Bioceramics: Status in Tissue Engineering and Regenerative Medicine (Part 2)

Hydroxyapatite (HAp), one of the calcium phosphate minerals, has been widely used for biomedical applications because of its similarity to bone mineral content. Synthetic nano HAp, despite being made from chemical precursors, differs in composition from that of natural hard tissues such as bone and teeth. The properties of synthetic HAp solely depend on the precursors and production processes employed. Biogenic calcium resources such as fish scales, bones of animals and fish, and shells from land, freshwater, and marine origin can be used to synthesise HAp, which has trace elements that mimic the constituents of bone. Also, we have emphasised that HAp can be synthesised economically from one of the abundantly available low-cost biowastes, namely eggshells. There are numerous biomedical uses like bone substitute material, scaffold for bone tissue engineering, drug delivery agent, etc., and environmental uses, notably as an adsorbent for heavy metal removal, dye degradation, etc. This chapter will help readers understand the significance of natural resources and methods for producing HAp from biogenic sources.

3D printing technologies have changed the manufacturing of tissue engineering scaffolds upside down, giving new possibilities to obtain complex shapes that perfectly resemble patient defects using old bioceramics or new materials especially developed as inks for 3D printing.

Bioceramics have been commonly used in tissue regeneration, mainly bone, due to their high biocompatibility and in some cases, bioactivity. Moreover, they can have different compositions and proportions, which give rise to a wide variety of properties. The main types of bioceramics are calcium phosphates and bioactive glasses, but there are other ceramics such as zirconia and alumina.

The 3D printing of bioceramics is usually performed by mixing particles or powders of ceramics with a polymer to obtain proper viscosity, and they can be printed through DIW, SLA or SLS. After printing, they can be sintered to obtain a pure ceramic body, or left as a composite. Additionally, there is a direct ceramic printing method based on SLS that does not need a polymer for printing.

These results indicated that 3D printing of bioceramics has the potential to produce large-scale tissue engineering scaffolds with accurate structure and functionality; however, further studies are needed to improve the biological response to the 3D printed scaffolds

In tissue engineering and regenerative medicine, bioactive glasses (BGs) offer many potential advantages. These inorganic substances belong to the bioceramics family and are traditionally produced in powder and granular formats via the sol-gel and melt-quenching synthesis routes. In order to mimic the native structure of human tissues, BGs should be fabricated into three-dimensional (3D) constructs (i.e., scaffolds). There are specific conventional fabrication methods for producing BGbased scaffolds (e.g., foam replication); however, they suffer from some critical limitations such as the lack of exact control on the pore dimension and distribution. In this regard, additive manufacturing (AM), also known as 3D printing, has emerged for the generation of precise and high-resolution BG-based scaffolds. Currently, 3D printing of BG-based scaffolds is performed by using a series of well-developed AM techniques, including direct 3D printing, selective laser sintering (SLS), robocasting, and stereolithography (SLA). In some methods, BGs are added to polymeric matrices and then introduced into the 3D printing machine as a raw material. In general, 3Dprinted constructs exhibit important advantages over conventionally-fabricated tissueengineering scaffolds in terms of reproducibility, scalability, architecture (e.g., controllable strut thickness, pore shape and size), and biomechanical properties. It is of significance that BGs can be simultaneously printed with mammalian cells (e.g., stem cells), known as 3D bioprinting. Still, some challenges (e.g., decreased cell viability) remain that should be addressed by conducting further research and proposing innovative solutions.

Mesoporous bioactive glasses (MBGs) are a special subclass of bioactive glasses (BGs), which have held great promise in biomedicine. Compared to meltderived BGs, MBGs exhibit higher bioactivity (apatite-forming capability) due to highly ordered nanoscale pores (2 to 50 nm) in their structure. The size and shape of well-ordered pores of MBGs depend on structure-directing agents (e.g., CTAB, Pluronic F-123, and Pluronic F-127) used during their sol-gel synthesis process. Having a mesoporous structure, MBGs provide great opportunities in tissue engineering and drug delivery applications. Although MBGs have been mainly explored for managing hard tissue injuries (e.g., bone defects), recent studies indicate their usefulness in soft tissue healing as well. In this regard, MBGs can be utilized for tissue reconstruction in different forms, including fine powders, granules, and scaffolds. In addition, MBGs have been found suitable vehicles for the delivery of a wide range of chemicals, bioactive molecules, and pharmaceutical drugs. Loading and delivery of antibacterial (e.g., antibiotics), pro-angiogenic, and anti-inflammatory substances are commonly being performed using MBGs for improved and accelerated tissue repair and regeneration. Furthermore, MBGs are regarded as promising DDSs for localized delivery of anticancer drugs. Currently, it is feasible to make MBGs as smart drug delivery systems (DDSs) with the help of chemical engineering approaches; for example, opening and closing MBGs’ pores are achievable by stimuli-responsive molecular gates. With the invention of three-dimensional (3D) printing technology, MBGs were successfully incorporated into polymeric inks to generate potent tissue substitutes capable of simultaneous tissue engineering and drug delivery.

Bioactive glasses and glass-ceramics are promising materials for both hard and soft tissue regeneration through gene activation mechanisms triggered by their dissolution products. This chapter presents a key property of bioactive glasses and glass-ceramics of growing interest in materials science i.e their antibacterial activity. The main compositions, including composites, with proven bactericidal action, were gathered. The current understanding of compositional effects on the bacteria-killing mechanisms is summarized as well as the main dopants used to enhance the antibacterial activity. Finally, examples of bioactive glass-based products that have being developed for many important applications in orthopedics are presented, such as the treatment of osteomyelitis, coating in metallic implants, the treatment of infected skin wounds, and also in dentistry, in the treatment of oral ailments.

Bioceramics form a versatile large family of biocompatible materials with diverse applications in the medical setting. These substances can be classified into distinct groups, including almost bio-inert ceramics (e.g., alumina), bioactive glasses and glass-ceramics, and moderately to quickly bioresorbable ceramics (e.g., hydroxyapatite and tricalcium phosphates, respectively). Bioceramics are conventionally used for healing hard tissue injuries due to their excellent properties, including mechanical performance. From a biological perspective, bioceramics exhibit outstanding features (e.g., inducing osteogenesis) in favor of bone reconstruction. Considering the central role of angiogenesis in tissue healing, different formulations of bioceramics have been demonstrated to have stimulatory effects on neovessel formation. Apart from physical properties (e.g., surface micron and nano topography), the chemical composition of bioceramics greatly affects their angiogenic capacity in vitro and in vivo. Several additional approaches are now well-established in order to increase the angiogenic activity of bioceramics, including adding pro-angiogenic dopants (e.g., copper and silicon) and loading pro-angiogenic bioactive molecules (e.g., vascular endothelial growth factor (VEGF)). In this sense, the degradation rate of bioceramics is a key property commonly mentioned to effectively promote angiogenesis. Cellular and molecular experiments have revealed the signaling pathways involved in angiogenesis which are activated by ionic dissolution products released from bioceramics. In this manner, this review highlights the new positive role that bioceramics can play in angiogenesis.

One of the key reasons for death is blood loss or hemorrhage from trauma or surgeries. Management of bleeding by utilizing suitable hemostatic agents is therefore important to diminish related complications and mortality. In recent years, the application of bioactive glasses for hemostasis has shown promising results in both in vitro and in vivo. In this chapter, we will highlight the mechanism of action of bioactive glasses in accelerating hemostasis, review various forms of bioactive glasses and their composites that have been assessed for potential application in promoting hemostasis and stopping bleeding, and briefly include future perspectives.

Bioactive glass nanoparticles (BGNs) are multifunctional building blocks of tissue engineering scaffolds or drug delivery platforms for bone tissue regeneration owing to their favorable osteogenic, angiogenic, immunomodulatory, and antibacterial activities. Natural polymer-based hydrogels are one of the most promising biomaterials for numerous biomedical applications, considering their extracellular matrix (ECM)- mimic structure, outstanding biocompatibility, and biodegradability. However, these hydrogels are intrinsically mechanically weak and lack biological functionalities, which impede their performance in bone tissue regeneration. Incorporating BGNs as rigid fillers in natural polymer-based hydrogels has been proposed as a feasible strategy to combine the advantages of both components leading to advanced nanocomposite hydrogels. Here the synthesis approaches of BGNs that determine the nanoparticles’ morphology and properties are first summarized. The interactions between BGNs and natural polymer-based hydrogels are also emphasized. The key physiochemical and biological properties of BGNs that are related to bone tissue formation are highlighted. Published results are evidence of the fact that the combination of BGNs and natural polymers toward nanocomposite hydrogels is a feasible strategy for successful bone regeneration.

Bioceramics applications in dental materials date back to 1892, and since then, many advances have allowed the development of bioceramics for applications in three main areas of dentistry: restorative, rehabilitative, and regenerative dentistry. This chapter will cover clinical situations in which dental tissues need clinical interventions using bioceramics. The main properties of these ceramics and their main advances and applications in restorative, rehabilitative, and regenerative dentistry will also be addressed. In summary, innovation in bioceramics has allowed the development of implants and restorative materials able to bind to the dentin and enamel, besides showing suitable aesthetics and mechanical properties for applications in load-bearing regions. These bioceramics have also been used as scaffolds in alveolar, mandibular, and maxillary bone regeneration, and recently computer-based technologies like CADCAM and 3D-printing have guided their advances. Finally, future perspectives and open questions are discussed at the end of the chapter.

This chapter provides an overview of wounds, distinguishing between acute and chronic types. It describes the dynamic process of wound healing, involving hemostasis, inflammation, proliferation, and maturation. The role of growth factors and cytokines in the healing process is highlighted, along with the importance of the extracellular matrix. The text emphasizes that chronic wounds, often associated with diseases like diabetes, tumors, or ischemia, have a higher likelihood of recurrence and a prolonged healing period. Additionally, factors such as infections, stress, age, hormonal issues, and medications can compromise the natural wound healing process. The current market offerings for wound dressings, such as gauze and films, often fall short in promoting effective wound healing due to various limitations. In contrast, specific types of bioceramics and bioactive glasses have shown potential for co-delivering therapeutic ions, presenting a smart approach to accelerate the wound healing process. The study emphasizes the need to explore and develop materials with therapeutic efficacy, moving beyond mere wound coverage to actively promoting healing and tissue regeneration.