which are similar to those found in natural tissues (Kadler, 2004). Collagen is resorbable with high swelling ability, low antigenicity, cytocompatibility, and tissue regeneration potential (Abou Neel et al., 2012). Collagen-bioactive ceramic composites can be fabricated in many forms such as 3D scaffolds, hydrogels, or dry powders (Villa et al., 2015; Laydi et al., 2013; Zhang et al., 2012). Collagen/CS/β-TCP (CCTP) based tissue engineering scaffolds were tested (Bian et al., 2016). In order to improve the regeneration ability of scaffold, raloxifene-loaded poly lactic-co-glycolic acid (PLGA) microsphere was embedded in the CCTP scaffold. To overcome the lack of neovascularization in bone tissue engineering, cobalt ion-incorporated bioactive glass/collagen glycosaminoglycan (GAG) scaffolds were developed which enhanced the expression of vascular endothelial growth factor by stabilizing the hypoxia inducible transcription factor (Quinlan et al., 2015). Induced pluripotent stem cell derived mesenchymal stem cells cultured on collagen/hydroxy apatite (HAP)/CS nanofibers showed enhanced osteogenic differentiation (Xie et al., 2015). A collagen network was incorporated into porous calcium phosphate ceramic by vacuum infusion, which was then coated with HAP by biomimetic mineralization. This three-level hierarchical CaP-collagen-HAP scaffold demonstrated better mechanical strength together with rapid and greater bone formation than normal CaP scaffolds when implanted ectopically in the dorsal muscles of rabbits (Zhou et al., 2014). Collagen CS gels reinforced with bioactive glass nanoparticles exhibited thermosensitive behavior. This gel can be injected in the body and is shown to have a great potential in bone tissue engineering on account of its relative ease of use and minimal surgical procedure (Moreira et al., 2016). Collagen hydrogels have also been used to test the ability of mesenchymal stem cells (MSCs) from different sources to undergo osteogenic differentiation (Schneider et al., 2010). Several other materials are incorporated into collagen in order to enhance mechanical properties and enhanced bone matrix interface strength. 3D collagen scaffolds were used to culture a wide variety of stem cells for different tissue engineering applications.

24.2.2 Fibrin Fibrin has captured the interest of bone tissue engineers due to its excellent biocompatibility, controllable biodegradability, and ability to deliver cells and biomolecules. Fibrin is one of the preferred biomaterials for tissue engineering applications. Fibrin gels promote cell migration, proliferation, and matrix synthesis through the incorporation of platelet-derived growth factors and transforming growth factor. Fibrin is particularly appealing because its precursors, fibrinogen, and thrombin, which can be derived from the patient’s own blood, enable the fabrication of completely autologous scaffolds (Noori et al., 2017). Addition of fibrin may also be used to enhance the behavior of cells on other natural polymers. Conjunction of

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fibrin on CS/nano-β-TCP composites markedly improved cellular functions on scaffolds including MSC attachment, density, proliferation, differentiation, and mineralization (Siddiqui and Pramanik, 2015). Studies have shown that fibrin alone is incapable of healing bone defects, and so, addition of other materials and/or biomolecules could yield better outcomes in tissue engineering (Linsley et al., 2016). The combination of fibrin with osteoconductive ceramics that allows the incorporation of growth factors, drugs, and metallic ions may enable the fabrication of multifunctional scaffolds to promote bone tissue remodeling (Kim et al., 2014). Hence fibrin is an attractive biomaterial for bone tissue engineering because of its excellent biocompatibility, biodegradability, intrinsic bioactivity, and other unique characteristics.

24.2.3 Alginate Alginate is a hydrogel comprising 1,4-linked b-D-mannuronic acid and a-L-guluronic acid, typically derived from brown seaweed and also bacteria. It has been extensively investigated and used for many biomedical applications, due to its biocompatibility, low toxicity, relatively low cost, and simple gelation by addition of divalent cations such as Ca21, Mg21, Ba21, and Sr21 (Wee and Gombotz, 1998). Alginate is a copolymer of D-mannuronic acid (M) and L-guluronic acid (G). The gelation of alginate occurs as blocks of guluronic acid bound to other G blocks via divalent cations, usually calcium ions (Wong, 2004). The modification of the chemical structure of alginate by combining it with other biopolymers can further extend the properties of this versatile material (Caterson et al., 2002). Alginate is readily processable for 3D scaffolding materials such as hydrogels, microspheres, microcapsules, sponges, foams and fibers, nanoparticles, and multilayers at physiological conditions ensuring the preservation of cell viability and function (Sun and Tan, 2013). Alginate allows efficient cell penetration into matrix and cell encapsulation. The alginate/hydroxyapatite composite scaffolds were prepared by internal gelation followed by a freeze drying procedure to obtain a porous structure. The nanoparticles can be prepared in the presence of a lactose-modified CS, which is adsorbed on the scaffolds and can be used as temporary resorbable bone implants (Marsich et al., 2013). Two different types of polymer scaffolds, that is, CS alginate and CS alginate with fucoidan, were developed by a freeze drying method, and each was characterized as a bone graft substitute (Venkatesan et al., 2014). CS alginate hybrid scaffolds displayed improved mechanical strength and structural stability and were shown to stimulate new bone formation and rapid vascularization. Alginate microparticle and microfiber-aggregated scaffolds were produced through the aggregation method. Such a porous structure allowed vascularization, oxygenation and cell migration, adhesion, and proliferation, which are biological events that are fundamental for bone tissue regeneration (Valente et al., 2012). An injectable and biodegradable scaffold based on oxidized alginate microbeads encapsulating periodontal ligaments and gingival mesenchymal stem cells was found to be a promising strategy for bone tissue engineering (Moshaverinia et al., 2012).

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A high porosity composite scaffold comprising alginate, CS, collagen, and hydroxyapatite without chemical cross-linking agent was used as a scaffold for regenerating bone tissue (Yu et al., 2013). Another composite comprising solid free-form fabricated polycaprolactone, bone morphogenetic protein (BMP-2), or bone formation peptide, and alginate is used for bone tissue regeneration (Kim et al., 2013b). The physicochemical and biological properties of hybrid materials fabricated from photocross-linked gelatin, alginate, and gelatin/alginate-based hydrogels combined with silica particles were studied by Lewandowska-Lancucka et al. (2017). It was confirmed that the addition of silica particles to gelatin as well as gelatin/alginatebased matrices increased the elastic modulus values when compared to pristine hydrogels and are promising candidates for bioactive scaffolds in tissue engineering. One of the disadvantages of the material are the inability to control its degradation rate in vivo and its low viscoelasticity, although this can be improved by increased cross-linking or addition of other substances, such as HA (Yuan et al., 2011). Alginate and alginate/HA mixtures have been used in bone and cartilage tissue engineering (Coluccino et al., 2016; Sarker et al., 2015; Wang et al., 2016).

24.2.4 Silk Silk fibroin (SF) is a natural fibrous protein and has been shown to be a potential biomaterial for a number of biomedical applications because of its excellent biocompatibility, nontoxicity, diverse physical characteristics, and ability towards cell attachment and proliferation. Silk, a natural polypeptide having very good biological properties either alone or in combination with other suitable materials, can be fabricated as scaffolds for tissue engineering applications. SF films and fibers exhibit good ability to support the adhesion and growth of various cells and hence they are proposed as scaffolds for skin and bone regeneration (Ribeiro et al., 2018; Li et al., 2018a). SFs are characterized as natural amphiphilic block copolymers composed of hydrophobic and hydrophilic blocks which combine together to give rise to the elasticity and toughness to SF (Zhang et al., 2009). Novel SF and carboxymethyl cellulose composite nanofibrous scaffold was developed to investigate its ability to nucleate bioactive nano-sized calcium phosphate by biomineralization for bone tissue engineering application. The developed scaffold has proved to be a novel and excellent candidate for bone tissue engineering with significant improvement in physicochemical, mechanical, and biological properties in comparison to the gelatin and pure SF nanofibrous scaffolds (Singh et al., 2016). SF/CS-based magnetic scaffolds showed optimal characteristics such as superparamagnetic behavior with decreased phosphate-buffered saline (PBS) uptake and degradation and, hence, can be used for bone tissue engineering applications (Aliramaji et al., 2017). Xie et al. (2016) developed novel bioscaffolds for bone regeneration, based on the combination of SF and calcium polyphosphate (CPP). It was found that Bombyx mori SF (BMSF) and Antheraea pernyi SF (APSF), prepared and applied into CPP scaffolds with glutaraldehyde cross-linking forms of the BMSF/CPP and APSF/CPP bioceramics, could be suitable for bone tissue engineering.

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Silk, when mixed with hydroxyapatite, serves as a convenient material for bone and dental tissue growth of extracellular matrix (Melke et al., 2016). Silk gel material is able to create a lasting 3D soft tissue augmentation; hence, it is useful in periodontal and maxillofacial therapies. Hexafluoroisopropanol (HFIP)-based silk is slower in degradation and supports soft dental pulp formation better than aqueousbased silk. Tooth bud cells seeded on HFIP silk scaffolds, with or without incorporated arginine glycine aspartate (RGD) peptides, have been shown to form mineralized tissue indicating the usefulness of these scaffolds in osteodentine formation (Zhang et al., 2011). Micron-sized silk fibers have been incorporated as a reinforcement in compact fiber composite to produce high strength biomaterial that would serve as load bearing bone grafts. These have favored human bone derived stem cells (hBMSC) differentiation and formation of bone-like tissue suggesting their use for bone engineering applications (Mandal et al., 2012).

24.2.5 Hyaluronate Hyaluronic acid (HA), a nonsulfated GAG, present in the extracellular matrix of connective tissues offers excellent potential as a scaffold for tissue regeneration. The poor mechanical strength and rapid in vivo degradation rate can be controlled by cross-linking and chemical modification of the polymers (Ouasti et al., 2011). Hyaluronic acid is capable of specific cell interaction via the CD4 receptor which promotes wound healing and induces chondrogenesis. HA has been chemically and physically incorporated into various tissue engineering scaffold matrices (Kim et al., 2013a). Hyaluronic acid (HA) hydrogels have been widely applied in the biomedical field because of their good biocompatibility and structural diversity. They possess some advantages, including facilitating proliferation of seeded cells and wound healing, good antiinflammatory ability, and promoting intracellular signaling (Collins and Birkinshaw, 2013). Porous hyaluronic acid scaffolds used for BMP-2 delivery for bone growth showed that the BMP-2 were continuously released for controlled times in an active form from the scaffolds (Kim and Valentini, 2002). Solid free-form fabrication of polylactic-co-glycolic acid grafted HA/PEG scaffolds has successfully delivered BMP-2 in vivo with controllable release from the scaffold for up to a month. Histological analyses and staining after implantation in rats revealed active bone regeneration, and the BMP-2 released from the scaffold was thought to contribute in enhanced bone regeneration (Park et al., 2011). A composite of alginate and hyaluronic acid gel showed improved physical, mechanical, and biological properties (Ganesh et al., 2013). The RGD peptides in hyaluronic acid hydrogel enhance cellular attachment, cellular spreading, and proliferation. Hyaluronic acid gels are injectable and hence serve as suitable scaffolds for pulp regeneration (Inuyama et al., 2010).

24.2.6 Chitosan CS a linear polysaccharide, derived from partial deacetylation of chitin, is a highly versatile biomaterial from crustacean exoskeletons. CS evokes minimal

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foreign-body response and fibrous encapsulation. CS is especially attractive as a bone scaffold material as it supports the attachment and proliferation of boneforming osteoblast cells as well as the formation of mineralized bone matrix (Seol et al., 2004). Pure CS is a suitable substrate for adhesion and proliferation of osteoblasts as well as matrix formation and mineralization, but the strength and structural stability of pure CS scaffolds is inadequate for bone tissue engineering applications. Studies have shown that modified CS scaffolds exhibit osteoconductivity in vivo in surgically created bone defects (Muzzarelli et al., 1994). CS can be processed in multiple ways to produce a variety of 3D scaffolds with different pore structures for use in bone tissue engineering. It can also be combined with different materials including ceramics and polymers to yield composite scaffolds with superior mechanical and biological properties (Levengood and Zhang, 2014). A major limitation in using CS as a standalone polymer for tissue engineering applications is its faster degradation. To overcome this problem, usually CS is either modified by adding other biocompatible polymers or by cross-linking with suitable cross linkers. Blending other polymers/bioactive materials in CS matrices resulted in functionally improved materials with respect to physicochemical and biological properties, and hence, CS-based nanofibers have wide relevance for their use in the field of bone tissue engineering (Balagangadharan et al., 2017). Modified CS, such as imidazole-modified CS and methylpyrrolidinone CS, are osteoconductive in vivo thereby promoting bone regeneration in surgically created bone defects (Kim et al., 2002). Importantly, CS is hydrophilic; that it should support adhesion and proliferation of cells. In vitro studies have demonstrated that CS promotes the adhesion and proliferation of osteogenic cells and mesenchymal stem cells. Osteogenic cells cultured on CS deposit extracellular matrix which becomes mineralized to yield bone tissue. In addition, CS has also been implicated in promoting osteogenic differentiation of mesenchymal stem cells (Yang et al., 2009; Mathews et al., 2011). CS combined with bioactive ceramics have a predominant role in bone tissue engineering as these composites exhibit tailored physical, biological, and mechanical properties favorable for bone regeneration as well as predictable degradation behavior. The presence of micro- or nanoscale calcium phosphate particles in CS scaffolds provides important functionalities, but the incorporation or immobilization of a second or even third functional component can further improve bone tissue engineering scaffolds’ structural stability and osteogenic response and thereby its clinical use. The incorporation of nanohydroxyapatite (nHAp) in the CS matrix by in situ nucleation in the presence of its precursor would provide distinct nanophase distribution of HAp particles and also improve the mechanical strength of the composite compared to simple mixing of nHAp in CS. In the case of fibrous scaffolds, addition of binders or synthetic polymers helps in the easy incorporation of nHAp into the organic solution (Shalumon et al., 2013; Wang et al., 2014). CS/nHAp prepared by cross-linking with glutaraldehyde when implanted to the calvarial bone defect showed new bone formation which was histologically confirmed as bioactive and neovascularized (Ma et al., 2011).

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Composite CS scaffolds, which incorporate other biocompatible polymers and/or micro- or nanoscale calcium phosphates, usually possess mechanical and biological properties superior to pure CS scaffolds. Mesenchymal stem cells introduced into a defect site may either actively participate in bone formation by synthesizing mineralized matrix or secrete trophic factors that activate endogenous cells. Heparin can be immobilized on CS scaffolds as a way to exploit naturally occurring noncovalent interactions between growth factors and extracellular matrix components.

24.2.7 Agarose Agarose is a natural polysaccharide polymer having unique characteristics that give reason to consider it for tissue engineering applications. It is one of the two principal components of agar and is purified from agar by removing agaropectin. Due to their soft tissue like mechanical properties and biocompatibility, agarose gels have been investigated as potential scaffolds for neural and cartilage tissue engineering (Zarrintaj et al., 2018). Hydroxyapatite agarose composites accelerate the new bone formation more than pure HA (Iwai et al., 2015). Biomimetic scaffold containing agarose and nHAp was used with dental pulp stem cells and periosteal stem cells to regenerate the bone (Annibali et al., 2013). Biodegradable, biocompatible, and injectable gel based on HA/agarose was developed for orthopedic, oral, and maxillofacial surgery (Watanabe et al., 2007).

24.2.8 Elastin Elastin is a key structural protein in extracellular matrix of all mammals which is responsible for the elastic action of various tissues in the body. Tropoelastin is the secreted soluble precursor of elastin. Although less abundant than collagen, elastin is present in large amounts within highly elastic tissues (Muiznieks and Keeley, 2013). Incorporation of elastin in biomaterials is especially significant when its elasticity or biological effects can be exploited. Major structural contributors to vertebrate ECM are the fibrous proteins collagen and elastin. Collagen provides tissues with essential tensile strength, enabling resistance to plastic deformation and rupture, while elastin imparts the properties of extensibility and reversible recoil, enabling tissues to withstand repetitive mechanical stress (Gosline et al., 2002; Rauscher and Pomes, 2012). Elastin can also be conveniently used in association with collagen for tissue engineering applications. Rapid growth of preosteoblast cells was demonstrated in a novel elastin-like polypeptide (ELP) -collagen composite material prepared in the hydrogel form for bone tissue engineering (Amruthwar and Janorkar, 2013). Porous polycaprolactone scaffolds impregnated with bovine elastin demonstrated improved mechanical and biological responses (Annabi et al., 2011). Chondrocytes cultured on coacervated or enzymatically cross-linked ELP hydrogels were shown to promote chondrogenesis in vitro (Betre et al., 2006).

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Synthetic biomaterials

24.3.1 Polyethyleneglycol PEG, also known as polyethylene oxide or polyoxyethylene, is the most commercially important polyether. Polyethers are oligomers or polymers of ethylene oxide. PEG is a synthetic polymer and offers the advantages of nontoxicity, biocompatibility, low immunogenicity, and ability to undergo in vivo degradation. It is resistant to cellular and protein adsorption and thereby reduces recognition by immune system and its rejection. In its hydrogel form, it has been widely tested as a scaffold material for tissue regeneration. PEG hydrogel modified with cell adhesion RGD peptides improves cell adhesion, cell survival, and matrix synthesis within the 3D scaffold network (Burdick and Anseth, 2002). This polymer can also help to seal cell membranes after injury, making it useful for avoiding cell death. Hydrophilic PEG hydrogels can be made through a variety of cross-linking schemes to develop scaffolds with different degradation as well as release rates. The mechanical strength of PEG hydrogel is determined by the molecular weight, cross-linking, and concentration of polymers. By adding cell binding motifs like RGD peptides into the PEG hydrogel network, cell adhesion can be considered as a crucial feature of PEG-based hydrogel (Lee et al., 2015). PEG has been used in regeneration of several tissues, including spinal cord/nerve, cardiac tissue, bone, and skin (Engebretson and Sikavitsas, 2012). Properties such as good biocompatibility, nonimmunogenicity, resistance to protein adsorption, and cell adhesion of PEG have made them more suitable hydrophilic polymers in biomedical applications including bioconjugation, surface modification, drug delivery, and tissue engineering (Zhu, 2010). Bioactive molecules such as cell adhesion ligands, enzyme-sensitive peptides, and growth factors have been incorporated into PEG hydrogels, to simulate one or more ECM biofunctions such as cell adhesion, proteolytic degradation, and growth factor-binding.

24.3.2 Poly-e-caprolactone Poly-e-caprolactone (PCL) is a semicrystalline material with good mechanical properties. PCL belongs to a family of poly(α-hydroxyl esters) and is one of the most widely used biodegradable polyesters for medical applications because of its biocompatibility, biodegradability, and flexibility (Lin et al., 1999). PCL scaffolds were used in bone tissue engineering, either alone or combined with hydroxyapatite (HA) (Weisgerber et al., 2018). PCL scaffolds are excellent in longer term use as they degrade over 2 years (Pitt et al., 1981). Compared with other polyesters, PCL has slower degradation kinematics and the degradation products are harmlessly metabolized via the tricarboxylic acid cycle (Woodward et al., 1985). Scaffolds fabricated using PCL are more resistant to hydrolysis, and consequently are capable of supporting the viability, proliferation, and differentiation status of encapsulated cells. The mechanical and degradation characteristics of PCL facilitate long-term in vitro cell culture before implantation into sites of injury. PCL scaffolds thus maintain structural integrity during the in vitro culture period, while MSCs

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differentiate and synthesize cartilaginous matrix. The electrospinned PCL nanofibrous scaffold supported multilineage differentiation of the human MSCs when cultured under a specific, differentiation-promoting culture condition (Yoshimoto et al., 2003). Electrospun composite scaffolds, made from PCL/gelatin/nHAp and PCL/gelatin, enhanced cell proliferation and odontogenic differentiation. It was shown that the PCL/HAp scaffold supported growth and osteogenic differentiation of all cells, suggesting the potential of 3D porous PCL/HAp scaffold as a good candidate material for bone tissue engineering (Chuenjitkuntaworn et al., 2016).

24.3.3 Polyglycolic acid Polyglycolic acid (PGA) is a rigid, thermoplastic, highly crystalline, aliphatic polyester, made by a ring-opening polymerization reaction of a cyclic glycolide. PGA is preferred in medical applications because its degradation products, lactic and glycolic acids, are biological metabolites. PGA has outstanding properties; however, its low solubility in organic solvents, faster degradation, and the high acidity of its degradation products have limited its biomedical applications (Nair and Laurencin, 2007). Though PGA has several applications in tissue engineering, its softness and inability to hold space make it less preferred in craniofacial defect repair.

24.4

Bioceramics

Bioceramics have attracted great attention in the field of bone tissue engineering. Bioceramics are fully, partially, or noncrystalline ceramics that are designed for the regeneration and reconstruction of diseased parts of the body. Bioceramics can create strong bonds to tissues, thereby stimulating osteogenesis and improving bone graft incorporation and osseointegration (Baino et al., 2015). The dissolution rate and tissue interaction are influenced by the characteristics such as the composition, crystallinity, particle size, and porosity which can be controlled during the processing of the bioceramics (Valerio et al., 2004). Current forms of application in clinical use include solid blocks, powders, and granules for bone filling, coatings on metal joint prostheses, injectable formulations, and porous scaffolds.

24.4.1 Tricalcium phosphate The major representatives of this class are calcium phosphates that are among the most widely used crystalline ceramics for bone tissue regeneration. This is due to their exceptional properties that include (1) similarity, in terms of structure and chemical composition, to the mineral phase of bone, and (2) osteoconductivity, that is, the ability of providing a biocompatible interface along with bone migrates, and thus allows bonding to the host tissue without the formation of scar tissue (LeGeros, 2002). They are used in the form of porous ceramic pieces and granules to reconstruct all kinds of bone defects, from augmentation of alveolar ridge defects after a tooth extraction and before implant positioning to sinus reconstruction

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correction of various deformities and bone reconstruction following injury or disease (Liu and Lun, 2012).

24.4.2 Hydroxyapatite Hydroxyapatite has been used for a variety of biomedical applications, including matrices for drug release control and bone tissue engineering materials (Ginebra et al., 2006). Although the synthetic and natural HA differ in terms of physical microstructure, crystal size, and porosity, chemical similarities to bone, in both forms, account for the osteoconductive potential of HA (Fig. 24.1) (Ramesh et al., 2018). When compared to β-TCP, HA resorbs slowly and undergoes a little conversion to a bone-like material after implantation. There have been efforts toward developing HA-based bioceramic materials that have been doped with ions. Strontium-HA, magnesium-HA, and silicon-HA have been tested to improve mechanical and biological properties for bone tissue engineering applications (Li et al., 2018b; Panzavolta et al., 2018; Andres et al., 2018). HA is commonly used for bone repair, bone augmentation, as well as coating of implants. The low mechanical strength of normal HA ceramics restricts its use mainly to low loadbearing applications. To overcome these limitations nanocrystalline HA was

Figure 24.1 3D-printed scaffold designs using synthetic biomaterials. 3D, Threedimensional.

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developed which showed improved sinterability and enhanced densification due to greater surface area (Zhou and Lee, 2011).

24.4.3 Tricalcium phosphate/hydroxyapatite biphasic ceramics (biphasic calcium phosphate) The biphasic calcium phosphate (BCP) concept is based on an optimum balance between the more stable phase (HA) and the more soluble phase (β-TCP). β-TCP is more rapidly replaced by bone than the hardly degradable HA, owing to its higher solubility (Petrov et al., 2001). Upon degradation of β-TCP through a process of dissolution and absorption, a normal bone structure in the regenerated bone can be achieved (Von Arx et al., 2001). The development of BCP ceramics (i.e., containing both HA and β-TCP) has provided materials in which bioactivity and degradation are controlled based on the ratios of the components (LeGeros et al., 2003). Several studies have shown that BCP granules have excellent biocompatibility and bioactivity and lead to new bone formation and degradation of the biomaterial (Valimaki et al., 2005). The rate of degradation or resorption of HA/TCP ceramics can be accelerated by increasing the amount of the more soluble phase, TCP. Studies have shown that BCPs with higher β-TCP ratio are expected to yield more replacement of biomaterial by new bone (Daculsi et al., 1990; Gauthier et al., 1998). BCP compounds containing approximately 60% of HA and 40% of β-TCP seemed to provide the optimal bone conductive properties (Rouvillain et al., 2009). Nery et al. (1992) reported optimal bone regeneration in surgically created bone defects with BCP containing HA/β-TCP ratio of 85/15. However, recently BCP products containing higher β-TCP ratios (BCP 60/40 and BCP 20/80) have been studied in prospect of its enhanced osteoconductive effect (Yang et al., 2014; Lee et al., 2013).

24.4.4 Bioactive glasses Bioactive glasses and glass ceramics, which are used in bone repair, are another type of bioceramics containing Ca, P, and Si ions with good mechanical strength. The original bioglass composition is 45% silica (SiO2), 24.5% calcium oxide (CaO), 24.5% sodium oxide (Na2O), and 6% phosphorous pentoxide (P2O5) in weight percentage (Hench and Wilson, 1984). Bioglasses are biocompatible, osteoconductive, and depending on their processing condition offer a porous structure which promotes their resorption and bone ingrowth (De Aza et al., 2003). Bioglass does not induce an inflammatory response, and the silica-based bioglass completely degrades in 6 months. Silicon has been found to promote differentiation of mesenchymal cells and bone formation. The SiO2 in combination with apatite is responsible for the inhibition of fibroblast proliferation at the bioimplant surface (Nandi et al., 2009). The borate-based bioglasses showed a faster degradation than silicabased bioglasses, but this degradation rate can be controlled by adjusting its composition. The phosphate-based bioglasses are a promising group of bioglasses for hard and soft tissue engineering, since their solubility can be controlled by manipulating

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the composition (Knowles, 2003). Bioglasses are quite brittle and present low mechanical strength and decreased fracture resistance. Thus their utilization should be selective or in association with other bone substitutes. Future research can be directed toward incorporating various other trace elements such as Zn, Cu, F, Mn, Sr, and B. These individual elements have been known for their osteogenic property and their incorporation in the compositional flexible glasses make them promising bioactive materials (Rahaman et al., 2011).

24.5

Metals

Several metals are used in craniofacial repair and regeneration. Metals currently in use clinically include gold, stainless steel, cobalt chromium, and titanium. Most of the metals are inert alloplasts which won’t integrate with adjacent tissues or induce new bone formation. Pure titanium and some of its alloys are widely used as implant materials under load-bearing conditions in dentistry and orthopedics. Metals have been long used especially in load-bearing areas in the oral cavity. They are used as implants to replace lost teeth, reconstruction posttrauma/cancer as plates, mesh, or screws.

24.5.1 Biodegradable metal scaffolds Biodegradable metal scaffolds have shown an interesting mechanical property that was close to that of human bone with tailored degradation behavior. Metals that can degrade in the physiological environment, namely, biodegradable metals, are proposed as potential materials for hard tissue scaffolding. These biodegradable metals may have superior mechanical properties in comparison to biodegradable polymers (Yusop et al., 2012; Yazdimamaghani et al., 2017). Metals that degrade in the physiologic environment, such as magnesium alloys possessing mechanical properties that are very similar to those of bone, yet retain the ability to naturally degrade when placed within an aqueous type of environment, are considered promising scaffolds (Staiger et al., 2006). The porous architecture of Mg scaffold has been proven to play a significant role in cell growth and proliferation. Efforts to design polymer magnesium composites are ongoing. Theoretically, the polymer matrix benefits from magnesium incorporation, as magnesium may confer higher mechanical strength and fracture toughness while the polymer may prevent premature degradation (Mantripragada et al., 2013). Porous Fe and Fe-phosphorous alloys have been investigated as biodegradable bone replacements, and the results showed that addition of phosphorus increased compressive strength higher than that of pure Fe which is comparable to that of typical bone (Hermawan et al., 2010). These alloys showed also faster in vitro degradation than pure Fe, hence alloying Fe with phosphorous seems to be a promising way to optimize both mechanical and degradation properties of Fe, especially for bone scaffold (He et al., 2016).

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Metallic nanoparticles have been incorporated into scaffolds with evidence of increased mechanical strength, increased cellular adhesion of osteoblasts and chondrocytes, and increased long-term osteoblast function, with notable improvements in collagen synthesis, alkaline phosphatase activity, and calcium deposition (Kim and Fisher, 2007; Tran and Webster, 2011). Biodegradable metals as tissue scaffolding materials have been viewed as alternative to polymers for hard tissue regeneration exploiting mostly their superior mechanical properties over biodegradable polymers.

24.5.2 Titanium Titanium is the most biocompatible and corrosion-resistant metal, its elasticity modulus corresponds to the elasticity modulus of the bone, and hence it is widely used in dentistry and orthopedics. Titanium and some titanium alloys are better received by human tissue when compared to the receptivity of other metal materials. According to the American Society for Testing and Materials, six types of titanium are listed as implant biomaterials. Depending on the various concentration of oxygen, nitrogen, hydrogen, iron, and carbon influencing the physical and mechanical properties, there are four grades of commercially pure titanium (cpTi) (Grades I IV) and two titanium (Ti) alloys (Grades V and VI)—Ti 6Al 4V and ¨ zcan and H¨ammerle, 2012). Grades I Ti 6Al 4V extra low interstitial alloys (O and II are the most commonly used cpTi types for the production of metal ceramic fixed dental prosthesis. In cases where good mechanical characteristics are required, ¨ zcan and such as in bone screws and plates, Ti 6Al 4V alloy is being used (O H¨ammerle, 2012; De Viteri and Fuentes, 2013). A superficial layer of titanium oxide that develops on the surface is responsible for corrosion-resistance as well as for the adhesion of glycoproteins in vivo, which is important for the biocompatibility. This oxide layer is maintained at physiological pH resisting ion formation tendency and has low reactivity with macromolecules making it highly resistant to corrosion (Sidambe, 2014). Osseointegration, a direct structural and functional connection, anchors the titanium dental implant with bone (Le Guehennec et al., 2007). Surface chemistry, topography, wettability, charge, surface energy, crystal structure, crystallinity, roughness, chemical potential, strain hardening, the presence of impurities, thickness of titanium oxide layer, and the presence of metal and nonmetal composites play a role in implant tissue interaction and osseointegration (Anil et al., 2011). Various approaches are employed to make implants more biomimetic from both biomechanical and biological perspectives. Alteration in titanium surface morphology is used to influence osteoblast attachment, differentiation, proliferation, and migration. Altering the macro-, micro-, and nanoscale surface topographies through plasma spraying, particle blasting, micromachining, grinding, polishing, and chemical methods such as acid etching, alkali etching, and anodization have resulted in higher bone implant contact (BIC) ratio and improved osseointegration (Subramani et al., 2018).

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Biochemical binding to bone can be achieved by coating with chemicals or biomaterials such as ceramics and polymers that are known to improve osteogenic properties. An in vivo study using micro arc oxidation method in phosphoric acid on titanium implants facilitated more chemical bonding sites for calcium ions during mineralization (Sul et al., 2002). Hydroxyapatite coating through various methods has shown precipitation of biological apatite nanocrystals with the incorporation of various proteins, which, in turn, promote cell adhesion, differentiation into osteoblast, and the synthesis of mineralized collagen, the extracellular matrix of bone tissue (Lavenus et al., 2010). Attempts have been made to improve and accelerate osseointegration by introducing bioactive factors such as known osteogenic drugs, antiinflammatory mediators, and growth factors to titanium surfaces. The effects of recombinant bone morphogenetic protein-2 (rhBMP-2) on the osseointegration of titanium implants have shown positive influences in experimental animal studies (Wikesjo¨ et al., 2002). Tetracycline-HCl, an antimicrobial agent, kills microorganisms that may be present on the contaminated implant surface. Further, it inhibits collagenase activity and increases cell proliferation as well as attachment and bone healing (Herr et al., 2008). Oral administration of drugs such as simvastatin have proved to have a positive impact on osteogenesis; hence, Yang et al. (2011), when studying the effect of simvastatin-loaded porous implant surfaces, demonstrated accelerated osteogenic differentiation of preosteoblasts. However, there are esthetic issues due to the gray color of titanium so that in areas where soft tissue is not optimal, the dark color shines through the thin mucosa, which has led to the pursuit of esthetic replacements to titanium (Saini et al., 2015). Titanium foams fabricated by a new powder metallurgical process have bimodal pore distribution architecture, mimicking natural bone. The mechanical properties of the titanium foam with low relative densities of approximately 0.20 0.30 are close to those of human cancellous bone (Wen et al., 2011). The titanium foam after a simple thermochemical pretreatment process followed by immersion in a simulated body fluid showed good ability to form a bone-like apatite layer throughout the foam. The thermochemical pretreatments for inducing bone-like apatite formation are attractive due to their simplicity, cost savings, and effectiveness (Kapat et al., 2017). The titanium foams are anticipated to be promising implant materials for bone tissue engineering applications due to their excellent biomechanical properties and bioactivity.

24.5.3 Zirconia Zirconia, a tooth-colored material, was first introduced as endosseous implants for bone regeneration to replace mainly the impaired esthetic outcomes of dark grayish color of titanium, visible through the periimplant mucosa. These include unfavorable soft tissue conditions such as thin mucosal biotype, gingival recession, and/or in the anterior maxillary or mandibular incisor replacements. It was also claimed that ceramic implants could manage soft tissue better due to less plaque accumulation than titanium (Ozkurt and Kazazoglu, 2011; Hoffmann et al., 2008). Zirconium implants show lower inflammatory response and increased angiogenic factors

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compared to titanium (Degidi et al., 2006). Zirconium dioxide in its pure phase is unstable and brittle with low shear strength. Hence, to improve the modulus of elasticity and stabilize the material, small amounts of aluminum oxide or yttrium oxide are added through the hot isostatic pressing method. Such additions also improve the toughness and crack propagation property. Of the two oxides, yttrium (yttriumstabilized tetragonal polycrystals) appears to offer improved advantages owing to its higher fracture resilience and higher flexure strength (Saini et al., 2015; Sennerby et al., 2005). Zirconium is used as an implant material by itself and zirconia particles as a coating material on titanium dental implants are also explored (Ozkurt and Kazazoglu, 2011). Huang et al. (2018) concluded that plasma-sprayed nanostructured-zirconium coating showed hierarchical surface morphology with better surface roughness and wettability than titanium implants. Histological analysis exhibited earlier and more condensed bone formation improving the BIC and thereby the osseointegration. Currently the majority of zirconium implants are produced as one-system implants. While microgaps between an implant and abutment is absent in such systems, the use of angular abutments to correct misalignment or secondary corrections to alter shape or vertical height is not possible as it may affect the fracture strength of zirconia (Cionca et al., 2017). Two-piece implant systems with screw-retained abutments are desirable for several reasons, although they are technically challenging because of the limitations of zirconia (Preis et al., 2016). The early failure rates of the zirconia implant systems developed and tested so far were generally higher compared with titanium implants. Technical failure as a result of fracture of the material is a sensitive issue and a critical factor for usability and acceptance in daily practice (Elnayef et al., 2017; Cionca et al., 2017).

24.6

Bioactive restorative materials

The bioactivity of the dental restoratives is an important feature in the preservation of the hard dental tissues; therefore it is of utmost significance to find a material which can be used to decrease the amount of excavated dentine during preparation of the tooth. Several materials have been used as possible dentine substitutes in repairing teeth damaged by caries. Materials with clear bioactive properties seems to be the ideal solution for this application. Bioglasses have been accepted as mineralizing agents in caries prevention, as well as desensitizing agents in the treatment of hypersensitive teeth caused by opened dentinal tubules (Gjorgievska et al., 2012).

24.6.1 Mineral trioxide aggregate Mineral trioxide aggregate (MTA) is a biomaterial that has been investigated for applications in restorative dentistry. Its multiple applications include direct and

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indirect pulp capping, formation of apical plug, root-end filling, perforation repair, furcation repair, repair of resorptive defects, and management of immature apices (Rajasekharan et al., 2014). The main components of MTA are tricalcium oxide, tricalcium silicate, bismuth oxide, tricalcium aluminate, tricalcium oxide, tetracalcium aluminoferrite, and silicate oxide. In addition, there are a few other mineral oxides, which are responsible for the chemical and physical properties of MTA. Studies revealed that MTA materials are biocompatible with an acceptable in vivo biologic performance when used for root-end fillings, perforation repairs, pulp capping and pulpotomy, and apexification treatment (Roberts et al., 2008).

24.6.2 Biodentine Biodentine (BD), a new calcium silicate-based material, has been introduced as a dentine substitute to repair the damaged dentine. BD has a wide range of applications including endodontic repair (root perforations, apexification, resorptive lesions, and retrograde filling material in endodontic surgery) and pulp capping and can be used as a dentine replacement material in restorative dentistry. BD was originally developed for use in direct and indirect pulp capping as a single application dentine substitute without any cavity conditioning treatment. Biological studies of this material indicated that it may be safely applied directly to the pulp, since it induces the formation of a dentine-like matrix (Laurent et al., 2008). It was also confirmed that BD can be used as a dentine substitute under a composite for posterior restoration (Koubi et al., 2013). BD can be used as a direct posterior restorative material. The modified composition of the powder, the addition of setting accelerators and softeners, and a new predosed capsule formulation for use in a mixing device have largely improved the physical and handling properties of this material (Wang et al., 2011). The cement has a faster setting time than other related materials and also higher compressive strength. The components of BD are provided in the form of a capsule containing a powder and an ampule containing a liquid, which are combined by adding the liquid to the capsule and mixing with an amalgamator. According to the manufacturer, the setting time of BD is short, between 9 and 12 minutes, owing to the addition of an accelerator (CaCl2) to the liquid. The push-out bond strength of BD is similar to that of MTA (Alsubait et al., 2014). It also has excellent color stability (Valles et al., 2013) and is, therefore, more preferred than MTA for use in anterior teeth. Furthermore, similar to MTA, BD shows complete dentine bridge formation when used for pulp capping (Nowicka et al., 2013). Bioactive and biocompatible characteristics of the material were confirmed. BD when placed directly in contact with the pulp showed enhanced proliferation, migration, and adhesion of human dental pulp stem cells (Luo et al., 2014). Considering the superior physical and biologic properties, BD could be used in the field of endodontics, dental traumatology, restorative dentistry, and pediatric dentistry.

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Three-dimensional printed scaffolds

3D printing provides a platform that helps to fulfill the hallmarks of tissue engineering, namely, rehabilitation, reconstruction, and regeneration. The technique allows construction of individualized, patient-specific bone substitutes (Bauermeister et al., 2016). The complexity and the multicellular interactions of the craniofacial structures can be managed by the application of 3D-printed scaffolds. 3D printing is fundamentally based on the additive manufacturing technology where a 3D construct is fabricated by adding materials layer by layer. Computed tomography, magnetic resonance imaging, or X-rays are used to create a patient’s specific scaffolds. 3D bioprinting promises precise printing of various biomaterials (bio-ink) with complex 3D architectures, while being able to use multiple cell sources simultaneously and being customizable to patient-specific needs (Fig. 24.2). Various classes of bio-inks (polymer hydrogels, inert metals, ceramics, composites, and cell aggregates) may be used for 3D biomanufacturing of scaffolds to replace damaged tissue, guide in reconstruction through fixation devices, screws, custom cutting guides, as well as to create craniofacial tissue analogs for tissue regeneration. Based on the underlying printing principles, bioprinting can be classified into inkjet-based, extrusionassisted, and laser-assisted (Obregon et al., 2015; Nyberg et al., 2017; Derby, 2012). Depending on the biomaterial properties, the appropriate bioprinting system is selected. Inkjet 3D printers are capable of applying low-viscosity bio-inks using a thermal or piezoelectrical controlling system; laser-assisted printers can print cell

Figure 24.2 Examples of various shapes of bioceramics for bone engineering applications: cylinder, block, root form, and granules as bone fillers.

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and biomaterial sources with various viscosities using laser source; and extrusion printers extrude high-viscosity and stiff polymeric sources at high temperatures (Amrollahi et al., 2016). Bone and cartilage regeneration can be achieved through scaffolds from extrusion-based printing systems as these areas demand high load bearing properties. In a clinical trial, bioprinted PCL tooth-shaped plugs have shown significant improvement in alveolar preservation (Goh et al., 2015). The possibility of combining two classes of materials, such as calcium sulfate hydrate and bioactive glass, was proven by Qi et al. Both in vitro and in vivo studies showed improved osteogenesis and thereby enhanced bone formation in calvarial defects (Qi et al., 2017). In the craniofacial region, the periodontal complex represents multiple tissues both soft and hard. Hence multiphase 3D printing using a composite (PCL-HA) with spatiotemporal arrangement and precise delivery of growth factor and BMP-2 led to the differentiation of distinctive progenitor cells of putative dentin/cementum, periodontal ligament (PDL), and alveolar bone complex (Lee et al., 2014). Similar attempts with biphasic scaffolds, cells, and gene delivery with tunable mechanical properties within the scaffold have been attempted in efforts toward bioengineering a whole tooth (Kim et al., 2010; Ikeda et al., 2009; Zhang et al., 2010). 3D-printed Grade V titanium dental implant with a novel dual-stemmed design, when tested in rabbits against conventional manufactured steel implants, showed better osteogenesis and comparable biocompatibility (Tedesco et al., 2017). Such advances promise more avenues for 3D printing in craniofacial regeneration.

24.8

Conclusion

Craniofacial reconstruction has undergone tremendous expansion since the inception of the concept of tissue engineering. Various materials such as metals, ceramics, natural and synthetic polymers, and even their composites have been explored as scaffolds to promote maxillofacial tissue regeneration. The progress in this field is taking several routes, including cell biology, the development of novel scaffolds, fabrication methods, and characterization techniques. Regenerating maxillofacial structures is challenging and requires the recapitulation of the biological development of several tissues and interfaces. Stem cell therapy and engineering of irreversibly damaged tissues is progressing toward a reality. Further research should be focused on the development of materials which promote rapid tissue regeneration; the development of processing methods to give scaffolds with designed architecture; and the delivery of therapeutic molecules, such as antibiotics and growth factors.

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