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Nanoengineered Biomaterials for Regenerative Medicine

Nanoengineered Biomaterials for Regenerative Medicine

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Nanoengineered Biomaterials for Regenerative Medicine

1,015 pages
11 hours
Sep 17, 2018


Nanoengineered Biomaterials for Regenerative Medicine showcases the advances that have taken place in recent years as an increasing number of nanoengineered biomaterials have been targeted to various organ tissues. The book systematically explores how nanoengineered biomaterials are used in different aspects of regenerative medicine, including bone regeneration, brain tissue reconstruction and kidney repair. It is a valuable reference resource for scientists working in biomaterials science who want to learn more about how nanoengineered materials are practically applied in regenerative medicine.

Nanoengineered biomaterials have gained particular focus due to their many advantages over conventional techniques for tissue repair. As a wide range of biomaterials and nanotechnology techniques have been examined for the regeneration of tissues, this book highlights the discussions and advancements made.

  • Provides a digestible reference source for surgeons and physicians who want to learn more on nanoengineered biomaterials and their use in effective medical treatments
  • Offers systematic coverage on how nanoengineered biomaterials are used for different types of medicine
  • Assesses the benefits and drawbacks of the use of bioengineered nanomaterials in different areas of regenerative medicine
Sep 17, 2018

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Nanoengineered Biomaterials for Regenerative Medicine - Elsevier Science


Chapter 1

An introduction to nanoengineered biomaterials

Masoud Mozafari⁎,§,¶; Jayakumar Rajadas†; David L. Kaplan‡    ⁎ Bioengineering Research Group, Department of Nanotechnology and Advanced Materials, Materials and Energy Research Center (MERC), Tehran, Iran

† Biomaterials and Advanced Drug Delivery Laboratory, School of Medicine, Stanford University, Palo Alto, CA, United States

‡ Department of Biomedical Engineering, Tufts University, Medford, MA, United States

§ Cellular and Molecular Research Center (CMRC), Iran University of Medical Sciences (IUMS), Tehran, Iran

¶ Department of Tissue Engineering & Regenerative Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran


In the early 2000s, regenerative medicine as an interdisciplinary field was revolutionized as a result of the exponential progress in nanotechnology and cell engineering. The combination of nanostructured materials, including nanoparticles, nanotubes, nano-assemblies, and nanopatterned surfaces with biocompatible platforms or systems functionalized with biomolecules, such as peptides and growth factors, were used to enhance cellular activities. These activities included cell adhesion, proliferation, and differentiation to promote tissue regeneration. Nanoengineered platforms for tissue regeneration should possess appropriate mechanical properties, improve biological performance, and enhance cellular activity. Nanotechnology has attracted attention because of its unique features, such as enhanced specific surface area and ion release behavior, which can pave the way for fabricating bio-inspired constructs to achieve more efficient or complete regeneration.


Regenerative medicine; Biocompatible platforms; Nanoparticles; Nanotubes; Biomaterials; Tissue

1 Where Bio Meets Nano: Nanoengineered Biomaterials

In the early 2000s, regenerative medicine as an interdisciplinary field was revolutionized as a result of the exponential progress in nanotechnology and cell engineering [1]. The combination of nanostructured materials, including nanoparticles, nanotubes [2], nano-assemblies [3], and nanopatterned surfaces [4] with biocompatible platforms [5] or systems functionalized with biomolecules, such as peptides and growth factors, were used to enhance cellular activities. These activities included cell adhesion, proliferation, and differentiation to promote tissue regeneration. Nanoengineered platforms for tissue regeneration should possess appropriate mechanical properties, improve biological performance, and enhance cellular activity [6]. Nanotechnology has attracted attention because of its unique features, such as enhanced specific surface area and ion release behavior, which can pave the way for fabricating bio-inspired constructs to achieve more efficient or complete regeneration [7].

2 Nano-Bio Interfaces: Pushing the Boundaries

Nanopatterning can be achieved by using nanosized materials such as carbon nanotubes (CNT) [8], which endow specific properties such as conductivity and antibacterial activity to the final system [9]. For instance, surface nanotopography of biomaterials based on pectin biopolymers was modified with germanium dioxide to provide improved antibacterial activity [10]. Nano-bioactive glass particles were added to a gelatin-based matrix to improve surface topology while enhancing the mechanical properties of the scaffolds; the topology, composition, and mechanical similarity of these scaffolds to natural human bone tissue facilitated regeneration [11]. Cellular activities were increased by using conductive substrates [12]. Synthesized conductive particles, such as nanohydroxyapatite-aniline tetramer as an inorganic-organic hybrid nanoparticle with polylactic acid (PLA) substrates, increased cellular activity compared with scaffolds without these nanopatterned structures [13]. Recently, renewed interest has developed in the use of magnetic nanoparticles for magnetic hyperthermia treatment for cancer [14]. Graphene is an important member of the nanostructure carbon family [15] that can be used in different formats, such as nanotubes, nanoribbons, and nanoplatelets, and can be integrated with cells related to drug delivery. Moreover, the integration of graphene with biomaterials has enhanced cellular activity and tissue regeneration [16]. Nanoscale self-assembly of conductive nanovesicles has been reported for controlled drug release. The amphiphilic properties of these substrates tend toward self-assembly to form nanoscale particles [3]. Polymersomes are another type of self-assembling material that can be synthesized as temperature-responsive [17] or enzyme/drug/growth factor carrier systems [18].

Materials have been engineered to mimic the structure of the ECM, and because of their resemblance to ECM surface structures, often nanoengineered nanofibrous biomaterials are ascribed to such systems [19]. For instance, bone ECM is composed of collagen type I, and cartilage ECM includes collagen type II, hyaluronic acid, and glycosaminoglycan (GAG); both types harbor collagenous fibers with < 1 μm diameter and exhibit osteogenic and chondrogenic properties [20]. Different methods have been utilized for nanofibrous scaffold fabrication, including electrospinning, self-assembly, and phase separation [7]. Electrospinning has been performed using high-static electrical charges to form nanofibrous structures [21]. In this method, the application of high voltage stretches a polymer solution to form a continuous jet. Then the solvent evaporates and forms fibers on the collector. Such structures based on silk fibroin were suggested as a delivery system for bone marrow stem cells as a fibrous platform exhibiting appropriate cell adhesion and proliferation [22]. The ECM resemblance of fibrous structures results in the formation of complex tissues like neural systems, appropriate for regeneration in comparison with conventional platforms. In this regard, electrospun polyvinyl alcohol (PVA)/chitosan nanofibrous scaffolds with relatively large-scale pores revealed that such scaffolds were a neural-friendly polymeric blend [23,24]. The scaffold pore sizes were adjusted by the addition of montmorillonite, where stem cell differentiation was guided in order to regenerate neural damage [25]. Manipulating the thermodynamic equilibrium conditions in which spontaneous molecular self-assembly occurred (e.g., with peptides and collagens) is another route to achieve nanofibrous structures. Amphiphilic peptides can self-assemble and form nanofibrous structures. Because of their similarity to ECM, peptides have exhibited promising results in tissue regeneration. Neural stem cells were seeded in self-assembling peptide nanofibers with the aim of regenerating the spinal cord after injury, and motor functions were improved [26].

The scalable synthesis of self-assembling nanomaterials remains a challenge. Recently, a self-templating assembly method began to address this need by using a bacteriophage-based biomimetic process. Various hierarchical structures were formed using bacteriophage liquid crystalline structures as nanofiber models that could be adjusted for hard and soft tissues [27]. The other method widely utilized for self-assembled nanofibrous materials is thermally induced phase separation (TIPS). TIPS was used to fabricate 3D networks of nanofibers based on gelatin/apatite for bone regeneration, mimicking the ECM structure because of similarities in the chemical composition and nanostructures [28]. Achieving controlled release from such systems is also challenging, and layer-by-layer deposition techniques have been proposed. A multilayer structure of poly-l-glutamic acid and poly-l-lysine nanocapsules was prepared to control the release of growth factors for tissue regeneration [29].

3 Nanoengineered Biomaterials for Tissue Regeneration

Nanoengineered biomaterials have been architecturally organized to mimic target tissues to enhance regeneration outcomes. A wide range of tissues/organs can be treated with nanoengineered biomaterials to compete with conventional techniques. For instance, nanotechnological tissue engineering strategies for addressing cardiovascular disease have endeavored to regenerate injured tissues caused by myocardial infarction (MI). Nanomaterials can play an essential role in cardiac tissue regeneration [30] with metal-like nanoparticles, such as carbon nanotubes or conductive polymers, to enhance cellular activity during regeneration [31]. Moreover, nanofibrous constructs can mimic ECM nanotopography to enhance regeneration [32]. Oxidative stress in the infarct region can hamper regeneration; therefore antioxidative nanoparticles can ameliorate this challenge during regeneration [33]. Iron oxide nanoparticles have been used widely as a diagnostic agent in cardiac tissue engineering and as contrast agents in magnetic resonance imaging (MRI). During the last few years, such nanoparticles have also been utilized for therapeutic purposes [34]. Iron nanoparticles improved the differentiation of mesenchymal stem cells to the cardiac lineage for enhanced cardiomyocytes-based tissue regeneration [35]. Conductivity in cardiac scaffolds is a promising method to improve regeneration. Gold nanoparticles and nanorods have contributed conductivity to cardiac scaffolds. Thermosensitive chitosan-based hydrogels with gold nanoparticles were synthesized for cardiac tissue engineering, where the gold nanoparticles propagated conductivity within the chitosan hydrogel and improved cell viability, metabolism, migration, and proliferation [36]. CNT and graphene oxide (GO) as members of the carbon family exhibited promising effects on myocardial regeneration. In an innovative study, graphene oxide/gelatin hydrogels were synthesized for cardiac tissue engineering and exhibited biocompatibility with the propagation and proliferation of cells [37]. GO has absorbed ECM and activated pro-angiogenic cytokine secretion and pro-survival pathways and stimulated cardiac cell expression [38]. GO in contact with mesenchymal stem cells reduced oxidative stress and enhanced cellular cardiomyoplasty without activating the immune response [38]. Cerium oxide nanoparticles have been used to destroy reactive oxygen species (ROS) by radical scavenging in a murine model of heart failure [39]. A series of peptide-based injectable hydrogels delivered cells and growth factors to a post-MI site to support regeneration [40]. Many similar systems for the delivery of cells and small molecules to the MI site have resulted.

Bone regeneration is a process in which dynamic progression starts with cell migration followed by osteoprogenitor cell proliferation and differentiation to repair the bone [11]. Natural bone covers a wide range of dimensions, from the nano to the micro scale. To mimic the ECM, various structures have been utilized for bone regeneration [41,42]. Fig. 1 illustrates the complex structure of bone; therefore scaffolds designed for such complex tissues necessitate a combination of features. Biomimic scaffolds for bone regeneration should be osteoconductive (promote osteogenic cell attachment, growth, and migration), osteoinductive (induce stem cells to osteoblastic lineage), and osteogenic (contain stem cell for regeneration) [43]. Recapitulating natural bone structure necessitates proper scaffolds with biochemical and physical features to stimulate stem cells, and nanotechnology can fill this aim [20]. Despite the fact that the main activities involved in regeneration occur at the nanoscale, conventional scaffolds offer only macroscopic features in which nanometric activities have often been neglected. Nanoengineered biomaterials have been utilized to mimic bone tissue with the aim of appropriate regeneration [44]. Nano-grooved patterns were applied to evaluate the behavior of human mesenchymal stem cells (hMSCs), which exhibited enhanced adhesion, migration, and differentiation. Moreover, nanotopographical density affected hMSCs [45]. Nanofibrous structures have exhibited significant effects on cell morphology, attachment, alignment, proliferation, and cytoskeleton organization [46]. Nanotopography, along with conductivity, boosted cellular activity and enhanced regeneration related to bone regeneration [46,47]. Bone is composed of collagen and crystalline hydroxyapatite (HA) (inorganic component). Nano-HA-based scaffolds have exhibited osteomimetic properties for bone regeneration [48]. HA-aniline tetramers as organic-inorganic nanoparticles with PLA nanofibers exhibited a strong effect on cell activity by mimicking the bone tissue [13].

Fig. 1 The microstructure and nanostructure of bone, and the nanostructured materials used in bone regeneration. (A) At the macroscopic levels, bone consists of a dense shell of cortical with porous cancellous structure at both ends. (B) Repeating osteon units within the cortical bone. In the osteons, 20 to 30 concentric layers of collagen fibers, called lamellae, are arranged at 90 degrees surrounding the central canal, which contain blood vessels and nerves. (C) Collagen fibers (100–2000 nm) are composed of collagen fibrils. The tertiary structure of collagen fibrils includes a 67 nm periodicity and 40 nm gaps between collagen molecules. The hydroxyapatite (HA) crystals are embedded in these gaps between collagen molecules and increase the rigidity of the bone. Nanostructures with features of nanopattern (D), nanofibers (E), nanotubers (F), nanopores (G), nanospheres (H), and nanocomposites (I) with structural components in nanoscales. Reproduced with permission from T. Gong, J. Xie, J. Liao, T. Zhang, S. Lin, Y. Lin, Bone Res. 3 (2015) 15029.

4 Physicochemical Features From Nanotechnology

Antimicrobial features are attractive in tissue regeneration because of their ability to prevent infections that can hinder tissue repair. Silver is a well-known element that acts as an antimicrobial agent. Silver nanoparticles have played a prominent role in wound healing by preventing infections in skin regeneration [49]. Silver nanoparticles decreased inflammatory macrophage numbers and neutrophil infiltration, thus preventing inflammatory cytokines and resulting in changes in metalloproteinase expression [34]. Furthermore, nitric oxide exhibited a vital role in immune response in promoting proliferation in wound healing, which significantly decreased wound closure time and enhanced epithelization and the secretion of proinflammatory cytokines to ameliorate fibroblast proliferation and migration [7]. Recent reports demonstrated that amphiphilic peptides self-assembled in the biological milieu; intrastromal injection of peptide amphiphile (PA) nanofibers exhibited regeneration in rat corneal wound healing [49a]. After postinjection of laminin peptide, significant migration of stromal keratinocytes was observed, improving the regeneration of damaged cornea tissue [50]. In addition, adding silver nanoparticles in collagen hydrogels contributed antimicrobial properties to these mimetic matrices [51]. Corneal diseases are seen as one of the most important factors in the cause of blindness. Various drugs have been utilized for corneal disease treatment; however, ocular surface properties require high doses of drugs, which can be problematic. Therefore nanoparticles have been introduced to assist in corneal disease treatment. Different types of nanoparticles ranging from 1 nm to 100 nm have been used (Fig. 2). Because of their small size, nanoparticles with a high aspect ratio and a high loading capacity can potentially penetrate to the intracellular level and deliver drugs to the targeted area [52]. Metallic nanoparticles such as gold, silver, and platinum have been used for this type of tissue regeneration. Gold and silver, which are nontoxic and cost-effective, have been used as drug carriers. Polymeric nanoparticles for drug delivery consist mostly of polyethylene imine (PEI), albumin, chitosan, and polyethylene glycol, which can deliver transgenes into cells [53,54]. Hybrid nanoparticles based on metallic and polymeric biomaterials exhibited a significant effect on tissue regeneration. For example, PEI conjugated with gold nanoparticles was used to deliver genes in the cornea, exhibiting low toxicity, high absorbance, and slow clearance [55].

Fig. 2 Schematic depicting nanomedicine techniques available for the treatment of corneal diseases. Reproduced with permission from S.S. Chaurasia, R.R. Lim, R. Lakshminarayanan, R.R. Mohan, J. Funct. Biomater. 6 (2015) 277–298.

The physical and chemical properties of nanoparticles determine their use and function. Maximum efficiency can be achieved using hybrid systems in which combined nanoparticles exhibit synergic effects. Hybrid nanoparticles based on gold/PLLA were utilized for skeletal muscle (SM) regeneration and exhibited biocompatibility, biodegradability, and conductivity, and they promoted cell alignment, vascularization, and innervation, all crucial for regeneration [56]. As mentioned earlier, conductive nanoengineered biomaterials improved cellular activity and regeneration, especially in neural systems because of their action potential [57]. Various nanoparticles, from organic to inorganic, have been used to impart conductivity to scaffolds for neural regeneration [58,59]. Electrical stimulation using gold nanoparticles was applied to neurite outgrowth from neural cells, and enhanced neurite outgrowth resulted [60]. However, some issues limit the utility of nanoengineered biomaterials, including safety concerns, which are a significant obstacle for clinical use. The toxicity of nanoparticles is related to the control of size, capping agents, and concentration [61], and the commercial use of nanomaterials will require clinical trials to evaluate their safety for human use (Fig. 3).

Fig. 3 Illustration of the application areas of nanomedicines for treatment and diagnostics. The nanomaterials are metals, polymers, ceramics, and naturally occurring biopolymer-derived materials that are nanoporous, or contain nanostructured surfaces, or are formulated as nanoparticles for use as drug carriers or as contrast agents. These nanoengineered biomaterials are used to repair tissues and to treat a range of diseases, including cancer, cardiovascular conditions, ocular aging, and inflammatory and infective diseases (shown in blue text; dashed border text in print versions). Nanostructured implants are used in several health care fields, including cardiology, orthopedics, dental, ophthalmology, aesthetic surgery, urology, neurology, and gastroenterology. The structural and chemical interfaces between nanomedicines or nanodiagnostic tools and biological tissues determine their biodistribution to the target site, which is important because of the interfacial area that affects many properties, such as mechanical wear, immune response, and potential for infection. Reproduced with permission from M. Kendall, I. Lynch, Nat. Nanotechnol. 11 (2016) 206–210.

5 State-of-the-Art and Future Perspectives

Because of their similarity to the native structure of tissues and because of their specific chemical properties, nanoengineered biomaterials can mimic the tissues' intrinsic properties and be used to regenerate tissues and organs. More advanced architectures and surface topologies have progressed in mimicking native tissue features aimed at reaching the appropriate interplay between tissue and material platforms. A deep understanding of tissue and cell interactions with nanoengineered biomaterials is a challenging issue in which the mechanisms related to regeneration remain obscure. The interaction at nanometric sizes need to be evaluated to characterize the fate of cells, which is essential for tissue engineering and regenerative medicine. Cell behavior on nano-platforms can be adjusted through the surface morphology because of the unique properties of nanosized materials, such as their high aspect ratio. Architectures related to the nanometric size features on the surface of such materials—via modifying roughness, grooves, and pits through various methods, such as vapor deposition, nanolithography, electrospinning, nanopatterning, and electrochemical etching—can all influence protein adsorption, cellular attachment, proliferation, and differentiation. Therefore cell destinies depend on these features. Thus, understanding the chemical interactions on the surface of nanoengineered biomaterials and their effect on bonding mechanisms with living tissues can significantly help advancement of tissue engineering and regenerative medicine. Because of the interdisciplinary nature of the field, materials scientists, biologists, and physicians need to work together to take advantage of nanoengineered biomaterials aimed at improving human health. Further investigations into the interactive mechanisms of nanoengineered biomaterials with living tissues and organs are needed to address critical questions. This book introduces the salient features of nanoengineered biomaterials, the hurdles that must be overcome to advance the field, the hopes associated with the field, and the practical constraints toward the development of this class of biomaterials for tissue engineering and regenerative medicine.


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Chapter 2

Nanoengineered biomaterials for bone/dental regeneration

Saeid Kargozar⁎; Peiman Brouki Milan†,¶; Francesco Baino‡; Masoud Mozafari†,§,¶    ⁎ Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

† Department of Tissue Engineering & Regenerative Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran

‡ Institute of Materials Physics and Engineering, Department of Applied Science and Technology (DISAT), Politecnico di Torino, Torino, Italy

§ Bioengineering Research Group, Department of Nanotechnology and Advanced Materials, Materials and Energy Research Center (MERC), Tehran, Iran

¶ Cellular and Molecular Research Center (CMRC), Iran University of Medical Sciences (IUMS), Tehran, Iran


Repair of bone and dental injuries and disorders is currently one of the main areas in the fields of tissue engineering and regenerative medicine. There are a range of biodegradable materials for the repair of these hard tissues. Among different materials, nanostructured biomaterials have demonstrated promising results. These type of nanoengineered biomaterials have shown superior advantages over conventional materials for bone and dental tissue engineering. Nano-scale components are also favorable to cell interactions, resulting in rapid cell attachment on the material's surfaces. Although this field of research is in its infancy, the potential to launch a new class of biomaterials in nano-scales is expected to meet more considerable future researches.


Biomaterials; Tissue engineering; Nanotechnology; Bone; Dental; Regenerative medicine

1 Introduction

Repair of bone and dental injuries and disorders is currently one of the main areas in the fields of tissue engineering and regenerative medicine. Based on previously reported statistics [1], bone damages requiring treatment will double by 2020, as a result of an aging population, accidents, genetic abnormalities, and obesity. Since being identified as one of the most common tissue transplants in clinical settings, and because of the prevalence of bone disease, bone grafts have dramatically increased, with more than 2.2 million performed each year worldwide [2]. Moreover, the direct and indirect costs of treating dental disease worldwide were estimated to be $442 billion in 2010 [3].

Conventional substitutions for the reconstruction of skeletal defects include autograft, allograft, and xenograft. However, these naturally derived substances have limitations, such as donor site morbidity, rejection, and risk of disease transmission [4–6]. Therefore the development of synthetically derived biomaterials for the replacement of damaged bones and teeth is currently of particular interest. Today large numbers of synthetic materials, such as bioactive glasses (BGs), polymers, and their composites, have been extensively used for repair and reconstruction of these hard tissues [7–11]. In reference to the natural structure of bone and teeth, the use of nanotechnology-based approaches has attracted much interest in recent years [12,13].

Nanotechnology is a branch of science that deals with objects smaller than 100 nm [14]. After Feynman's talk about nanotechnology in 1959, the use of this newly proposed technology in the various fields of science attracted a great deal of attention [15]. Today nanotechnology is considered as one of the most powerful engineering approaches, with a great impact on tissue engineering [16]. It has been shown that nanotechnology can be a useful tool for removing current limitations, such as impaired cellular proliferation and differentiation and inadequate mechanical strength of scaffolds, in engineering strategies for bone tissue regeneration [17]. In this chapter, we will focus on the role of nanoengineered biomaterials used for bone/tooth tissue repair and regeneration. Moreover, an emphasis is placed on the usability of nanotechnology for fabricating nanostructured scaffolds, which can be effective in improving physicochemical interactions, mechanical stability, and biocompatibility.

2 Structure and Function of Natural Tissue Needing Repair

2.1 Bone Tissue

Bone is a specialized connective tissue containing various cells, fibers, and a matrix ground substance. As opposed to other soft connective tissues, extracellular components of bone tissue are mineralized, which results in its high strength and rigidity. Natural bone can be described as a polymer matrix composite of organic collagen fibrils (30% w/v) reinforced with inorganic calcium phosphate [mainly hydroxyapatite (HAp)] nanocrystals (70% w/v). This composite is organized in a highly ordered structure over multiple size scales (Fig. 1).

Fig. 1 Schematic of the organization of bone tissue from its smallest components (right side) to whole tissues (left side). Reproduced with permission from R. Kane, P.X. Ma, Mimicking the nanostructure of bone matrix to regenerate bone, Mater. Today, 16 (2013) 418–423.

The collagen proteins of bone tissue are 200 nm long and 2–3 nm in diameter and are assembled into fibrillar structures that undergo further aggregation to form fibrils with a diameter of 500 nm. The regular stacking pattern of collagen molecules provides small gaps that act as a suitable place for plate-shaped nanocrystals (10–20 nm in length and 2–3 nm in width) made of a mineral that closely resembles the synthetic mineral hydroxyapatite (Ca10(PO4)6(OH)2) [18]. Based on the type of bone (Table 1), these mineralized fibers are arranged into larger tissue-level structures.

Table 1

Four different cells have been identified in bone tissue—osteoprogenitor cells, osteoblasts, osteocytes, and osteoclasts—and they play important roles in bone remodeling. Osteoprogenitors are undifferentiated cells, located in the deep layers of periosteum and endosteum and in marrow, that can develop into osteoblasts. Osteoblasts are fully differentiated cells located in the growing portion of the bone (e.g., periosteum and endosteum) and are responsible for new bone formation through the secretion of matrix and collagen fibers. Osteocytes, which are entrapped in the bone matrix, are indeed mature cells with the ability to maintain the mineral concentration of the matrix. Osteoclasts are large, multinucleate cells (formed via the fusion of precursor cells) that are usually found in bone surfaces and at sites of old and injured bone, helping the bone remodeling process through the breakdown of bone matrix and the release of calcium.

As previously mentioned, bone tissue is a highly dynamic organ that is continuously remodeled by the intricate communication among the above-mentioned cell types [19]. The remodeling comprises three distinct steps in a cycle. The first step is the initiation of bone resorption by increasing the number of osteoclasts in response to hypocalcemia. This step is followed by the activation of osteoblasts that lay down the new bone matrix (osteoid) at the sites of the previous resorption. When the new bone formation is completed, osteoblasts are inactivated and differentiate into osteocytes on the surface of the new bone [20]. It has been shown that a variety of local factors (e.g., growth factors and cytokines) and systemic factors (e.g., calcitonin and estrogens) control this process. Any imbalance of bone resorption and formation may lead to bone diseases like osteoporosis. It is worth noting that bone has several important functions in the body, including storing vital elements (e.g., calcium and phosphorus), providing internal support and locomotion, protecting soft organs from traumas, and providing attachment sites for muscles and tendons [21].

2.2 Dental Tissue

Teeth are hard and mineral-rich structures that can be found in the jaws of a large number of vertebrates. They originate from the ectoderm, and their main function is to break down food. Teeth are not made of bone similar to that of the rest of the skeleton; instead, they have their own unique structure.

From a histological point of view, a tooth is made of strong tissues (enamel, dentin, and cementum) and dental pulp (Fig. 2) [22]. The strong parts are composed of inorganic components, while dental pulp is made of only organic materials.

Fig. 2 Photograph (right) and diagram (left) of a human third molar tooth after extraction. Reproduced with permission from A.A. Volponi, Y. Pang, P.T. Sharpe, Stem cell-based biological tooth repair and regeneration, Trends Cell Biol. 20–206 (2010) 715–722.

As the hardest tissue in the human body, enamel is an acellular and translucent zone that forms the external surface of the teeth. Polygonal rods (2–3 μm in diameter) made from small hexagonal crystals with nanometric dimensions are the basic components of the enamel. Chemically, the enamel comprises an inorganic component, mainly HAp (97 wt%), and organic proteins, that is, amelogenin, enamelin, ameloblastin (3 wt%).

As the main structure of the tooth, the dentin is covered by enamel in the crown and by cement in the root. The odontoblasts are responsible for the formation of this part of the tooth throughout its life. Histologically, the dentin has a nanoscale structure made of collagen fibers and hydroxyapatite crystals. However, it has been shown that their dimensions are of an order of magnitude smaller than those found in the enamel and define the hard, elastic consistency of the tissue. The composition of the dentin includes an inorganic phase of HAp (70%) with replacements of sodium carbonate or magnesium, an organic phase of type II collagen fibers (20%), and water (10%).

The cementum is a hard tissue similar to bone and is responsible for covering the tooth root. There are two types of this tissue, acellular cementum and cellular cementum. Cementoblasts and cementocytes are the main cells of this tissue located in gaps similar to those of the bones. The dental attachment point of periodontal ligament (PDL) fibers is acknowledged as the main function of the cementum.

The dental pulp is a loose connective tissue located in the pulpal cavity. Originating from the mesenchyme, dental pulp comprises hyaline substance, various cells (odontoblasts, fusiform and stellar fibroblasts, and macrophages), collagen fibers, vessels, and nerves. Moreover, this tissue presents subsequent layers, the predentin, the odontoblasts layer, the cells layer, and the stroma.

From a cellular point of view, some cell populations with stem cell characteristics have been identified in different parts of the tooth, that is, dental pulp stem cells (DPSCs) [23], stem cells from exfoliated deciduous teeth (SHED) [24], periodontal ligament stem cells (PDLSCs) [25], stem cells from apical papilla (SCAP) [26], alveolar bone-derived mesenchymal stem cells (ABMSCs) [27], gingiva-derived MSCs (GMSCs)[28], dental follicle stem/progenitor cells (DFPCs) [29], and tooth germ progenitor cells (TGPCs) [30].

3 Repair Process

3.1 Bone Repair

Because of its presence in most parts of the body (except the abdominal cavity), bone tissue is exposed to various injuries. After any injury (e.g., fractures), bone tissue has the ability to repair itself owing to the integration of cells, growth factors, and the extracellular matrix. Bone repair is a multistep process restoring the continuity of the damaged tissues and ultimately function, without increasing bone volume [31]. Four general stages have been identified in the fracture repair of bones: (1) hematoma formation, (2) fibrocartilaginous callus formation, (3) bony callus formation, and (4) bone remodeling. In stage 1, a blood clot (hematoma) is formed as a result of tearing blood vessels in the bone and periosteum. In stage 2, capillaries grow into the hematoma site, and phagocytes clean up the debris. Then fibroblasts and osteoblasts migrate to the injured area and produce collagen fibers to bridge the gap, followed by the formation of spongy bone and cartilage. In stage 3, the formed fibrocartilaginous callus is replaced by spongy bone over three to four weeks after the injury. Finally, excess material is removed in stage 4, and compact bone is produced between the shaft walls.

From a molecular point of view, bone repair is regulated by various cell signaling molecules that are categorized into three groups: (1) proinflammatory cytokines, (2) transforming growth factor-beta superfamily (TGF-β) members, and (3) angiogenic factor (for more information, see [31]) (Fig. 3).

Fig. 3 Representative schematic showing the different steps of bone repair. Reproduced with permission from W. Wang, K.W. Yeung, Bone grafts and biomaterials substitutes for bone defect repair: a review, Biomed. Mater. (2017).

3.2 Dental Repair

Dental caries, trauma, and congenital anomalies are the main reasons for tooth loss in humans. It has been documented that the cellular components of teeth respond to different injuries [32]. In slowly progressing caries recognized as middle injuries, the activity of odontoblasts is stimulated, resulting in the production of reactionary dentin. Upon the formation of a reparative dentin matrix, a layer of odontoblast-like cells covers the injury site, and migration of pulp cells terminates. However, in more intensive injuries such as deep, chronic dentinal caries lesions, the pulp is responsible for the reparative activities [32]. After an injury, some of the odontoblasts are usually damaged and undergo apoptosis. Therefore the cell renewal occurs in order to form a new generation of odontoblasts. It has been proposed that this process is performed through differentiation of the cells of the subodontoblastic layer or of pulp fibroblasts into odontoblast-like cells

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