Bioceramics: Status in Tissue Engineering and Regenerative Medicine (Part 1) E-Book
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Bioceramics: Status in Tissue Engineering and Regenerative Medicine (Part 1) provides an in-depth look into the recent advancements in biocompatible ceramics, glasses, and composites for tissue engineering and regenerative medicine. It explores topics ranging from the structure and processing of bioactive glasses to the applications of bioinert and bioresorbable ceramics in medical treatments. The book discusses key aspects of bioceramics, including their therapeutic potential in soft tissue healing and cancer therapy, along with challenges and opportunities for future research. Researchers, bioengineers, and professionals in biomedical sciences will find this volume an essential resource for understanding both the fundamentals and applications of bioceramics.
Key Features:
- Comprehensive coverage of bioceramics, bioactive glasses, and composites, including their manufacturing techniques.
- State-of-the-art insights into bioceramics and glass-ceramics in tissue engineering and regenerative medicine.
- Focus on preclinical assessment, clinical applications, challenges, and future perspectives.
Readership:
Academia, Ph.D. or Postgraduate Researchers, and Industry Professionals.
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Seitenzahl: 518
Veröffentlichungsjahr: 2024
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FOREWORD
The use of bioceramics for tissue engineering and regenerative medicine extends over two centuries. Dorozhkin provided a detailed review of the history of bioceramics [1]. He noted that Johan Gottlieb Gahn and Carl Wilhelm Scheele first described the presence of calcium and phosphorus in bone in the second half of the eighteenth century [1, 2]. The first use of bioceramics in medicine occurred in the late nineteenth century when Junius E. Cravens distributed a calcium orthophosphate powder called “Lacto-Phosphate of Lime” for capping the dental pulp during dental restorations [1, 3, 4]. Larry Hench's discovery in 1969 that a sodium-calcium-phosphorous-–silicate glass possesses bone bonding functionality gave rise to the clinical use of “bioactive glass” materials for bone repair [5, 6]. The term “bioceramics” was first used shortly thereafter in 1971 [7]. The bioceramics field is now truly global in nature and includes research, pre-clinical, and clinical activities involving various types of bioactive and bioinert inorganic materials.
This is Part 1 by Saeid Kargozar, a research fellow in the Department of Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, and Francesco Baino, an associate professor in the Department of Applied Science and Technology at the Politecnico di Torino, provides a comprehensive overview of the use of bioceramics for tissue engineering and regenerative medicine. The first part of the book (Part 1) focuses on the fundamentals of biocompatible ceramics, bioactive glasses and composites, and collects 10 chapters. In Chapter 1, Kargozar and Baino provide a description of the status of bioceramics in tissue engineering and regenerative medicine. Chapter 2, by Moghanian et al., provides an introduction to biocompatible glasses, ceramics, and glass ceramics. Batool et al. consider recent advances in bioactive glasses and glass ceramics in Chapter 3. Chapter 4, by Bahati et al., describes the structure, properties, and processing of bioactive glasses. Kargozar et al. focus on the biocompatibility of bioactive glasses in Chapter 5. In Chapter 6, Moghanian and Nasiripour describe the use of bioinert ceramics for biomedical applications. Moghanian et al. review the processing and properties of bioresorbable ceramics in Chapter 7. Dorozhkin reviews the use of calcium orthophosphates in tissue engineering in Chapter 8. In Chapter 9, Hosseini et al. consider the use of carbon nanostructures for tissue engineering and cancer therapy. Benedini and Messina describe advances in polymer/ceramic composites for bone tissue engineering in Chapter 10. The second part of the book (Part 2) will be addressed to the applications of the bioceramic materials discussed in the present volume.
In this volume, Professors Kargozar and Baino as well as the chapter contributors have provided the bioceramics community with a comprehensive consideration of the bioceramics field. I anticipate that their volume will be beneficial to students as well as researchers in academia, government, and industry as they continue efforts to improve our understanding of the use of bioceramic materials for tissue engineering and regenerative medicine applications.
REFERENCES
[1]Dorozhkin SV. A detailed history of calcium orthophosphates from 1770s till 1950. Mater Sci Eng C 2013; 33(6): 3085-110.[http://dx.doi.org/10.1016/j.msec.2013.04.002] [PMID: 23706189][2]Dorozhkin SV. A history of calcium orthophosphates (CaPO 4 ) and their biomedical applications. Morphologie 2017; 101(334): 143-53.[http://dx.doi.org/10.1016/j.morpho.2017.05.001] [PMID: 28595833][3]Dorozhkin SV. Calcium orthophosphates as a dental regenerative material 2019.[http://dx.doi.org/10.1016/B978-0-08-102476-8.00016-5][4]Cravens JE. Lacto-phosphate of lime; Pathology and treatment of exposed dental pulps and sensitive dentine. Dent Cosmos 1876; 18: 463-9.[5]Hench LL. The story of Bioglass®. J Mater Sci Mater Med 2006; 17(11): 967-78.[http://dx.doi.org/10.1007/s10856-006-0432-z] [PMID: 17122907][6]Hench LL, Splinter RJ, Allen WC, Greenlee TK. Bonding mechanisms at the interface of ceramic prosthetic materials. J Biomed Mater Res 1971; 5(6): 117-41.[http://dx.doi.org/10.1002/jbm.820050611][7]Blakeslee KC, Condrate RA, Sr. Vibrational spectra of hydrothermally prepared hydroxyapatites. J Am Ceram Soc 1971; 54(11): 559-63.[http://dx.doi.org/10.1111/j.1151-2916.1971.tb12207.x]List of Contributors
Bioceramics: Status in Tissue Engineering and Regenerative Medicine
Saeid Kargozar1,*,Francesco Baino2,*Abstract
Tissue engineering and regenerative medicine seek biomaterials with potent regenerative potential in vivo. The bioceramics superfamily represents versatile inorganic materials with exceptional compatibility with living cells and tissues. They can be classified into three distinctive groups including almost bioinert (e.g., alumina and zirconia), bioactive (bioactive glasses (BGs)), and bioresorbable (e.g., calcium phosphates (CaPs)) ceramics. Regarding their physicochemical and mechanical properties, bioceramics have been traditionally used for orthopedic and dental applications; however, they are now being utilized for soft tissue healing and cancer theranostics due to their tunable chemical composition and characteristics. From a biological perspective, bioceramics exhibit great opportunities for tissue repair and regeneration thanks to their capability of improving cell growth and proliferation, inducing neovascularization, and rendering antibacterial activity. Different formulations of bioceramics with diverse shapes (fine powder, particles, pastes, blocks, etc.) and sizes (micro/ nanoparticles) are now available on the market and used in the clinic. Moreover, bioceramics are routinely mixed into natural and synthetic biopolymers to extend their applications in tissue engineering and regenerative medicine approaches. Current research is now focusing on the fabrication of personalized bioceramic-based scaffolds using three-dimensional (3D) printing technology in order to support large-volume defect tissue regeneration. It is predicted that more commercialized products of bioceramics will be available for managing both hard and soft tissue injuries in the near future, either in bare or in combination with other biomaterials.
INTRODUCTION
Tissue engineering is a multidisciplinary field that aims to regenerate damaged tissues by applying the principles of engineering, materials science, biology, and medicine. Pioneers in the field have introduced biomaterials, cells, and bioactive molecules as the three main building blocks of tissue engineering and regenerative medicine field [1]. Naturally, human tissues are formed from differentiated or undifferentiated cells located in an extracellular matrix (ECM) (mostly collagen) containing bioactive molecules (e.g., growth factors). As a rule of thumb, the ECM of tissues is greatly destroyed following severe injuries and damages; therefore, various biocompatible materials can be utilized as three-dimensional (3D) scaffolds to restore the destroyed ECM. Up to now, many types of natural and synthetic materials have been successfully processed, developed, and used for managing different tissue damage and injuries [2, 3]. Naturally occurring substances suffer from critical restrictions including the risk of disease transmission, batch-to-batch variations, and limited availability [4, 5]. Accordingly, there is a great interest in the use of synthetic materials in tissue reconstruction approaches. Regarding the nature of hard tissues (e.g., bone), bioceramics are recognized as the ideal implant materials for the replacement of degenerated or traumatized osseous tissues.
Bioceramics represent biocompatible ceramic materials that are being continuously developed for use as medical implants. In fact, they are inorganic biomaterials that comprise crystalline ceramics, amorphous glasses, and glass-ceramics. In other words, the bioceramics superfamily members can be classified into three distinct generations, i.e., almost bioinert (e.g., alumina and zirconia), bioactive (e.g., bioactive glasses (BGs)), and bioresorbable (e.g., most calcium phosphates (CaPs)). These substances are commonly synthesized in the laboratory using high temperatures and used in different formats, including fine powder, granules, and dense blocks. Furthermore, bioceramics can be fabricated into tissue-mimicking scaffolds through well-established techniques and protocols (e.g., sponge replication method). In recent years, great efforts have been made to produce bioceramics-based constructs using 3D printing machines in order to fit the size and shape of the lost tissues. It should be mentioned that some types of bioceramics (BGs) are being utilized as coatings for other ceramics or metal implants.
The most fascinating feature of bioceramics for orthopedic and dental applications is related to their mechanical properties which are in the range of naïve hard tissues. In addition, bioceramics (e.g., BGs and glass ceramics) exhibit excellent biological properties, including the ability to induce osteogenesis, osteoconduction, osteoinduction, and osteointegration. Moreover, bioceramics can be employed for the loading and delivery of various drugs, chemicals, and bioactive molecules to desired locations in the body. Although the first and foremost application of bioceramics is to restore hard tissue lesions, recent trends have also confirmed their suitability in soft tissue repair and regeneration (e.g., skin wound healing). In this sense, they can be utilized as additives in polymeric substrates for improving particular biological events (e.g., angiogenesis), and the reported data have been quite interesting. Still, some challenges remain to be solved regarding the widespread use of bioceramics in soft tissue healing strategies, including defining the most suitable composition and formulation. Since implantable materials must be compatible with living systems (e.g., cells and tissues), bioceramics have been extensively examined for their potential adverse effects (toxicity) in vitro and in vivo. In general, bioceramics are known as safe substances for human beings; their main components (elements like silicon, calcium, phosphorus, etc.) are commonly found in low concentrations in the body and needed for the proper function of human cells [6]. However, some potentially toxic elements (e.g., cobalt) can be incorporated into the basic composition of bioceramics for rendering particular activities, such as improving angiogenesis. In this case, caution should be taken to avoid any unwanted adverse effects on the human body at molecular and cellular levels. In addition, the positive potential effects of any new formulation of bioceramics may be of interest to researchers and scientists in the field.
In this chapter, we first introduce the structure, properties, and classifications of bioceramics and then highlight their possibilities in tissue engineering and regenerative medicine. The main challenges ahead will be discussed to shed light on their future applications for managing injured tissues.
BIOCERAMICS: STORY AND SIGNIFICANCE
The human body is a “marvelous machine” that efficiently incorporates different materials for different functions, such as structural support, filtration capacity, energy generation and storage, gas exchange, flexibility, and self-healing/regenerative ability, into one fascinating, integrated, and well-orchestrated bio-system. In other words, the human body is an exceptional “collection” of highly functional materials. Ideally, these materials should retain their functionality for many decades throughout the human lifespan, which is 73.2 years on average worldwide [7]. However, the biomaterials of the body are at risk of many harsh conditions and situations (e.g., overuse, trauma, or different pathologies like osteoporosis) over years and sometimes fail. This is becoming more common as worldwide populations age owing to the overall increase in life expectancy. Hence, the development of “spare parts” for the restoration of injured and diseased tissues/organs/structures of the body is becoming of utmost importance.
The use of ceramic materials in biomedicine dates back to the 10th century AD when ancient Egyptians used calcium sulfate for the restoration of broken bones of cadavers and mummies [8]. The first official report about the implantation of calcium sulfate in living human patients to fill voids resulting from tuberculous osteomyelitis was published in 1892 [9]. After the Second World War, high-purity pellets of calcium sulfate (also called “plaster of Paris”) started being routinely used as a bone substitute following the seminal work of Peltier in the early 1960s [10]. In the same years, other very important classes of bioceramics – i.e. alumina for joint prostheses, hydroxyapatite, and bioactive glasses for bone tissue regeneration in orthopedics and dentistry – began to attract the researchers’ interest and to be systematically investigated for use in contact with bone [11].
At present, bone is globally the second tissue needing replacement after blood [12]. The bone restoration can be completed by using a variety of natural and synthetic substances including autografts from the patient, allografts from another donor/cadaver, xenografts from animals, as well as man-made bioceramics. Over the years, numerous compositions of bioceramics have been developed and explored for the replacement of injured bones. The common forms of bone grafts include monolithic devices (used in the reconstruction of middle ear small bones or orbital floor), fine particles, porous granules, rigid scaffolds for filling large bone defects, moldable pastes (e.g., injectable blocks of cement for spine surgery), coatings on metallic prostheses and composites involving the dispersion of ceramic inclusions in a soft polymeric matrix. New emerging applications are mainly addressed to multifactorial tissue engineering and may involve special extra-functionalities, such as therapeutic actions in contact with soft tissues and controlled drug/ion delivery.
OVERVIEW OF BIOCERAMICS APPLICATIONS WITH FOCUS ON TISSUE ENGINEERING AND REGENERATIVE MEDICINE
Historically, bioceramics have been widely used for managing hard tissue lesions due to their appropriate physico-chemical, mechanical, and biological properties. Almost all bioinert ceramics (e.g., alumina (Al2O3), zirconia (ZrO2), titania (TiO2)) form the first generation of bioceramics and have been successfully used as musculoskeletal (hip and knee replacements) and dental implants. Indeed, this kind of ceramics exhibits excellent mechanical properties (e.g., tensile, compressive, hardness, low wear, toughness) for long-term implantation in the body. Moreover, they show good corrosion resistance which makes them suitable devices for long-lasting implantation. Nonetheless, bioinert ceramics usually need to be coated with other types of bioceramics (e.g., BGs and CaPs) in order to improve their biological characteristics (e.g., osteoconduction, osteointegration, and osteogenesis) [13]. Interestingly, bioinert ceramics have been utilized for coating alloys (e.g., Ti6Al4V) without causing any negative impacts on cell viability and proliferation [14].
As the second generation of bioceramics, BGs, and glass-ceramics offer great opportunities for tissue engineering and regenerative medicine strategies. These biocompatible substances can bind to the living tissues (both hard and soft) through a hydroxycarbonate apatite (HCA) layer which is formed on their surface upon contacting physiological fluids (e.g., blood plasma). There are plentiful experimental studies in the literature that indicate the great suitability of BGs for the repair and regeneration of bone tissue [15]. BGs were first invented by Prof. Larry Hench in 1969 at the University of Florida; 45S5 Bioglass® is known as the parent of silicate-based BGs with the composition of 45SiO2–24.5CaO–24.5NaO–6P2O5 (wt%) [16]. Since then, two other subgroups of BGs have been successfully developed and named phosphate- and borate-based BGs. The primary application of BGs was to restore damaged bone and teeth due to their excellent inherent properties. BGs can induce the osteogenesis process (i.e., supporting new bone growth) and thereby are known as osteoinductive materials [17]. Additionally, BGs can support human cell growth, proliferation, and differentiation, leading to accelerating bone tissue reconstruction [18]. Interestingly, BGs have been found as angiogenesis-inducing materials that can encourage new blood vessel formation in vitro, ex vivo, and in vivo [19, 20]. This potential can greatly accelerate bone regeneration since angiogenesis plays a pivotal role in all stages of the tissue healing process. As bacterial infections are a life-threatening issue in the clinic, particular types of BGs were developed and confirmed to act against both Gram-positive and Gram-negative bacteria [21]. Recent studies have revealed that specific formulations of BGs may modulate inflammatory responses through the stimulation of M1 to M2 phenotype switching of macrophages [22]. The main mechanism behind the mentioned biological activities is associated with the ion release process from BGs into the surrounding physiological environment [23]. Accordingly, several attempts have been made to incorporate metallic and non-metallic ions into the basic composition of BGs to enhance and extending their biological performance. For example, copper-doped BGs may show antibacterial and angiogenic effects [24]; while barium-containing BGs can elicit anti-inflammatory responses [25]. Focusing on tissue engineering and regenerative medicine, BGs have been selected in order to generate 3D scaffolds for bone tissue engineering applications [26, 27]. However, BG-based constructs suffer from low mechanical properties due to their brittle nature. Therefore, they are usually mixed with biocompatible natural and synthetic polymers to fabricate composite scaffolds having improved mechanical properties. On the other hand, BGs are added to otherwise-bioinert polymeric constructs for rendering specific biological features (e.g., improving angiogenesis). The current research aims to utilize BGs for the fabrication of 3D printed scaffolds in the concept of personalized medicine [28].
Recently, BGs have been suggested as suitable additives for soft tissue healing (e.g., skin wound healing) [29]. In fact, they were proposed for soft tissue engineering due to their outstanding biological features, including biocompatibility, angiogenesis-induction, and antibacterial activity.
The third generation of bioceramics is represented by bioresorbable ceramics that are prone to dissolution and degradation by the body cells. Bioresorbable bioceramics include amorphous calcium phosphates (CaPs), nano-sized HAp, α-/β-tricalcium phosphates (TCPs), and calcium sulfates (including plaster of Paris). Prior reports have shown that the resorption rate of different CaPs varies as the following trend of α-TCP > β-TCP > HAp. Apart from the mentioned compositions, other types of bioresorbable CaP-based materials have been developed and proven to be resorbed in the body, including dicalcium phosphate dihydrate (DCPD; CaHPO4·2H2O), dicalcium phosphate (DCP; CaHPO4), octocalcium phosphate (OCP; Ca8H2(PO4)6·5H2O). Compositionally, CaPs exhibit the greatest similarity to the minerals found in the natural bone tissue; therefore, they are extensively used for bone tissue engineering applications (e.g., spinal surgery) [30]. The bioresorption process of these materials is determined by two main factors, including solubility kinetics and in vivo conversion [31]; hence, their degradation can be regulated by two main mechanisms of physico-chemical- and cell-mediated dissolution [32]. Many experimental studies have confirmed that by-products of bioresorbable ceramics are not toxic to human cells and tissues [32]. The possibility of generating nano-scaled bioresorbable ceramics has revolutionized their applications in orthopedic surgery. For tissue engineering and regenerative medicine, bioresorbable ceramics-based products in different forms and formulations (fine powders/particles, paste, etc.) have been successfully commercialized and utilized for clinical applications of hard tissue lesions [33]. These substances were proven to induce the osteogenic differentiation of bone-related cells (i.e., osteogenesis) and stimulate neovessel formation, either in dopant-free or doped forms [34, 35]. The fabrication of 3D-printed scaffolds from CaPs has opened up new horizons in the field regarding the next generation of patient-specified constructs [36]. Still, the low mechanical properties of CaPs have limited their use in load-bearing applications; they are commonly mixed into polymeric materials for generating composite constructs in different shapes (e.g., 3D scaffolds, hydrogels, etc.) [37, 38]. It should be stated that CaPs can be used as coatings on metal alloys as well as bone cement [39]. Moreover, they are currently employed for drug delivery applications thanks to their suitable structure that enables loading and delivering various therapeutical drugs [40]. It is of interest that recent studies have elucidated some types of CaPs (e.g., HAp) that can be used for managing soft tissue healing, like skin tissue repair and regeneration [41, 42].
CONCLUDING REMARKS
Bioceramics are routinely used for healthcare applications and the relevant market for these products is significant. The introduction of novel cost-effective therapeutics has been always welcome in the biomedical industry; thus, advancements in the field of biomaterials are progressing faster than just a few years ago due to the continuous introduction of new, smart materials options. In this context, bioceramics indeed play a pivotal role. Bioceramics make bonds to the human body and can provide great support for damaged and diseased tissues and organs. Regarding aging populations and the need for more sophisticated tissue replacements, a bright future with great opportunities can be forecast for ceramic-based technologies. In this regard, implantable biomaterials were previously estimated to have a global market of around $110 billion in 2019 [43].
In terms of the future of healthcare, regenerative medicine is a big business. Tissue engineering and regeneration-based technologies were previously estimated to have a global market of around $25 billion in 2018 and are predicted to reach $109.9 billion by 2023, representing an impressive growth rate [43]. While bone is a significant focus of this market, the attention is moving to soft tissues as well. On this matter, cardiovascular and gastrointestinal systems, muscle, neural, and skin tissues have been treated with some types of bioceramics with promising results in vitro and in vivo [29]. Also, there is potential for many different types of materials in this broad field. In the field of regenerative medicine and tissue engineering, no one material is going to tackle all the challenges. Many of the ceramic- and glass-based strategies to heal tissues often combine these bioactive materials with non-bioactive/resorbable organic phases, for example in polymer-matrix composites or hydrogels [44, 45]. For more progress in the field, it seems necessary to make more collaboration between different areas of science including materials science and engineering, biology, pharmacology, and medicine. In this regard, understanding genetic upregulation and activation by ionic stimuli released from bioactive ceramics and glasses offers the possibility of developing patient-specific therapies, which is a huge challenge for the aging population.
The next generation of biomaterials and scaffolds with the capability of simultaneous treatment of different tissues can meet the future of tissue engineering and regenerative medicine. In this regard, multifunctional stimuli-responsive biomaterials can be effective in facing coordinated and complex responses of the human body to any implanted substances. In this regard, additive manufacturing technologies [46] combined with biofabrication principles [47], involving the manipulation and printing of biomaterials (e.g. bioactive ceramics/glasses), biomolecules, and living cells, will be an exceptional resource.
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Amirhossein Moghanian1,*,Zahra Miri2,Danna Valentina Sánchez3,Amir K. Miri3Abstract
Glass ceramics and ceramics have a vast range of applications in tissue engineering and regenerative medicine. Biocompatible glasses and ceramics, including bioinert ceramics, bioactive glasses (BGs), and calcium phosphate have been reviewed in this chapter detailing the history, properties, structure, and application. Ceramics and glasses with bioactivity and biocompatibility properties are pioneer solutions for a variety of clinical needs. The capacity of ceramics in hydroxyapatite formation (HA) has also been explained in this section. This chapter includes the invention of the first generation of ceramics and an explanation of how significant are their clinical applications.
INTRODUCTION
Biomaterials appeared 2000 years ago when applied for prosthetics and similar cases [1]. Biomaterials are selected to mimic both the physical and chemical properties of human organs and tissues [2]. Forming a bond with the host tissue, and defining the fidelity of an appropriate environment for cell and bone growth
[1, 3]. Among current biomaterials, ceramics such as cement, porcelain, and glass are used in energy, environment, health, and transportation sectors because of their corrosion resistance, osteoconductivity, brittleness, and stiffness [5]. In clinics, ceramics have been used for bone reconstruction and implantations (known as bioceramics) [4].
Dental regeneration is a recent application because of its 3D scaffold structure [6-8]. To illustrate, teeth composition contains dentine and enamel, and teeth cannot self-repair like bones when injured. Bioceramics have been recognized as materials that meet the significant demands for different dental repairs and treatments. Bioceramics are categorized based on their composition, solid structure, non-metallic or inorganic substrate content, and response to the host tissue [4]. Bioinert ceramics are known for corrosion resistance without inflicting on the tissue. Bioactive ceramics, including glass and BGs, have excellent bioactivity properties and interact with the targeted tissue for other processes. Bioresorbable ceramics involve calcium carbonates, calcium phosphates, and calcium silicates. Several glass ceramics can have magnetic properties for different clinical applications. Glass ceramics have shown thermal, chemical, biological, and dielectric properties leading to significant recognition of glass ceramics for clinical treatments [9].
CERAMICS
Structure
Ceramic materials have different atoms arrangements, which depend on the size of atoms and the bonding in the structure [10]. The bonding between atoms in ceramics is covalent or ionic and can be a combination of both, affecting their chemical and physical system [11].
Classifications
Bioinert Ceramics
Bioinert ceramics are characterized by their hardness, excellent mechanical behavior, corrosion resistance, and durability. Zirconia (ZrO2) and alumina (Al2O3) are two famous bioinert ceramics in this field [12, 13] being promising materials for orthopedic applications because of their compressive strength [13, 14]. The first generation of Al2O3 was introduced in the 1970s, not only being applied in dentistry [15], but also used to replace corneal and bone, dental implants, and maxillofacial regeneration [16]. On the other hand, ZrO2 has a different crystalline structure depending on the temperature: below 1170 °C, it has a monoclinic system, at 1170 °C, it is tetragonal, and lastly, at 2370 °C, it is cubic. The structural transformation is visible on the ceramics’ surface when placed in body fluid, improving the implant's durability [19]. ZrO2 enhances differentiation and cell proliferation for osteogenic and osseointegration applications [20]. Alumina-toughened zirconia (ATZ) or zirconia-toughened alumina (ZTA) is a mixed composition of Al2O3 with ZrO2 to increase the toughness degree and versatility [17, 18]. Bioactive materials differ from inactive materials because of the chemical reaction when placed in the biological fluid [21]. Both Al2O3 and ZrO2 are biocompatible while they are passive without a direct bond with the bone and tissue.
Glass-Ceramics and Bioactive Glasses (BGs)
Glass-ceramics and BGs are superior materials in tissue engineering. When glass is heated, it crystallizes and improves its toughness and strength. Glasses contain main ions, including silica (Si), sodium (Na), calcium (Ca), and phosphate (P), which are released when BGs dissolve. By releasing ions, BGs can promote various biological events such as angiogenesis and vascularization [22-24]. The first generation of biomaterials, invented by Larry Hench, was called 45S5 bioactive glass. It contained 45%SiO2, 24.5%Na2O, 24.5%CaO and 6%P2O5 (mol.%). Studies showed that 45S5 has good osteoconduction and biocompatibility, playing an important role in bone regeneration [25]. The in vivo and in vitro evaluations on 45S5 highlight properties such as bioactivity and its capacity to interact with the host tissue by forming hydroxyapatite (HA) particles. 45S5 is a silica-based BG, with Si particles playing an important role in bone regeneration by improving osteogenesis [26]. Phosphates (PO4) are found in a tetrahedral shape and are asymmetric in nature; consequently, it has a high level of solubility when placed in biological fluid [29]. Similar BGs involve a network containing SiO4 tetrahedrons and oxygen surrounded by two numbers of silicon; this open structure breaks into a solution [27]. The first applicable glass based on borosilicate was discovered by Brink in 1997. This glass had reactive properties with a lower level of chemical durability.
In 1987, BGs were first defined as materials with specific biological responses [30]. BGs became essential for bone applications because of their ability to form an HA layer on a bone surface and provide a substrate for the generation of injured tissue [31-33]. It is also recognized because of their high bioactivity property by placing these materials in simulated body fluid (SBF) solutions with a similar composition to the human body plasma. The formation of HA on the surface is essential and determining in some processes such as regeneration, treatment of injured tissue, and osteoblast stimulation [33].
BGs have applications in dentistry, implantation, and drug delivery [28, 29]. For instance, the first BG 45S5 was mainly used as an implant for hearing loss patients [34, 35]. Other glass ceramics have also been applied to treat dental roots if inert [36]. The ion-releasing property of BGs opened a new understanding of its applications. Ionic dissolution helps the stimulation of angiogenesis critical for healing in the body [37]. BGs that contain magnetic properties cause cytocompatibility during the HA formation between the bioactive material and mineralization of cells and can be used for cancer therapy by the induction of magnetic hyperemia. These BGs can influence the death of tumor cells because of heat generation. During this process, tumor cells go under apoptosis while the other cells remain viable [38]. Biological improvements of BGs have been recently suggested by adding fluoride (F), P, and borate (B) [39]. The process of bioactivity happens through the corrosion of glass and different mechanisms and chemical operations [40], shown schematically in Fig. (1).
Fig. (1)) The bioactivity process of BGs; 1 to 5 steps is a chemical process and from 6 to 12 is a biochemical process.The Formation of HA Layer on BGs’ Surface
The formation of HA is caused by the exchange of Na+ and Ca2+ ions, which increases the pH’s solution. Na+ ions exchange with the H3O+ and H+ from the fluid. Si-O-Si bonds break, and Si-O bonds form between the tissue and glass. The silica-gel is formed by the silanols’ condensation and ions such as PO43- and Ca+ migrate from the fluid to the glass surface. A layer containing phosphorous and calcium oxides overlaps with the silica gel. Calcium phosphate then converts to the crystallized structure called hydroxyapatite (HA). This formation happens by the CO32- and OH- incorporation from the fluid. These five steps can occur in the in vitro environment with SBF solution, whereas an in vivo environment is needed to continue the process. When the HA layer forms, it is not recognized as a foreign or harmful material since its composition is similar to bone tissue minerals. The HA layer stimulates stem cells to attach while cell differentiation can create diverse cells. This process helps the bone to generate a matrix and crystallize so that bone can be generated [41, 42].
Factors on the Formation of Apatite
Many ions can inhibit or promote the formation of HA on the BGs’ surface. It has been reported that P ions have a leading role in HA formation [43]. Different ions such as strontium (Sr) can be substituted instead of Ca for a greater impact on HA formation [44]. By contrast, HA formation can be inhibited by magnesium (Mg) ions [45]. Moreover, for some applications, faster HA formation is required, while for others slower; therefore, the composition should be designed accordingly [44].
Different BGs with Diverse Compositions
Many ranges of glasses have been introduced so far. Each of them has a specific composition and unique properties. Some different BGs are displayed in Table 1 [39].
Synthesis of BGs
Two different methods have been recognized for synthesizing BGs: melt quench and sol-gel. The melt quench method consists of high temperature; however, for sol-gel, the room temperature is enough. Additionally, the structure of sol-gels obtained is purer than the melt quench [46].
Melt-Quench Method
The first generation of 45S5 was produced by the melt quench method [47]. The targeted glass is produced by the melt and fusion process of different components. The raw materials and precursors are mixed to a prominent point to the highest pure degree to prevent contamination. The final powder should be dried in the air and then the melting process can start. The melting process is done in crucibles and at a varied temperature between 1200°C and 1500°C. The temperature depends on the kind of BGs. The mentioned temperature can be chosen for BGs based on borate and silicate. Lower temperatures between 1000°C and 1200°C can be designed for phosphorous-based BGs [48].
Sol-Gel Method
Graham proposed the sol-gel method approximately 150 years ago [49]. He reported that it is possible to form a glass based on SiO2 if the tetraethyl orthosilicate (TEOS) is hydrolyzed. The name sol-gel is based on the colloidal suspension. When sol has been produced, a rigid network of gel is produced. The gel has a porous structure and contains chains of silicate. The TEOS is the primary material and precursor for the sol-gel process for silica [50-51]. The sol-gel method has two important processes: poly-condensation and hydrolysis [38]. The sol-gel method has been recognized as a more effective process for producing BGs with better properties in tissue engineering than the melt-quench method [52]. The highlighted advantage of sol-gel is its lower temperature capacity [53].
Calcium Phosphates
There is a similarity between calcium phosphate and the mineral part of the tissue. Therefore, it can be used in various dental and orthopedic applications [54-56]. Calcium phosphate has been recognized as a biocompatible, bioresorbable, and osteoconductive material. After an ionic release, there is an absorption of protein and the formation of a physical layer [57]. Calcium phosphates have different dissolution rates due to diverse chemical compositions, pore sizes, and porosity [58]. Furthermore, calcium phosphates have poor strength being applied as filler or coating [52, 59]. The common calcium phosphates are CDHA, biphasic calcium phosphates (combination of TCP and HAp), β-TCP, HAp, and α-TCP [41, 46]. HAp is stable and has a crystalline structure. It can be produced by different processes such as hydrothermal, precipitation, and solid-state reactions with temperatures above 1200 °C [60, 61]. β-TCP can be obtained at a lower temperature than HAp above 800°C. Three materials can introduce TCP: β-TCP can stay stable at a temperature under 1120 °C, α-TCP stays from 1120 °C to 1470 °C, and finally, α’-TCP at a temperature more than 1470°C. β-TCP is considered a biodegradable material that can extensively be used as a substitute for bone [55]. α-TCP can be produced by β-TCP. α-TCP also is a biodegradable and biocompatible material [62]. Although HAp and β-TCP have a similar chemical composition, HAp has a slower resorption rate than β-TCP [63, 64]. CDHA can be gained by precipitation in a solution that has a pH higher than 7 [54]. It has poor crystallinity, and its solubility can increase by decreasing the molar ratio of Ca-P, size, and crystallinity and can be decomposed if heated to more than 700 °C [65]. Calcium phosphates have properties such as bioactivity, biocompatibility, resorbability, and enough compressive strength for different applications [41, 57, 63, 66].
Fig. (2)) Different bioactive glasses’ applications.Bioceramics Applications
Bioceramics have been recognized as materials applicable in numerous fields such as dental [67], treatment and replacement of the knee, ligaments, hips [68], implantation [69], reconstruction of maxillofacial [70], and so on. The use of ceramics in bone tissue engineering has been widely suggested recently [71], shown schematically in Fig. (2).
Arthrodesis Application
Ceramics based on silicon nitride are recognized as ceramics with high mechanical properties and are very influential as an implant. Many clinical experiments were conducted on this ceramic to prove its effectiveness spine of the lumbar as an arthrodesis piece [72]. Ceramics were successfully used as an implant in the improvement of the backbone of the thoracolumbar and cervical. Silicon-nitride ceramic can be more applicable in the articulation fields [72]. Bioceramics can be applied as a bone graft for the fusion of the lumbar spine because of its advantages compared to other bone graft materials, including flexibility, safe profile, inertness, and easier sterilization. By contrast, the lower tensile strength and sensitivity to fracture of bioceramics can limit their usage [73].
Bioceramics Coating
The materials used as a coat for different implants are osteoconductive, biocompatible, and have appropriate mechanical properties based on the targeted application. The used skin has antibacterial activity, avoiding infections [74, 75]. Bioceramics are more applicable and practical for articulating prostheses because of their high resistance against wear, therefore, the wear rate can be minimized. This coat can be a barrier between the bones or tissue and implants, minimizing the allergy in the human body [75]. Also, when bioceramics involve an electrospray for the surface coating, it can be influential for drug delivery applications and cell behavior control affecting the interaction of protein [76-78].
Hydroxyapatite (HA) Coating
In orthopedic implants, the use of HA as a coat is essential. HA contains calcium phosphate, which can potentially improve osteoconductivity, adhesion, and osteoblast differentiation through the exchange of ions between biological fluid and HA coating in clinical experiments and in vitro evaluations [38]. Adding different ions to the HA enhances and promotes its ability. For instance, fluoride (F) substitution in the HA layer stimulates cell proliferation and differentiation. Recently, a new process of HA coating has been reported for obtaining better results, such as plasma-spraying, thermal spraying, pulsed-laser deposition, sputter coating, dip coating, hot isotactic pressing, and electrophoretic deposition, among others [79-81].
Calcium Phosphate Coating
TCP and HA are two famous members of the calcium phosphate group for orthopedic implantation applications. For coating on femoral prostheses, HA has been suggested to prevent the complications of using PMMA. Some properties of HA, such as low tensile strength, caused fewer compositions for bone grafts [82]. In another study, however, it has been reported that there is no specific evidence about the effect of HA on the improvement of prostheses [82]. It has been illustrated that many factors are involved in the fixation process, such as the thickness of the coat, the composition of HA, the roughness of the surface, and the kind of substrate.
BG Coating
All BGs are biocompatible, osteoconductive, and antimicrobial, therefore applied for different clinical applications. One of the recent applications of BGs is a coating for other implants. The majority of implants do not have bioactivity properties for the formation of HA, so they lack the shape of a silica-layer rich pivotal in connection with tissue. BGs provide a solution for diverse implants, using them as a coat for metal implants to protect them from corrosion and avoid toxic in vivo environments by releasing cations [83]. BGs application for coating is still limited as these glasses are highly bioactive, dissolve quickly, and can put implants in direct contact with the tissue [38]. Different methods have been suggested for applying the BGs for coating implants, including dipping or deposition by sintering the particles of glasses or thermal spraying [38].
Nitride Coating
Since 1980, titanium-based implants have been coated with titanium nitride. The coating is applied from 1 to 1.5 (µm) thickness and used for resurfacing hip implants for arthroplasty of the whole hip or as a component of the femoral knee [72, 84].
Bone Tissue Engineering (BTE)
Treating injured and damaged bone has been the main concern for surgeries. For bone-tumor surgeries or spinal fixation, BTE has been investigated for the use of stem cell mesenchymal instead of autografts [85
