Bioceramics: Status in Tissue Engineering and Regenerative Medicine (Part 1)

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.

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.

Bone is a self-healing part of the body, which if damaged, repairs itself in the natural course of events. However, this healing process is deficient if the defect is too large or malignant to mend naturally. Bone regeneration is an age-dependent phenomenon where the older generation is at a disadvantage as compared to the younger generation due to the compromised biological performance as a result of aging. Therefore, it is crucial to create novel and effective ways to treat bone-related troubles. Bioactive glasses (BGs) and glass ceramics (GCs) belong to the thirdgeneration bioactive materials. They not only have the potential to survive in the harsh physiological environment but can also renovate the defects present around them. They also come with the advantage of tunable chemical, physical, and biological properties. Designing an implant or scaffold while playing with distinct characteristics of metals, polymers, and ceramics, bestows a large selection pane in front of humankind for customized and patient-specific products. In this chapter, an overview of the recent advances in the BGs and GCs application in coatings and hydrogels for bone tissue engineering (BTE) is presented. BGs and GCs incorporated coatings and hydrogels loaded with metallic ions, growth factors, and biomolecules provide a complete bundle of features essential for bone repair and growth. Although many BGs and CGs-based products have made it into the market, some inherent challenges like high brittleness and low fracture toughness persist to overcome to date.

Bioactive glasses, as pioneering artificial biomaterials, uniquely establish strong bonds with hard and soft native tissues by forming a bone-like hydroxyapatite layer in contact with physiological body fluid. This hydroxyapatite layer, mimicking the inorganic phase of natural bone, adds a fascinating dimension to their biomedical significance. Comprising three primary components; network formers, network modifiers, and intermediate oxide components; bioactive glasses allow tailored properties through component variation. While extensively explored for broadening biomedical applications, especially in regenerative medicine, their use is constrained by inherent mechanical shortcomings such as brittleness, fragility, and poor elasticity. Ongoing studies focus on incorporating bioactive glasses into composite/hybrid biomaterials with biopolymers, aiming to optimize mechanical properties for diverse biomedical applications, especially in load-bearing sites of hard tissues. Despite successful applications, the mechanical limitations persist, prompting investigations into the influence of composition and processing methods on bioactive glass properties. Notably, doping bioactive glasses with metallic ions at lower concentrations emerges as a promising avenue, enhancing mechanical and biological attributes, including bioactivity, osteogenicity, osteoinductivity, and antibacterial effects. This chapter provides a comprehensive examination of three bioactive glass types, accentuating their structures, properties, and processing methods. Additionally, it delves into property modifications facilitated by metallic ion dopants, contributing valuable insights to the evolving landscape of biomaterials.

Bioactive glasses (BGs) form a versatile class of biocompatible materials that can be utilized for various therapeutic strategies, including bone tissue engineering, soft tissue healing, and cancer therapy. Commonly, BGs are classified into three distinct categories, namely silicate, phosphate, and borate glasses. Several commercial BG-based products are now available on the market, and new generations with unique therapeutic features are also expected to introduce them in the near future. Due to their clinical significance, the biological behaviors of BGs have been one of the most interesting topics in tissue engineering and regenerative medicine. Although BGs are generally recognized as biocompatible materials in medicine, any new composition and formulation should be carefully tested through a series of standard in vitro and in vivo tests provided by international agencies (e.g., Food and Drug Administration (FDA)) and regulatory bodies (e.g., the International Organization for Standardization (ISO)). As a rule of thumb, the release of ionic dissolution products from BGs into the surrounding biological environment is regarded as the main parameter that modulates cellular and molecular phenomena. This process is even more crucial when specific elements (strontium, copper, etc.) are added to the basic composition of BGs to improve their physico-chemical properties, mechanical strength, and biological performance. Moreover, it is now well-established that some physical (e.g., the topography) aspects of BGs can directly affect their compatibility with the living systems (cells and tissues). Therefore, a multifaceted design and testing approach should be applied while synthesizing BGs in the laboratory, and the collaboration of materials and chemical engineers with biologists and medical experts can be really helpful for producing optimized formulations.

Bioinert ceramics are a form of bioceramics that is characterized based on how they react biologically in the human body. Bioinert ceramics are often classified as biologically inert nature or bioinert ceramics that do not elicit a suitable reaction or interact with nearby living tissues when implanted into a biological system. In other words, exposing bioinert ceramics to the human environment will not cause any chemical interactions between the implant and the bone tissue. Bioinert ceramic materials have been used in the form of medical devices and implants to replace or reestablish the function of degenerated or traumatized organs or tissue of the human body due to their excellent chemical stability, biocompatibility, mechanical strength, corrosion restriction behavior, and wear resistance. Materials based on titanium, alumina, and zirconia are used in bioinert nanoceramics., In a biological environment, they are bioinert, fracture-tough, and have high mechanical strength. Because of their corrosion resistance, titanium and titanium-based alloys are widely used in bone tissue repair. 

In synthetic ceramic materials, the types of interactions that occur in the physiological environment during body implants and tissues are defined as bioinert, bioactive, and bioresorbable. Bioresorbable materials, whether polymers, ceramics, or composite-based systems, are widely used in a variety of biomedical applications. Designing a bioresorbable device requires careful consideration of an accurate way of forecasting the biosorption of this class of materials. Bioresorbable ceramics possess the ability to undergo in vivo absorption and consequent replacement by the newly formed bone. They have a bonding pattern that is similar to bioactive ceramics. However, the fact that bioresorbable ceramics frequently fail to make solid contact with bone limits their potential medical uses. Bioactive and bioresorbable ceramics have a narrower application range than bioinert ceramics.

 CaPO4 (calcium orthophosphate) is an ideal class of materials for bone tissue engineering applications due to the similarity of its set of chemical compositions and structures with mammalian bones and teeth. The use of CaPO4 -based biomaterials in dental and orthopedic applications has become widespread in recent years. The biocompatibility, biodegradability, and varying stoichiometry of CaPO4 scaffolds make them suitable candidates for drug loading and tissue engineering strategies. Therefore, calcium phosphate compounds, particularly hydroxyapatite (HA) and tricalcium phosphates (TCP) are highly attractive as bone grafts or drug delivery agents. Specifically, three-dimensional (3D) scaffolds and carriers made from calcium phosphate are created to promote osteogenesis and angiogenesis. These scaffolds are typically porous and can accommodate a range of drugs, bioactive molecules, and cells. In recent years, stem cells and calcium phosphate compounds have been used increasingly as bone grafts. This chapter explores the advantages, sources, and fabrication methods of CaPO4 scaffolds for possible usage in tissue engineering.

Carbon nanostructures have enticed significant attention in biomedical areas over the past few decades owing to their unique electrical, physical, and optical features, biocompatibility, and versatile functionalization chemistry. These nanostructures can be categorized into diverse groups based on their morphology, including fullerenes, nanotubes (e.g., single-walled carbon nanotube (SWCNT) and multi-walled carbon nanotube (MWCNT)), nanodiamonds, nanodots, graphite, and graphene derivatives. Emerging biomedical trends indicate the usefulness of carbon nanostructures in gene/drug delivery, cancer theranostics, and tissue engineering and regenerative medicine, either alone or in combination with other biocompatible materials. This chapter presents a comprehensive overview of various types of carbon family nanostructures and their characteristics. We further highlight how these properties are being utilized for various medical applications.

Tissue engineering and regenerative medicine have accomplished enormous progress in the last few years. The application of recently designed nano-textured surface characteristics has shown increased enhancement in bone tissue regeneration. The development of materials that fulfill the exact requirements of bone tissue is still under investigation. However, we are approaching this aim. Composite materials are some of those materials under consideration, and they have emerged as a consequence of the logical unraveling of bone composition. Principal components of bone tissue are inorganic and organic matrices and water, in other words, ceramics and polymers. Accordingly, the design of these materials by combining different types of ceramics and polymers has opened a wide range of possibilities for bone regeneration treatments. Not all polymers nor all ceramics can be used for this purpose. Materials must gather particular properties to be applied in bone tissue engineering. Both types have to be safe, which means biocompatible and non-toxic. They, additionally, should have efficient surface behavior, bioactivity, and suitable mechanical properties. Sometimes, composites could behave as in situ drug delivery systems. Composites are engineering materials formed by two or more components, each bringing a unique physical property, and generating synergism. For these reasons, in this work, we will discuss features of host tissue, concepts such as bioactivity, osteoconductivity, and osteoinductivity, and the most significant polymers and ceramics used for developing composed materials. Finally, we focus on examples of composite materials based on these components applied for bone tissue regeneration.