Effect of Dopants on the Physical, Mechanical, and Biological Properties of Porous Scaffolds for Bone Tissue Engineering

The design of scaffolds with multifunctional properties is attractive for tissue engineering due to their potential to provide and improve the quality of life of people who require surgery or have bone diseases or defects. The scaffolds for these applications must be bioactive and comply with the effects of biocompatibility and biodegradability. They must also promote osseointegration to facilitate the formation of bone tissue on its surface and allow the adhesion with the surrounding living tissue when implanted into the human body. Bioactive glasses have proven to be suitable for the fabrication of scaffolds since they are osteoconductive as well as osteoinductive. The incorporation of specific metal ions such as Cu, Ag, Mg, Zn, Sr, and Co is currently of interest because they can improve angiogenic and osteogenic performance, antibacterial activity, and physical and mechanical properties. Therefore, this review summarizes the effect of dopants in various bioglass scaffold compositions. Specific and important aspects are shown, such as the effect of the addition of doping elements on the microstructure, mechanical, and thermal properties, as well as bioactivity, cell proliferation, and antibacterial properties. To evaluate the bioactivity, viability, and antibacterial activity, several authors have manufactured doped bioglass scaffolds for multiple applications and have resorted to multiple studies, including in vitro bioactivity analyses in simulated body fluid, microbial activity using various strains of bacteria, cytotoxicity, viability, and cell proliferation using various cell lines.


Introduction
Bone defects caused by trauma, tumors, or degenerative diseases have reduced the quality of life of patients.Although autologous, allogeneic, and xenogeneic bone grafts have been accepted for use in bone repair, they may present problems and/or induce immune rejection [1].In most cases, the body's self-healing ability depends on the size of the affected area and the conditions.In these cases, external help in the form of bone grafting procedures is required to achieve healing [2].Tissue engineering is an option for these situations since it applies the principles of engineering and life sciences toward understanding and developing biological substitutes that restore, maintain, or improve tissue and even whole organ functions [3].Porous scaffolds designed with 3D architecture could promote tissue regeneration and/or remodeling thanks to their porous structure that allows the adhesion of osteoprogenitor cells or osteoblasts that produce cytokines, extracellular matrix, and growth factors, in addition to the flow of body fluids and nutrients that will facilitate the repair of tissue [4,5].Bioactive glasses have gained much attention in biomedical science due to their bioactivity, biocompatibility, and biodegradability characteristics as well as their ability to enhance osteogenesis and angiogenesis.As a consequence of their excellent characteristics, they are widely used in orthopedic, dental, and maxillofacial surgery and in tissue engineering [6,7].To improve bioactivity, biodegradability, and bioresorbability and avoid the presence of bacterial infections at the implant site and the surrounding structures and tissues, doping elements, such as Cu, Ag, Mg, Zn, Sr, and Co, have been incorporated into the glass network.Furthermore, it has been shown that doped glasses can adjust the pH without affecting the bioactivity of the glass [8,9].The addition of metal ions to silicate, phosphate, and borate bioactive glasses has emerged to develop new bioglass formulations with specific therapeutic functionalities, including antibacterial, angiogenic, and osteogenic properties [10].Both the physical and biological properties are affected or favored by the addition of doping agents in the glass structure, which changes their behavior.The study of the incorporation of doping elements in the composition of bioglass for its application in the manufacture of porous scaffolds in recent years has generated an interesting area of research in order to study its effect on the physical and biological properties of the scaffold.The bioglass is intended to later be used as a bone graft to improve the clinical needs that have arisen in recent years due to injuries, fractures, or degenerative diseases.An important drawback in the study of the addition of dopants is the possibility of infection, which is a serious problem that often results from unhygienic conditions and inhibits healing and could even result in graft rejection.The work is organized into different sections.The Introduction section shows and justifies the importance of adding ions to the glass structure.The following sections show the effect of the addition of dopants on the microstructure, mechanical and thermal properties, bioactivity, cell proliferation, and antibacterial properties of glasses for their application in bone tissue engineering.

Tissue Engineering
Tissue engineering is an important field of regenerative medicine that aims to develop new biofunctional tissues that intend to regenerate and repair damaged or diseased tissues.It involves combining living cells with a natural, synthetic, or bioartificial support to develop a biological substitute or a living 3D construct that is structurally, mechanically, and functionally the same as tissue.The template is designed and constructed in such a way that cells can be nourished, while a new matrix is generated, blood vessel growth occurs, and the function is restored.[11][12][13].As a key component in most bone tissue engineering strategies, materials such as polymers, ceramics, metals, or combinations of these can be applied in various forms, such as membranes and threedimensional (3D) scaffolds [14].Figure 1 shows a graphic representation of the components of scaffolds to be used as bone grafts.

Scaffolds
Scaffolds are three-dimensional porous, fibrous, or permeable biomaterials that provide mechanical stability to cells and allow the transport of body fluids.They also promote cell adhesion and proliferation and extracellular matrix (ECM) deposition with minimal inflammation and toxicity Fig. 1 Representative diagram of bone tissue engineering [15] while biodegrading at a certain controlled rate.Thanks to these characteristics, they can be used as a template for the reconstruction of defects in nerves, muscles, bones, etc. [16,17].One of the main characteristics of the scaffolds is that they present a microstructure and mechanical properties similar to those of bone tissue; hence, they are candidates to be used in bone regeneration.

Microstructure and Mechanical Properties of Bone Tissue
Bone is a highly vascularized and dynamic natural compound that is in constant remodeling throughout the life of human beings.It has excellent mechanical properties and resistance to fracture, and it also provides shape and protects the internal organs, facilitates locomotion, and acts as a storage place for minerals [18].The architecture of bone tissue is an important characteristic since it influences both the mechanical properties and the biological response.The highly porous structure of the scaffolds with interconnected pores allows cell growth and migration, as well as the passage of nutrients; it also carries out the vascularization.Furthermore, an optimal design must provide sufficient surface area for cell-scaffold interactions and, at the same time, facilitate oxygen diffusion and excretion of waste products [15].The minimum pore size is 100 μm due to cell size, migration, and nutrient transport.Pore sizes of 300 μm or larger are recommended to facilitate the formation of blood vessels and new bone; nevertheless, high porosity will lead to low mechanical strength [19].Table 1 presents the values of the mechanical properties of cortical and trabecular bone according to the different mechanical loads.
One of the main requirements in tissue engineering is to obtain biocompatible scaffolds that, when in contact with physiological fluids, do not cause any type of negative reaction, hence the importance of manufacturing scaffolds based on biocompatible materials; bioglasses are an option due to their bioactive properties.

Bioactive Glasses
Since their discovery in 1969 by Hench, bioactive glasses have been the subject of intense research as biomaterials for bone tissue repair and replacement.Their relevance lies in their ability to chemically bond to the living bone by establishing a strong material/tissue interface.When a bioactive glass is implanted, it gradually dissolves, and the released ions promote the growth of a layer of carbonated hydroxyapatite (CHA) on its surface which is responsible for its strong bond with the surrounding tissue.Bioactive glasses are also reported to release ions that activate osteogenic gene expression and stimulate angiogenesis.The first bioactive glass was formulated by Professor Hench and named 45S5 Bioglass® with composition 45% SiO 2 , 24.5% Na 2 O, 24.5% CaO, and 6% P 2 O 5 in weight [21,22].Table 2 shows inorganic glasses used in the biomedical field.The most used are silicate glasses; nevertheless, borate and phosphate glasses have gained attention due to their unique properties, which are different from those of silicate glasses.
Bioactive glasses have some limitations in terms of solubility and biological properties; nevertheless this could be improved by incorporating doping elements into the bioglass composition in order to provide new biological functionalities [24].

Inorganic glass Characteristics
Silicate Good bioactivity and easy bonding with the host tissue.There are some drawbacks, such as poor mechanical properties (caused by its amorphous nature) and its tendency to crystallize during sintering, so the presence of crystalline phases delays the formation process of the hydroxyapatite layer Borate They are characterized by their higher bioactivity compared to silica-based glasses, resulting in faster bioactive kinetics Phosphate They are resorbable and bioactive materials and their dissolution rate can be adjusted according to their oxide composition

Doping Elements
There are different trace elements such as iron, iodine, fluoride, copper, zinc, chromium, selenium, manganese, and molybdenum which are present in the human body and are vital for maintaining human health.Some of these elements could act as an essential cofactor in several critical enzymes.Figure 2 shows the incorporation of ions as therapeutic agents in bone structure to stimulate bone formation, inhibit bone resorption, and with antibacterial properties.
To cover various aspects of the treatment of bone diseases, dopant elements such as Cu, Ag, Mg, Zn, Sr, and Co have been incorporated into the structure of the silicate, borate, and phosphate bioglasses (Table 3).The presence of these ions in the glass structure is a key factor due to their role as antibacterial agents, promoters of osteogenesis, and inducers of angiogenesis.Among them, Cu 2+ and Co 2+ have been recognized to enhance angiogenesis [6].Angiogenesis is the process of creating new blood vessels, it is a crucial phase in wound healing, and occurs during the regeneration of tissues (skin and bone).
In particular, the addition of these metal ions influences the microstructure and mechanical properties as well as the thermal behavior, but mainly, the dissolution behavior of the scaffold causing effects on the bioactivity, cell proliferation, and a possible antibacterial effect.

Effect of Dopant Addition on the Microstructure and Mechanical Properties of Scaffolds
Ideally, a tissue engineering scaffold must have adequate mechanical stability, mechanical strength, and a highly open porous structure, so that tissue can develop and tissue fluids and nutrients can be freely transferred; pore size and pore size distribution must be suitable for cell growth [35].By controlling the architecture and pore size distribution, the mechanical properties of the implants could be tailored to specific tissue applications.In general, interconnected pores larger than 400 μm are adequate for vascularization, while the minimum pore size for osteogenesis is 100 μm [36].
Zamani et al. [37] fabricated alginate composite scaffolds with bioglass containing ZnO and MgO particles (60SiO 2 -26CaO-4P 2 O 5 -5ZnO-5MgO, mol%) by lyophilization method.The results obtained by SEM (see Fig. 3) presented a wide pore distribution for the different scaffolds with two pore sizes of approximately 75 and 275 μm.The wide pore distribution enhanced cell function and bone regeneration, while the ultrafine pores allowed cell attachment and protein adhesion.The increase in bioglass content to alginate led to a decrease in the pore size due to the presence of Zn and Mg, which present higher binding energy with respect to the Ca present in the bioglass.
Barua et al. [38] studied the effect of the incorporation of ZnO on the properties of hydroxyapatite (HAp)/ poly(methylmethacrylate) (PMMA)/ZnO composite scaffolds developed by the gas foaming process.The images obtained by SEM (Fig. 4) show a porous structure of the scaffolds.In the case of the HP 70/30 scaffolds, they showed a porous structure with pore sizes of 167.7 μm with the HAp particles evenly distributed throughout the structure (Fig. 4a).On the other hand, the HPZ scaffolds with 2.5 wt% ZnO exhibited maximum pore sizes of 149.9 μm and HAp particles dispersed within the PMMA matrix (Fig. 4c); the microstructure obtained with 2.5 ZnO presented a similar morphology to that of HP 70/30, but with the presence of small, bright white ZnO agglomerated nanoparticles.The greater the amount of ZnO, the greater the amount of these agglomerates.HPZ scaffolds with 5, 7.5, and 10 wt% of ZnO exhibited pore sizes of 154, 170, and 123.7 μm, respectively.In the same study, the authors observed that the pore size increased when increasing the ZnO content up to 7.5 wt% but then decreased with 10 wt%, due to the formation of particle agglomerates caused by a high filler load that obstructs the pores.Baruba et al. also carried out the mechanical evaluation of the scaffolds with and without the addition of ZnO.The results showed how the addition of 2.5-and 5-wt% ZnO improved the compressive strength (from 5.44 to 9.56 and 19.16 MPa, respectively), modulus (from 30 ± 15 to 420 ± 22 and 460 ± 29 MPa, respectively) and porosity % (from 76.6 ± 1.2 to 78.9 ± 1.5 and 82.4 ± 0.9, respectively), while the addition of 7.5-and 10-wt% ZnO decreased the mechanical properties (Fig. 5a and b).It was observed that the addition of 2.5-and 5-wt% ZnO decreased the grain size from 28.05 to 18.56 nm, allowing a dense and compact structure and increasing the resistance and the compression modulus.While the addition of 7.5-and 10-wt% ZnO increased the grain size from 22.92 to 23.39 nm.From the SEM images, the addition of 2.5-and 5-wt% ZnO leads to the agglomeration of particles that improve the contact surface.In the case of scaffolds with 7.5-and 10-wt% ZnO, the excessive agglomeration of the particles may affect the interatomic filler-matrix bonding.This could lead to an increase in stress concentration generating cracks at higher load conditions, thus degrading the overall compressive properties.The authors concluded that the addition of 5-wt% ZnO exhibited the best properties suitable for bone tissue engineering applications.
To observe the effect of the addition of ZnO on the structure of β-TCP, a SEM analysis of both pure ZnO and β-TCP powders was performed, in addition to the analysis of the etched and unetched scaffolds.The authors observed that the β-TCP and ZnO powders were not uniform (Fig. 7a and  b).The non-etched scaffold surface revealed a smooth structure (Fig. 7c), while the etched scaffolds (Fig. 7d-h) showed clear demarcation in the grain boundaries.The mean grain size of the undoped β-TCP scaffold was calculated to be 1.54 µm; nevertheless, it decreased by adding 0.5-, 1.5-, and 2.5-wt% ZnO to 1.01, 0.72, and 0.29 µm, respectively.The reason for this behavior is that ZnO is a refractory metal oxide and has an inhibitory effect on grain growth during the sintering process.
Feng et al. also evaluated the effect of the ZnO content on the compressive strength and stiffness of the scaffolds.They observed that the increase of ZnO from 0 to 2.5 wt% caused an increase in the compressive strength and stiffness from 3.01 to 17.89 MPa and from 112.86 to 313.48 MPa, respectively.Densification, microhardness, and fracture toughness also increased from 91.2 to 95.3%, from 3.51 to 4.20 GPa, and from 1.09 to 1.40 MPam 1/2 , respectively, while the addition of 3.5-wt% ZnO caused a decrease in the microhardness, fracture toughness, compressive strength, and stiffness at 4.08 GPa, 1.35 MPam 1/2 , 16.12 MPa, and 297.74 MPa, respectively.Hence, the authors concluded that the addition of 0 to 2.5-wt% ZnO decreased the grain size, while 3.5-wt% ZnO increased the grain size, which means that the larger the size, the lower the mechanical properties.
Ye et al. [40] fabricated HAp scaffolds with mesoporous bioactive glass (MBG) coatings with a composition of 15CaO-5P 2 O 5 -80SiO 2 , with different CuO contents (2 and 5 mol%), using the sol-gel technique.The authors observed how the untreated HAp-based scaffold presented a white color, while the HAp-treated scaffold changed to light blue and even gray when increasing the CuO content in the coating layer.The porosity of the scaffolds decreased slightly after the modification of xCu-MBG, from 75.5 ± 1.5% for HAp to 74.4 ± 1.3, 74 ± 2.1, and 74.1 ± 1.6% for 0Cu-MBG, 2Cu-MBG, and 5Cu-MBG, respectively.The untreated HAp scaffold exhibited a macroporous structure with pore sizes from 200 to 500 μm.As for the HAp scaffold coated with Cu-MBG, it also revealed a porous structure, and the coating did not affect the interconnectivity of the macropores.The untreated HAp showed highly crystalline hydroxyapatite grains in the pore walls, while the Cu-MBG-modified samples showed flat walls.The authors concluded that the Cu-MBG coating did not significantly influence the microstructure of the HAp scaffolds.
Shuai et al. [41] fabricated biosilicate (Mg 2 SiO 4 /CaSiO 3 ) scaffolds with the addition of SrO by selected laser sintering (SLS).The SEM images in Fig. 8 showed a microstructure with the presence of grains attributed to Mg 2 SiO 4 and small CaSiO 3 particles, located between the gaps of the Mg 2 SiO 4 grain boundaries.From the EDS analyses, it is observable that the Sr content is always higher in the CaSiO 3 phase than in Mg 2 SiO 4 .In the 0.5SrO and 1SrO scaffolds, the CaSiO 3 phase increased, but the Mg 2 SiO 4 grain size decreased.SrO acted as a sintering additive that could promote densification and refine the grain during the sintering process.Compressive strength, as well as fracture toughness, remained almost constant when SrO increased from 0 to 1 wt%.The compressive strength as well as the fracture toughness of the scaffolds with 1-wt% SrO reached values of 39.55 ± 1.48 and 2.38 ± 0.06 MPa, respectively.But the compressive strength decreased as the SrO content increased to 2 and 3 wt% (see Fig. 9).
Yin et al. [42] fabricated and characterized Sr-doped borate-based bioactive glass scaffolds by the polymer foam replication technique.The images obtained by SEM showed the microstructure of the polyurethane foam It is important in the formation of apatite, and it decreases the degradability of bioglass and improves the bioactivity of biomaterials [29,30] Zn It has an anti-inflammatory effect and antibacterial and anti-gingivitis properties.The incorporation of zinc in bioglass makes it a versatile material for dental repair and bone augmentation [26,31] Sr Improves the bone microarchitecture and increases the bone mineral density with various biological functions, including the induction of osteogenesis by enhancing the proliferation and differentiation of preosteoblast cells into osteoblasts and the inhibition of osteoclast genesis by reducing the differentiation, activity, and bone resorption by osteoclasts [32,33] Co The addition of Co plays a key role in the formation of amino acids and some proteins in nerve cells and in the creation of neurotransmitters that are essential for the homeostasis of an organism [34] (Fig. 10a), as well as that of the scaffolds with 80% porosity and pore size in the range of 200-500 µm, forming an interconnected network like that of the polyurethane foam.
From the mechanical evaluation of the scaffolds, it was observed that the addition of Sr increased the compressive strength; in the case of porosity, an increase was observed 1 3 with the addition of 3-mol% Sr but it decreased with 6 and 9 mol% (see Table 4).The reason for the increase in the compressive strength and the decrease in the porosity is that Sr promotes densification and grain refinement during the scaffold sintering process.Finally, Table 5 summarizes the values obtained for compressive strength, pore size, and porosity of bioactive glass scaffolds and the effect of the addition of some metal ions on their microstructure.
Evidently, the addition of doping agents to the bioactive glass composition for the manufacture of scaffolds allowed changes in its microstructural behavior such as a decrease in particle size and porosity, to mention a few; this caused changes in its mechanical behavior, as previously described.On the other hand, the addition of dopants has a significant influence on the glass network and thus on the transformation temperatures, such as glass transition, crystallization, and fusion, respectively; hence the importance of studying its effect on thermal behavior.

Effect of Metal Ions on Thermal Behavior
In recent years, bioactive glasses have gained interest as bone regeneration systems, due to their excellent bioactivity and ability to release therapeutic molecules [47].Understanding the effect of dopant ion incorporation on the structure, thermal behavior, and chemical durability of bioactive glasses is critical for the design of new compositions with personalized biological functions and applications [48].The addition of metal ions causes discontinuities in the glass lattice because they expand or weaken the lattice, leading to changes in chemical durability, thermal stability, and other properties.To further improve the bioactivity, mechanical properties, and biological response of bioactive glasses, metal ion elements have been incorporated into their composition.Table 6 shows the effect of metal ions on thermal behavior.
As it is observed in Table 6, the addition of dopants improves or promotes the crystallinity of the bioglass [50,53,55,56,58].The presence of crystalline phases tends to delay the formation of the hydroxyapatite layer so they become less bioactive in simulated body fluid [24].In reference [50], the addition of Cu and La (1 and 5 wt%) promoted the formation of different crystalline phases at 800 °C (cristobalite, quartz, and pseudowollastonite) and 1000 °C (cristobalite and pseudowollastonite) which hindered the bioactivity of the glass in physiological fluids without affecting the biocompatibility of the material.Wang et al. [61] showed only the formation of hydroxyapatite phase and no crystalline phases were attributed to the presence of Ag, so its addition did not affect the biocompatibility of the scaffold, allowing the proliferation and adhesion of the MC3T3-E1 cells, as well as the production of alkaline phosphatase.On the other hand, Goodarzi et al. [62] observed by XRD analysis in their collagen/β-TCP/SrO scaffolds the presence of small peaks attributed to Sr and SrO and crystalline phases, such as calcium phosphate, calcium pyrophosphate, and hydroxyapatite.Despite the presence of these reflections, the scaffolds did not present biocompatibility problems allowing the proliferation of rBM-MSCs cells as well as the increase of alkaline phosphatase.As reported, the addition of doping elements allows an expansion of the bioglass network, causing an increase or decrease in the characteristic glass transition, crystallization, and fusion temperatures, which will affect the rate of dissolution of the bioglass when in contact with physiological fluids.

Effect of Metal Ions on the Bioactivity of Bioactive Glasses
The in vitro bioactivity of the materials is the measure of the biocompatible surface mineralization capacity (HAp  [39].https:// creat iveco mmons.org/ licen ses/ by/4.0/ crystal formation) under physiological conditions.When bioactive glasses come into contact with aqueous solutions (e.g., body fluids), they begin to dissolve and release ions, such as calcium and phosphate.As a result of this release of ions, there is the formation of a surface layer of apatite, which is often called "bioactivity" [63].Hence, the formation of HA on material surfaces after immersion in simulated acellular body fluid (SBF) is considered a qualitative measure of bioactivity [64].Table 7 shows the effect of dopants on the scaffolds when in contact with physiological fluids.
As previously observed, the incorporation of metal ions causes a change in the rate of dissolution of bioglass in physiological fluids for the formation of the hydroxyapatite layer, the main mineral of bone tissue.Furthermore, the addition of dopants and the formation of HA will play an important role in cell proliferation in order to carry out the reconstruction of bone tissue.

Effect of Dopant Addition on Cell Proliferation
Transition metal ions are essential micronutrients for all living organisms and play an important role in bone metabolism [85].For this reason, specific metal ions with therapeutic effects have been incorporated into the chemical structure of bioglass (BG) for their use in different biomedical applications.Its incorporation into biomaterials can stimulate angiogenesis and osteogenesis.Furthermore, its release control could achieve bone formation ability [86,87].Table 8 shows the effect of dopants against different cell lines.
As it was depicted in Table 8, the addition of dopants to the scaffold composition did not cause cytotoxic effects, since their addition promotes or enhances cell proliferation.The addition of the different metal ions does not affect the biocompatibility of the scaffold because they are considered promising agents to improve bone formation capacity, which could be achieved by controlling the release of specific ions Reproduced from Ref. [41] with permission from the Royal Society of Chemistry.https:// creat iveco mmons.org/ licen ses/ by/3.0/ during the in vivo dissolution of the scaffold, in addition to improve the physical properties of scaffolds.The biocompatibility of the scaffold goes hand in hand with the concentration of dopant in the composition that ranges between a few ppm and a few percentage [104].For instance, Ryan et al. [105] fabricated bioactive glass scaffolds doped with collagen and 2-mol% Cu (CuBG-CS) where the addition of Cu did not cause cytotoxicity to MC3T3-E1 preosteoblast cells.While Ali et al. [44] studied the effect of adding different amounts of Cu (0, 1, 2, and 3 mol%) to bioglass (54.6-XSi O 2 -6Na 2 O-7.9K 2 O-7.7MgO-22CaO-1.74P 2 O 5 -XCuO) and observed that the addition of 3-mol% CuO improved the cell viability without showing toxicity to SCC-25 human squamous cells.On the other hand, Leite et al. [106] fabricated scaffolds of composition 55SiO 2 -40CaO-5P 2 O 5 doped with 10-mol% Sr which replaced partially the CaO; this addition stimulated the proliferation of human umbilical vein endothelial cells (HUVEC) without showing toxic effects.Aina et al. [107] added different concentrations of Zn (5 and 20 mol%) to the 45S5 bioglass, where the addition of 5 mol% of Zn promoted the proliferation of BAE-1 cells without causing toxicity, while 20 mol% of Zn had a negative effect on biocompatibility when in contact with BAE-1 cells.One of the drawbacks of adding dopants is the concentration.At lower concentrations it causes beneficial and positive effects, while at high concentrations it may cause the scaffolds to be toxic to cells and healthy tissue.
Despite the excellent biological properties of glass in developing scaffolds for bone regeneration, they have limitations such as not providing protection against the formation of some type of bacteria, which could be caused by an unhygienic environment for the patient.Therefore, there is a need to incorporate doping elements that help prevent bacterial infections on the implant surface.

Effect of Dopant Addition on Antibacterial Activity
It is very important not only to obtain a good and strong biological bond with the living bone but also to prevent bacterial infection since the colonization of bacteria on the implant surface could lead to infection with serious consequences, implant failure, and sometimes the need for a second surgery [7].The control of bacterial infections is of particular importance in the field of tissue engineering.Recently, much attention has been paid to the use of bioactive glasses for antibacterial strategies, mainly due to their ability to act as carriers for the local release of antimicrobial agents [108].The incorporation of metal ions in bioglass aims at specific biological functions and strengthens its efficiency by modifying its structural framework [109].Various ions are capable of inducing differentiation of osteoblast precursors through growth factor signaling pathways or of stimulating other processes that support bone tissue growth [110].The incorporation of antibacterial metal ions, including Cu, Ag, Mg, Zn, Sr, and Co, to mention a few, is promising for use in tissue engineering.Table 9 shows the effect of the addition of dopants on the composition of the scaffolds when in contact with bacterial strains.

Current Status
Bioactive glasses have been of great importance in medicine due to their excellent biocompatibility and hence their use in the manufacture of functional materials.Currently, porous scaffolds made from bioactive glasses for their application in bone tissue regeneration continues to be a subject of research due to their chemical similarity with the mineral Lowered the crystallization ( T c ), the glass transition ( T g ), and the melting ( T m ) temperatures [52] Ag/Ti 46S6 Reduced the melting temperature ( T m ) and implied variations in the crystallization ( T c ) and glass transition ( T g ) temperatures They did not show interference in thermal stability [60] components of bone, their adequate biocompatibility, and their remarkable capacity for osteogenesis [131].Nevertheless, the use of bioactive glass is not only limited to the manufacture of porous scaffolds but also for many other applications.Currently, bioactive glasses can be used in the form of microspheres or nanoparticles as promising carriers for drugs, proteins, and growth factors since they offer more controlled degradation and release kinetics due to their uniform spherical shape and particle size; also, they can be used as injectable systems in orthopedic and dental applications.Specifically, bioactive glass nanoparticles doped with Te have been applied for cancer treatment since the release of Te ions induces apoptosis of cancer cells.On the other hand, the addition of Zn and Mn can provide antibacterial and osteogenic properties, respectively, to mesoporous bioactive glass nanoparticles (MBGNs).Moreover, the mixture of these MBGNs with zein, a natural biopolymer found in corn, produces composites that have been electrophoretic deposited on metal implants as coatings showing their corrosion resistance properties and their efficacy against S. aureus and E. coli, as well as their bioactivity properties to form a hydroxyapatite layer after immersion in SBF [132][133][134][135][136]. Other research currently being carried out is the incorporation of metal ions such as Sr and Ag in bioactive glass microspheres, since it has showed a positive response in antibacterial capability, in vitro bioactivity, and osteoblast cell viability [137,138].For their part, bioactive glasses nanospheres doped with rare earths, such as La, Ce, Pr, Nd, Eu, and Dy, among others, are currently being studied to improve biological performance for bone regeneration and provide additional functionalities to bioglass, such as fluorescence, luminescence, radiation protection, antiinflammatory and antibacterial properties [139].Finally, it is noticeable the use of bioactive glass in the manufacture of dental implants, orthodontics, endodontics, and in oral care products (e.g., toothpastes) since they release antibacterial agents, stimulate remineralization, and reduce hypersensitization [140][141][142].In environmental terms, the production of thermoelectric energy and the combustion of coal generate large amounts of solid waste, including fly ash which, due to its very fine granulometry and large surface area, has currently been used to manufacture ceramic bioscaffolds for applications, such as medical implants [143].

Conclusion
In this review, relevant information from the literature related to the effect of the addition of dopants in the composition of bioactive glasses for the manufacture of scaffolds with porous structure for use in the biomedical field is summarized.It is understood that the doping elements described in this review are capable not only of directly influencing the composition of the glass but also the physical characteristics in terms of morphology, topography and crystallinity, which in turn directly influence the microstructure and mechanical properties of the scaffold.Another important point in this review is the behavior of the addition of the different dopants in terms of the biological response after being in contact with the physiological fluid, cells, or bacteria.So, it could be said that the addition of dopants does not affect the biocompatibility of the material.But, on the other hand, certain ions promote not only the action of inhibiting the growth of bacteria but also obtaining an anti-inflammatory, antimicrobial, and antifungal response.
Based on what is reported in the literature, a complete and clear study of the concentrations of dopants in the composition of bioglass for the manufacture of porous scaffolds is suggested.In this way, it would be easier to select the type and amount of dopant and monitor the biological response.

Fig. 9
Fig.9 Results of a compressive strength and fracture toughness and b stress-strain curves with standard deviation error *p > 0.05, **p < 0.05.Reproduced from Ref.[41] with permission from the Royal Society of Chemistry.https:// creat iveco mmons.org/ licen ses/ by/3.0/ transition temperature ( T g ) and increased the crystallization temperature ( T c ) due to the substitution of Ca by Mg and Zn [56] Zn SiO 2 -CaO-Na 2 O-P 2 O 5 Induced a decrease in the melting temperature ( T m ) and increased thermal stability [57] Zn/Sr SiO 2 -CaO-Na 2 O-P 2 O 5 Decreased the melting temperature ( T m ) of glass with Zn and increased the crystallization temperature ( T c ) of glass with Sr [58] Sr P 2 O 5 -CaO-Na 2 O-MgO Caused a slight decrease in T g with a marked effect on T c [59] Sr/Mg Na 2 O-K 2 O-CaO-P 2 O 5 -SiO 2

Table 1
Summary

Table 3
Metal ions that act as doping elements in bioactive glasses Metal ion Functions References Cu It acts as an antibacterial agent; in addition, it elicits angiogenic and wound-healing responses in vivo and in vitro.It increases the bonding capacity of the tissue with the bioactive glass and promotes bone growth and mineralization

Table 5
Effect of metal ions on the microstructure and mechanical properties of scaffolds

Table 6
Effect of metal ions on thermal behavior

Table 7
Effect of dopants on in vitro bioactivity of bioactive glasses

Table 8
Effect of metal ions on cell proliferation

Table 9
Effect of metal ions in antibacterial tests