Role of bioglass derivatives in tissue regeneration and repair: A review
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Yang Gao
Abstract
Bioceramics are significantly contributing in repairing and reconstructing the defective areas of the musculoskeletal system. Bioactive glass is a non-crystalline bioceramic that has been widely used in regeneration due to its extensive bone-forming ability and biocompatibility. The plethora of bioactive glass research has been buried over the years in the area of bone construction in various forms. The composition of the bioactive glass with its network formers and modifier plays a vital role in bone-forming ability and prevents crystallization. The hybrid polymer and metal ion-doped bioactive glass add advantages to bone tissue repair. The development and the challenge during the preparation of bioactive glasses have been discussed in this review. Based on the orthopedic defect, their porous size, volume, and even mechanical properties can be tailored to obtain the desired scaffold combined with the therapeutic delivery of bioactive compounds. Bone tissue engineering is inevitable without the process of osteoinduction, osteoconduction, and osteointegration, and their role in bioactive glass was reported. Bioactive glass is the key contributor to the glass age, and it has been subjected to medicinal applications for tissue repair, regeneration, and therapeutic agent delivery.
1 Introduction
Earlier research on implant materials was mainly focused on being inert and as first-generation materials. They were followed by calcium phosphate (CaP) implants like synthetic hydroxyapatite (HAP) and tricalcium phosphate (TCP), which are crystallographically and chemically similar to bone minerals. Since the researchers have widely utilized the materials in clinics, research on the epitome of the regeneration scaffold has flourished. Implant materials should be bioactive and tough so that they can mimic cancellous bone having open porous in it. They should also share the load with the bone and stimulate the inherent regenerative mechanism in humans as well as pave the way for the penetration of blood for the bone to survive and degrade over time [1]. The disadvantages of ceramics are their brittleness, excessive fragileness, and limited crack resistance [2]. Their non-bioactive nature limited their application and paved the way for the alternative. Prof. Larry’s development changed the trend from being inert to regenerative materials. Due to the bioactive nature of interacting with live tissues, glass can be called bioactive as it can bond with both hard and soft live tissues [3].
Bioactive glass is a non-crystalline ceramic, and different glass formulations have also been developed. The first one developed was silicate-based glass 45S5 by Larry Hench and co-workers, which is now called by its commercial name “bioglass” [1]. It is a quaternary inorganic oxide system of Na2O–CaO–SiO2–P2O5 and consists mainly of silicon dioxides. Bioactive glass is synthesized by a sequential five-step reaction mechanism of ion exchange, followed by polycondensation for the high surface area [4]. Bioglass is made of minerals that naturally exist in the human body, and its molar ratio of Ca and P is similar to bone [5,6]. When bioglasses are subjected to a biological fluid, the silica-CaO/P2O5 surface forms apatite crystals essential for forming new bone cells [6]. The nucleation of apatite crystal begins, followed by proliferation, differentiation, and generation of the new bone [4,7]. The detailed mechanism of the silicate glass reaction is discussed below.
Significantly, the chemical composition of apatite crystals formed in the biological fluid mirrors the mineral content of the bone; it adheres to the bone due to the dissolution of glass and the chemical reaction activates the immune system [7]. The composition of the bioactive glass is critical for developing a stable and bound interface with the living tissue, which renders their properties [4,8]. Even though a plethora of research on bioactive glasses has flourished, the introduction of bioactive glass to the market in late 1960 aroused researchers’ interest in bioactive glasses and their biological uses. Figure 1 shows the increasing number of relevant research reports each year from the discovery of bioactive glass to the present century. Earlier it was less, but as years went by, there has been a rapid and steady growth in the number of research reports but the real potential of bioactive glass is yet to be attained.
Number of research articles published per year from the late nineteenth century to the present in the field of bioactive glass (January 4, 2023) using the search query “Bioactive glass” from the Pubmed search engine.
The number of publications of the search query “Bioactive glass” and results were collected between 1975 and 2023 from the Pubmed search engine. A free search engine primarily accesses topics related to the biological sciences and medicine. The X-axis and Y-axis represent the year of publications and the number of publications, respectively, and it is presented on a logarithmic scale.
1.1 Composition of the bioactive glass material
Bioactive glass comprises three oxides: network formers, network modifiers, and intermediate oxides. As the name indicates, the network former is used to build the glass network and linked to each other, viz., bridging oxygen, e.g., SiO2, P2O5, and B2O3. The glass can be made either with one or more network forms, such as silicate glass, borate glass, borosilicate, phosphosilicate, or boron phosphate glasses. Network modifiers break the glass network by linking to the non-bridging oxygen at the end, e.g., Na2O, CaO, MgO, K2O, and intermediate oxide, which are either network former or modifiers [9,10]. Thus, by varying the composition of oxides, different glasses were obtained and entered the mainstream of medical applications. Figure 2 illustrates the bioactive glass with the network formers like silicon and boron; crystallization can be prevented by the tailored composition of network modifiers like calcium and sodium oxides.
A general illustration of the bioactive glass formation via its network former and network modifier.
1.1.1 Silicate glass and its composites
Silicate glass, borate glass, and phosphate glass are the three premier bioactive glasses; among them, silicate glass was the genesis of the bioactive glass evolution. Initially, Larry developed 45S5: 45 signifies the network’s former weight percentage, i.e., SiO2 and 5 specifies the Ca and P molar ratio. The glass composition includes 45% of SiO2, 24.5% of Na2O and CaO, and 6% of P2O5, a quaternary oxide system. The above-mentioned silicate glass composition was considered the first man-made inorganic material capable of forming a stable and firmly bonded contact with biological bone tissues. The first bioactive glass was prepared using the melt-quenching method and studied with the rat’s femoral implants both in vitro and in vivo, as each test provides interfacial bonding with the bone through apatite formation [11].
The University of Florida trademarked the original 45S5 composition as Bioglass® [1], as the bioactive glass emphasizes the regular paradigm response to the bioactive material and induces the controlled reaction in the biological environment. Larry Hench’s original concept was to mix a lot of components in the human body and obtain a proportion that encourages the fast alkali dissolution from the glass surface. So, they selected the Na2O–CaO–SiO2 system, where P2O5 was added in a small amount [1].
Due to the tetravalence of silicon (Si4+), silicon dioxide is the most prominent network former. The tetrahedron corners of SiO4 covalently bond to four other bridging oxygens. When network modifiers are added to the composition, they disconnect the glass network by connecting to the non-bridging oxygen [10]. Thus, the bioinert response is emphasized to the bioactive response [6]. The parent of all silicate glasses is 45S5, and different formulations of bioactive glass have been obtained by altering the ions [12]. Table 1 illustrates different compositions of bioactive glass, resulting in several types of bioactive glasses being designed to satisfy the defect’s specific needs for tissue regeneration.
Different compositions of silicate glass materials with the ratio of the constituents
| Grade | SiO2 (%) | CaO (%) | Na2O (%) | P2O5 (%) | K2O (%) | MgO (%) | Properties | Ref. |
|---|---|---|---|---|---|---|---|---|
| 45S5 | 45.0 | 24.5 | 24.5 | 6.0 | — | — | Binds with bone and soft tissues | [1] |
| S53P4 | 53.0 | 23.0 | 20.0 | 4.0 | — | — | Osteoconductive and osteostimulative bone substitute with antibacterial properties | [12] |
| 58S | 60.0 | 36.0 | — | 4.0 | — | — | Demonstrated cell viability without cytotoxicity | [23] |
| 60S | 59.9 | 38.4 | — | 1.7 | — | — | Able to bind with the bone | [26] |
| 13-93 | 53.0 | 20.0 | 6.0 | 4.0 | 12.0 | 5.0 | Glass transition temperature (T g) is lower than that of 45S5 | [12] |
S53P4 is a silicate bioactive glass, commercialized as BonAlive® [1]. Lindfors et al. performed a multinational study with 116 osteomyelitis patients as they were substituted with S53P4 as part of their treatment. While 84.5% of patients were treated only with S53P4, 15.5% were treated with both antibiotics and S53P4. After 1 year of follow-up, 90% of patients showed rapid recovery; hence, the researchers concluded that S53P4 could be used as a one-step treatment to treat osteomyelitis without the use of antibiotics. Because the pH and osmotic pressure increase due to the immediate dissolution of ions soon after implantation and its osteostimulative and osteoconductive nature is established, it is a clinically proven antibacterial substitute [13]. But the resorption of S53P4 is comparatively low compared to the original 45S5 bioglass due to its high silicon content [1].
A combination of an inorganic and organic matrix is essential for targeting bone tissue repair. With further development of the bioactive glass ceramic series, hybrid materials can be prepared using polymers for better therapeutic nature in medical applications. It can be tailored to meet specific properties for bone regeneration. The inorganic matrix promotes bioactivity and mechanical strength, while the organic matrix offers resilience and shape formability [14]. El-Fiqi et al. prepared the polycaprolactone (PCL)-gelatin-incorporated mesoporous silicate-based-bioactive glass nanoparticles with dexamethasone and reported that the prepared material showed promising osteogenic ability with better tensile and mechanical strength. The incorporation of an osteogenic drug showed sustainable releases [14]. Bioactive silicate glass in polymer nanocomposites reveals new potential and effective tactics in tissue regeneration and dentistry. Silicate glass combined with synthetic and natural polymers can be developed for mechanical usage [15]. Mansur and Costa constructed a composite employing silicate glass (58SiO2–33CaO–9P2O5) with two different hydrolyzed poly (vinyl alcohol) (PVA), one blended with chitosan and the other without the chitosan through a sol–gel process. Both hybrid scaffolds had a macropore 3D structure of 10–500 µm in size, which is suitable for the regeneration of the cancellous bone as they exhibit a hierarchical structure. A high-degree hydrolysis PVA has better mechanical properties, and thus, changes in the concentration and hydrolysis grade of PVA significantly impact the porosity, gelation, and interconnectivity [15]. Brink et al. prepared 26 types of a Na2O–K2O–MgO–CaO–B2O3–P2O5–SiO2 glass system using the melt-quenching method by varying their composition, and their in vivo bioactivity was investigated by implanting it in rabbit for 8 weeks. Glasses with 14–30% of alkali and alkaline earth metals and less than 59% of silicon are considered to be bioactive. Glasses containing K and Mg showed similar bone-bonding ability as the bioactive glass [16,17]. Similarly, Blaker et al. investigated bioactivity and viability in MG-63 cells by silicate glass with poly(dl-lactic acid) (PDLLA) composite, which is highly porous, using the melt method, as they exhibited apatite formation within the first 3 days with better proliferation ability. Its formation continued with the cells showing biocompatible nature, and the porous interior is an excellent composite for tissue engineering [18]. The addition of polymer to silica enabled us to fabricate a tough material for bone tissue regeneration formed through a strong chemical interaction [19]. With controlled interaction, such hybrid materials can be fabricated with tailorable abilities. Mahony et al. synthesized a silica-based scaffold using gelation, a toughening polymer using sol–gel and freeze-drying methods in which the porosity of the prepared scaffold had a prominent impact on dissolution and mechanical abilities. It is due to the coupling between the organic and inorganic matrixes with the formation of hybrid materials [19]. Meka et al. synthesized silicon-based nanofibers with a single-phase solution containing PCL and morpholine as a pH regulator. The significant release of ions increased the angiogenic activity of human umbilical vein endothelial cells (HUVECs) and the osteogenic differentiation of human mesenchymal stem cells (hMSCs) by in vitro analysis [20]. The authors also fabricated a similar silicate polymer nanofiber with PCL, using citric acid as the pH catalyst. Citric acid and silicon ions were eluted from fibers, effectively boosting angiogenic activity. Additionally, the silicate fibers promoted osteogenesis in hMSCs in the presence of minerals. In situ silicate fibers are interesting multi-biofunctional materials for orthopedic applications. These findings indicate that the polymer/ceramic nanofibrous scaffolds have several biofunctional properties, making them intriguing candidates for tissue regeneration [21]. A 58S bioactive glass was electrospun with polylactic acid and doped with two distinct strontium and cobalt ions by Souza et al. All three bioactive glasses generated demonstrated more than 70% cell viability without cytotoxicity [22]. Similarly, Sultan et al. used polylactic acid with the 45S5 bioglass by the thermally induced phase separation technique. The results demonstrated that the prepared scaffold was patient-specific with tunable pore structure and mechanical characteristics [23]. In order to create scaffolds with a pore size gradient, Daskalakis et al. synthesized PCL/bioglass pellets using an easy melt quenching method. The findings demonstrate that the inclusion of bioglass enhanced the scaffolds’ mechanical capabilities [24]. Kukulka and Souza developed the fiber with 58S bioactive glass and PCL through the electrospinning method by doping with Mg and Li ions. The fiber showed all of the glass component ions and the polymer exhibited cell viability with mineralization nodules. The excellent osteoinductive properties for the application of bone regeneration were attained by the fiber [25].
Silicate glass may cause separation and devitrification with thermal treatment [16]. It also turns crystalline during the sintering process. Yet, by amending the chemical composition of the glass, crystallization can be prevented [1]. The main reason for devitrification is the presence of an alkaline metal; therefore, the crystallization can be overcome by incorporating the alkaline earth material, such as MgO, rather than the alkaline material [27]. Bioactive glass loses its ability to bind with the bone if the silica’s chemical composition exceeds 58% [26]. Different compositions of silicate glass materials with the ratio of the constituents [2,5] are given in Table 1.
1.1.2 Borate glass and its composites
Boron is considered to enhance the effectiveness of several metabolic processes, and lack of it is implicated in underdeveloped or aberrant bone development as boron is a vital bioactive element for both humans and animals for promoting bone health defects [28]. The boron concentration differs between healthy and unhealthy bones. The healthy bone has 56 ppm of boron, whereas the arthritic bone has only 3 ppm, which indicates maintaining the optimal level of boron; thus, boron release enhances the osteogenic differentiation of mesenchymal stem cells (MSCs) [28]. Brink and Vitale-Brovarone first developed borate glass for biomedical applications having silicon as the network former and a varying amount of B2O3 to reach bioactivity [29]. Different forms of borate glass, such as borate glass, borosilicate glass, hybrid borate glass with polymer, and ion-doped borate glass, are being developed. The glass structure, bioactivity, biocompatibility, biodegradability, processing-characteristics, and cytotoxicity are all significantly impacted by the addition of boron percentage to the bioactive glasses [28]. Over the past decade, boron-containing bioactive glass, ranging from 0.2 wt% of boron in silicate bioactive glass to 53 wt% in borate bioactive glass for new bone formation with osteoinductivity [28] has been fabricated and studied. Due to its chemical durability, the borate bioactive glass forms an apatite layer faster than the original silicate bioactive glass [29]. The 19–93 is a silicate bioactive glass; by either partially or fully replacing silicon with boron, borosilicate glass and borate glass can be formed, respectively. Fu et al. compared the two glasses 19–93B1 and 19–93B3; in the first one, one-third of the silicon was replaced, and in the second, full silicon content was replaced with boron. As the concentration of the borate increased, the conversion of the apatite layer on the surface increased. The 19–93B3 borate bioactive glass has high field strength; thus, an interesting matrix can be made upon incorporating network modifiers. The fast dissolution of ions has shown more clinical results in soft tissue applications [30].
The thermal bonding of two different bioactive glass fibers was reported using MLO-A5 cells for osteogenic response by Gu et al. [31]; the 19–93 silicate glass showed good capability for proliferation compared to that of the 19–93B3 borate glass. The 13–93 glass is partly convertible to HAP, whereas 19–93B3 can be entirely converted to tubular morphology. The boron released from the 19–93B3 exhibited osteoinductive properties, such as stimulating the formation of the bone in 13–93 defect sites. The authors concluded that the scaffolds made of an optimal blend of both glasses, i.e., silicate and borate glass, could provide architectural support. Bioactive glasses are needed to assist the regeneration of the bone while allowing for controlled disintegration for better bone and tissue repair. Compared to silicate glass, borate glass (13–93B3) has a higher degradation rate [32].
Likewise, silicate and borate composites with the combination of poly-(ε)-caprolactone were compared by Mohammadkhah et al.; they found that the borate 19-93B3 composite degraded faster than the 45S5 glass. The polymer’s addition in neurite extension showed zero negative properties [14]. In parallel, the eight novel glasses with all three main network formers (silicate, phosphate, and borate glasses) were compared by Mancuso et al. They concluded that borate glass also showed biocompatibility and zero toxic effect with ion release, and they promote the proliferation and differentiation of osteoblast cells [33].
Li et al. developed bioactive bone cement and found it to be an excellent injectable composite. It was prepared using borosilicate, magnesium, and phosphate cement, and released Mg2+, B3+, and Si4+ ions for cell proliferation, faster degradation rate, and stimulated bone formation. For bone regeneration, incorporating B2O3 is critical as it can enhance the proliferation of osteogenic cells [34]. Borosilicate with a poly-l-lactic acid (PLLA) scaffold was prepared using the wet spinning method. The structure shows high porous nature with the interconnected network. It promoted degradability and bioactivity on immersion in ultrapure water and stimulated body fluid (SBF). It shows good adhesion and proliferation through the inner surface and does not show a toxic effect on treating osteosarcoma cells (Saos-2). Overall, the borosilicate with polymer could replicate the bone’s physiological environment, and scaffolds exhibited tuned kinetics on releasing inorganic species and controlled biological response [35].
By using boron-based bioactive glass systems, we could understand how boron affects the character of the glass by regulating interactions with cells in vitro and in vivo can be explained. The ions, such as Cu+, Zn+, Sr2+, Mg2+, and Al3+, doped with the glass to increase angiogenesis and osteogenesis are currently being explored using boron-doped borosilicate and borate bioactive glass in diverse morphologies [28]. Thus, even by altering the trivial part of the composition, fresh glass can be developed as it influences the structural, thermal, and mechanical ability of the glass and hence the borate glass performance and the controlled interaction both in in vitro and in vivo performance.
1.1.3 Phosphate glass and its composites
Phosphate glass, like silicate glass, can be obtained using traditional melt and sol–gel methods. It can be employed in tissue applications, such as dental and orthopedic defects. Challenges of the earlier evolved glass paved the new door for the new formulation of glass [36]. Like silicon dioxide, phosphorous has a tetrahedron basic unit and oxygen affinity; one main difference is that the interatomic force is comparatively less than that of silicate glass due to the sharing of the oxygen atoms [36]. Phosphate glass has gained attention because of its similar ionic composition to hard tissue and its drug delivery, degradation, and antibacterial effects [37,38]. Lee et al. reported a composite of orthophosphosilicate glass with PLA; such an anisotropic scaffold has been used to improve bone density and bone quality by releasing the therapeutic ions, thereby enhancing bone formation and cell alignment [39]. The results show that the constructed scaffolds can control osteoblast and calcification direction as per the morphology of the bone. The discharged ions increase bone stimulation quality. The phosphate glass with PCL at different concentrations of the composite was obtained by thermal and solvent extraction methods [40]. The vancomycin loaded in the phosphate glass/PCL composite and the inclusion of glass accelerated the degradation by the PCL. The drug release of the composite was faster with time when compared to pure PCL. The improved drug degradation and regulated drug release of P-glass/PCL composites were attributed to the differing water absorption and dissolution rates [40]. CaP glass doped with Cu2+ exhibits an antibacterial activity as in the bone composite [41]. The composite can be a bioresorbable antibacterial material for hard tissue regeneration. The bioactive glasses discussed above overcame all the limitations produced by commercially available CaP implants like synthetic HAP and TCP.
2 Preparation methods of bioactive glass
The bioactive glass was generally prepared either by the melt-quenching method or the sol–gel method [29]. In the melt quenching method, the mixed composition of the bioactive glass is heated at a higher temperature; then, the melt is poured into the mold to obtain the desired shape. The molten material is quenched in cold water and ball-milled to obtain a frit. An alternative to the melting quenching method is the sol–gel synthesis, which mainly involves hydrolysis and polycondensation. The typical precursor for glass is metal alkoxide, i.e., tetraethyl orthosilicate for silicon and nitric acid as a catalyst, along with triethyl phosphate, calcium nitrate hexahydrate, and sodium nitrate. It is subjected to acid hydrolysis and the polycondensation reaction to form the Si–O–Si bond [26,29]. Then, it is cast in Teflon and sealed at room temperature (RT), which leads to the sol formation. Small holes are made in sealed containers to eliminate water and nitrate residue, and subjected to drying and thermal treatment. Figure 3 shows the pictorial representation of both preparation methods. The typical precursor for the borate glass is boric acid, which is dissolved in ethanol and magnetically stirred at 40°C. Then, the calcium and phosphate precursors are added at different time intervals of 30 min; the procedure is similar to that of the silicate glasses. Once the gel attained high viscosity, it was further stirred at 37°C for further gelation. Then, it was subjected to the stages of gelling, drying, and calcination [42]. The sol–gel-derived material had a higher surface area for the ion-exchange process, and exhibited a higher HAP formation rate than the materials prepared by the melt-quench method. The synthesized sol–gel material has been used in biomedical and non-biomedical applications [29,43]. One of the significant physical differences between the two methods is that the melt glass is dense, whereas the sol–gel glass has inherent porosity.
Synthesis of the bioactive glass using melt-quench and sol–gel methods.
Apart from these two most common methods, bioglass has also been prepared using flame or microwave-assisted methods. In the flame synthesis, an appropriate combination of the precursors was introduced into the flame reactors. The nanopowder was collected from the filter, which was filtered above the flame [44].
Microwave irradiation is carried out under electromagnetic radiation where the composition is adjusted to the sintering process from 700 to 1,000°C. It is an inexpensive hydrothermal method, even though it is considered the standard method to accelerate the chemical reaction. It distributes the energy directly to the precursors, which may disturb the nature of the reactants [45]. Even if there are several ways to synthesize bioactive glass, melt-quenching and sol–gel synthesis are the two methods most commonly utilized.
2.1 Challenges using sol–gel and melt-quenching methods
As materials synthesized from the sol–gel method are not exposed to high temperatures, the problems caused due to sintering have been eliminated [1]. Meka et al. reported that the change in the pH in the environment would reduce osteoblast activity; when the melt-quenching method is used, the pH shift is due to the composition’s high sodium content [21]. One of the prime reasons to use sodium in melt synthesis is to reduce the temperature and increase the bioactivity of the glass. If the glass is synthesized using the sol–gel method, the need for sodium is constrained at RT. The bioactivity of the bioactive glass can be retained even in the absence of sodium, i.e., fewer components are being used in the sol–gel method [1,26]. One such challenge for sol–gel glass materials is to produce crack-free materials. When the materials are subjected to drying and evaporation, shrinking occurs, which leads to the capillary stress in the pore network of the monolithic glass, mainly because of the large surface area. Thus, tortuosity can be eliminated by tailoring the increased pore size with a small cross-section [1]. However, if the synthesis is not performed under controlled conditions, it can result in inhomogeneity and phase separation [46]. It has been mentioned earlier that if the silicon content exceeds 58% of the glass composition, the glass prepared is not bioactive; thus, the bioactivity of the glass decreases by increasing the silicon content [37]. However, if the glass has been obtained using the sol–gel method, the bioactivity silicon content exceeds 90% of the content [17].
3 Discussion: the apatite layer formation mechanism on the surface of bioactive glasses
Many researchers developed bone repair and regeneration materials through regenerative bone-mimicking compounds such as CaP, HAP, bioactive glasses, etc. [11]. Bioactivity has been regarded as the most important factor. The controlled release of the ions is the main phenomenon of the nucleation of apatite formation to form a new bone. It took decades to understand the apatite formation, and, still, complete knowledge of the host’s biological interaction in the HAP layer is not clear. The atomic structure of the bioactive glass determines the ion dissolution; the accumulation of ions causes both chemical composition changes and the change in the pH for the apatite nucleation in in vivo and in vitro investigation [1,46]. Figure 4 shows the step-by-step mechanism of apatite layer formation as the apatite formation mimics the native inorganic bone mineral phase on the glass surface, which is attributed to the new bone tissue formation. The dissolution of the network leads to a change in the pH. Eventually, it leads to polycondensation and the formation of silanol, which has a large surface area and more sites for heterogeneous nucleations [6]. By exchange of the ions, the Ca2+ and P5+ ions diffuse and form the layer at a usually faster rate than the apatite formation executed by the bioactive glass [1,10]. Thus, the HAP layer growing on the bioactive glass provides an epitome environment for the cellular reaction, including colonization and proliferation of the osteoblast cells, causing the bone to differentiate to form a mechanically strong bone [6].
![Figure 4
The mechanism of apatite layer formation on the surface of the bioactive glass materials is based on the starting material composition and the Si–O–Si bonds for each Si atom. The formation can take a few hours to a few days [1,3,46].](/document/doi/10.1515/rams-2022-0318/asset/graphic/j_rams-2022-0318_fig_004.jpg)
3.1 Scaffold of bioactive glass materials
The preparation of the bioactive glass is not unpleasant; there are only a few criteria to be fulfilled, such as being biocompatible without causing a toxic environment, as it is mandatory for the existing bone tissue bonding. The utmost purpose of the scaffold is to provide temporary support so that they can construct the bone of the desired shape and properties and should be able to degrade without causing any serious environment to the host [47]. A scaffold should allow the blood vessels to penetrate through its interconnected porous connectivity. It should also have good mechanical properties so that it can withstand the cyclic load created by the patient [46]. Based on the dimension of the bone defect, the scaffold should be able to be tailored to fit inside it. It should be able to resorb and remodel at the same time once implanted, and its dissolution ions should be non-toxic [46]. Among the other mentioned properties, the 3D structure using an additive manufacturing technique plays an easy and magnificent role by giving a friendly environment for the adhesion and growth of the cells. It provides a temporary framework for the improvement of the regeneration of the bone [38]. Biodegradable polymeric materials, such as synthetic or natural polymers, are commonly used to make scaffolds for tissue engineering. To regenerate the load-bearing bone, polymer scaffolds are not suitable due to their poor mechanical toughness; thus, several attempts have been made to develop an ideal scaffold with biodegradable polymers [47]. Figure 5 depicts the ideal qualification of the scaffold bioactive glass materials for bone regeneration.
Representation of an ideal scaffold.
3.2 Importance of the bioactive glass materials
The bioactive glass should possess biocompatible, biodegradable, and bioactive properties. Among them, biocompatibility is essential for any material to be used as an implant as it should not create any toxic effect on the implanted physiological environment. On implantation, they should be capable of interacting with the live tissue and able to proliferate the cells to form the apatite layer on the materials, which is fundamental for the new bone formation. They should not undergo crystallization and must withstand thermal treatment; while designing the scaffold for regeneration, along with the porous network, it should provide a pathway for vascularization, should be present in The design of a scaffold, and should have a porous 3D structure, which enables the diffusion of the nutrient, and vascularization of the blood, and cause easier cell proliferation for their penetration. To avoid a structural breakdown during the material processing and the patient’s cyclic activities, they must have the requisite mechanical qualities to endure any pressure or strain along with the electrical properties. Mechanical properties, including hardness, compressive strength, bending strength, Young’s modulus, and fracture toughness, are essential during the preparation of the ideal bone implant. For improved compatibility, the scaffolds must have mechanical qualities equal to those of the tissues to be replaced. Thus, it should be economically viable while retaining the desired properties for commercialization. As a result, these parameters are desirable for generating bioactive glasses suited for biological and technical applications [5,48]. Figure 6 shows the essential properties of the bioactive glass for the formation and execution of its function.
Important properties of silicate, borate, and phosphate bioactive glass for the new bone formation or bone repair.
3.3 Mesoporous nature of bioactive glass ceramics
Depending on the porous size, the materials are categorized as micro-, meso-, and macroporous materials, and their porous size ranges from <2 nm, 2 to 50 nm, and >50 nm, respectively [49]. Over recent years, scrutiny of the mesoporous bioactive glass (MBAG) material has flourished; one of the main reasons for the development is to overcome the constraints of traditional bioactive glasses, such as the lack of ordered mesopore structures and poor bioactivity, which are essential for drug delivery and cell proliferation. So, it is critical to fabricate a new biomaterial standard that blends active drugs with outstanding bioactivity [37]. The first generation of bioactive glasses was obsessed with only inert materials; the second generation was engaged with either being absorbable or bioactive; the third generation was focused on balancing both [6]. The third generation of bioactive glasses, MBAG, was synthesized using a sol–gel technique with supramolecular surfactant chemistry [49]. They have excellent properties when compared to the non-MBAG, such as nanopore volume with the best surface area along with the enriched apatite formation and the ability of the controlled delivery of the drug with good cytocompatibility [38,49]. Highly porous MBAGs using block polymer as the template was synthesized by Yan et al., who concluded that mesoporous glass is superior when compared to conventional bioactive glasses [50]. The result has opened a new door for the use of nano techniques in regenerative medicine by fusing the drugs with bioactive materials [37]. The structural bioactivity of the mesoporous materials is completely different from the conventional bioactive glass. Structure-directing agents such as cetyltrimethylammonium bromide, EO20-PO70-EO20 (P123), and EO106-PO70-EO106 (F127) are required to generate well-ordered structures, as they are pertinent for influencing the size, structure, surface, and volume of the MBAG [37]. It has been reported that in vitro bioactivity of MBAG is determined by the Si/Ca ratio and calcination temperature; their textual properties, such as pore size and pore volume, can be tailored and controlled [51]. The novel standard of biomaterials might exhibit distinct in vivo bioactivity, and the composite’s bioactivity relies on the bioactive glass’s surface area, which is lacking in the traditional bioactive glass when compared to the MBAG. Thus, MBAG differs from traditional bioactive glasses [52]. Thus, to showcase the advantage of the MBAG, Li et al. performed a comparison between MBAG and conventional bioactive glass by incorporating PCL to investigate the in vitro bioactivity. MBAG is more effective than traditional bioactive glass in terms of hydrophilicity and dense HAP formation, which is due to the higher bioactivity of the MBAG\PCL composite [52]. Thus, the MBAG improves bioactivity and cell attachment by absorbing and releasing drug and growth factors [53]. Various co-templating technologies have been used to create an MBAG scaffold based on macroporous architecture and ordered mesoporous texture mimics spongy bone and allows for continuous release of drug [53]. Mesoporous glass is ideal for controlled drug release because of its superior textural qualities, stability, biocompatibility, and capacity to alter surface properties [7]. Silica-based mesoporous materials are considered the most trustworthy materials for these drug releases among the many types of bioactive glasses. Functionalizing the silanol groups on the silicate MBAG surfaces is critical in enabling drug loading and release [1]. In terms of drug release, controlled drug release is more challenging; thus, the researchers concluded that functionalized MBGs (N-MBGs) are more efficient than the conventional bioactive glass as the 3-aminopropyl triethoxysilane functional group modified [54]. It has a greater drug-loading capacity and a longer duration of drug release along with the increased surface area; the higher the surface area, the stronger the drug intake potential. Different chemical compositions with polyurethane sponge and P123 surfactants were prepared using the evaporation-induced self-assembly procedure. Among the different compositions, MBAG 80S15C composition showed the best apatite formation ability right after 7 days [55]. To fabricate the best bone-forming material and understand the relationship between the structure and bioactivity, it is essential to evaluate the size of the pore and architecture of the bioactive glass on different scales [50].
3.4 Bioactive glass in bone tissue engineering
Bone is dynamic and vascularized tissue that gradually remodels an individual’s life span through osteoblast and osteoclast cells [5]. Bone regeneration is a complicated process that may be witnessed when a typical bone fracture heals. Bone remodeling occurs continuously throughout adulthood. However, numerous clinical situations require considerable regeneration, such as skeletal rebuilding after trauma, tumor removal, infection, and skeletal anomalies. Tissue engineering is a promising subject of investigation designed to repair and replace damaged or diseased tissue using biomaterial elements by interacting with the cells and stimulating its ability for regeneration and drug delivery [56]. Nowadays, biomaterials with engineered structures support bone reconstruction. Apart from powders and granules, the 3D scaffold has an interconnected network. It is most suited for the large bone defect as it fits in well and allows the proliferation of cells to deliver nutrients and therapeutic ions and enhance vascularization [55].
Composite materials which are designed for bone tissue engineering must have the right level of bioactivity to encourage cell growth and adhesion. Vukajlovic et al. prepared a natural polymer-based composite with and without bioactive glass; they concluded that the presence of bioactive glass stimulates the apatite in new bone formation. The release of Si4+ ions from the bioactive glass promotes bone repair and bone density because other polymer composites without bioactive glass do not display apatite crystal formation [57]. In addition, the bioactive glass acts as an excellent drug carrier due to its outstanding osteoconductive factors and degradability character [58]. Figure 7 illustrates the role of bioactive glass in medical applications where the incorporation of the metal flavor overcomes the limitation due to defects or aging.
Role of bioactive glasses with their different combinations in various medical applications.
The systematic activities of the normal bone are impeded due to osteoporosis [58,59]. Osteoporosis is a chronic bone disease associated with aging marked by reduced bone mass and microarchitectural bone deterioration, as the possibility of being vulnerable to other bone sites [59,60]. The main reason for the increased number of osteoblasts is estrogen deficiency in women [61]. According to WHO, osteoporosis is diagnosed using the bone mineral density test, which gives the amount of bone mineral density in the bone tissue. It is calculated as the T score; if the T score is less than −2.5, then it implies osteoporosis. The smaller the score, the more serious the osteoporosis. Thus, it is vital to use the bioactive scaffold in tandem with osteoconductive elements to regenerate the bone in people living with osteoporosis. With an aging population, osteoporosis-related disorders are expected to become a big demand in healthcare, requiring sustainable treatment alternatives [61,62]. Thus, by using bioactive glass as a drug carrier, Zhu et al. proposed a system with an amino group-modified MBAG system for the delivery of the alendronate. Bisphosphonate is the most prescribed drug for osteoporosis, and the modified MBAGs show the chemical interaction between the phosphonate group with higher osteogenic potential and lower degradation rate, whereas the unmodified phosphonate shows weak interactions. The therapeutics ions, i.e., Ca2+ and Si4+ ions from the prepared SiO2–CaO–P2O5 glass system, stimulate bone tissue regeneration [58]. Strontium ions induce bone growth by employing bone formation and by inhibiting resorption; due to their nature, they can be a pharmaceutical agent to treat osteoporosis [63]. Similarly, Kargozar et al. concluded that the incorporation of an alkaline earth metal, i.e., Sr2+ as the network modifier in the bioactive glass composition using sol–gel provides the controlled release of Sr2+ ions as it can enhance the osteoblast activity than osteoclast, as it can proceed to the desired pore size [64]. In the regeneration of osteoporotic bone defects in the femur for ovariectomized rats right after a few weeks of implantation, the bone regeneration process revealed that the Sr-incorporated bioactive glass shows enhanced bone formation than the bioactive glass scaffold alone [65]. Osteoporosis treatment has mostly focused on inhibiting bone resorption and stimulating bone formation, with less emphasis on repairing the deficiency. The MBAG/silk fibrin scaffolds with growth factors such as PDGF-b and adBMP-7 allow the formation of new bone. They could benefit patients with osteoporotic fractures using growth fractures [61].
3.4.1 Osteoinduction, osteoconduction, and osteointegration processes
Osteoinduction, osteoconduction, and osteointegration are comparatively similar but their phenomena are not identical. Osteoinduction is the regular process of healing a normal bone and is eventually responsible for new bone formation. In contrast, the implant material can act as osteoinductive but is not a prerequisite for the induction of the bone. Considering osteoconduction, where it has been used along with the implant material as the conjunction, it depends on the biological factors and the host material’s reactive response. Being implanted plays a pivotal role in the process of osteoconduction, and the process is for shorter periods. Similarly, osteointegration depends upon the response of the implant and its biological factor. The successful osteointegration process should enable the bone to anchor the cyclic load created for longer [66].
3.4.1.1 Osteoinduction property
Osteoinduction is a process that induces the process of osteogenesis, where the immature cell is subjected to stimulate the cell lineage of the bone cell formation where preosteoblast develops [66]. The undifferentiated cell is being recruited to perform this. The 45S5 bioglass is said to be osteoinductive as it supports the development of new bone along with the implant interface [47]. Stimulation of bone regeneration occurs due to the combination of ions being released by the glass [47]. Tavakolizadeh et al. examined the osteoinductive result of the bioactive glass and compared it with 45S, 58S, and 63S bioactive glasses and concluded that the 45S bioactive glass has the highest osteoinductive properties among others [67]. When the osteoinductive material is implanted in non-osseous areas, often known as heterotopic or ectopic sites, it should cause bone formation. The osteogenic development of osteoprogenitor or undifferentiated MSCs in contact with potential graft bone substitutes can be tested in vitro to determine their osteoinductive potential [68]. The osteoconductivity of the biomaterial depends on the composition, and the structure plays a pivotal, influential role in the process of osteoinduction [68]. Similarly, biomimetically modified bioactive glass has an osteogenic impact on bone marrow MSCs [69]. The osteogenic capabilities of the 45S5 bioactive glass are due to its dissolution products, which activate osteoprogenitor cells in vitro [68]. Bi et al. compared bioactive borate glasses and found that the trabecular scaffolds had a higher amount of new bone formation and superior osteoinductive capacity; thus, the borate glass showed fewer osteoinductive effects [70]. Yuvan et al. showed that bioactive glass materials are not naturally osteoinductive unless extra-biological elements or osteogenic cells are added [71]. Likewise, biopolymer favors osteoinductive activity; such a study was performed using an MBAG with biopolymer and an osteoinductive fibrous scaffold as they serve as an excellent bioactive material along with drug delivery of osteogenic in the long term [14].
3.4.1.2 Osteoconduction nature
Osteoconduction is a process that conducts the formation of the bone surface, thus allowing the material to grow in space [66]. The undifferentiated cells activated by osteoinduction are placed in their position, and penetration of the blood is essential for proper bone conduction. Osteoconduction depends not only on the bone defect but also on the material being used and plays a vital role as the biomaterial being implanted supports the formation [66]. A common substitute for CaP ceramics is known for its osteoconductive ability in bioactive glass [68]. The 45S5 bioglass is said to be the first man-made osteoconductive material and was implanted within and away from the interface of the bone implant [47]. When compared to silicate, borate glass tends to have osteoconductive properties. Bi et al. concluded that Cu doping of the borate glass appeared to promote bone formation near the fibrous scaffold, which was mainly influenced by osteoconductivity [70]. Hybrid glass system can be developed with the incorporation of natural polymer. Anionic collagen matrices can be used to treat bone deficiencies because of their inexpensive production costs, biocompatibility, and osteoconductivity performance [72]. The bone cement is made of bioactive glass and magnesium phosphate, and the surface-modified magnesium alloy rod shows HAP apatite formation within 6 weeks. But, the strength is likely to decrease, and its load-bearing activity depends on magnesium alloy rods. More importantly, in vitro and in vivo activities exhibit excellent osteoinductivity and is due to the bioactive glass/magnesium phosphate cement matrix [73]. Similarly, they prepared the HAP/bioactive glass composite film using pulsed laser deposition and 20 wt% bioglass 45S5 is induced; the c-axis-oriented HAP is crystallized. The composite film of c-axis-oriented apatite has been shown to boost the effectiveness of the implant’s osteoconduction and the adherence of bone tissue to the implant’s surface [74]. Considering the natural polymer, chitosan has conductive properties; thus, it might exhibit excellent osteoconductive ability when used in a hybrid glass system, as confirmed by Khoshakhlagh et al. using chitosan bioactive glass composites [75]. The 3D chitosan-cross-linked bioactive glass with the vanillin composite, where the aldehyde in the vanillin group and the amine in the chitosan group form the Schiff base between them, does not enable them to form a stable composite suitable for bone tissue engineering. Thus, they have used the bioactive glass, which acts as the pH adjustor that favors the formation of the imines and acts as a co-crosslinker to the scaffold; thus, it enhanced mechanical properties, osteoconductivity, and antibacterial activity [76]. Synthetic PDLLA and PCL show good osteoconductive performance [77,78]. Erdemli et al. prepared the matrix with calcium sulfate to PCL bioactive glass composite, which has osteoconductive activity [79].
3.4.1.3 Osteointegration properties
Osteointegration is the process that integrates, or the attachment amid the bone and the material being implanted begins, where the material being implanted is anchored to the bone tissue. Even though the osteoconduction mentioned above and osteoinduction are interrelated with one another, osteointegration occurs all the time [66]. Chitosan exhibits osseointegration; when the hybrid glass has to be processed, the addition of chitosan to the bioactive glass could play the role of osteointegration. The osteointegration of 45S5 bioglass and Ti-alloy implants coated with HAP after 4, 8, 12, and 16 weeks in rat cancellous bone was examined. It revealed that the bioactive glass enhanced osteointegration with a biomechanical shear strength equal to that of HAP [80,81]. Figure 8 illustrates the osteoinduction, osteoconduction, and osteointegration processes in bone regeneration.
Osteoinduction, osteoconduction, and osteointegration in bone tissue regeneration.
3.5 Restriction of bioactive glass materials in medicinal applications
The bioactive glass system is chemically and crystallographically comparable to the mineral constituents of the human bone. Due to its amorphous glass network, it has short fracture toughness and mechanical fragility; therefore, using it in load-bearing applications makes it unbearable. Even though bioactive glass has all the properties essential for bone regeneration, it also has some limitations, such as weak mechanical and electrical properties, when compared to natural bone [82]. Compared to cancellous and cortical bones, bioactive glasses are porous and often have low mechanical characteristics [15]. However, they exhibit lower fracture toughness and larger elastic moduli than those of the human cortical bone [83]. It also generates a cytotoxic environment due to the high Na content and poor sintering ability that makes the preparation of 3D scaffold challenging. Even though melt-derived BAG has several drawbacks, the 45S5 bioglass is still regarded as the go option for bioactive glasses. One of the main restrictions is that it must be melted at a very high-temperature environment (>1,300°C); in addition, its structure lacks a microporous feature within the materials; as a result, its bioactivity is mostly dependent on the SiO2 concentration [49].
3.6 Enhancement of the activity
To alleviate these limitations of weak mechanical and electrical properties, Verma et al. suggested incorporating bioactive glass with the piezoelectric material, as the piezoelectrical material converts mechanical energy into electrical energy. It performs domain alignment and toughens the composite, improving the implant’s functional activity. A solid-state synthesis technique was used to make three different bioactive glass sodium–potassium–niobate (NKN) composites with high densification. BG20NKN stands out among all the produced compositions with increased Vickers hardness maximum, flexural strength, and fracture toughness, showing antibacterial effects on both the Gram-negative and Gram-positive bacteria. Thus, in tissue engineering, the composites are combined with the bioactive glass phase with the polymers, which are biodegradable and show excellent interest because they interact at the molecular level, and thus, their mechanical, physical properties and rate of degradation of the polymer can be tailored. It can also be deployed in biomedical applications as they allow the formation of new tissues, and it naturally overtakes the job of load-bearing with excellent mechanical properties [82].
In comparison, the hybrid system produces the required bioactivity and mechanical strength due to an excellent balance between strength and toughness [15]. The polymer phase acts as a carrier matrix for bioactive molecule delivery and increases mechanical stability. Reiter et al. found that bioactive glass-based scaffolds covered with gelatin had a good mix of mechanical robustness and bioactivity and proper delivery of drugs. Organic coating materials can impact cell adhesion and proliferation while providing a substrate for integrating biomolecules and medicines [84]. Moreover, synthetic resorbable polymers can be utilized to obtain a complex structure. Still, such polymers exhibit inflammatory responses during the degradation process, and it might not be enough for orthopedic applications [18]. Similarly, Jo et al. compared the nanofibers’ bioactive glass with bioactive glass for the bioactivity and mechanical properties, where the nanofibers’ composite shows greater potential when compared to others [85]. All the constraints can be resolved by altering the composition of the bioactive glass composition to obtain the structure of glass along with its biocompatibility, degradation percentage, ease with which the scaffold can be processed, and a controlled number of therapeutic ions can be released [10]. Table 2 shows the bioactive glass and its composites that have been used for biomedical applications.
Bioactive glass-based composites and their method of preparations
| Glass type | Method of preparation | Polymer | Others | Author | Ref. |
|---|---|---|---|---|---|
| Silicate glass | Sol–gel | PVA/chitosan | — | Mansur and Costa | [15] |
| Bioglass 45S5 | Melt-quenching | PDLLA | — | Blaker et al. | [18] |
| Borosilicate glass | Wet spinning and fiber bonding techniques | PLLA | — | Fernandes et al. | [35] |
| Orthophosphosilicate glass | Melt-quenching | PLLA | — | Lee et al. | [39] |
| Phosphate glass | Solvent extraction and thermal pressing method | PCL | — | Kim et al. | [40] |
| MBAG | 3D-printing technique | PCL | Fe3O4 | Zhang et al. | [38] |
| Mesoporous bioactive glass (Silicate glass) | solvent casting-particulate leaching method | PCL | EO20PO70EO20 (P123) | Li et al. | [52] |
| Bioglass 45S5 | Freeze-drying | Chitosan | Boronic acids | Vukajlovic et al. | [57] |
| MBAG (Silicate glass) | Evaporation-induced self-assembly process | Polyurethane sponge | Non-ionic block copolymer EO20PO70EO20 (P123) surfactant as co-templates | Wang et al. | [55] |
| MBAG (Silicate glass) | Freeze-drying | Silk fibrin | — | Zhang et al. | [61] |
| Silicate glass | Sol–gel | Chitosan | — | Khoshakhlagh et al. | [75] |
| Bioglass 45S5 | Cross-linking technique | Chitosan | Vanillin | Hu et al. | [76] |
| Bioglass 45S5 | Thermally induced phase separation process | PDLLA | — | Verrier et al. | [77] |
| Bioglass 45S5 | Solvent casting method | PDLLA | — | Leal et al. | [78] |
| Bioglass 45S5 | Compression molding method | PCL | — | Erdemli et al. | [79] |
| Bioactive glass nanofibers (silicate) | Sol–gel via the electrospinning process | PCL | — | Jo et al. | [85] |
3.7 Minerals in bioactive glass
The incorporation of metal ions acts as therapeutic agents in tissue engineering; they act as a catalyst and stimulate metabolism during tissue regeneration [86]. Recently, to improve bioactivity, many metal ions like Ag+, B3+, Cu+, Cu2+, Co2+, Ce3+, Zn2+, Ga3+, and Sr2+ have been incorporated [9]. Thus, knowing their interaction and stimulating mechanism enables us to tailor the advanced scaffold with a controlled biological response [86]. By increasing the metal ions, the toxicity level should be controlled. Among different ions, an alkaline earth metal, i.e., Sr2+, is a trace component in the skeleton of humans and has gained more interest in its favorable biological activities [63,64]. When Sr is doped with the bioactive glass, the HAP formation rate was increased [10]. Calcium can be replaced by strontium; due to charges and ionic radium similarities, it has been used as a viable method for developing materials for bone repair and regeneration treatments [64,87].
Like calcium and phosphorous, zinc is also a trace element necessary for healthy bone growth and maintenance as it boosts bone metabolism [88,89]. On controlled composition, the number of cells is qualitatively higher on performing the live/dead assay [89]. Even though Zn-doped bioactive glass fulfills the basic requirement by stimulating the acellular emergence of the CaP layer on the interface with the fluid, it is not consistent and inhibits or delays the HAP formation. Along with Zn, the incorporation of Fe bioactivity also increases [86]. The Zn-doped bioactive glass can be prepared using the spray pyrolysis method, an inexpensive and non-vacuum procedure to synthesize the materials [90]. Ag+ ions are known for their antibacterial activity and they inhibit bacterial growth without jeopardizing their biocompatibility [86,91,92]. On bacterial examination, both bioactive glasses have no bacteriostatic or bactericidal activity [91]. It was reported that bioactive glass has no antibacterial effects on its own [93]. When Ag has been doped with bioactive glass, it inhibits both Gram-positive and Gram-negative bacterial strains like Escherichia coli and Staphylococcus aureus [86,91,92]. Such properties are not altered when released with other ions [91]. Even though it serves as the eligible candidate, a high concentration could turn toxic; control ion release is to be considered, i.e., less than 20 ppm shows good bacteriostatic effects. Such candidates cannot be prepared using the melt-quenching method as it disturbs the metal ions, so the go-to option is the sol–gel synthesis [92]. In addition to anti-inflammatory properties, wound healing is a bonus point [86].
Magnesium is abundant and essential for human metabolism. As around half of the physiological magnesium is present in bone tissues, it is one of the most significant mineral components in the bone matrix [94]. The incorporation of magnesium into the glass system reduces the crystalline rate of HAP [6]. It was inherently present in biological HAPs; Mg improves their integration which is caused due to poor cell adhesion of the implants. Mg plays a critical protagonist in osteoporosis patients, and increasing Mg orally in osteoporosis patients appears to improve the patients’ radial bone mass; these are the main reasons magnesium has been doped with bioactive glass. Thus, magnesium doping influences bioactivity, notably during the glass-dissolving stage [95]. Mg2+ plays a dynamic role in the physio-chemical kinetic reactions, thus promoting the silica network’s dissolution and decelerating the HAP layers’ crystallization process [94]. Fe2+ ions are crucial in significantly boosting bone metabolism as they have been doped into MBGs due to their antibacterial and bioactive nature. It also shows low crystallization with prolonged drug release to HAP formation in SBF. Thus, the Fe-incorporated scaffold also shows greater formability than the non-Fe-doped scaffold. On the other hand, when doping with large concentrations of Fe, cytotoxic hazards must be taken into account since they may have an impact on the biological environment [96,97]. Table 3 describes the in vivo and in vitro response of the metal ion when incorporated into the bioactive glass and for therapeutic delivery. Rath et al. prepared the scaffold using melt-derived 45S5 bioglass doped with Cu2+ by the foam replica method, and the rapid formation of apatite in the SBF solution confirmed their bioactivity. Osteogenic capabilities, angiogenic potential, and antibacterial effects were confirmed from the release of 0.3 to 4.6 ppm Cu2+ from the composite. The copper-doped bioactive glass decreases the glass network’s transition temperature [98]. Similarly, in vivo studies of the copper-doped bioactive glass were carried out by Hoppe et al. in the MSCs and confirmed their improved angiogenic capacity. In concurrence with MSCs, as it stimulates the endothelial cells, they act as better candidates for bone tissue engineering applications [99].
In vivo and in vitro responses due to the ions in the bioactive glass
| Ions in bioactive glass | In vivo and in vitro responses and their ability | Ref. |
|---|---|---|
| Sr2+ |
|
[76] |
| [87] | ||
| [9] | ||
| Zn2+ |
|
[9] |
| [10] | ||
| Ag+ |
|
[92] |
| Mg2+ |
|
[95] |
| [94] | ||
| [39] |
The above-mentioned ions play a fundamental role in bioactivity, biocompatibility, and new bone formation, which is crucial for living tissue bonding. The addition of these ions to the bioactive glass network not only has biological benefits but also affects the network’s structure and processability. The rare earth element, once considered “exotic” or less frequently used, is being used recently in the bioactive glass network to improve its biological and physical characteristics [100]. However, unrelated biological responses, concentration, and dissolution products from the system are considered to avoid toxicity.
4 Conclusion
The development of suitable biomaterials for bone regeneration is an intricate problem in biomedical research. The study of bioactive glasses is an interesting research subject with promising results. It has been intensively investigated over the last few decades, and numerous problems have been addressed in the field of bone tissue engineering. In this review, the bioactive glasses were examined in general, focusing on the most prevalent bioactive glass formulations, preparation process, physical characteristics, and their clinical outcomes in the biomedical field. Bioactive glass composites can be improvised to become further bioactive. Shortly, bioactive glasses can change and evolve in regenerative medicine because of their high biocompatibility and bioactivity as hard tissue materials. The osteoconductive, osteoinductive, and osteointegration processes were reported in the MBAG for the ordered structure and sustainable drug release of bioactive compounds. On tailoring, bioactive glass could provide a well-balanced composition for challenging bone regeneration and tissue engineering applications. We may attain the full regeneration of bone with a deeper understanding of the bioactive glass network. However, such accomplishments rely more on in vivo research to establish their reliability, effectiveness, and precise mechanisms of action.
5 Future direction
Furthermore, in recent years, regenerative medicine made a lot of significant advances. More research and knowledge of bioactive glass might lead to complete bone regeneration and enhanced soft tissue regeneration. These accomplishments should be based on intricate methodologies with extensive investigations and in vivo examinations to prove their reliability, competence, and precise mechanisms of action. With the growing number of in vivo studies and excellent outcomes, more healthcare practitioners will incorporate these procedures and technology into their regular practices. Forthcoming research should concentrate on developing gradient porosity scaffolds to produce bioactive and resorbable composites with graded mechanical, resorption, and bioactive properties, particularly tissue regeneration using the ion-doped glass. As the material being implanted differs on insertion, there is a need to prioritize the biological method of preparation so that the composite replicates with appropriate mechanical properties, as well as a deeper decipherment of the response and rebuttal of the bone and its biological delivery system. Thus, such fabricated ceramics would make a whole other emergence in the field of tissue engineering in the near future. A new generation of gene-activating biomaterials customized to individual medical history should be available. Tissue-engineered constructions based on the patient’s cells may be created and utilized to determine the best treatment. Perhaps, more importantly, bioactive stimuli may be employed to activate genes in a preventive therapy to maintain the health of tissues as we grow. This might appear unthinkable now. However, materials that are not rejected by living tissues seemed impossible years ago.
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Funding information: M. Rajan acknowledges significant financial support from the plan of the Science and Engineering Research Board (Ref: EEQ/2020/000201), New Delhi, India, and Rashtriya Uchchatar Shiksha Abhiyan (RUSA), Madurai Kamaraj University (File No. 007-R2/RUSA/MKU/2020-21).
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Conflict of interest: The authors state no conflict of interest.
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- Study on the uniaxial compression constitutive relationship of modified yellow mud from minority dwelling in western Sichuan, China
- Ultrasonic longitudinal torsion-assisted biotic bone drilling: An experimental study
- Green synthesis, characterizations, and antibacterial activity of silver nanoparticles from Themeda quadrivalvis, in conjugation with macrolide antibiotics against respiratory pathogens
- Performance analysis of WEDM during the machining of Inconel 690 miniature gear using RSM and ANN modeling approaches
- Biosynthesis of Ag/bentonite, ZnO/bentonite, and Ag/ZnO/bentonite nanocomposites by aqueous leaf extract of Hagenia abyssinica for antibacterial activities
- Eco-friendly MoS2/waste coconut oil nanofluid for machining of magnesium implants
- Silica and kaolin reinforced aluminum matrix composite for heat storage
- Optimal design of glazed hollow bead thermal insulation mortar containing fly ash and slag based on response surface methodology
- Hemp seed oil nanoemulsion with Sapindus saponins as a potential carrier for iron supplement and vitamin D
- A numerical study on thin film flow and heat transfer enhancement for copper nanoparticles dispersed in ethylene glycol
- Research on complex multimodal vibration characteristics of offshore platform
- Applicability of fractal models for characterising pore structure of hybrid basalt–polypropylene fibre-reinforced concrete
- Influence of sodium silicate to precursor ratio on mechanical properties and durability of the metakaolin/fly ash alkali-activated sustainable mortar using manufactured sand
- An experimental study of bending resistance of multi-size PFRC beams
- Characterization, biocompatibility, and optimization of electrospun SF/PCL composite nanofiber films
- Morphological classification method and data-driven estimation of the joint roughness coefficient by consideration of two-order asperity
- Prediction and simulation of mechanical properties of borophene-reinforced epoxy nanocomposites using molecular dynamics and FEA
- Nanoemulsions of essential oils stabilized with saponins exhibiting antibacterial and antioxidative properties
- Fabrication and performance analysis of sustainable municipal solid waste incineration fly ash alkali-activated acoustic barriers
- Electrostatic-spinning construction of HCNTs@Ti3C2T x MXenes hybrid aerogel microspheres for tunable microwave absorption
- Investigation of the mechanical properties, surface quality, and energy efficiency of a fused filament fabrication for PA6
- Experimental study on mechanical properties of coal gangue base geopolymer recycled aggregate concrete reinforced by steel fiber and nano-Al2O3
- Hybrid bio-fiber/bio-ceramic composite materials: Mechanical performance, thermal stability, and morphological analysis
- Experimental study on recycled steel fiber-reinforced concrete under repeated impact
- Effect of rare earth Nd on the microstructural transformation and mechanical properties of 7xxx series aluminum alloys
- Color match evaluation using instrumental method for three single-shade resin composites before and after in-office bleaching
- Exploring temperature-resilient recycled aggregate concrete with waste rubber: An experimental and multi-objective optimization analysis
- Study on aging mechanism of SBS/SBR compound-modified asphalt based on molecular dynamics
- Evolution of the pore structure of pumice aggregate concrete and the effect on compressive strength
- Effect of alkaline treatment time of fibers and microcrystalline cellulose addition on mechanical properties of unsaturated polyester composites reinforced by cantala fibers
- Optimization of eggshell particles to produce eco-friendly green fillers with bamboo reinforcement in organic friction materials
- An effective approach to improve microstructure and tribological properties of cold sprayed Al alloys
- Luminescence and temperature-sensing properties of Li+, Na+, or K+, Tm3+, and Yb3+ co-doped Bi2WO6 phosphors
- Effect of molybdenum tailings aggregate on mechanical properties of engineered cementitious composites and stirrup-confined ECC stub columns
- Experimental study on the seismic performance of short shear walls comprising cold-formed steel and high-strength reinforced concrete with concealed bracing
- Failure criteria and microstructure evolution mechanism of the alkali–silica reaction of concrete
- Mechanical, fracture-deformation, and tribology behavior of fillers-reinforced sisal fiber composites for lightweight automotive applications
- UV aging behavior evolution characterization of HALS-modified asphalt based on micro-morphological features
- Preparation of VO2/graphene/SiC film by water vapor oxidation
- A semi-empirical model for predicting carbonation depth of RAC under two-dimensional conditions
- Comparison of the physical properties of different polyimide nanocomposite films containing organoclays varying in alkyl chain lengths
- Effects of freeze–thaw cycles on micro and meso-structural characteristics and mechanical properties of porous asphalt mixtures
- Flexural performance of a new type of slightly curved arc HRB400 steel bars reinforced one-way concrete slabs
- Alkali-activated binder based on red mud with class F fly ash and ground granulated blast-furnace slag under ambient temperature
- Facile synthesis of g-C3N4 nanosheets for effective degradation of organic pollutants via ball milling
- DEM study on the loading rate effect of marble under different confining pressures
- Conductive and self-cleaning composite membranes from corn husk nanofiber embedded with inorganic fillers (TiO2, CaO, and eggshell) by sol–gel and casting processes for smart membrane applications
- Laser re-melting of modified multimodal Cr3C2–NiCr coatings by HVOF: Effect on the microstructure and anticorrosion properties
- Damage constitutive model of jointed rock mass considering structural features and load effect
- Thermosetting polymer composites: Manufacturing and properties study
- CSG compressive strength prediction based on LSTM and interpretable machine learning
- Axial compression behavior and stress–strain relationship of slurry-wrapping treatment recycled aggregate concrete-filled steel tube short columns
- Space-time evolution characteristics of loaded gas-bearing coal fractures based on industrial μCT
- Dual-biprism-based single-camera high-speed 3D-digital image correlation for deformation measurement on sandwich structures under low velocity impact
- Effects of cold deformation modes on microstructure uniformity and mechanical properties of large 2219 Al–Cu alloy rings
- Basalt fiber as natural reinforcement to improve the performance of ecological grouting slurry for the conservation of earthen sites
- Interaction of micro-fluid structure in a pressure-driven duct flow with a nearby placed current-carrying wire: A numerical investigation
- A simulation modeling methodology considering random multiple shots for shot peening process
- Optimization and characterization of composite modified asphalt with pyrolytic carbon black and chicken feather fiber
- Synthesis, characterization, and application of the novel nanomagnet adsorbent for the removal of Cr(vi) ions
- Multi-perspective structural integrity-based computational investigations on airframe of Gyrodyne-configured multi-rotor UAV through coupled CFD and FEA approaches for various lightweight sandwich composites and alloys
- Influence of PVA fibers on the durability of cementitious composites under the wet–heat–salt coupling environment
- Compressive behavior of BFRP-confined ceramsite concrete: An experimental study and stress–strain model
- Interval models for uncertainty analysis and degradation prediction of the mechanical properties of rubber
- Preparation of PVDF-HFP/CB/Ni nanocomposite films for piezoelectric energy harvesting
- Frost resistance and life prediction of recycled brick aggregate concrete with waste polypropylene fiber
- Synthetic leathers as a possible source of chemicals and odorous substances in indoor environment
- Mechanical properties of seawater volcanic scoria aggregate concrete-filled circular GFRP and stainless steel tubes under axial compression
- Effect of curved anchor impellers on power consumption and hydrodynamic parameters of yield stress fluids (Bingham–Papanastasiou model) in stirred tanks
- All-dielectric tunable zero-refractive index metamaterials based on phase change materials
- Influence of ultrasonication time on the various properties of alkaline-treated mango seed waste filler reinforced PVA biocomposite
- Research on key casting process of high-grade CNC machine tool bed nodular cast iron
- Latest research progress of SiCp/Al composite for electronic packaging
- Special Issue on 3D and 4D Printing of Advanced Functional Materials - Part I
- Molecular dynamics simulation on electrohydrodynamic atomization: Stable dripping mode by pre-load voltage
- Research progress of metal-based additive manufacturing in medical implants
Articles in the same Issue
- Review Articles
- Progress in preparation and ablation resistance of ultra-high-temperature ceramics modified C/C composites for extreme environment
- Solar lighting systems applied in photocatalysis to treat pollutants – A review
- Technological advances in three-dimensional skin tissue engineering
- Hybrid magnesium matrix composites: A review of reinforcement philosophies, mechanical and tribological characteristics
- Application prospect of calcium peroxide nanoparticles in biomedical field
- Research progress on basalt fiber-based functionalized composites
- Evaluation of the properties and applications of FRP bars and anchors: A review
- A critical review on mechanical, durability, and microstructural properties of industrial by-product-based geopolymer composites
- Multifunctional engineered cementitious composites modified with nanomaterials and their applications: An overview
- Role of bioglass derivatives in tissue regeneration and repair: A review
- Research progress on properties of cement-based composites incorporating graphene oxide
- Properties of ultra-high performance concrete and conventional concrete with coal bottom ash as aggregate replacement and nanoadditives: A review
- A scientometric review of the literature on the incorporation of steel fibers in ultra-high-performance concrete with research mapping knowledge
- Weldability of high nitrogen steels: A review
- Application of waste recycle tire steel fibers as a construction material in concrete
- Wear properties of graphene-reinforced aluminium metal matrix composite: A review
- Experimental investigations of electrodeposited Zn–Ni, Zn–Co, and Ni–Cr–Co–based novel coatings on AA7075 substrate to ameliorate the mechanical, abrasion, morphological, and corrosion properties for automotive applications
- Research evolution on self-healing asphalt: A scientometric review for knowledge mapping
- Recent developments in the mechanical properties of hybrid fiber metal laminates in the automotive industry: A review
- A review of microscopic characterization and related properties of fiber-incorporated cement-based materials
- Comparison and review of classical and machine learning-based constitutive models for polymers used in aeronautical thermoplastic composites
- Gold nanoparticle-based strategies against SARS-CoV-2: A review
- Poly-ferric sulphate as superior coagulant: A review on preparation methods and properties
- A review on ceramic waste-based concrete: A step toward sustainable concrete
- Modification of the structure and properties of oxide layers on aluminium alloys: A review
- A review of magnetically driven swimming microrobots: Material selection, structure design, control method, and applications
- Polyimide–nickel nanocomposites fabrication, properties, and applications: A review
- Design and analysis of timber-concrete-based civil structures and its applications: A brief review
- Effect of fiber treatment on physical and mechanical properties of natural fiber-reinforced composites: A review
- Blending and functionalisation modification of 3D printed polylactic acid for fused deposition modeling
- A critical review on functionally graded ceramic materials for cutting tools: Current trends and future prospects
- Heme iron as potential iron fortifier for food application – characterization by material techniques
- An overview of the research trends on fiber-reinforced shotcrete for construction applications
- High-entropy alloys: A review of their performance as promising materials for hydrogen and molten salt storage
- Effect of the axial compression ratio on the seismic behavior of resilient concrete walls with concealed column stirrups
- Research Articles
- Effect of fiber orientation and elevated temperature on the mechanical properties of unidirectional continuous kenaf reinforced PLA composites
- Optimizing the ECAP processing parameters of pure Cu through experimental, finite element, and response surface approaches
- Study on the solidification property and mechanism of soft soil based on the industrial waste residue
- Preparation and photocatalytic degradation of Sulfamethoxazole by g-C3N4 nano composite samples
- Impact of thermal modification on color and chemical changes of African padauk, merbau, mahogany, and iroko wood species
- The evaluation of the mechanical properties of glass, kenaf, and honeycomb fiber-reinforced composite
- Evaluation of a novel steel box-soft body combination for bridge protection against ship collision
- Study on the uniaxial compression constitutive relationship of modified yellow mud from minority dwelling in western Sichuan, China
- Ultrasonic longitudinal torsion-assisted biotic bone drilling: An experimental study
- Green synthesis, characterizations, and antibacterial activity of silver nanoparticles from Themeda quadrivalvis, in conjugation with macrolide antibiotics against respiratory pathogens
- Performance analysis of WEDM during the machining of Inconel 690 miniature gear using RSM and ANN modeling approaches
- Biosynthesis of Ag/bentonite, ZnO/bentonite, and Ag/ZnO/bentonite nanocomposites by aqueous leaf extract of Hagenia abyssinica for antibacterial activities
- Eco-friendly MoS2/waste coconut oil nanofluid for machining of magnesium implants
- Silica and kaolin reinforced aluminum matrix composite for heat storage
- Optimal design of glazed hollow bead thermal insulation mortar containing fly ash and slag based on response surface methodology
- Hemp seed oil nanoemulsion with Sapindus saponins as a potential carrier for iron supplement and vitamin D
- A numerical study on thin film flow and heat transfer enhancement for copper nanoparticles dispersed in ethylene glycol
- Research on complex multimodal vibration characteristics of offshore platform
- Applicability of fractal models for characterising pore structure of hybrid basalt–polypropylene fibre-reinforced concrete
- Influence of sodium silicate to precursor ratio on mechanical properties and durability of the metakaolin/fly ash alkali-activated sustainable mortar using manufactured sand
- An experimental study of bending resistance of multi-size PFRC beams
- Characterization, biocompatibility, and optimization of electrospun SF/PCL composite nanofiber films
- Morphological classification method and data-driven estimation of the joint roughness coefficient by consideration of two-order asperity
- Prediction and simulation of mechanical properties of borophene-reinforced epoxy nanocomposites using molecular dynamics and FEA
- Nanoemulsions of essential oils stabilized with saponins exhibiting antibacterial and antioxidative properties
- Fabrication and performance analysis of sustainable municipal solid waste incineration fly ash alkali-activated acoustic barriers
- Electrostatic-spinning construction of HCNTs@Ti3C2T x MXenes hybrid aerogel microspheres for tunable microwave absorption
- Investigation of the mechanical properties, surface quality, and energy efficiency of a fused filament fabrication for PA6
- Experimental study on mechanical properties of coal gangue base geopolymer recycled aggregate concrete reinforced by steel fiber and nano-Al2O3
- Hybrid bio-fiber/bio-ceramic composite materials: Mechanical performance, thermal stability, and morphological analysis
- Experimental study on recycled steel fiber-reinforced concrete under repeated impact
- Effect of rare earth Nd on the microstructural transformation and mechanical properties of 7xxx series aluminum alloys
- Color match evaluation using instrumental method for three single-shade resin composites before and after in-office bleaching
- Exploring temperature-resilient recycled aggregate concrete with waste rubber: An experimental and multi-objective optimization analysis
- Study on aging mechanism of SBS/SBR compound-modified asphalt based on molecular dynamics
- Evolution of the pore structure of pumice aggregate concrete and the effect on compressive strength
- Effect of alkaline treatment time of fibers and microcrystalline cellulose addition on mechanical properties of unsaturated polyester composites reinforced by cantala fibers
- Optimization of eggshell particles to produce eco-friendly green fillers with bamboo reinforcement in organic friction materials
- An effective approach to improve microstructure and tribological properties of cold sprayed Al alloys
- Luminescence and temperature-sensing properties of Li+, Na+, or K+, Tm3+, and Yb3+ co-doped Bi2WO6 phosphors
- Effect of molybdenum tailings aggregate on mechanical properties of engineered cementitious composites and stirrup-confined ECC stub columns
- Experimental study on the seismic performance of short shear walls comprising cold-formed steel and high-strength reinforced concrete with concealed bracing
- Failure criteria and microstructure evolution mechanism of the alkali–silica reaction of concrete
- Mechanical, fracture-deformation, and tribology behavior of fillers-reinforced sisal fiber composites for lightweight automotive applications
- UV aging behavior evolution characterization of HALS-modified asphalt based on micro-morphological features
- Preparation of VO2/graphene/SiC film by water vapor oxidation
- A semi-empirical model for predicting carbonation depth of RAC under two-dimensional conditions
- Comparison of the physical properties of different polyimide nanocomposite films containing organoclays varying in alkyl chain lengths
- Effects of freeze–thaw cycles on micro and meso-structural characteristics and mechanical properties of porous asphalt mixtures
- Flexural performance of a new type of slightly curved arc HRB400 steel bars reinforced one-way concrete slabs
- Alkali-activated binder based on red mud with class F fly ash and ground granulated blast-furnace slag under ambient temperature
- Facile synthesis of g-C3N4 nanosheets for effective degradation of organic pollutants via ball milling
- DEM study on the loading rate effect of marble under different confining pressures
- Conductive and self-cleaning composite membranes from corn husk nanofiber embedded with inorganic fillers (TiO2, CaO, and eggshell) by sol–gel and casting processes for smart membrane applications
- Laser re-melting of modified multimodal Cr3C2–NiCr coatings by HVOF: Effect on the microstructure and anticorrosion properties
- Damage constitutive model of jointed rock mass considering structural features and load effect
- Thermosetting polymer composites: Manufacturing and properties study
- CSG compressive strength prediction based on LSTM and interpretable machine learning
- Axial compression behavior and stress–strain relationship of slurry-wrapping treatment recycled aggregate concrete-filled steel tube short columns
- Space-time evolution characteristics of loaded gas-bearing coal fractures based on industrial μCT
- Dual-biprism-based single-camera high-speed 3D-digital image correlation for deformation measurement on sandwich structures under low velocity impact
- Effects of cold deformation modes on microstructure uniformity and mechanical properties of large 2219 Al–Cu alloy rings
- Basalt fiber as natural reinforcement to improve the performance of ecological grouting slurry for the conservation of earthen sites
- Interaction of micro-fluid structure in a pressure-driven duct flow with a nearby placed current-carrying wire: A numerical investigation
- A simulation modeling methodology considering random multiple shots for shot peening process
- Optimization and characterization of composite modified asphalt with pyrolytic carbon black and chicken feather fiber
- Synthesis, characterization, and application of the novel nanomagnet adsorbent for the removal of Cr(vi) ions
- Multi-perspective structural integrity-based computational investigations on airframe of Gyrodyne-configured multi-rotor UAV through coupled CFD and FEA approaches for various lightweight sandwich composites and alloys
- Influence of PVA fibers on the durability of cementitious composites under the wet–heat–salt coupling environment
- Compressive behavior of BFRP-confined ceramsite concrete: An experimental study and stress–strain model
- Interval models for uncertainty analysis and degradation prediction of the mechanical properties of rubber
- Preparation of PVDF-HFP/CB/Ni nanocomposite films for piezoelectric energy harvesting
- Frost resistance and life prediction of recycled brick aggregate concrete with waste polypropylene fiber
- Synthetic leathers as a possible source of chemicals and odorous substances in indoor environment
- Mechanical properties of seawater volcanic scoria aggregate concrete-filled circular GFRP and stainless steel tubes under axial compression
- Effect of curved anchor impellers on power consumption and hydrodynamic parameters of yield stress fluids (Bingham–Papanastasiou model) in stirred tanks
- All-dielectric tunable zero-refractive index metamaterials based on phase change materials
- Influence of ultrasonication time on the various properties of alkaline-treated mango seed waste filler reinforced PVA biocomposite
- Research on key casting process of high-grade CNC machine tool bed nodular cast iron
- Latest research progress of SiCp/Al composite for electronic packaging
- Special Issue on 3D and 4D Printing of Advanced Functional Materials - Part I
- Molecular dynamics simulation on electrohydrodynamic atomization: Stable dripping mode by pre-load voltage
- Research progress of metal-based additive manufacturing in medical implants
