==== Front Materials (Basel) Materials (Basel) materials Materials 1996-1944 MDPI 33291305 10.3390/ma13235560 materials-13-05560 Review A Review of Bioactive Glass/Natural Polymer Composites: State of the Art Sergi Rachele Bellucci Devis https://orcid.org/0000-0001-7161-5297Cannillo Valeria * Dipartimento di Ingegneria Enzo Ferrari, Università degli Studi di Modena e Reggio Emilia, Via P. Vivarelli 10, 41125 Modena, Italy; rachele.sergi@unimore.it (R.S.); devis.bellucci@unimore.it (D.B.) * Correspondence: valeria@unimore.it; Tel.: +39-059-205-6240 06 12 2020 12 2020 13 23 556013 11 2020 04 12 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Collagen, gelatin, silk fibroin, hyaluronic acid, chitosan, alginate, and cellulose are biocompatible and non-cytotoxic, being attractive natural polymers for medical devices for both soft and hard tissues. However, such natural polymers have low bioactivity and poor mechanical properties, which limit their applications. To tackle these drawbacks, collagen, gelatin, silk fibroin, hyaluronic acid, chitosan, alginate, and cellulose can be combined with bioactive glass (BG) nanoparticles and microparticles to produce composites. The incorporation of BGs improves the mechanical properties of the final system as well as its bioactivity and regenerative potential. Indeed, several studies have demonstrated that polymer/BG composites may improve angiogenesis, neo-vascularization, cells adhesion, and proliferation. This review presents the state of the art and future perspectives of collagen, gelatin, silk fibroin, hyaluronic acid, chitosan, alginate, and cellulose matrices combined with BG particles to develop composites such as scaffolds, injectable fillers, membranes, hydrogels, and coatings. Emphasis is devoted to the biological potentialities of these hybrid systems, which look rather promising toward a wide spectrum of applications. natural polymersbioactive glassescompositesmechanical propertiesbiological performance ==== Body 1. Introduction Over the past 40 years, life expectancy in industrialized countries has continued to rise thanks to many factors such as healthier nutrition, health care system and public health efforts, medical treatments, and more salubrious lifestyles [1,2]. However, this progress goes hand in hand with an increase of pathologies and work-related accidents such as spinal problems, arthritis, joint dysfunction, traumatic injuries, and lacerations [3,4]. Such diseases imply dramatic suffering for patients and might cause severe and long-term pain, work limitation, and disability. In this context, biomaterials’ science can make an important contribution to medicine, thanks to the possibility to design increasingly advanced prostheses and implants to be used in several clinical applications to correct and improve irregularities and abnormalities (i.e., spinal rods, pacemaker, stent), to assist in recovery from injury (structural, pharmaceutical effects), and to replace body parts that lose function (total hip, heart). Therefore, new biomaterials with greater biological response, biocompatibility, and thermal and mechanical properties have been increasingly studied [5,6]. Biomaterials, which should be biocompatible, intrinsically non-toxic, non-carcinogenic, and non-allergenic, can be classified as first generation, second generation, and third generation according to their response in the host. First-generation biomaterials had the aim to achieve a proper combination of mechanical and biological properties that correspond to those of the replaced tissue. Typically, these biomaterials do not cause or undergo chemical or biological changes in the host. On the contrary, second-generation biomaterials can promote a specific biological response on the biomaterials’ surface. Therefore, second-generation biomaterials can stimulate the formation of new bone by inducing a controlled action and reaction mechanisms in a biological environment [5,7]. On the other hand, a specific response at the molecular level is promoted by third-generation biomaterials [8]. In fact, such devices can be gradually degraded and substituted by living host tissues. Biomaterials may include ceramics, glasses, metals, and polymers with their specific properties [9,10]. Since polymers are the most versatile class of biomaterials, they have been extensively used in industrial applications such as farming, food sectors, pharmaceutical, and biomedical fields. Polymers are classified into synthetic and natural types: a large number of synthetic polymers are synthesized from petroleum oil through a series of chemical reactions, while natural polymers are extracted from animal waste or plants in nature [11,12,13]. Synthetic polymers can be classified as (i) hydrophobic, non-water absorbing materials (i.e., polyethylene (PE), polypropylene (PP), poly(methylmethacrylate) (PMMA)); (ii) more polar systems (i.e., copoly(lactic-glycolic acid) (PLGA)) (iii) water-swelling materials (i.e., poly (hydroxyethyl methacrylate) (PHEMA)); and (iv) water-soluble materials (i.e., poly (ethylene glycol) (PEG)). On contrary, natural polymers can be broadly categorized as (i) proteins such as collagen, gelatin, and silk fibroin; (ii) polysaccharides such as chitosan, hyaluronic acid, alginate, and cellulose; (iii) and polynucleotides (DNA, RNA) [12,14]. Regardless of whether they are synthetic or natural, small repeating units constitute the long chain molecule of polymers [12,15]. In synthetic polymers, the small units (i.e., monomers) and the polymerization process influence the characteristic of the final system, such as its crystallinity, molecular weight, and melting temperature [16,17]. Some synthetic polymers lose their integrity once implanted in the body; the degradation kinetic varies from a few weeks to a few years depending on the polymers’ chemical composition and on the surrounding physiological environment [15]. Their gradual degradation begins when the surface of the system starts to absorb components such as water, proteins, and ions from the surrounding environment [15]. Of course, the degradation products released from synthetic polymers should be non-toxic for the host organism. However, as this does not always happen, the efforts of many researchers have been focused on natural polymers, which usually degrade into soluble, non-toxic chemical species [11]. These chemical species are recognizable and metabolized by the body [18], being body-friendly species. Furthermore, synthetic polymers have been partially replaced by natural ones because the latter do not lack in cells recognition sequences [19,20], and the stimulation of a chronic immunological reaction is avoided [21]. Furthermore, natural polymers show more similarity to the extracellular matrix (ECM, network of biomacromolecules including glycosaminoglycans, which are polysaccharides and fibrous proteins such as collagen, laminin, elastin, and fibronectin [12]), being readily recognizable by the body compared to the synthetic ones. Such similarity to ECM could be summarized as a suspension of macromolecules that support everything from local tissue growth to the maintenance of an entire organ. In this context, since ECM provides structural support and modulates the activity of growth factors, it represents one of the main footprints for designing biomaterials [22]. Thus, the ideal biomaterial for tissue engineering applications should be able to recreate the dynamic biochemical, structural, and mechanical properties of the naturally occurring ECM. However, despite these positive aspects, natural polymers show lower stability in terms of physical and mechanical properties compared to synthetic ones [11]. Moreover, natural polymers suffer some limitations due to their solubility and industrially acceptable processability: (i) variation in the final properties of polymer due to their source, (ii) some contamination caused by the presence of microbes, (iii) uncontrolled water uptake, and (iv) an unpredictable degradation route. Furthermore, since most natural polymers are water-soluble, various crosslinking methods to control their structure, water uptake, and degradation in aqueous environment have been developed [23,24]. Generally, natural polymers have been combined with one another to improve workability; in addition, natural polymers are typically combined with ceramics fillers (i.e., ceramics, glass-ceramics, bioactive glasses) to reinforce the structure of the final system and, thus, to produce composites with a better mechanical performance [25,26]. It is known that bioactive glasses (BGs), and especially the “gold standard” 45S5 Bioglass® [27], have been widely used in several clinical applications in regenerative medicine, tissue engineering, and dentistry [27,28,29,30,31] by virtue of the ability of bonding to bone. The bonding ability to bone of BGs is mediated by the formation of bone-like hydroxy carbonate apatite (HCA) on the surface of BGs once in contact with physiological fluids. The structure and chemistry of HCA is similar to natural apatite, which is the mineral phase of bones; thus, the deposition of HCA on the surface of biomaterials is typically considered one of the initial steps that lead to the formation of a stable bond at the implant/tissue interface [32,33]. Indeed, the rapid physiochemical reciprocal influence between the surface of biomaterials and the surrounding environment with the silica layer and HCA layer formation represent the first step to the success of an implant. Additionally, 45S5 Bioglass® is osteoinductive and able to bond to both soft and hard tissues [34]. However, in recent years, many BGs have been developed, especially those containing the so-called therapeutic ions such as strontium and magnesium [35,36,37,38,39,40,41,42,43,44,45,46,47]. The addition of specific and therapeutic ions that are released during bioactive glass degradation [48,49] aims at enhancing specific cellular response in the host, favoring regenerative processes. Special attention has been paid to the development of sodium containing BGs and/or borate bioactive glasses to improve reactivity in terms of bioactivity and biological response. On the other hand, Cu, Zn, and Ag ions have been incorporated to achieve bioactive glasses with antibacterial properties [50,51,52,53,54]. For these reasons, BGs can be added to natural polymers, which behave as a matrix in order to obtain innovative composites (i) with improved bioactive behavior [55], (ii) with the ability to release therapeutic ions which stimulate a specific molecular response, (iii) and/or with the capability to release alkali ions that counteract the acid by-products from polymers degradation. This review presents the state of the art about the production of composites based on BGs combined with natural polymers: (i) proteins such as collagen, gelatin, silk fibroin, and (ii) polysaccharides such as hyaluronic acid, chitosan, alginate, and cellulose, which are widely used as biomaterials and look particularly promising for several clinical applications. A specific emphasis is given here on the biological performance of such innovative systems, which could open interesting scenarios in the field of biomaterials. Figure 1 schematizes the natural polymers that can be combined with bioactive glasses to fabricate advanced composites, as described in the following. 2. Natural Polymers: Proteins Proteins are assemblies of various amino acids and are monodisperse [12]; various moieties can attach on the amino acid side chain, leading to different physical and biochemical properties of the original protein. Proteins have potential limitations such as immunogenicity as well as batch-to-batch differences consequent to purification processes. Furthermore, proteins materials are generally harvested from animal sources, complicating translation to a clinical setting [56]. Proteins such as collagen, elastin, silk fibroin, and gelatin have been studied as potential scaffolds for tissue applications [12]. Such protein-based materials are useful in sutures, drug delivery vehicles, etc. Proteins-based materials as well as biomaterials in general have to offer tunable degradability providing control over the sequestration and delivery of specific bioactive factors to improve and guide healing and regeneration over a long period. Collagen, gelatin, and silk fibroin with the incorporation of bioactive glasses are considered below. 2.1. Collagen/Bioactive Glass Composites Collagen is a protein that forms the structural basis for much of the extracellular matrix (ECM) of our tissues; therefore, it is the most studied polymer among natural ones. In the human body, among several types of collagen, types I–IV are the most common [12]. In bone, type I collagen is combined with hydroxycarbonate apatite nanocrystals to create a bio-composite tissue that is highly organized from the nano to macroscopic length scale [57]. In particular, fibers of type I collagen promote cell adhesion and proliferation: cells typically adhere on the collagen surface by integrin α2β1, which is a primary adhesion receptor used by osteoblast-like cells to bond to the collagen surface (i.e., the substrate), favoring cell–cell interaction and cell–matrix binding [15,58]. Furthermore, collagen stimulates the differentiation of stromal cells of bone marrow [59]. Therefore, as the key component of the ECM, collagen induces bone regeneration and remodeling [60,61] by stimulating bone cells’ metabolic activity [62]. Collagen is suitable for different biomedical applications because it can mimic the mineralization as well as the mechanical and biological properties of osteoid [63]. In addition, its hydrophilic properties, hemostatic capability [12], high processability, and versatility in terms of physical forms give the possibility of using collagen for various products such as injectable gels, films, meshes, and fibers [64,65,66,67], bone and cartilage repair constructs [68,69], skin grafts [70], and wound dressings [71,72]. Despite its versatile form, collagen suffers from a high degradation rate and low mechanical properties (i.e., mechanical strength and stiffness), which can be enhanced by adding a specific reinforcing phase [12,73]. In this context, bioactive glasses (BGs) look particularly interesting as a second phase in a collagen-based composite to improve the mechanical properties of the system as well as the biological ones. It has been reported that bioglass nanofibers added to collagen can reduce infections and induce skin regeneration, thus making the final composite more suitable for clinical uses [73]. Therefore, the appropriate combination of bioactive glasses and collagen leads to biomedical devices that mimic the composition of natural bone. In particular, artificial scaffolds have been developed to solve the limitations of autografts, i.e., limited resources, additional pain, and the morbidity of donor sites [74]. The microporous structure of artificial scaffolds has high porosity and interconnected pores, which permit the spreading and growth of cells, while allowing the flow of nutrients and growth factors (GFs) toward cells and waste products from cells to the surrounding environment [75,76]. This microporous interconnectivity aids cells in multiplying and differentiating into the mature type of tissues [77]. However, an adequate balance between the porosity and bulk structure should be achieved to avoid the failure of structure. In this regard, BGs incorporated in collagen scaffolds resulted in improving compression and elastic modulus compared to pure collagen scaffolds [78]. Furthermore, BGs improved biological responsiveness as well [78]. As mentioned in the introduction, the incorporation of specific ions into the BGs composition enhances the specific cellular response in the host. Indeed, the biological responsiveness and performance of collagen/BGs composites is also associated with bioactive glasses composition [40,79]. The ionic sources such as Ca, Si, and P from bioactive glasses accelerate the precipitation of mineral phase on the surface of scaffolds. The hydroxy carbonate apatite (HCA) was detected on collagen/bioactive glass scaffolds 3 days after soaking in Simulated Body Fluid (SBF) solution [79,80]. The mineralization during immersion in SBF affects the mechanical properties of collagen/45S5 scaffolds, resulting in a transition from a soft to hard tissue with higher resistance to compressive stress [80]. Additionally, the mineralization involves the gradual degradation of BGs, inducing partial degradation of the composite. The degradation rate of composites should be equal to the rate of formation of new tissues [81]. The BGs degradation results in ion releasing, which stimulate the bioactivity as well as cells adhesion and proliferation on collagen/bioactive glass scaffolds compared to pure collagen scaffolds [79,80,82]. Indeed, it is known that the ions released by BGs regulate the gene expression and differentiation of cells to progenitor or stem cells as reported in [83,84]. Once in contact with human body, the typical ions in BGs composition (i.e., Ca, Si, P) influence bone metabolism and angiogenesis. For instance, the Si ion is essential for the metabolic process and for the formation and calcification of bone tissue [85,86]; the Ca ion enhances osteoblast proliferation, differentiation, and extracellular matrix (ECM) differentiation [87,88,89]; the P ion stimulates the expression of matrix protein, which is a key regulation of bone formation [90,91]. Therefore, the introduction of BGs, which release ions directly involved in tissue growth, in particular bone growth, could improve the final properties of collagen/BGs composites compared to collagen scaffolds only [92]. Although scaffolds have acquired extra importance in the regeneration and repair of damaged tissues [93,94,95], to overcome the limit of their rigid structure, injectable systems for small and irregular defects of both hard and soft tissues have been developed [40,82,96,97,98]. Collagen/BGs (CaO-P2O5-SiO2) hydrogels developed by Eglin et al. [96] showed an HCA layer after immersion in SBF solution, confirming that the presence of bioactive glass particles enhances the bioactivity of collagen. The chemical interaction between collagen molecules and bioactive glass nanoparticles should enable a more chemically stable network [99,100], avoiding the faster and total degradation of BGs phase with respect to the degradation of the collagen phase. Furthermore, the amount of bioactive glass particles into biomedical devices should not exert an excessive inflammatory response during degradation. The inflammatory response could cause an anti-angiogenesis effect, leading to a failure of collagen/BGs composites [97]. For these reasons, the amount of BGs in collagen and the degradation rate of the composite could be controlled by tailoring BGs composition and relative volume fraction, for example. To further control the degradation rate of BG, an improvement of the chemical interaction between collagen and bioactive glass (binary composition of 85% SiO2–15% CaO in mol %) should be reached [98]. In this regard, the amination process aims at forming a strong chemical link between the additional amino group of bioactive glasses and the carboxyl group of collagen [98]. This process resulted in a preservation of the original shape and in improving mechanical properties of collagen/85% SiO2–15% CaO hydrogels [98]. Improved mechanical properties were measured also for collagen/bioactive glass (BG, Si/Ca/P = 80:15:5) nanofibers developed by the electrospinning technique [101]. Furthermore, collagen/bioactive glass nanofibers promoted the adhesion and proliferation of human dermal fibroblasts (HDFs) cells inducing the secretion of type I collagen (COL-I) and vascular endothelial growth factor (VEGF) [101]. It has been demonstrated that COL-I forms most of the connective tissue in wound healing [102,103] and VEGF stimulates angiogenesis, which could be related to Si ions from BGs, as such ions have been shown to enhance angiogenesis [29,104,105]. The increased angiogenic capability of collagen/bioactive glass composites was coincident with a weaker inflammatory response compared to that of collagen films [101]. By tailoring the amount and composition of bioactive glasses as well as the morphological characteristics of composites, a specific molecular response and improved angiogenesis can be achieved [106,107]. Composites with good mechanical properties and improved biological performances could provide better 3D condition for progenitor or stems cells [108,109,110]. Table 1 summarizes collagen/bioactive glass composites. 2.2. Gelatin/Bioactive Glass Composites Gelatin is a translucent natural nontoxic colorless and brittle natural polymer. It is obtained from collagen that is thermally denaturized or physically/chemically degraded to break its natural triple helix. The manufacturing process of gelatin consists of (i) the pre-treatment of raw materials for the main extraction step; (ii) the main extraction step, which is the hydrolyzation of collagen into gelatin, and (iii) the final steps to eliminate water from gelatin solution to obtain dried, blended, and ground final gelatin. Being the denaturized form of collagen, gelatin can overcome the concerns about causing an immune response and a transmission of pathogens related to collagen [12]. Furthermore, the unique sequences of amino acids (i.e., glycine, proline, and hydroxyproline) of gelatin influence its biocompatibility and enhance cellular adhesion and proliferation. Therefore, the biocompatibility, biodegradability, and very low antigenicity of gelatin make it appropriate for both hard and soft tissue applications. Unfortunately, the fast degradation rate in physiological fluids and poor mechanical properties of gelatin limit its application [12]. However, these deficiencies can be mitigated by stabilizing gelatin in a physiological environment using crosslinking agents (i.e., glutaraldehyde and genipin). Since glutaraldehyde could induce cytotoxicity effects, methacrylic anhydride (i.e., a chemical crosslinker) has raised interest due to its inherent biocompatibility, biodegradability, and simplicity in synthesis [111]. Gelatin methacryloyl (GelMA) was produced by adding to type A gelatin (in PBS) the methacrylic anhydride under stirring, as described in detail in [111]. However, gelatin methacryloyl as pure gelatin showed lower ability in promoting tissue regeneration in the absence of bioactive materials. In fact, the development and fabrication of composites for biomedical devices using biodegradable polymers and bioactive materials is currently an open challenge. In the last decades, bone tissue engineering has become a promising approach to channel this challenge in which composites, bioactive materials, cells, and signaling biomacromolecules could be combined to achieve tissue regeneration. In this regard, the delivery of cells using carriers (i.e., porous scaffolds) has been shown to be a more efficient method compared to the direct administration of cells in situ. The incorporation of endothelial cells in gelatin/bioactive glass scaffolds further enhanced bone regeneration by improving vascularity compared to simple gelatin/bioactive glass scaffolds [112]. In addition, a novel and high impact gelatin/bioactive glass (64SiO2-5P2O5-31CaO mol%) scaffold, seeded with bone marrow mesenchymal stem cells (BM-MSCs) delivering bone morphogenetic protein-7 (BMP-7), exhibited a successful combination to enhance osteogenesis in bone defects [113]. An appropriate bonding between BM-MSCs/scaffolds and the host bone was related to the capability of bioactive glasses to form bonds with calcified tissues [113]. Indeed, bioactive glasses (BGs) are well known to be both osteoconductive and osteoinductive as well as biocompatible and highly bioactive. Unfortunately, BGs are brittle and exhibit poor mechanical properties, which limits their use in load-bearing applications. Thus, bioactive glasses incorporation into gelatin matrices to fabricate composites represent a feasible solution. The chemical bonding reaction between the nanoparticles of bioactive glass (nBG, 64SiO2-5P2O5-31CaO mol%) and gelatin is characterized by three major steps as reported elsewhere [114,115,116]: (i) a critical reaction between Ca2+ ions of nBG and gelatin molecules; (ii) the Ca2+ ions complexing with gelatin molecules, which are assembled with PO43−ions; and (iii) the –COOH and –NH2 groups in the gelatin molecule form chemical bonds with the P–O and O–H groups of nBG, resulting in a gelatin layer strongly attached to the surface of nBG. Gelatin/bioactive glass (64SiO2-5P2O5-31CaO mol%) scaffolds developed for bone tissue applications showed improved mechanical properties compared to gelatin scaffolds and human osteoblast-like cells (SaOS-2) cultured on gelatin/bioactive glass (64SiO2-5P2O5-31CaO mol%) scaffolds were well attached to the pores of scaffolds, as confirmed by their numerous lamellipodia and filopodia [114,115,116]. The SaOS-2 can be used to study mechanisms that involve the late osteoblastic differentiation stage in human cells because of SaOS-2’s capacity to deposit a mineralization-competent extracellular matrix (ECM). In addition, the formation of a hydroxy carbonate apatite layer on the biomaterials’ surface represents one of the necessary requisites to bond with living bone. By incorporating BGs into gelatin matrices, the mineralization was supported compared to pure gelatin composites [116,117,118,119]. The topography, porosity, and surface of scaffolds contributed to a successful interaction with tissues as well as the incorporation of bioactive glasses. High porous 3D dimensionally interconnected bioactive glass/gelatin composite scaffolds using a direct foaming process were developed [120]. This technique involves little or no organic solvents or hazardous chemicals being an appropriate alternative to conventional techniques used to fabricate synthetic polymer scaffolds and gelatin/BG scaffolds. Another alternative technique to fabricate scaffolds with a grid-like microstructure was developed by Gao et al. [121]. The solid free form fabrication (SFF) method offered high control on scaffolds structure using a computer-aided design and robotic deposition [121]. Porous 3D gelatin/bioactive glass (70SiO2-25CaO-5P2O5 mol %) scaffolds with high ability to form mineralized bone nodules by combined sol–gel and robocasting technique were developed [121]. On the other hand, the microsphere leaching technique using polymethylmethacrylate (PMMA) as a porogen agent was used to control the porosity of scaffolds [122]. The particle size of the sacrificial polymer spheres determines the porosity; therefore, a well-controlled and open porosity can be obtained by tailoring the size of particles [122]. Furthermore, PMMA can be easily dissolved in acetone, preserving the composite matrix. During the fabrication of composites containing bioactive glasses, particular attention should be paid to maintaining the bioactive glass composition unchanged. Indeed, the uncontrolled leaching of alkali and alkaline-earth elements alters the property of BGs. The rate of degradation could be partially controlled by tailoring the BGs composition, which is also responsible for a wide range of biological and chemical responses in the host. In this regard, the incorporation of Sr-doped bioactive glass into gelatin matrix was shown to enhance cell infiltration and neovascularization compared to scaffolds containing bioactive glasses without SrO [123]. The releasing of ions exhibited beneficial effects on bone formation at both cellular and tissue levels [123]. On the other hand, an Mg-Zn doped bioactive glass (SiO2-CaO-P2O5-MgO-ZnO) was added to the gelatin matrix to fabricate composite scaffolds for bone tissue engineering [124], aiming at stimulating cell growth and proliferation. Mg enhances the expression of collagen I and alkaline phosphatase (ALP) activity [37]. Zinc is involved in protein synthesis and is fundamental for the replication of DNA; it is a cofactor for enzymes, and it is engaged during bone cell growth, development, and differentiation [124]. For this reason, ZnO whiskers were added to gelatin/BGs scaffolds to improve cells proliferation; the addition of ZnO whiskers increased rat mesenchymal stem cells (rMSCs) proliferation [125]. Additionally, ZnO whiskers showed antibacterial properties that were favorable for obtaining multifunctional gelatin/BG composite scaffolds with antimicrobial activity [125]. Implanted devices could enhance the chance of infections causing implant failure, hospitalization, and sometime mortality of patients. Therefore, composites with antimicrobial properties would be highly desired. In this regard, a simple and “green” method was used to synthesize in situ silver nanoparticles in gelatin (i.e., a natural reducing and stabilizing agent) by reduction under heating [126]. The incorporation of BGs and silver nanoparticles enhanced human mesenchymal stem cells (hMSC) viability compared to gelatin scaffolds and increased the antibacterial effect of scaffolds with increasing silver nanoparticles [126]. Furthermore, Cu-BGN (95SiO2-2.5CaO-2.5CuO mol %)/gelatin coatings were used to successfully coat bioactive glass scaffolds introducing antibacterial properties without compromising the highly interconnected and porous structure of scaffolds [127]. It is worth noting that the concentration of bioactive glass particles in gelatin matrices should be carefully controlled to obtain desired improvements in terms of mechanical and biological properties and antibacterial effects. Table 2 summarizes gelatin/bioactive glass composites. 2.3. Silk Fibroin/Bioactive Glass Composites Silkworm Bombyx mori (B. mori) and various species of spiders secrete silk fibroin, which is a natural fibrous protein. Since spiders’ silks are different in nature, usually, silks from silkworm are used to fabricate silk-based biomaterials [128]. The raw silk is made of two parallel fibroin fibers held together with a layer of sericin on their surfaces [129]. Sericin should be removed, because it is thought to be responsible for allergic and inflammatory reaction. The fibroin fibers appear shiny and soft to the touch after the degumming process to remove sericin [129]. A light (L) chain polypeptide and heavy (H) chain polypeptide linked together make up the structure of silk fibroin through the formation of the H-L complex [129]. The superior mechanical properties of silk fibroins depend on the H chain, which can form β-sheet crystallites, while the L chain has a small role in the mechanical properties of silk fibroin due to its smaller size [129]. In general, increased β-sheet content has a protective effect on silk degradation, which is likely in part due to the fact that most proteases act outside of the β-sheet regions [130]. Silk fibroin has been widely used for its advantageous strength, biodegradability, elasticity, and low tissue reactivity [12]. In fact, silk fibroin has attractive mechanical properties showing a balance of modulus, breaking strength, and elongation. The hierarchical structure of silk as well as the health of the silkworm (from which silk fibroin is obtained) influence the mechanical properties of silk fibroin [129]. For these favorable properties, silk fibroin has been used as a biomaterial to produce scaffolds, sponges, hydrogels, films, and mats for tissue engineering applications (i.e., vascular tissue, neural tissue, bone tissue [131], cartilage, ligament and tendon tissues [132], wound dressing [133], hepatic tissue, tracheal tissue, etc.). Although it has these impressive properties, silk fibroin lacks the potential to induce osteogenesis, which is of pivotal importance, especially in bone tissue applications. Therefore, bioactive ceramics (i.e., hydroxyapatite, β-tricalcium phosphates, bioactive glasses) have been added to silk fibroin to fabricate composites that are able to mimic the bone structures. Among bioactive ceramics, bioactive glasses (BGs) possess greater osteoconductive capacity and a greater ability to bond to bone without forming fibrous tissue. In addition, bioactive glass particles act as reinforcement being beneficial for mechanical properties as well. Indeed, mesoporous bioactive glass (MBG)/silk fibroin scaffolds showed improved compressive strength and better spreading of cells compared to pure silk scaffolds [134] and to non-mesoporous glass/silk scaffolds [135]. Although mesoporous glass destroys the inner structure of silk fibroin, it shows a larger surface area and pore volume with respect to non-mesoporous glass. Thus, during the fabrication process, part of the solution of silk fibroin can enter into the pores of mesoporous glass leading to a stronger bond with silk fibroin after freeze-drying [135]. Additionally, mesoporous glass/silk fibroin scaffolds showed a better apatite mineralization ability probably due to the faster dissolution rate [135,136]. The faster dissolution rate may give a favorable environment for cell adhesion and proliferation and for further tissue growth. The interaction between biomaterials and cells is known to be a crucial process for the following bone mineralization. Human mesenchymal stem cells (hMSC) cells on silk fibroin hierarchical scaffolding matrices functionalized by a Cu-containing bioactive glass (70S, 70SiO2-22CaO-5P2O5-3CuO molar ratio) coating were found to go toward a differentiated osteoblast phenotype [137]. The Cu-containing bioactive glass coatings improved the ingrowth of new bone tissue in vivo [137]. Ideal scaffolds should possess a structure that mimics the structure of the host tissues in terms of porosity, mechanical, and biological properties to facilitate osteoinduction, vascularization, and tissue formation. In recent years, various strategies to achieve a better control of the micro and macro structural features of scaffolds have been developed ranging from the biphasic structure [138] to an indirect 3D printing technique [139]. The biphasic scaffolds were developed by an electrospinning technique and the two phases (i.e., bioactive glass and silk fibroin) preserved their own porous structure, resulting in good integration at the same time [138]. Therefore, the bioactive glass phase, which has the capability to enhance the osteogenic precursor cells, and the silk fibroin phase, which is able to drive the tissue regeneration, constitute the biphasic scaffolds. In vitro experiments demonstrated an enhanced ALP activity and the absence of adverse immune response [138]. An enhanced ALP activity was also shown by bioactive glass/silk fibroin scaffolds fabricated by an indirect 3D printing technique [139]. The differentiation of osteoblasts was enhanced by the releasing of ions from BGs [139]. Indeed, the incorporation of bioactive glass improved the biological performance of silk fibroin scaffolds, mediating cellular response. The release of ions and surface features such as roughness and hydrophilicity greatly influenced the biological performance. The high hydrophilic nature of bioactive glass/silk fibroin composites compared to pure silk composites enhanced the interaction with cells, which is further improved by BGs, which release ions. Nano bioactive glass particles embedded into silk fibroin films were shown to enhance the hydrophilic nature of silk fibroin, its bioactivity, and ALP activity in in vitro tests [140]. The increase of nano bioactive glass particles in silk fibroin films resulted in more silanol groups on the films surface, which in turn generated an increase in cellular activity. Previous studies have shown that silanol groups bind to proteins through different functional groups, producing a favorable surface environment for cell growth [140]. Table 3 summarizes silk fibroin/bioactive glass composites. 3. Natural Polymers: Polysaccharides Polysaccharides derive from both plant and animal sources and therefore are widely distributed in nature. There are hundreds of known polysaccharides, and they can be categorized based on their type of sources: (i) animals (i.e., hyaluronic acid, chitin, chitosan); (ii) algal (i.e., alginates, galactans, and carrageenan); (iii) plants (i.e., starch, cellulose, arabic gum); and (iv) microorganisms (i.e., dextran, gellan gum, and xanthan gum). The position of O-glycosidic linkages, the molecular weight, and the chain of polysaccharides strongly influence their physical and chemical properties [12]. A considerable number of polysaccharides are water soluble and oxidize beyond their melting point when elevated temperatures are reached. Their tunable degradation and their feasibility make them appropriate for numerous biomedical applications. 3.1. Hyaluronic Acid/Bioactive Glass Composites Hyaluronic acid or hyaluronate is a linear polysaccharide constituted by repeating the disaccharide unit of β(1,4)-glucuronic acid (GlcUA)-β(1,3)-N-acetylglucosamine. Hyaluronic acid is one of the principal parts of extracellular matrix (ECM) [141,142], and it promotes cellular migration and proliferation. The inevitable drawbacks in the extraction process of hyaluronic acid from animal sources are (i) the endogenous hyaluronidase activity in animal tissues and (ii) the difficult conditions of extraction [143]. Additionally, although the hyaluronic acid extracted from animal sources should be extensively purified from contaminants (i.e., proteins and nucleic acids) to reach the high-quality standards for medical applications, the extraction from animal sources remains the principal technology used for commercial products [143], and it is still the most important source for hyaluronic acid. On the other hand, hyaluronic acid can be also synthesized from enzymes; this process still represents a new perspective that can reduce the contamination risks caused by the extraction from animal waste [143]. Hyaluronic acid, along with being used as a component of body lotions, has been used for defective bones and teeth due to its capacity to avoid toxicity, inflammatory, and immunogenicity response in the host. Hyaluronic acid is generally coupled with other polymers (i.e., cohesion promoters) such as chitosan and alginate to improve washout resistance [144,145]. Therefore, hyaluronic acid did not represent the principal polymer used to develop composites [146,147,148,149]. However, hyaluronic acid is selected as a source of polymeric solution because of its excellent biocompatibility, viscoelastic characteristic, and because it is involved in the production of extracellular matrix (ECM) by operating as an organizing core to connect complex intracellular aggregates [150]. Therefore, hyaluronic acid was selected as a polymeric solution by Sohrabi et al. [151] to develop composite injectable pastes with the introduction of bioactive glasses (BGs). The addition of BGs allowed the formation of direct chemical bonds to surrounding tissues, due to their bioactivity and osteoconductivity. Composite injectable pastes must be injected without any resistance and phase separation; the different morphology of bioactive glass embedded into hyaluronic acid influenced the rheological properties of pastes. Bioactive glass particles with high pore volume and low size of particles induce high viscosity of paste. This behavior is probably caused by the penetration of liquids in some pores of BGs reducing available liquid between particles [151]. Although in vitro investigations are surely needed, hyaluronic acid/bioactive glass pastes were developed without coupling polymers [151]. Table 4 summarizes the hyaluronic acid/bioactive glass composite using hyaluronic acid only, without other blending polymers. 3.2. Chitosan/Bioactive Glass Composites Chitosan is a linear polysaccharide formed by a deacetylated unit (β-(1-4)-linked d-glucosamine) and acetylated unit (N-acetyl-d-glucosamine) distributed in a random manner. Chitosan is obtained from shrimps and shells of various crustaceans using alkali NaOH to eliminate the acetamide group (i.e., deacetylation). Deacetylation is never complete: it varies from 30% to 95%. Chitosan biocompatibility decreases with increasing (i) deacetylation degree (DD), (ii) solubility, and (iii) degradation rate. Additionally, the solubility of chitosan is influenced by the positive charge of amino groups; in fact, chitosan is soluble in diluted acid (pH < 6) only. Furthermore, the hemostatic activity of chitosan is promoted by its positive charge, which is able to bond the negative charge of the membranes of blood cells [152,153]. In fact, chitosan interacts with erythrocyte membranes, attracting platelets and accelerating clot formation [12,153]. The amine and hydroxylic groups enhance the growth of osteoblast and the bone formation in vivo [152,154,155]; the chemical backbone of chitosan is similar to glycosaminoglycan, which is a major component of bones and cartilages. Therefore, chitosan is a suitable candidate for bone grafts [156,157]. Additionally, although the mechanism is still unknown [158,159,160], chitosan shows antimicrobial effects. Two possible mechanisms are considered: (i) the negative charge of chitosan alters the permeability of the membranes of bacteria; and (ii) chitosan prevent the synthesis of RNA by bonding the DNA of bacteria [152,161]. Therefore, chitosan possesses excellent biocompatibility, biodegradability, and antimicrobial effects being a suitable biomaterial for biomedical devices. However, chitosan has low mechanical properties, especially for load-bearing bones [162,163]. To solve this problem by offering synergistic effects among mechanical properties, biocompatibility, and bioactivity, bioactive glasses (BGs) have been widely added to pure chitosan [164]. The improved mechanical properties of chitosan/BG composites were attributed to the addition of BGs, which increased the hardness of chitosan by distributing the applied stress and inhibiting cracks propagation. In general, the addition of BG particles higher than 12.5% w/w led to a significant increase in the storage modulus and specific storage modulus of hydrogels [165]. Presumably, the bonding between the BG surface and chitosan functional groups served to maintain the dispersion of the BG within the chitosan matrix, resulting in better mechanical properties. This hypothesis was corroborated by the storage and loss moduli obtained for bioactive glass-injectable systems, which increased with an increasing amount of BG [166]. Furthermore, the addition of BG nanoparticles also improved the hardness of chitosan fibers as shown in [167]; this enabled also a distribution of the applied stresses over the entire structure of the composite. The compressive strength of chitosan/BG (6Na2O, 8K2O, 8MgO, 22CaO, 54B2O3,2P2O5 mol %) injectable cement well matched the compressive strength of human trabecular and cortical bone [168]. Therefore, chitosan/BG injectable cement could be suitable for healing non-load bearing and load-bearing defects of bone. Biomaterials are usually employed under hydrated condition (i.e., physiological fluids), which could strongly affect their mechanical properties: such properties are different than the ones under dry condition. In this regard, the mechanical properties of SiO2:CaO:P2O5 = 55:40:5 mol % nanoparticles (BG-NPs) scaffolds were tested under hydrated condition [169], and chitosan/bioactive glass membranes for periodontal regeneration were investigated under both dry and wet conditions [170], since the mechanical properties affect both clinical application and the bone-healing capacity of composites [171,172]. The metabolic activity of cells on chitosan/bioactive glass membranes was higher compared to pure chitosan membranes, indicating a positive effect of bioactive glass incorporation [170]. Therefore, the development of composites aimed at finding a balance between biological performance [173,174,175] and stable structure under mechanical stresses. The design of the implant’s features, such as the porosity and interconnected pores [176,177] to allow cells migration and nutrients, is relevant as well as ions released from implants. The ionic products of BGs stimulate cell viability and proliferation. For instance, Si ions promoted the production of collagen I and enhanced osteoblastic differentiation [84,105,178,179] and extracellular matrix differentiation [87,89,180]. Additionally, Si ions activated Ca-sensing receptors in osteoblast cells, increasing the expression of insulin-like growth factors (i.e., IGF-I or IGF-II) [49,181,182,183]. Higher cellular viability and a stronger bone formation of chitosan/bioactive glass with high bioactive glass content were measured by Khoshakhlagh et al. [184] compared to that of chitosan/bioactive glass with lower bioactive glass content. By controlling the amount of bioactive glasses inside the chitosan matrix, the degradation rate and the cellular viability could be affected. In addition, by tailoring the chemical composition of bioactive glasses by the addition of different ions (i.e., Sr, Mg, Zn, Ga, Cu), it was possible to stimulate cellular specific responses [178,185]. For instance, Sr ions promoted cellular activity through the membrane-bond Ca-sensing receptor in both osteoblasts and osteoclasts [186,187,188]. Furthermore, Sr ions demonstrated stimulatory effects on osteoblasts, resulting in an increase in bone density and resistance [189,190,191,192]. Indeed, the injectable cement of chitosan and Sr-containing bioactive glasses (CS/SrBG) developed by Zhang et al. [193] significantly enhanced the expression of osteogenic genes and type I collagen, which is an early terminal osteoblast differentiation [192,194]. In vivo CS/SrBG cement enhanced osteogenesis, stimulated bone formation, and showed higher bone–implant contact compared to chitosan/bioactive glass cements without Sr ions. The better ability in improving bone regeneration and bone implant contact was due to the ability of CS/SrBG (i) to mineralize to hydroxy carbonate apatite (HCA), (ii) to promote the delivery of Sr ions in defect areas, and (iii) to improve the secretion of angiogenic factors [193]. On the other hand, Luz et al. [195] developed chitosan/bioactive glass composites with Mg-containing bioactive glasses with enhanced cellular viability and higher ALP activity compared to chitosan/bioactive without Mg ions. As it is well known, Mg ion is not only a cofactor of enzymes that stabilize the structure of RNA and DNA [48,196], but it also influences the phenotype of osteogenic cells and has a pivotal role in the development of skeletal and in the remodeling of bone [107,197]. Furthermore, Mg increases the expression of type X collagen and vascular endothelial growth factor (VEGF), and it increases cell spreading, cell proliferation, and ALP activity [85]. Additionally, chitosan/bioactive glasses with MgO, SrO (BGMS10 [38]), and ZnO (BGMS_2Zn [54]) showed higher cellular viability compared to the cellular viability of chitosan wound dressings [198]. Thus, composites with bioactive glass containing therapeutic ions could represent a promising application for both hard and soft tissues. However, in general, bioactive glasses containing or not some therapeutic ions (i.e., Sr, Mg, Ag, Zn, Cu) are more bio-reactive and show higher capability in stimulating cellular response compared to chitosan matrix. Thus, cells preferentially adhered and proliferated in the area with bioactive glasses with respect to the chitosan area, as found in chitosan/bioactive glass (SiO2:CaO:P2O5 = 55:40:5 mol%) composites developed by microcontact printing [199]. Higher cellular viability and a higher spreading of cells were also found on chitosan/bioactive glass scaffolds developed by Peter et al. [200]. On the contrary, chitosan/bioactive glass (60SiO2-36CaO-4P2O5 mol%) foam developed by Martins et al. [201] did not show higher cell viability compared to pure chitosan foam. However, chitosan/bioactive glass foams showed improved mechanical behavior in terms of elastic modulus and shape recovery compared to chitosan foams. This can be attributed to the chemical crosslinking, which probably resulted from intermolecular reactions between carbonyl and amino groups of chitosan and the silanol group of bioactive glasses [201]. Table 5 summarizes chitosan/bioactive glass composites. 3.3. Alginate/Bioactive Glass Composites Alginate is typically derived from brown algae (Phaeophyceae; including aminaria hyperborean, laminaria digitate, laminaria japonica, ascophyllum nodosum, acrocystis pyrifera) through treatment with aqueous alkali solutions, usually NaOH [202,203,204]. Alginates are formed by (1–4) linked β-D-mannuronic acid (M units) and its C-5 epimer α-L-guluronic acid (G units). The natural copolymer is a component found in algae such as kelp, and an exopolysaccharide found in bacteria (Pseudomonas aeruginosa). M units and G units interspersed with MG sequences form alginates [205]. Even though alginate’s structure is similar to that of an extracellular matrix (ECM), alginate is not degradable inside mammalians because of the absence of the alginate enzyme, which breaks the polymer chain. For this reason, the polymer chain should be partially oxidized with sodium periodate to make alginate degradable in a physiological environment [205]. Therefore, the alginate degradation rate depends especially on the oxidation degree, pH, and temperature of the surrounding environment. Even though the biocompatibility of alginate is still under discussion for possible impurities due to the alginate extraction method [206], alginate is widely used in biomedical applications [204]. Its biocompatibility, biodegradability, hydrophilicity, and relatively low cost make alginate a suitable biomaterial for regenerative medicine [206,207,208]. Additionally, the capability of alginate to generate stable hydrogel in the presence of specific divalent or trivalent cations (i.e., Ca2+, Sr2+, Al3+, Ga3+) permits the fabrication of good scaffolds [209]. Alginate hydrogels have been previously used for cell encapsulation [210] and for vascular and cartilage regeneration [211,212]. Additionally, alginate can be dissolved in aqueous solutions without the aid of any solvents. In addition, alginate can be easily modified with peptides, proteins, and inorganic biomaterials. Therefore, alginate is a promising choice for allografts and autografts because alginate does not show the drawbacks such as morbidity and lengthening of the procedure during the process of harvesting [213]. Despite good properties, alginate exhibits poor mechanical strength, bioactivity, and osteoconductivity; thus, bioactive glasses can be combined to ameliorate the biological performance in terms of reactivity [214]. BGs affect the differentiation of osteoblast by increasing the level of ALP, osteocalcin, and osteopontin markers, which control genes involved in cell cycle and progression. Thus, these markers improve osteogenesis by controlling cells during progression toward mature osteoblasts [215]. Additionally, the osteogenesis and ALP activity are directly influenced by the releasing of Si, Ca, Na, and P from the bioactive glass, which activate and upregulate gene expression in cells [216]. In this regard, a higher ALP activity was observed for nano bioactive glass ceramic/alginate scaffolds compared to pure alginate scaffolds [217]. Therefore, the incorporation of bioactive glass contributes to ALP activity, cell adhesion, and proliferation through the release of ions and the increase in the roughness of the composites’ surface [218]. Furthermore, the addition of therapeutic ions could further improve the biological performances of composites, as already mentioned. Thus, 13–93 bioactive glass was used instead of 45S5 to develop composite alginate 3D-printed scaffolds [219]. The addition of 13–93 enhanced the mechanical strength, the mineralization capability of apatite, and the cellular adhesion and differentiation of alginate/13–93 with respect to neat alginate scaffolds. The reason for the higher mechanical strength of alginate/13–93 was that bioactive glass particles showed a high surface area and nanopore volume [220]. The incorporation of 13–93 in alginate increased the pH of PBS, which favored ALP activity; it has been reported that optimum ALP activity occurs at 8.5 pH during bone regeneration [221]. Furthermore, the releasing of Mg2+ and SiO4- from 13–93 improved cells’ attachment, proliferation, and differentiation [219]. Indeed, the Mg ion improves cellular proliferation and differentiation, and it has an important role in bone metabolism as well. Mg ions together with Zn ions promoted ALP activity, which stimulated bone metabolism [222]. In addition, the mechanical properties of BGs were improved by the addition of both Mg and Zn ions, because Mg-O and Zn-O bonds have higher bonding energy compared to Ca-O bonds [223]. Therefore, Mg and Zn containing bioactive glass were embedded in alginate to fabricate composite scaffolds with enhanced biological performance and ameliorated mechanical properties [224]. However, the incorporation of bioactive glass in an alginate matrix decreased the micro-porosity and increased the stiffness of alginate. The porosity of scaffolds should guarantee cell spreading and proliferation; thus, the average pore size should be around 100 μm [225]. Even though the porosity decreased with increasing bioactive glass content, a greater cell viability and ALP activity on alginate/bioactive glass (60SiO2, 26CaO, 4P2O5, 5ZnO, and 5MgO mol%) scaffolds compared to alginate scaffolds were detected [224]. This behavior could be due to the dissolution of ions that stimulate the formation of hydroxy carbonate apatite (HCA), which in turns stimulates osteogenic cell attachment and proliferation [226]. In this regard, Sr ions, which promote osteogenic and osteoblast differentiation, are usually added to bioactive glasses [227]. In fact, the Sr ion has been already employed as strontium ranelate in the treatment of osteoporosis due to its anabolic and anti-resorptive effect on bone [228]. Both Sr and Zn act as enhancers in bone formation, simultaneously decreasing bone resorption. The synergistic effect of Sr and Zn rebalances the bone turnover in favor of bone formation, resulting in an increased bone mass and strength [229]. Therefore, Sr and Zn containing bioactive glasses were used as fillers for alginate to improve both mechanical properties and in situ osseointegration [230,231]. The inclusions of bioactive glasses significantly increased the collapse stress/yield stress of the alginate/bioactive glass scaffolds compared to neat alginate scaffolds. Furthermore, HCA mineralization improves the formation, growth, and maintenance of the tissue–scaffold interface [232,233]. During the immersion, the alkaline pH promotes cells to form new bone [221,234], while the alkaline products of bioactive glasses neutralize the products from alginate degradation [235]. In addition, bioactive glasses decrease the swelling properties of scaffolds because they decrease the polymers surface, which usually binds water molecules [236]. Indeed, the swelling capacity of alginate scaffolds decreased as much as the content of bioactive glasses increased [224,230]. Although it is proved that early swelling enhances cellular adhesion and growth [237,238], a controlled swelling behavior is required for not compromising the mechanical properties of scaffolds [224]. Therefore, to retard and reduce the swelling behavior, alginate is usually crosslinked by bivalent cations such as Ca or Sr, which bond with the carboxyl functional group of G units of the polymer chain [239]. The full crosslinking of alginate limits ions’ availability, allowing control over the kinetics of gels. This is mainly provided by the inclusion of trivalent ions (i.e., Al3+ and Ga3+), which produce charge balancing and a tetrahedral structure. Ga3+ was also crosslinked with alginate in order to control gallium release [240] during degradation. Additionally, Ga/alginate composites showed higher compression strength compared to that measured for Al/alginate composites because Ga is expected to exhibit a higher degree of alginate crosslinking [241]. The compressive strength and elastic modulus increased with an increasing amount of gallium (Ga) in bioactive glass composition as in [242], and the reactive oxygen species (ROS) were reduced by Ga ions [243]. Furthermore, Ga showed an inhibition in bacteria growth [244]: the proposed mechanism is that Ga can disrupt the iron metabolism, increasing the vulnerability of the microorganisms because they are not able to distinguish between Fe3+ and Ga3+ where the former is redox active and the latter is redox inactive [244]. Therefore, the incorporation of Ga can be used to prevent possible bactericidal colonization of tissue engineering scaffolds after implantation. On the other hand, a novel combination of glass nanoparticles and alginate to achieve a tunable release capability of Ca2+ [245] and Ca2+ together with Cu2+ were developed [246]. The release of Ca2+ and Cu2+ enhance cellular growth and differentiation. Such ions stimulated rat bone marrow-derived mesenchymal stem cells (rBMSCs) differentiation toward the osteogenic lineage and improve human umbilical vein endothelial cells (HUVEC) proliferation and vascular endothelial growth factor (VEGF) secretion [246]. Indeed, it is known that Ca2+ ions stimulate the differentiation of bone cells, the proliferation of osteoblasts, and the mineralization and metabolism of bone tissue [87,187,188]. On the other hand, Cu2+ ions play a pivotal role in bone vessel growth [247,248,249] and in the proliferation of endothelial cells [250,251], being also a natural antimicrobial element [252] showing a synergistic antimicrobial effect with Ca2+ [253]. Table 6 summarizes alginate/bioactive glass composites. 3.4. Cellulose/Bioactive Glass Composites Cellulose is the most abundant biopolymer in the biosphere, and it can be obtained from a broad range of plants and animals. Generally, cellulose is obtained from plant sources; however, it can be extracted from bacteria (i.e., bacterial cellulose). The monomer unit of cellulose (β-D-anhydroglucopyranose) is connected covalently through acetal functions to another monomer unit (β-1, 4-glycosidic bonds). These β-1,4-glycosidic bonds guarantee the resistance of cellulose to chemical/enzymatic attack [12,254]. The degree of linearity and –OH groups in the cellulose structure drive the formation of intermolecular and intramolecular hydrogen bonds through the polymer chain [12]. The chains of cellulose are organized in parallel arrangements (i.e., crystalline regions and amorphous-like regions), which influence the physical and chemical properties of cellulose itself [254]. At least five allomorphic forms of cellulose exist: cellulose I, which is the one found in nature, and other crystal structures named cellulose II, III, and IV, where cellulose II is the most stable structure [12]. The three –OH groups in each glucose unit of cellulose influence its reactivity. Anyways, cellulose has low solubility in common solvents and low dimensional stability, and it shows poor hydrophilicity, bioactivity, and antibacterial properties. Thus, a physical and/or chemical modification of cellulose is required [12]. In addition, bioactive glasses (BGs) can be added to the cellulose matrix to fabricate composites with improved bioactivity and biocompatibility. Cellulose nanofibrils/BG scaffolds with porous microstructure that are able to grow and regenerate bone were developed and investigated [255,256]. By combining cellulose with bioactive glasses, the two main drawbacks (i.e., cellulose bioactivity and bioactive glasses mechanical properties) found in the individual use of such materials could be surpassed. In this sense, the incorporation of CuO oxide, where the Cu ion is known as an essential participant in angiogenesis, could significantly affect the wound healing [255]. The incorporation of CuO did not influence negatively the in vitro mineralization; samples were covered by a hydroxycarbonate apatite (HCA) layer after being soaked in SBF [255,256]. Additionally, the rough surface of HCA favors cell functions in tissue engineering. Such roughness resulted similar to that of cellulose/bioactive glass scaffolds (CC-Bio). These CC-Bio stimulated differentiation into osteoblastic lineage and bone formation [256]. The morphology of the surface in contact with the host tissue is as important as the chemistry of the surface and its capability to release specific ions. For this reason, the surface of metallic devices has been modified with bioactive materials to prevent or postpone second surgeries. The aim was to improve the bone-to-implant contact, reducing infections and surface corrosion. Cellulose matrix embedding bioactive glasses are considered a promising alternative to conventional bio-ceramic coatings (e.g., [257,258]). The use of cellulose (i) enhances the bond at the interface of surface–devices, (ii) improves the strength of the coatings, (iii) and reduces the releasing rate of ions from bio-ceramic materials. Cellulose nanocrystal (CNC) and bioactive glass coatings on 316L stainless steel by a one-step electrophoretic deposition (EPD) process were fabricated as an alternative to conventional coatings [259,260]. Cellulose acted as a binder, strengthening the connection between the substrate and coatings, leading to a more stable adhesion. The coatings preserved their porous structure as assessed by contact angle measurement [260] and showed higher roughness with respect to the surface of the implant. On the other hand, BGs accelerated the mineralization on the surface of the coatings [259,260] as well as ALP activity, which is the marker of increased bone formation [259]. Table 7 summarizes alginate/bioactive glass composites. 4. Additional Remarks Finally, natural polymers’ advantages and disadvantages, due to their own properties, structure, and methods used to obtain them from natural sources, are summarized in Table 8. 5. Conclusions and Future Challenges The papers reported in this review have shown that collagen, gelatin, silk fibroin, hyaluronic acid, chitosan, alginate, and cellulose containing bioactive glasses represent interesting materials for biomedical devices, for both hard and soft tissue, not least because of their biocompatibility and non-toxicity. The addition of nano-sized and micro-sized bioactive glass particles has been shown to improve mechanical properties, to enhance bioactivity, and to promote the cells’ viability, adhesion, proliferation, and differentiation. However, the strength and cellular response of composites could be compromised when the content of BGs overcome the threshold limit. An appropriate balance between bioactive glasses as filler and good mechanical properties should be considered while developing such composites. Indeed, the hydroxycarbonate apatite on the surface of bioactive glasses has a stimulatory role on the differentiation of stem cells toward osteoblast cells, especially when therapeutic ions are introduced [263]. Additionally, the incorporation of bioactive glasses offers a chance to adjust the elasticity of polymers and the cellular response. The elasticity of natural polymers represents a pivotal feature that affects the cellular response both in vitro and in vivo. Overall, combining natural polymers with bioactive glass particles to produce composites for both hard and soft tissues can represent an efficient strategy to heal different damages of the body. Considering the in vitro behavior, further research involving the investigation of different cell lines needs to be considered, gaining more relevant data on the osteogenic, odontogenic, and angiogenic behavior of natural polymer composites. Furthermore, it is worth noting that preclinical studies in animals should be improved and become the focus of future studies. In addition, future studies should pay attention to investigate the most advantageous combination of natural polymers and bioactive glasses to achieve good mechanical and biological performances of composites. Indeed, a better understanding of how specific properties of natural polymer/bioactive glass composites affect cells activation and behavior will allow the optimization of composite production with specific biological responses. Additionally, more investigations on the response induced by specific natural polymers once implanted should be done to further avoid an undesired reaction after implantation. Figure 2 summarizes future challenges of natural polymer/bioactive glass composites. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author Contributions Investigation, writing—original draft preparation, R.S., D.B.; conceptualization, writing—review and editing, supervision, V.C. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Schematic graph of natural polymers combined with bioactive glasses to fabricate advanced composites. Figure 2 Future challenges. materials-13-05560-t001_Table 1Table 1 Summary of collagen/bioactive glass composites for various biomedical applications. Bioactive Glass Technique Composites’ Characteristics Applications Ref. BGMS10 (2.3Na2O-2.3K2O-25.6CaO-10.0MgO-10.0 SrO-2.6 P2O5-47.2 SiO2 mol%) Manually mixing Non-cytotoxic; putties containing bioactive glass enhanced cell proliferation Dentistry and reconstructive surgery [40] 65SiO2-30CaO-5P2O5 wt% Slurry-dipping technique Porosity of 81 ± 4.6% and pore size of 40–200 μm; water adsorption 52.26 ± 11.37%; compression strength 5.80 ± 1.60 MPa; elastic modulus 0.35 ± 0.10 GPa; flexure strength 1.90 ± 0.15 MPa; flexure modulus 27.90 ± 1.32 MPa; tensile strength 3.56 ± 0.22 MPa; tensile modulus 82.00 ± 17.40 MPa. The mechanical properties well-matched with the mechanical properties of trabecular bones; good biocompatibility Scaffolds for hard tissue [78] 58S, 70S Freeze-drying and lyophilization technique Porosity 87–88%; density 0.0015–0.0016 g/cm3. Induced bone mineral-like phase, signs of in vitro bone bioactivity Scaffolds for hard tissue [79] 45S5 (nanoparticles) Plastic compression technique Good cell viability, high ALP activity, crystalline carbonated hydroxyl apatite growth Scaffolds for potential bone tissue engineering [80] 58SiO2-38CaO-4P2O5 Freeze-drying technique Average thickness 181 μm. Active induction of apatite minerals; significantly high ALP levels Membranes and scaffolds for bone regeneration [82] CaO-P2O5-SiO2 or silica particles Mixing solution In vitro osteoconductivity properties Hydrogels for bone repair and tissue engineering [96] 45S5 Compression molding Early angiogenic response Films for tissue engineering and regenerative medicine [97] Mesoporous bioactive glass nanoparticles mBGn (85SiO2–15CaO mol%) Solvent casting Improved chemical stability, reduced hydrolytic and enzymatic degradation, and increased resistance to loading and stiffness. Storage modulus (E’) of collagen (Col) = 75 kPa, E’ of collagen/bioactive glass (Col-mBGn) = 130–160 kPa and E’ Col–mBGn (Aminated) = 150–280 kPa Hydrogel for hard tissue engineering [98] Si/Ca/P = 80:15:5 mol% Electrospinning Improved tensile strength, promotion the secretion of type I collagen (COL-I) and vascular endothelial growth factor (VEGF) in human dermal fibroblast (HDFs), in vivo: skin regeneration in the wound area Skin wound dressing [101] materials-13-05560-t002_Table 2Table 2 Summary of gelatin/bioactive glass composites for various biomedical applications. Bioactive Glass Technique Composites’ Characteristics Applications Ref. 40SiO2-45CaO-15P2O5 Sequential physical and chemical crosslinking (gelation + UV) approach Average pore size = 90–200 μm. Compressive modulus: “regular” composites hydrogels (0, 2.5, 5 and 10% w/v BG) = 54.1, 51.2, 50.2, 46.0 kPa; “enhanced” composite hydrogels were approximately 4.4-, 3.8-, 3.5-and 3.3-folds greater than those of “regular” composites hydrogels at 0 to 10% w/v BG. High apatite forming ability. Highly biocompatible; enhanced ALP activity Hydrogels for bone regeneration [111] 64S Layer solvent casting combined with freeze-drying and lamination techniques Porosity = 85%; average pore size = 200–500 μm. No cytotoxic effect on the cell survival and proliferation in vitro; bone regeneration in vivo Scaffolds for tissue-engineered bone defects [112] 64SiO2-5P2O5-31CaO mol% Freeze-drying technique Total porosity = 80%; micro-sized porous surface structure = 200–500 μm; elastic modulus = 64 ± 1.3 MPa; compressive yield strength = 4.3 ± 0.23 MPa. No cytotoxic effects; good viability of cells in vitro. Woven bone tissue formation in vivo Scaffolds for bone defects [113] nBG (64SiO2 -5P2O5 - 31CaO mol%) Layer solvent casting combined with freeze-drying and lamination techniques Pore size = 200–500 μm; elastic modulus = 50–80 MPa. Good cellular migration and osteoconductivity Scaffolds for tissue engineering [114] BaG (64SiO2 -5P2O5 - 31CaO mol%) Layer solvent casting combined with freeze-drying and lamination techniques Parallel aligned and inter-connected pores = 200–500 μm; porosity = 70–86%; Young’s modulus = 50–80 MPa. Improved attachment and penetration of cells into the pores Scaffolds for bone tissue engineering [115] BaG (64SiO2 -5P2O5 - 31CaO mol%) Freeze-drying technique Pore size = 200–500 μm; porosity = 70–86%. Young’s modulus: 10% BaG = 51 ± 1.8 MPa, 20% BaG = 58 ± 2.1 MPa, 30% BaG = 64 ± 1.3 MPa, 40% BaG = 72 ± 1.7 MPa, 50% BaG = 78 ± 1.2 MPa. Compressive yield strength: 10% BaG = 2.8 ± 0.26 MPa, 20% BaG = 3.7 ± 0.19 MPa, 30% BaG = 4.3 ± 0.23 MPa, 40% BaG = 4.9 ± 0.30 MPa, 50% BaG = 5.6 ± 0.61 MPa. Improved cell culture response Scaffolds for bone tissue engineering implant [116] 45S5 Casting technique Tensile stress = 0.75–2.1 MPa Films for soft tissue engineering [117] 70SiO2–25CaO–5P2O5 mol% Electrospinning technique Free from bead-like defects; average fiber diameter = 192 ± 8 nm; tensile strength = 4.3 ± 1.2 MPa; elongation to failure = 168 ± 14%. 14 days after seeding, surfaces covered by multicellular layers; improved ALP activity Hybrid scaffolds for bone regeneration [118] BG (75SiO2–25CaO wt%) Sol–gel method Porosity = 90%; after immersion in physiological fluids: compressive strength of class I (without covalent linkages between organic–inorganic networks) BG-gelatin = 1 kPa at 10% deformation and of class II (with covalent linkages between organic– inorganic networks) BG-gelatin = 108 kPa at 10% deformation; Young’s modulus class II BG-gelatin = 5-166 MPa; yield strength class II BG-gelatin = 0.2–4 MPa Hybrid scaffolds for bone regenerative medicine and tissue engineering [119] 70S30C Modified direct foaming technique Modal pore size = 160–170 μm; effective stiffness = 5.87 ± 2.22 MPa; maximum compressive strength = 0.32 ± 0.03 MPa. Samples crosslinked: approximate stiffness = 7.19 ± 2.78 MPa, compressive strength = 0.24 ± 0.04 MPa. Rapid formation of apatite in SBF; excellent cell attachment 3 days after seeding Scaffolds for bone augmentation and clinical applications [120] 70SiO2-25CaO-5P2O5 mol% Solid free form fabrication (SFF) method Large shrinkage after deposition and drying = 33% linear shrinkage in the plane of deposition and 40–50% in thickness; compressive strength = 3.7 ± 0.2 MPa; compressive strength crosslinked = 5.1 ± 0.6 MPa. Enhanced proliferation, ALP activity, and mineralization of osteogenic MC3T3-E1 (line of mouse pre-osteoblastic cells) in vitro Hybrid scaffolds for bone regeneration [121] 75SiO2–25CaO wt % Mixing solution and drying Total porosity = 91 ± 1%; average pore size = 187 ± 6 μm with pores ranging from 105 to 295 μm; average interconnection diameter = 74 ± 4 μm with diameters ranging from 25 to 115 μm Scaffolds for tissue engineering [122] 45S5, BG/Sr (SiO2-CaO-SrO-P2O5) Gel = gelatin Freeze-drying technique Pore size: Gel-45S5 15% = 215 ± 12 μm; Gel-BG/Sr 5% = 201 ± 15 μm; Gel-BG/Sr 10% = 164 ± 10 μm; Gel-BG/Sr 15% = 154 ± 16 μm. Porosity: Gel-45S5 15% = 95 ± 2.0%; Gel-BG/Sr 5% = 89 ± 3.25 %; Gel-BG/Sr 10% = 85 ± 1.5 %; Gel-BG/Sr 15% = 80 ± 2.8 %. Young Modulus: Gel-45S5 15% = 14.36 ± 1.3 MPa; Gel-BG/Sr 5% = 10.21 ± 2.0 MPa; Gel-BG/Sr 10% = 19.30 ± 0.68 MPa; Gel-BG/Sr 15% = 70.62 ± 1.91 MPa. ALP secretion significantly enhanced in cells on Gel-BG/Sr15%; cell infiltration and migration enhanced for Gel-BG/Sr15% in vivo Scaffolds for bone tissue engineering [123] SiO2-CaO-P2O5-MgO-ZnO Freeze-drying technique Pore diameter in the range of 100–500 μm; average Young’s modulus = 28 ± 2 MPa; average yield strength = 4 ± 0.4 MPa. Insignificant reduction in cells proliferation and no severe toxicity Scaffolds for bone tissue [124] BG (60SiO2-36CaO-4P2O5 mol%) mixed 0 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt% tetrapod-like ZnO whiskers (indicated as BGZ0, BGZ1, BGZ2, BGZ3, BGZ4) Freeze-drying technique Pore size = 100–800 μm; porosity = 80–90%; compression strength (MPa): BGZ0 = 2.62 ± 0.23, BGZ1 = 3.11 ± 0.28, BGZ2 = 3.69 ± 0.30, BGZ3 = 3.24 ± 0.12, BGZ4 = 2.97 ± 0.13. Elastic modulus (MPa): BGZ0 = 112.3 ± 15.9, BGZ1 = 154.6 ± 26.7, BGZ2 = 208.6 ± 31.4, BGZ3 = 147.3 ± 12.6, BGZ4 = 119.6 ± 10.8. Flexure strength (MPa): BGZ0 = 7.28 ± 0.82, BGZ1 = 8.54 ± 1.23, BGZ2 = 9.41 ± 0.72, BGZ3 = 8.48 ± 0.83, BGZ4 = 7.51 ± 1.09. Flexural modulus (MPa): BGZ0 = 612.6 ± 89.5, BGZ1 = 711.5 ± 121.5, BGZ2 = 883.4 ± 45.5, BGZ3 = 756.2 ± 80.9, BGZ4 = 666.0 ± 70.7. Increased proliferation of rat mesenchymal stem cells (rMSCs) Scaffolds for bone repair [125] Silver nanoparticles, 63S Freeze-drying and crosslinking technique Pore size of gelatin/nanosilver/bioactive glass scaffolds = 350–635 μm. Gelatin/nanosilver scaffolds high water uptake; gel fraction = 70–85%. Improved human mesenchymal stem cells (hMSC) viability. Antibacterial effects against E. coli and S. aureus Antibacterial scaffolds for bone tissue engineering [126] Cu-BGN (95SiO2-2.5CaO-2.5CuO mol%) Dip coating technique Porosity = 91%; The obtained scaffolds were designated as 5Cu-BGS and 20Cu-BGS according to the ratios (in wt%) of Cu-BGN/gelatin used (5 and 20 wt%). Compressive strength: 0Cu-BGS = 1.3 ± 0.2 MPa, 5Cu-BGS = 1.2 ± 0.2 MPa, 20Cu-BGS = 0.7 ± 0.3 MPa. Good HCA formation; improved mouse preosteoblastic cell lines (MC3T3-E1) proliferation and improved osteogenic activity Coatings on BG scaffolds for bone regeneration/repair [127] materials-13-05560-t003_Table 3Table 3 Summary of silk fibroin/bioactive glass composites for various biomedical applications. Bioactive Glass Technique Composites’ Characteristics Applications Ref. MBG (mesoporous bioactive glass) 3D printing Compressive strength = 19.9 ± 0.6 MPa. Improved ALP activity. Expression of bone morphogenic protein (BMP-2) = 0.22 ± 0.05 Scaffolds for bone tissue engineering [134] Non-mesoporous glass BG, mesoporous bioactive glass MBG (Si/Ca/P = 80/15/5 mol%) Freeze-drying technique Porosity: MBG/silk = 76 ± 4%; BG/silk = 76 ± 2%. Compressive strength: MBG/silk = 420 kPa, BG/silk = 300 kPa. Compressive modulus: MBG/silk = 0.7 MPa, BG/silk = 0.5 MPa. MBG/silk and BG/silk good bone repair ability Scaffolds for bone tissue repair [135] Mesoporous bioactive glass nanoparticles (MBGNs) Freeze-drying technique Pore diameter = 36.2 ± 9.3 μm. Good adhesion and spreading and proliferation of bone marrow stromal cells (BMSCs) Scaffolds for orthopedic applications [136] 70S (70SiO2-22CaO-5P2O5-3CuO mol%) Freeze-drying and lyophilization technique Average pore size: -silk fibroin scaffolds without reinforcement 175–145 μm; -silk fibroin matrices reinforced with unmodified silk microfibers 112–143 μm; -composite silk fibroin matrices reinforced with functionalized silk microfibers 108–119 μm. Compressive strength: Silk fibroin matrices reinforced with functionalized silk microfibers 91–123 kPa. Favored homing of endothelial cells through C-X-C chemokine receptor type 4 (CXCR4/SDF-1) signaling in vitro. Facilitated the neo-osseous tissue formation in vivo Scaffolds as resorbable bone grafts [137] 70S (70SiO2-25CaO-5P2O5 mol%) Electrospinning technique Contact angle bioactive glass/silk fibroin (B. mori silk) biphasic: Silk fibroin side = 73.51 ± 1.8°, bioactive glass side = 24.2 ± 2.2°; contact angle bioactive glass/silk fibroin (A. assama) biphasic: Silk fibroin side = 47.14 ± 2.9°, bioactive glass side = 51.23 ± 2.2°. Elastic modulus: bioactive glass/silk fibroin (B. mori silk) = 29.36 ± 1.38 MPa; bioactive glass/silk fibroin (A. assama) = 27.48 ± 3.96 MPa. Elongation at break: bioactive glass/silk fibroin (B. mori silk) = 2.28 ± 0.59%; bioactive glass/silk fibroin (A. assama) = 8.52 ± 1.43%. Enhanced ALP activity Biphasic scaffolds for osteochondral tissue repair [138] 45S5 Combination of indirect 3D inkjet printing and freeze-drying methods Size of macropores = 500–600 μm; pore size = 20–30 μm. Water uptake: silk fibroin (SF) and 45S5 nanoparticles (nBG) while 45S5 microparticles (μBG) SF-nBG = 85.19 ± 1.6%, SF-μBG = 87.14 ± 0.86%; swelling ratios: SF-nBG = 5.79 ± 0.76%, SF-μBG = 6.79 ± 0.5%. Contact angle: SF-nBG = 63.65 ± 0.74°, SF-μBG = 73.9 ± 0.72°. Compressive strength: SF-nBG = 942 ± 81 kPa, SF-μBG = 1210 ± 80 kPa; compressive modulus: SF-nBG = 8660 ± 660 kPa, SF-μBG = 10353 ± 620 kPa. Viability of cell significantly high on SF-nBG; high ALP activity on SF-nBG and SF-μBG Scaffolds for bone tissue regeneration in high load-bearing applications [139] 58sNBG (58SiO2-23CaO-9P2O5 wt%) Solvent casting method Thickness = 50–200 μm. Water contact angle = 60–67°. Improved hydrophilicity and in vitro bioactivity. Enhanced proliferation of osteoblasts Films for bone tissue engineering [140] materials-13-05560-t004_Table 4Table 4 Summary of hyaluronic/bioactive glass composites. Bioactive Glass Technique Composites’ Characteristics Applications Ref. 64SiO2-31CaO-5P2O5 Manually mixing Better apatite formation ability of bioactive glass/hyaluronic acid (BG2–HAc) compared to bioactive glass/hyaluronic acid (BG1–HAc), where BG1 is the bioactive glass developed by a one-step acid-catalyzed process, while two-step acid–base sol–gel processing was used to produce BG2 bioactive glass. BG2/HAc paste had higher viscosity than BG1/HAc paste. Injectable pastes for the treatment of hard and even soft tissues [151] materials-13-05560-t005_Table 5Table 5 Summary of chitosan/bioactive glass composites for hard and soft tissue applications. Bioactive Glass Technique Composites’ Characteristics Applications Ref. BG (46.08SiO2-22.96Na2O-27.18CaO-3.77P2O5 wt%) Solvent casting Water contact angle chitosan/bioactive glass microparticles (CS/μBG) control = 7.45 ± 6.5°, CS/μBG 7d in PBS = 86.4 ± 6.5°; chitosan/bioactive glass nanoparticles (CS/nBG) control = 65.0 ± 6.3°, CS/nBG 7d in PBS = 81.2 ± 14.6°; Young’s Modulus CS/μBG = 17 MPa, Young’s Modulus CS/nBG = 20 MPa. Excellent hydroxyapatite forming ability Membranes for bone regeneration [164] 55SiO2-40CaO-5P2O5 mol% Dispensing the precursor solutions in wettable spots previously patterned onto superhydrophobic surfaces Storage modulus = 0.03-5 MPa. Enhanced proliferation and spreading of pre-osteoblast cell line with a fibroblast-like phenotype (MC3T3-E1) Hydrogels for bone tissue engineering [165] BG (55SiO2-40CaO-5P2O5 mol%) Mixing solution BG nanoparticles: 0% (control), 10%, 20%, 30%, 40% and 50% (wBG/wchitosan) Storage modulus: BG10 = 24.1 Pa, BG20 = 76.2 Pa, BG30 = 65.0 Pa, BG40 = 105.2 Pa, BG50 = 107.2 Pa. Loss modulus: BG10 = 17.0 Pa, BG20 = 19.8 Pa, BG30 = 16.7 Pa, BG40 = 18.2 Pa, BG50 = 17.7 Pa. Gelation point BG10 = 38.3 °C, BG20 = 29.3 °C, BG30 = 37.0 °C, BG40 = 36.9 °C; BG50 = 36.8 °C Injectable systems for small bone defects [166] 60SiO2-36CaO-4P2O5 mol% Needle punching process Porosity (%) = 77.52 ± 1.67; water absorption (%) = 58.89 ± 7.3; compression strength = 7.68 ± 0.38 MPa; elastic modulus = 0.46 ± 0.02 GPa; flexure strength = 6.0 ± 0.4 MPa, flexure modulus = 102.0 ± 10 MPa; tensile strength = 3.11 ± 0.24 MPa; tensile modulus = 196.0 ± 17.0 MPa; fracture toughness = 0.24 ± 0.02 MPa m1/2. Good biocompatibility Scaffolds for bone tissue engineering [167] 6Na2O-8K2O-8MgO-22CaO-54B2O3-2P2O5 mol% Mixing chitosan solution and glass particles Injectability = 84–97%; compressive strength = 8–32 MPa; density = 2–3 gcm−3; disintegration resistance = 90–95%. Enhanced proliferation and ALP activity; in vivo stimulation of new bone formation Injectable systems for healing bone defects [168] BG-NPs (55SiO2-40CaO-5P2O5 mol%), where NPs means nanoparticles Freeze-drying technique Maximum swelling reached for 100 vol% of water = 358%; Young’s Modulus = 55 kPa; strain recovery under deformation strain 30% = 10–80 %; shape fixity ratio = 98.2 ± 0.7 and shape recovery ratio = 89.9 ± 2.7 under deformation strain = 30%. Enhanced apatite formation in vitro Scaffolds for bone tissue engineering [169] 55SiO2-40CaO-5P2O5 mol% Solvent casting Young’s Modulus = 2639 ± 212 MPa (dry), 4.7 ± 0.3 MPa (wet); ultimate tensile strength = 49.6 ± 9.2 MPa (dry), 3.3 ± 0.6 MPa (wet); elongation at break = 2.5 ± 0.6% (dry), 71.6 ± 11.6 % (wet); water uptake = 130 ± 9 %. Enhanced metabolic activity of human periodontal ligament cells (hPDL) and human bone marrow stromal cells (hBMSC) Membranes for guided tissue regeneration (GTR) and guided bone regeneration (GBR). [170] 64SiO2 -31CaO-5P2O5 mol% Mixing solutions In vitro hydroxyapatite formation and enhanced cell proliferation. In vivo high rate of new bone regeneration Injectable system for bone substitute [184] Sr-BBG (6Na2O-8K2O-8MgO-9SrO, 22CaO-54B2O3-2P2O5 mol%); BBG (6Na2O-8K2O-8MgO-22CaO-54B2O3-2P2O5 mol%) Manually mixing Injectability: Sr-BBG = 98 ± 1%, BBG = 95 ± 1%. Compressive strength: Sr-BBG = 19 ± 1 MPa, BBG = 20 ± 1 MPa. Enhanced proliferation and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) in vitro; good capacity to regenerate bone at the implant bone interface in vivo Injectable system to treat irregularly shaped bone defects [193] 55SiO2-40CaO-5P2O5 mol%; 64SiO2-26CaO-5P2O5-5MgO mol% Solvent casting High hydrophilicity, good osteoblastic response toward cellular differentiation and mineralization Membranes for guided tissue regeneration: orthopedic field [195] 45S5, BGMS10 (47.2SiO2-2.3Na2O-2.3K2O-25.6CaO-2.6P2O5-10MgO-10SrO mol%); BGMS_2Zn (47.2SiO2-2.3Na2O-2.3K2O-25.6CaO-2.6P2O5-8MgO-10SrO-2ZnO mol%) Manually mixing Enhanced bioactivity, cellular viability, and cells migration rate of chitosan/bioactive glass wound dressings Wound dressings suitable for healing devices [198] BG_NPs (55SiO2-40CaO-5P2O5 mol%), where NPs means nanoparticles Solvent casting Nucleation and growth of apatite. Density of cells on the patterned substrate increased with increasing culture time Membranes pattern with BG to promote guided tissue regeneration in the bone side [199] Bioactive glass ceramic nanoparticles (nBGCs) Lyophilization technique Interconnected pores 150–300 μm, controlled swelling behavior, good attachment and spread of cells Scaffolds for tissue applications [200] 60SiO2-36CaO-4P2O5 mol% Foaming method Young’s modulus = 750 ± 0.08 KPa; compressive strength = 120 ± 0.09 KPa; toughness = 1936 ± 0.07 KPa. Total porosity = 65.0 ± 3.6%; average pore size = 118.2 ± 8.2 mm; highly interconnected pore system = 99.8 ± 0.1%. Increased swelling at low pH; adequate cells viability Scaffolds for tissue regeneration and stimulation of healing [201] materials-13-05560-t006_Table 6Table 6 Summary of alginate/bioactive glass composites for biomedical applications. Bioactive Glass Technique Composites’ Characteristics Applications Ref. Biosilicate® Manual mixing Injectability time = 198–119 s; storage modulus = 10–77 kPa. Cell viability = 800RFU Injectable systems for bone regenerative [209] 80SiO2-15CaO-5P2O5 mol% Self-crosslinking process Porosity = 60–75%; compressive strength = 0.3–2.5 MPa; compressive modulus = 5–65 MPa. Relatively excellent apatite formation ability in vitro. Promotion of early cell adhesion Scaffolds for bone regeneration [216] CaO–SiO2–P2O5 nano bioactive glass ceramic particles (nBGC) Lyophilization technique Pore size 100–300 μm; swelling ability; limited degradation; enhanced biomineralization. Good protein adsorption; good cell attachment; good cell proliferation Scaffolds for periodontal tissue regeneration [217] Mesoporous bioactive glass (MBG) 3D plotting Pore size = 190–415 μm; porosity = 50–69%; compressive strength = 0.4–1.6 MPa; compressive modulus = 1.5–6 MPa. Increased apatite mineralization and cytocompatibility Scaffolds for bone tissue engineering [218] 13-93 BG 3D printing Pore size = 250–500 μm; porosity = 65–87%; compressive strength = 9–16 MPa; modulus = 40–80 MPa. Increased apatite mineralization; rat bone mesenchymal stem cells (rBMSC) spread, adhere and improved osteogenical differentiation - [219] 60SiO2-26CaO-4P2O5-5ZnO-5MgO mol% Freeze-drying technique Pore size = 75–275 μm; compressive strength = 0.2–1.7 MPa; elastic modulus = 3.5–18 MPa; toughness = 0.25–0.75 MJ/m3. Improved degradation rate; improved HA formation; good MG-63 cell line (CRL-1427, 14 years, Caucasian, Passage 4) response (viability, attachment and proliferation); restrict growth of both S. aureus and E. coli Scaffolds for bone tissue engineering [224] A0 (36.4SiO2-6.0P2O5-26.5CaO-2.2CaF2-26.5SrO-2.2SrF2-0Na2O-0K2O-0ZnO mol%); A1 (44.0SiO2-5.0P2O5-15.0CaO-0CaF2 -15.0SrO-0SrF2-10.0Na2O-10.0K2O-1.0ZnO mol%) Freeze-drying technique Pore size = 100–133 μm; Young’s Modulus = 1.6–2.8 MPa Scaffolds for bone applications [230] ICIE16M (49.46SiO2-6.60Na2O-27.27CaO-3.00SrO-6.60K2O-3.00MgO-3.00ZnO-1.07P2O5 mol %); ICIE16 (49.46SiO2-6.60Na2O-36.27CaO-0SrO-6.60K2O-0MgO-0ZnO-1.07P2O5 mol%) Freeze-drying technique Average pore size of 110 µm and maximum pore size of 309 µm; average collapse stress/yield stress = 0.175 ± 0.04 MPa; average Young’s Modulus = 1.83 ± 0.66 MPa Scaffolds for bone applications [231] AL100 (0.33SiO2-0.18Al2O3-0.00Ga2O3-0.23CaO-0.11P2O5-0.15CaCl2 mol%); AL067 (0.33SiO2-0.12Al2O3-0.06Ga2O3-0.23CaO-0.11P2O5-0.15CaCl2 mol%); GA067 (0.33SiO2-0.06Al2O3-0.12Ga2O3-0.23CaO-0.11P2O5-0.15CaCl2 mol%); GA100 (0.33SiO2-0.00Al2O3-0.18Ga2O3-0.23CaO-0.11P2O5-0.15CaCl2 mol%) Mixing solutions Ultimate compressive strength = 10–70 kPa; elastic modulus = 70–340 kPa. High biocompatibility Hydrogels for applications in tissue enginnering [241] 46SiO2-23Na2O-27CaO-4P2O5 wt% Solvent casting, drying and crosslinking technique Young’s modulus = 0.3–1.45 GPa. Improved acellular bioactivity; enhanced osteoblast-like cell proliferation Films with prophylaxis effect against infections and potential use in bone tissue engineering [244] 45S5 Solvent casting Tensile strength = 7 MPa. Improved biomineralization in vitro Scaffolds for bone tissue engineering [245] Nbg: nominal composition close to Bioglass 45S5 (46SiO2-27CaO-23Na2O-4P2O5 wt%) Solvent casting and drying Ultimate strength = 6.5–7 MPa. Enhanced bioactivity; stimulation of rat bone marrow-derived mesenchymal stem cells (rBMSCs) differentiation; enhanced human umbilical vein endothelial cells (HUVEC) proliferation and vascular endothelial growth factor (VEGF) secretion Scaffolds for bone tissue engineering [246] materials-13-05560-t007_Table 7Table 7 Summary of cellulose/bioactive glass composites for biomedical applications. Bioactive Glass Technique Composites’ Characteristics Applications Ref. MBGSi80 (molar ratio Si/Ca/P = 80/15/5); MBGSi78Cu2 (molar ratio Si/Cu/Ca/P = 78/2/15/5); MBGSi75Cu5 (molar ratio Si/Cu/Ca/P = 75/5/15/5 Freeze-drying and lyophilization technique Angiogenic effect in the angiogenesis assay; enhanced the gene expression Membranes for wound healing dressings [255] BG Freeze-casting technique Pore size = 135 ± 33 μm. Improved hydroxyapatite formation; enhanced cellular proliferation Scaffolds for bone tissue engineering [256] 45S5 One step electrophoretic co-deposition process Thickness = 28 μm. Enhanced attachment, proliferation, and differentiation of cells; accelerated mineralization capability Hybrid coatings for orthopedic implants [259] 45S5 One-step electrophoretic deposition process As-deposited thickness = 14.0 ± 0.9 μm; after 14d in SBF thickness = 7.1 ± 0.6 μm Coatings for bio-functionalization of metallic orthopedic implants [260] materials-13-05560-t008_Table 8Table 8 Summary of respective advantages and disadvantages of natural polymers previously analyzed. Polymer Advantages Disadvantages Refs. Collagen Biodegradable, biocompatible, hemostatic, easily modifiable and versatile. Compatible with synthetic polymers Poor mechanical strength and stiffness. Variability of isolated collagen, hydrophilicity [12,73,261] Gelatin Biodegradable, biocompatible, very low antigenicity, good cell recognition Fast degradation rate in physiological fluids, brittle [12] Silk fibroin Biodegradable, biocompatible, good structural stability, strength, biodegradability, elasticity, low tissue reactivity Lacks the potential to induce osteogenesis, sericin needs to be removed [12,128] Hyaluronic acid Biodegradable, biocompatible High risk of biological contamination, high purification costs [142] Chitosan Biodegradable, biocompatible, hemostatic, hydrophilicity, antibacterial activity, its structure allows specific modifications without too many difficulties Long period for bone formation, crosslinkers needed to maintain the integrity of structure [262] Alginate Biodegradable, non-immunogenicity, hydrophilicity, formation of gels capable of encapsulating cells, drugs and other biological entities, relative low cost Biocompatibility under discussion for possible impurities due to the alginate extract, partial oxidation required to make alginate degradable in physiological environment [205,206] Cellulose Biodegradable, biocompatible, most abundant Low dimensional stability, and it showed poor hydrophilicity, bioactivity, and antibacterial properties [12] ==== Refs References 1. Linden M. Ray D. Life expectancy effects of public and private health expenditures in OECD countries 1970–2012: Panel time series approach Econ. Anal. Policy 2017 56 101 113 10.1016/j.eap.2017.06.005 2. Vaupel J.W. Biodemography of human ageing Nature 2010 464 536 542 10.1038/nature08984 20336136 3. Daware M.A. Review Article Osteoporosis in Elderly Vidarbha. J. Intern. Med. 2014 17 19 27 4. Lorentzon M. Cummings S.R. Osteoporosis: The evolution of a diagnosis J. Intern. Med. 2015 277 650 661 10.1111/joim.12369 25832448 5. Hench L.L. Biomaterials: A forecast for the future Biomaterials 1998 19 1419 1423 10.1016/S0142-9612(98)00133-1 9794512 6. Blackwood D.J. Biomaterials: Past Successes and Future Problems Corros. Rev. 2003 21 97 124 10.1515/CORRREV.2003.21.2-3.97 7. Pirhonen E. Fibres and Composites for Potential Biomaterials Applications Ph.D. Thesis Tampere University of Technology Tampere, Finland 2006 1 84 8. Hench L.L. Polak J.M. Third-generation biomedical materials Science 2002 295 1014 1017 10.1126/science.1067404 11834817 9. Griffith L.G. Polymeric biomaterials Acta Mater. 2000 48 263 277 10.1016/S1359-6454(99)00299-2 10. Boccaccini A. Gough J. Tissue Engineering Using Ceramics and Polymers Woodhead Publishing Limited Cambridge, UK 2007 1 587 11. Bhatia S. Natural Polymer Drug Delivery Systems Springer Berlin/Heidelberg, Germany 2016 1 225 12. Kumbar S. Laurencin C. Deng M. Natural and Synthetic Biomedical Polymers Elsevier Berlin/Heidelberg, Germany 2014 1 402 13. Sabu T. Neethu N. Sneha M. Elizabeth F. Natural Polymers, Biopolymers, Biomaterials and Their Composites, Blends and IPNS Apple Academic Press Toronto, ON, Canada 2012 1 407 14. Kulkarni V. Butte K. Rathod S. Natural Polymers—A Comprehensive Review Int. J. Res. Pharm. Biomed. Sci. 2012 3 1597 1613 15. Ratner B. Hoffman A. Schoen F. Lemons J. Biomaterials Science an Introduction to Materials in Medicine 2nd ed. Elsevier Amsterdam, The Netherlands 2004 1 851 16. Odian G. Principles of Polymerization 4th ed. Odian G. Wiley Interscience a John Wiley & Sons Hoboken, NJ, USA 2004 1 812 17. Maitz M.F. Applications of synthetic polymers in clinical medicine Biosurface Biotribology 2015 1 161 176 10.1016/j.bsbt.2015.08.002 18. Leite A. Mano J. Biomedical applications of natural-based polymers combined with bioactive glass nanoparticles J. Mater. Chem. B 2017 5 4555 4568 10.1039/C7TB00404D 32264298 19. Marelli B. Ghezzi C.E. Barralet J.E. Boccaccini A.R. Nazhat S.N. Three-dimensional mineralization of dense nanofibrillar collagen-bioglass hybrid scaffolds Biomacromolecules 2010 11 1470 1479 10.1021/bm1001087 20443577 20. Dziadek M. Stodolak-Zych E. Cholewa-Kowalska K. Biodegradable ceramic-polymer composites for biomedical applications: A review Mater. Sci. Eng. C 2017 71 1175 1191 10.1016/j.msec.2016.10.014 21. Mano J.F. Silva G.A. Azevedo H.S. Sousa P.B. Sousa R.A. Silva S.S. Boesel L.F. Oliveira J.M. Santos T.C. Marques A.P. Natural origin biodegradable systems in tissue engineering and regenerative medicine: Present status and some moving trends J. R. Soc. Interface 2007 4 999 1030 10.1098/rsif.2007.0220 17412675 22. Badylak S.F. The extracellular matrix as a biologic scaffold material Biomaterials 2007 28 3587 3593 10.1016/j.biomaterials.2007.04.043 17524477 23. D’Ayala G.G. Malinconico M. Laurienzo P. Marine derived polysaccharides for biomedical applications: Chemical modification approaches Molecules 2008 13 2069 2106 10.3390/molecules13092069 18830142 24. Klouda L. Mikos A.G. Thermoresponsive hydrogels in biomedical applications—A review Eur. J. Pharm. Biopharm. 2011 68 34 45 10.1016/j.ejpb.2007.02.025 25. Araújo M. Viveiros R. Philippart A. Miola M. Doumett S. Baldi G. Perez J. Boccaccini A.R. Aguiar-Ricardo A. Verné E. Bioactivity, mechanical properties and drug delivery ability of bioactive glass-ceramic scaffolds coated with a natural-derived polymer Mater. Sci. Eng. C 2017 768 342 351 10.1016/j.msec.2017.03.169 26. Harini B. Shadamarshan R.P.K. Rao S.H. Selvamurugan N. Balagangadharan K. Natural and synthetic polymers/bioceramics/bioactive compounds-mediated cell signalling in bone tissue engineering Int. J. Biol. Macromol. 2017 110 88 96 28917940 27. Stanić V. Variation in Properties of Bioactive Glasses after Surface Modification Springer International Publishing AG Berlin/Heidelberg, Germany 2017 1 467 28. Carvalho S.M. Moreira C.D.F. Oliveira A.C.X. Oliveira A.A.R. Lemos E.M.F. Pereira M.M. Bioactive Glass Nanoparticles for Periodontal Regeneration and Applications in Dentistry Nanobiomaterials in Clinical Dentistry Elsevier Inc. Amsterdam, The Netherlands 2019 351 383 29. Ali S. Farooq I. Iqbal K. A review of the effect of various ions on the properties and the clinical applications of novel bioactive glasses in medicine and dentistry Saudi Dent. J. 2014 26 1 5 10.1016/j.sdentj.2013.12.001 24526822 30. Profeta A.C. Prucher G.M. Bioactive-glass in periodontal surgery and implant dentistry Dent. Mater. J. 2015 34 559 571 10.4012/dmj.2014-233 26438980 31. Montazerian M. Zanotto E.D. A guided walk through Larry Hench’s monumental discoveries J. Mater. Sci. 2017 52 8695 8732 10.1007/s10853-017-0804-4 32. Kokubo T. Apatite formation on surfaces of ceramics, metals and polymers in body environment Acta Mater. 1998 46 2519 2527 10.1016/S1359-6454(98)80036-0 33. Bellows C.G. Aubin J.E. Heersche J.N.M. Initiation and progression of mineralization of bone nodules formed in vitro: The role of alkaline phosphatase and organic phosphate Bone Miner. 1991 14 27 40 10.1016/0169-6009(91)90100-E 1868267 34. Hench L.L. The story of Bioglass® J. Mater. Sci. Mater. Med. 2006 17 967 978 10.1007/s10856-006-0432-z 17122907 35. O’Donnell M.D. Hill R.G. Donnell M.D.O. Influence of strontium and the importance of glass chemistry and structure when designing bioactive glasses for bone regeneration Acta Biomater. 2010 6 2382 2385 10.1016/j.actbio.2010.01.006 20079468 36. Bellucci D. Sola A. Salvatori R. Anesi A. Chiarini L. Cannillo V. Role of magnesium oxide and strontium oxide as modifiers in silicate-based bioactive glasses: Effects on thermal behaviour, mechanical properties and in-vitro bioactivity Mater. Sci. Eng. C 2017 72 566 575 10.1016/j.msec.2016.11.110 37. Aydin H. Magnesium supplementation and bone Magnes. Hum. Health Dis. 2013 57 149 157 38. Bellucci D. Cannillo V. A novel bioactive glass containing strontium and magnesium with ultra-high crystallization temperature Mater. Lett. 2018 213 67 70 10.1016/j.matlet.2017.11.020 39. Bellucci D. Salvatori R. Anesi A. Chiarini L. Cannillo V. SBF assays, direct and indirect cell culture tests to evaluate the biological performance of bioglasses and bioglass-based composites: Three paradigmatic cases Mater. Sci. Eng. C 2019 96 757 764 10.1016/j.msec.2018.12.006 40. Bellucci D. Salvatori R. Giannatiempo J. Anesi A. Bortolini S. Cannillo V. A New Bioactive Glass/Collagen Hybrid Composite for Applications in Dentistry Materials 2019 12 2079 10.3390/ma12132079 31261615 41. Bellucci D. Veronesi E. Strusi V. Petrachi T. Murgia A. Mastrolia I. Dominici M. Cannillo V. Human Mesenchymal Stem Cell Combined with a New Strontium-Enriched Bioactive Glass: An ex-vivo Model for Bone Regeneration Materials 2019 12 3633 10.3390/ma12213633 31694164 42. Elsayed H. Romero A.R. Bellucci D. Cannillo V. Bernardo E. Advanced open-celled structures from low-temperature sintering of a crystallization-resistant bioactive glass Materials 2019 12 3653 10.3390/ma12223653 31698838 43. Bellucci D. Veronesi E. Dominici M. Cannillo V. On the In vitro biocompatibility testing of bioactive glasses Materials 2020 13 1816 10.3390/ma13081816 32290545 44. Sergi R. Cannillo V. Boccaccini A.R. Liverani L. Incorporation of bioactive glasses containing Mg, Sr and Zn in electrospun PCL fibers by using benign solvents Appl. Sci. 2020 10 5530 10.3390/app10165530 45. Di Tinco R. Sergi R. Bertani G. Pisciotta A. Bellucci D. Carnevale G. Cannillo V. Bertoni L. Effects of a novel bioactive glass composition on biological properties of human dental pulp stem cells Materials 2020 13 4049 10.3390/ma13184049 46. Bellucci D. Veronesi E. Dominici M. Cannillo V. A new bioactive glass with extremely high crystallization temperature and outstanding biological performance Mater. Sci. Eng. C 2020 110 110699 10.1016/j.msec.2020.110699 47. Sergi R. Bellucci D. Salvatori R. Anesi A. Cannillo V. A novel bioactive glass containing therapeutic ions with enhanced biocompatibility Materials 2020 13 4600 10.3390/ma13204600 48. Cacciotti I. Bivalent cationic ions doped bioactive glasses: The influence of magnesium, zinc, strontium and copper on the physical and biological properties J. Mater. Sci. 2017 52 8812 8831 10.1007/s10853-017-1010-0 49. Hoppe A. Güldal N.S. Boccaccini A.R. A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics Biomaterials 2011 32 2757 2774 10.1016/j.biomaterials.2011.01.004 21292319 50. Balasubramanian P. Strobel L.A. Kneser U. Boccaccini A.R. Zinc-containing bioactive glasses for bone regeneration, dental and orthopedic applications Biomed. Glas. 2015 1 51 69 10.1515/bglass-2015-0006 51. Huang M. Hill R.G. Rawlinson S.C.F. Zinc bioglasses regulate mineralization in human dental pulp stem cells Dent. Mater. 2017 33 543 552 10.1016/j.dental.2017.03.011 28366235 52. Kim Y. Antibacterial and remineralization effects of orthodontic bonding agents containing bioactive glass Korean J. Orthod. 2018 48 163 171 10.4041/kjod.2018.48.3.163 29732302 53. Bari A. Bloise N. Fiorilli S. Novajra G. Vallet-Regí M. Bruni G. Torres-Pardo A. González-Calbet J.M. Visai L. Vitale-Brovarone C. Copper-containing mesoporous bioactive glass nanoparticles as multifunctional agent for bone regeneration Acta Biomater. 2017 55 493 504 10.1016/j.actbio.2017.04.012 28412552 54. Sergi R. Bellucci D. Salvatori R. Maisetta G. Batoni G. Cannillo V. Zinc containing bioactive glasses with ultra-high crystallization temperature, good biological performance and antibacterial effects Mater. Sci. Eng. C 2019 104 109910 10.1016/j.msec.2019.109910 55. Nour S. Baheiraei N. Imani R. Rabiee N. Khodaei M. Bioactive Materials: A Comprehensive Review on Interactions with Biological Microenvironment Based on the Immune Response J. Bionic. Eng. 2019 16 563 581 10.1007/s42235-019-0046-z 56. Sengupta D. Heilshorn S.C. Protein-engineered biomaterials: Highly tunable tissue engineering scaffolds Tissue Eng. Part B Rev. 2010 16 285 293 10.1089/ten.teb.2009.0591 20141386 57. Weiner S. Wagner H.D. The material bone: Structure-mechanical function relations Ann. Rev. Mater. Sci. 1998 28 271 298 10.1146/annurev.matsci.28.1.271 58. Zhang D. Wu X. Chen J. Lin K. The development of collagen based composite scaffolds for bone regeneration Bioact. Mater. 2018 3 129 138 10.1016/j.bioactmat.2017.08.004 29744450 59. Ignatius A. Blessing H. Liedert A. Schmidt C. Neidlinger-Wilke C. Kaspar D. Friemert B. Claes L. Tissue engineering of bone: Effects of mechanical strain on osteoblastic cells in type I collagen matrices Biomaterials 2005 26 311 318 10.1016/j.biomaterials.2004.02.045 15262473 60. Geiger M. Li R.H. Friess W. Collagen sponges for bone regeneration with rhBMP-2 Adv. Drug Deliv. Rev. 2003 55 1613 1629 10.1016/j.addr.2003.08.010 14623404 61. Lutolf M.P. Weber F.E. Schmoekel H.G. Schense J.C. Kohler T. Müller R. Hubbell J.A. Repair of bone defects using synthetic mimetics of collagenous extracellular matrices Nat. Biotechnol. 2003 21 513 518 10.1038/nbt818 12704396 62. Guilak F. Cohen D. Estes B. Gimble J. Liedtke W. Chen C. Control of stem cell fate by physical interactions with the extracellular matrix Bone 2012 23 17 26 10.1016/j.stem.2009.06.016 19570510 63. Prodanov L. te Riet J. Lamers E. Domanski M. Luttge R. van Loon J.J.W.A. Jansen J.A. Walboomers X.F. The interaction between nanoscale surface features and mechanical loading and its effect on osteoblast-like cells behavior Biomaterials 2010 31 7758 7765 10.1016/j.biomaterials.2010.06.050 20647152 64. Sundararaghavan H.G. Monteiro G.A. Firestein B.L. Shreiber D.I. Neurite growth in 3D collagen gels with gradients of mechanical properties Biotechnol. Bioeng. 2009 102 632 643 10.1002/bit.22074 18767187 65. Ma W. Fitzgerald W. Liu Q.Y. O’Shaughnessy T.J. Maric D. Lin H.J. Alkon D.L. Barker J.L. CNS stem and progenitor cell differentiation into functional neuronal circuits in three-dimensional collagen gels Exp. Neurol. 2004 190 276 288 10.1016/j.expneurol.2003.10.016 15530869 66. Law J.X. Liau L.L. Saim A. Yang Y. Idrus R. Electrospun Collagen Nanofibers and Their Applications in Skin Tissue Engineering Tissue Eng. Regen. Med. 2017 14 699 718 10.1007/s13770-017-0075-9 30603521 67. Sheehy E.J. Cunniffe G.M. O’Brien F.J. Collagen-based biomaterials for tissue regeneration and repair Peptides and Proteins Biomaterials of Tissue Regeneration Repair Elsevier Duxford, UK 2018 127 150 68. Matsuno T. Nakamura T. Kuremoto K. Notazawa S. Development of β-tricalcium Phosphate/Collagen Sponge Composite for Bone Regeneration Dent. Mater. J. 2006 25 38 144 10.4012/dmj.25.138 69. Zhang Z. Ma Z. Zhang Y. Chen F. Zhou Y. An Q. Dehydrothermally crosslinked collagen/hydroxyapatite composite for enhanced in vivo bone repair Colloids Surfaces B Biointerfaces 2018 163 394 401 10.1016/j.colsurfb.2018.01.011 29366982 70. Powell H.M. Supp D.M. Boyce S.T. Influence of electrospun collagen on wound contraction of engineered skin substitutes Biomaterials 2008 29 834 843 10.1016/j.biomaterials.2007.10.036 18054074 71. Chen R. Wang G. Chen C. Ho H. Sheu M.-T. Development of N,O-(Carboxymethyl) chitosan/Collagen Matrixes as a Wound Dressing Biomacromolecules 2006 7 1058 1064 10.1021/bm050754b 16602721 72. Chen J.P. Chang G.Y. Chen J.K. Electrospun collagen/chitosan nanofibrous membrane as wound dressing Colloids Surfaces A Physicochem. Eng. Asp. 2008 313 183 188 10.1016/j.colsurfa.2007.04.129 73. Sarker B. Hum J. Nazhat S.N. Boccaccini A.R. Combining collagen and bioactive glasses for bone tissue engineering: A review Adv. Healthc. Mater. 2015 4 176 194 10.1002/adhm.201400302 25116596 74. Cancedda R. Giannoni P. Mastrogiacomo M. A tissue engineering approach to bone repair in large animal models and in clinical practice Biomaterials 2007 28 4240 4250 10.1016/j.biomaterials.2007.06.023 17644173 75. Karageorgiou V. Kaplan D. Porosity of 3D biomaterial scaffolds and osteogenesis Biomaterials 2005 26 5474 5491 10.1016/j.biomaterials.2005.02.002 15860204 76. Shekaran A. Garcia A. Extracellular matrix-mimetic adhesive biomaterials for bone repair J. Biomed. Mater. Res. A 2012 96 261 272 10.1002/jbm.a.32979 77. Lanza R. Langer R. Vacanti J. Principles of Tissue Engineering 3rd ed. Elsevier Amsterdam, The Netherlands 2007 1 1291 78. Long T. Yang J. Shi S.S. Guo Y.P. Ke Q.F. Zhu Z.A. Fabrication of three-dimensional porous scaffold based on collagen fiber and bioglass for bone tissue engineering J. Biomed. Mater. Res. Part B Appl. Biomater. 2015 103 1455 1464 10.1002/jbm.b.33328 79. Hong S.J. Yu H.S. Noh K.T. Oh S.A. Kim H.W. Novel scaffolds of collagen with bioactive nanofiller for the osteogenic stimulation of bone marrow stromal cells J. Biomater. Appl. 2010 24 733 750 10.1177/0885328209338956 19671619 80. Marelli B. Ghezzi C.E. Mohn D. Stark W.J. Barralet J.E. Boccaccini A.R. Nazhat S.N. Accelerated mineralization of dense collagen-nano bioactive glass hybrid gels increases scaffold stiffness and regulates osteoblastic function Biomaterials 2011 32 8915 8926 10.1016/j.biomaterials.2011.08.016 21889796 81. Rezwan K. Chen Q.Z. Blaker J.J. Boccaccini A.R. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering Biomaterials 2006 27 3413 3431 10.1016/j.biomaterials.2006.01.039 16504284 82. Kim H.-W. Song J.-H. Kim H.-E. Bioactive glass nanofiber–collagen nanocomposite as a novel bone regeneration matrix J. Biomed. Mater. Res. 2006 79 698 705 10.1002/jbm.a.30848 16850456 83. Hattar S. Loty S. Gaisser D. Berdal A. Sautier J.M. Effects of 58s sol-gel glasses on the temporal expression of bone markers during mouse osteoblastic differentiation J. Biomed. Mater. Res. Part A 2006 76 811 819 10.1002/jbm.a.30637 16345098 84. Xynos I.D. Edgar A.J. Buttery L.D.K. Hench L.L. Polak J.M. Ionic products of bioactive glass dissolution increase proliferation of human osteoblasts and induce insulin-like growth factor II mRNA expression and protein synthesis Biochem. Biophys. Res. Commun. 2000 276 461 465 10.1006/bbrc.2000.3503 11027497 85. O’Neill E. Awale G. Daneshmandi L. Umerah O. Lo K.W.H. The roles of ions on bone regeneration Drug Discov. Today 2018 23 879 890 10.1016/j.drudis.2018.01.049 29407177 86. Dashnyam K. El-Fiqi A. Buitrago J.O. Perez R.A. Knowles J.C. Kim H.W. A mini review focused on the proangiogenic role of silicate ions released from silicon-containing biomaterials J. Tissue Eng. 2017 8 1 13 10.1177/2041731417707339 87. Maeno S. Niki Y. Matsumoto H. Morioka H. Yatabe T. Funayama A. Toyama Y. Taguchi T. Tanaka J. The effect of calcium ion concentration on osteoblast viability, proliferation and differentiation in monolayer and 3D culture Biomaterials 2005 26 4847 4855 10.1016/j.biomaterials.2005.01.006 15763264 88. Gao X. Wang S. Dong Y. Chen X. Gong W. A novel nano-sized bioactive glass stimulates osteogenesis via the MAPK pathway RSC Adv. 2017 7 13760 13767 89. Humeau J. Bravo-San Pedro J.M. Vitale I. Nuñez L. Villalobos C. Kroemer G. Senovilla L. Calcium signaling and cell cycle: Progression or death Cell Calcium 2018 70 3 15 10.1016/j.ceca.2017.07.006 28801101 90. Allen-Durrance A.E. A Quick Reference on Phosphorus Vet. Clin. N. Am. Small Anim. Pract. 2017 47 257 262 10.1016/j.cvsm.2016.09.003 91. Julien M. Khoshniat S. Lacreusette A. Gatius M. Bozec A. Wagner E.F. Wittrant Y. Masson M. Weiss P. Beck L. Phosphate-dependent regulation of MGP in osteoblasts: Role of ERK1/2 and Fra-1 J. Bone Miner. Res. 2009 24 1856 1868 10.1359/jbmr.090508 19419315 92. Wang Y. Xu C. Meng Y. Xiang A.P. Su P. Yu W. Xiang A.P. Wang Y. Biocompatibility and osteogenesis of biomimetic Bioglass-Collagen-Phosphatidylserine composite scaffolds for bone tissue engineering Biomaterials 2010 32 1051 1058 20980051 93. Freyman T.M. Yannas I.V. Gibson L.J. Cellular materials as porous scaffolds for tissue engineering Prog. Mater. Sci. 2001 46 273 282 10.1016/S0079-6425(00)00018-9 94. Naahidi S. Jafari M. Logan M. Wang Y. Yuan Y. Bae H. Dixon B. Chen P. Biocompatibility of hydrogel-based scaffolds for tissue engineering applications Biotechnol. Adv. 2017 35 530 544 10.1016/j.biotechadv.2017.05.006 28558979 95. Jafari M. Paknejad Z. Rad M.R. Motamedian S.R. Eghbal M.J. Nadjmi N. Khojasteh A. Polymeric scaffolds in tissue engineering: A literature review J. Biomed. Mater. Res. Part B Appl. Biomater. 2017 105 431 459 10.1002/jbm.b.33547 96. Eglin D. Maalheem S. Livage J. Coradin T. In vitro apatite forming ability of type I collagen hydrogels containing bioactive glass and silica sol-gel particles J. Mater. Sci. Mater. Med. 2006 17 161 167 10.1007/s10856-006-6820-6 16502249 97. Vargas G. Durand L. Cadena V. Romero M. Mesones R. Mackovic M. Spallek S. Spiecker E. Boccaccini A.R. Gorustovich A.A. Effect of nano-sized bioactive glass particles on the angiogenic properties of collagen based composites J. Mater. Sci. Mater. Med. 2013 24 1261 1269 10.1007/s10856-013-4892-7 23430337 98. El-fiqi A. Ho J. Lee E. Kim H. Collagen hydrogels incorporated with surface-aminated mesoporous nanobioactive glass: Improvement of physicochemical stability and mechanical properties is effective for hard tissue engineering Acta Biomater. 2013 9 9508 9521 10.1016/j.actbio.2013.07.036 23928332 99. Heinemann S. Heinemann C. Jäger M. Neunzehn J. Wiesmann H.P. Hanke T. Effect of silica and hydroxyapatite mineralization on the mechanical properties and the biocompatibility of nanocomposite collagen scaffolds ACS Appl. Mater. Interfaces 2011 3 4323 4331 10.1021/am200993q 21942510 100. Desimone M.F. Hélary C. Rietveld I.B. Bataille I. Mosser G. Giraud-Guille M.M. Livage J. Coradin T. Silica-collagen bionanocomposites as three-dimensional scaffolds for fibroblast immobilization Acta Biomater. 2010 6 3998 4004 10.1016/j.actbio.2010.05.014 20493975 101. Zhou T. Sui B. Mo X. Sun J. Multifunctional and biomimetic fish collagen/bioactive glass nanofibers: Fabrication, antibacterial activity and inducing skin regeneration In vitro and in vivo Int. J. Nanomed. 2017 12 3495 3507 10.2147/IJN.S132459 102. Ayuk S.M. Houreld N.N. Abrahamse H. Collagen Production in Diabetic Wounded Fibroblasts in Response to Low-Intensity Laser Irradiation at 660 nm Diabetes Technol. Ther. 2012 14 1110 1117 10.1089/dia.2012.0125 23057714 103. Constantin V.D. Carap A. Bobic S. Budu V. Albu Kaya M. Marin Ş. Marin M.M. Socea B. Tissue Engineering—Collagen Sponge Dressing for Chronic Wounds Proceedings of the ICAMS 2018—7th International Conference on Advanced Materials and Systems Bucharest, Romania 18–20 October 2018 63 68 104. Gorustovich A.A. Roether J.A. Boccaccini A.R. Effect of Bioactive Glasses on Angiogenesis: A Review of In vitro and In vivo Evidences Tissue Eng. Part B Rev. 2010 16 199 207 10.1089/ten.teb.2009.0416 19831556 105. Li H. Chang J. Bioactive silicate materials stimulate angiogenesis in fibroblast and endothelial cell co-culture system through paracrine effect Acta Biomater. 2013 9 6981 6991 10.1016/j.actbio.2013.02.014 23416471 106. Oates M. Chen R. Duncan M. Hunt J.A. The angiogenic potential of three-dimensional open porous synthetic matrix materials Biomaterials 2007 28 3679 3686 10.1016/j.biomaterials.2007.04.042 17517430 107. Bose S. Tarafder S. Bandyopadhyay A. Effect of Chemistry on Osteogenesis and Angiogenesis towards Bone Tissue Engineering Using 3D Printed Scaffolds Ann. Biomed. Eng. 2017 45 261 272 10.1007/s10439-016-1646-y 27287311 108. Engler A.J. Sen S. Sweeney H.L. Discher D.E. Matrix Elasticity Directs Stem Cell Lineage Specification Cell 2006 126 677 689 10.1016/j.cell.2006.06.044 16923388 109. Zandstra P.W. Discher D.E. Mooney D.J. Growth Factors, Matrices, and Forces Combine and Control Stem Cells Science 2009 324 1673 1677 19556500 110. Discher D.E. Janmey P. Wang Y.L. Tissue cells feel and respond to the stiffness of their environment Science 2005 10 1139 1143 10.1126/science.1116995 111. Zheng J. Zhao F. Zhang W. Mo Y. Zeng L. Li X. Sequentially-crosslinked biomimetic bioactive glass/gelatin methacryloyl composites hydrogels for bone regeneration Mater. Sci. Eng. C 2018 89 119 127 10.1016/j.msec.2018.03.029 112. Kazemi M. Azami M. Johari B. Bone Regeneration in rat using a gelatin/bioactive glass nanocomposite scaffold along with endothelial cells (HUVECs) Int. J. Appl. Ceram. Technol. 2018 15 1427 1438 10.1111/ijac.12907 113. Kargozar S. Jafar S. Soleimani M. Brouki P. Acceleration of bone regeneration in bioactive glass/gelatin composite scaffolds seeded with bone marrow-derived mesenchymal stem cells over-expressing bone morphogenetic protein-7 Mater. Sci. Eng. C 2017 75 688 698 10.1016/j.msec.2017.02.097 28415516 114. Mozafari M. Moztarzadeh F. Rabiee M. Azami M. Nezafati N. Moztarzadeh Z. Tahriri M. Development of 3D bioactive nanocomposite scaffolds made from gelatin and nano bioactive glass for biomedical applications Adv. Compos. Lett. 2010 19 91 96 10.1177/096369351001900204 115. Mozafari M. Moztarzadeh F. Rabiee M. Azami M. Development of macroporous nanocomposite scaffolds of gelatin/bioactive glass prepared through layer solvent casting combined with lamination technique for bone tissue engineering Ceram. Int. 2010 36 2431 2439 10.1016/j.ceramint.2010.07.010 116. Mozafari M. Rabiee M. Azami M. Maleknia S. Biomimetic formation of apatite on the surface of porous gelatin/bioactive glass nanocomposite scaffolds Appl. Surf. Sci. 2010 257 1740 1749 10.1016/j.apsusc.2010.09.008 117. Gupta N. Santhiya D. In situ mineralization of bioactive glass in gelatin matrix Mater. Lett. 2017 188 127 129 10.1016/j.matlet.2016.11.045 118. Gao C. Gao Q. Li Y. Rahaman M.N. Teramoto A. Abe K. In vitro Evaluation of Electrospun Gelatin-Bioactive Glass Hybrid Scaffolds for Bone Regeneration J. Appl. Polym. Sci. 2013 127 2588 2599 10.1002/app.37946 119. Lao J. Dieudonné X. Fayon F. Montouillout V. Jallot E. Bioactive glass-gelatin hybrids: Building scaffolds with enhanced calcium incorporation and controlled porosity for bone regeneration J. Mater. Chem. B 2016 4 2486 2497 10.1039/C5TB02345A 32263198 120. Nadeem D. Kiamehr M. Yang X. Su B. Fabrication and In vitro evaluation of a sponge-like bioactive-glass/gelatin composite scaffold for bone tissue engineering Mater. Sci. Eng. C 2013 33 2669 2678 10.1016/j.msec.2013.02.021 121. Gao C. Rahaman M.N. Gao Q. Teramoto A. Abe K. Robotic deposition and In vitro characterization of 3D gelatin-bioactive glass hybrid scaffolds for biomedical applications J. Biomed. Mater. Res. Part A 2013 101 2027 2037 10.1002/jbm.a.34496 122. Lacroix J. Jallot E. Lao J. Gelatin-bioactive glass composites scaffolds with controlled macroporosity Chem. Eng. J. 2014 256 9 13 10.1016/j.cej.2014.06.022 123. Jalise Z.S. Bagheiraei N. Bagheri F. The effects of strontium incorporation on a novel gelatin/bioactive glass bone graft: In vitro and in vivo characterization Ceram. Int. 2018 44 14217 14227 10.1016/j.ceramint.2018.05.025 124. Raz M. Moztarzadeh F. Kordestani S.S. Sol-gel Based Fabrication and Properties of Mg-Zn Doped Bioactive Glass/Gelatin Composite Scaffold for Bone Tissue Engineering Silicon 2018 10 667 674 10.1007/s12633-016-9510-0 125. Guo W. Zhao F. Wang Y. Tang J. Chen X. Characterization of the mechanical behaviors and bioactivity of tetrapod ZnO whiskers reinforced bioactive glass/gelatin composite scaffolds J. Mech. Behav. Biomed. Mater. 2017 68 8 15 10.1016/j.jmbbm.2017.01.032 28135640 126. Yazdimamaghani M. Vashaee D. Assefa S. Walker K.J. Madihally S.V. Köhler G.A. Tayebi L. Hybrid Macroporous Gelatin/Bioactive-Glass/Nanosilver Scaffolds with Controlled Degradation Behavior and Antimicrobial Activity for Bone Tissue Engineering J. Biomed. Nanotechnol. 2014 10 911 931 10.1166/jbn.2014.1783 24749388 127. Zheng K. Wu J. Li W. Dippold D. Wan Y. Boccaccini A.R. Incorporation of Cu-Containing Bioactive Glass Nanoparticles in Gelatin-Coated Sca ff olds Enhances Bioactivity and Osteogenic Activity ACS Biomater. Sci. Eng. 2018 4 1546 1557 128. Kundu B. Rajkhowa R. Kundu S.C. Wang X. Silk fibroin biomaterials for tissue regenerations Adv. Drug Deliv. Rev. 2013 65 457 470 10.1016/j.addr.2012.09.043 23137786 129. Koh L.-D. Yu H.-D. Han M.-Y. Teng C.-P. Zhang Y.-W. Khin Y.-W. Loh X.-J. Tee S.-Y. Low M. Ye E. Structures, mechanical properties and applications of silk fibroin materials Prog. Polym. Sci. 2015 46 86 110 10.1016/j.progpolymsci.2015.02.001 130. Thurber A.E. Omenetto F.G. Kaplan D.L. In vivo bioresponses to silk proteins Biomaterials 2015 71 145 157 10.1016/j.biomaterials.2015.08.039 26322725 131. Melke J. Midha S. Ghosh S. Ito K. Hofmann S. Silk fibroin as biomaterial for bone tissue engineering Acta Biomater. 2016 31 1 16 10.1016/j.actbio.2015.09.005 26360593 132. Ma D. Wang Y. Dai W. Silk fibroin-based biomaterials for musculoskeletal tissue engineering Mater. Sci. Eng. C 2018 89 456 469 10.1016/j.msec.2018.04.062 133. Farokhi M. Mottaghitalab F. Fatahi Y. Khademhosseini A. Kaplan D.L. Overview of Silk Fibroin Use in Wound Dressings Trends Biotechnol. 2018 36 907 922 10.1016/j.tibtech.2018.04.004 29764691 134. Du X. Wei D. Huang L. Zhu M. Zhang Y. Zhu Y. 3D printing of mesoporous bioactive glass/silk fibroin composite scaffolds for bone tissue engineering Mater. Sci. Eng. C 2019 103 109731 10.1016/j.msec.2019.05.016 31349472 135. Wu C. Zhang Y. Zhou Y. Fan W. Xiao Y. A comparative study of mesoporous glass/silk and non-mesoporous glass/silk scaffolds: Physiochemistry and in vivo osteogenesis Acta Biomater. 2011 7 2229 2236 10.1016/j.actbio.2010.12.019 21185954 136. Shen X. Yu P. Chen H. Wang J. Lu B. Cai X. Icariin controlled release on a silk fibroin/mesoporous bioactive glass nanoparticles scaffold for promoting stem cell osteogenic differentiation RSC Adv. 2020 10 12105 12112 10.1039/D0RA00637H 137. Moses J.C. Nandi S.K. Mandal B.B. Multifunctional Cell Instructive Silk-Bioactive Glass Composite Reinforced Scaffolds Toward Osteoinductive, Proangiogenic, and Resorbable Bone Grafts Adv. Healthc. Mater. 2018 7 1701418 10.1002/adhm.201701418 138. Joseph M.C. Reardon P.J.T. Konwarh R. Knowles J.C. Mandal B.B. Mimicking Hierarchical Complexity of the Osteochondral Interface Using Electrospun Silk—Bioactive Glass Composites ACS Appl. Mater. Interfaces 2017 9 8000 8013 28181432 139. Bidgoli M. Tamjid E. Khafaji M. Alemzadeh I. Vossoughi M. Fabrication of hierarchically porous silk fibroin-bioactive glass composite scaffold via indirect 3D printing: Effect of particle size on physico- mechanical properties and in vitro cellular behavior Mater. Sci. Eng. C 2019 103 109688 10.1016/j.msec.2019.04.067 140. Zhu H. Liu N. Feng X. Chen J. Fabrication and characterization of silk fibroin/bioactive glass composite films Mater. Sci. Eng. C 2012 32 822 829 10.1016/j.msec.2012.01.033 141. Rubert M. Alonso-Sande M. Monjo M. Ramis J.M. Evaluation of alginate and hyaluronic acid for their use in bone tissue engineering Biointerphases 2012 7 44 10.1007/s13758-012-0044-8 142. Fallacara A. Baldini E. Manfredini S. Vertuani S. Hyaluronic acid in the third millennium Polymers 2018 10 701 10.3390/polym10070701 143. Boeriu C.G. Springer J. Kooy F.K. van den Broek L.A.M. Eggink G. Production Methods for Hyaluronan Int. J. Carbohydr. Chem. 2013 624967 10.1155/2013/624967 144. Liu H. Li H. Cheng W. Yang Y. Zhu M. Zhou C. Novel injectable calcium phosphate/chitosan composites for bone substitute materials Acta Biomater. 2006 2 557 565 10.1016/j.actbio.2006.03.007 16774852 145. Wang X. Chen L. Xiang H. Ye J. Influence of Anti-Washout Agents on the Rheological Properties and Injectability of a Calcium Phosphate Cement J. Biomed. Mater. Res. Part B Appl. Biomater. 2007 81B 410 418 10.1002/jbm.b.30678 17022060 146. Wu L. Zhu F. Tao G. In-Vitro Biocompatibility Evaluation of Collagen-Hyaluronic Acid/Bioactive Glass Nanocomposite Scaffold J. Macromol. Sci. Part A 2013 50 1121 1125 10.1080/10601325.2013.829360 147. Zhou Z. He S. Ou B. Huang T. Zeng W. Liu L. Liu Q. Chen J. Zhao Y. Yang Z. Influence of Nano-Bioactive Glass (NBG) content on properties of gelatin-hyaluronic acid/NBG composite scaffolds J. Macromol. Sci. Part B Phys. 2014 53 1145 1155 10.1080/00222348.2014.895610 148. Lou J. Stowers R. Nam S. Xia Y. Chaudhuri O. Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture Biomaterials 2018 154 213 222 10.1016/j.biomaterials.2017.11.004 29132046 149. Mohan N. Mohanan P.V. Sabareeswaran A. Nair P. Chitosan-hyaluronic acid hydrogel for cartilage repair Int. J. Biol. Macromol. 2017 104 1936 1945 10.1016/j.ijbiomac.2017.03.142 28359897 150. Almond A. Deangelis P.L. Blundell C.D. Hyaluronan: The Local Solution Conformation Determined by NMR and Computer Modeling is Close to a Contracted Left-handed 4-Fold Helix J. Mol. Biol. 2006 358 1256 1269 10.1016/j.jmb.2006.02.077 16584748 151. Sohrabi M. Hesaraki S. Kazemzadeh A. Alizadeh M. Development of injectable biocomposites from hyaluronic acid and bioactive glass nano-particles obtained from different sol-gel routes Mater. Sci. Eng. C 2013 33 3730 3744 10.1016/j.msec.2013.05.005 152. Croisier F. Jérôme C. Chitosan-based biomaterials for tissue engineering Eur. Polym. J. 2013 49 780 792 10.1016/j.eurpolymj.2012.12.009 153. Bano I. Arshad M. Yasin T. Ghauri M.A. Younus M. Chitosan: A potential biopolymer for wound management Int. J. Biol. Macromol. 2017 102 380 383 10.1016/j.ijbiomac.2017.04.047 28412341 154. Levengood S.K.L. Zhang M. Chitosan-based scaffolds for bone tissue engineering J. Mater. Chem. B 2014 2 3161 10.1039/c4tb00027g 24999429 155. Nandi S.K. Kundu B. Basu D. Protein growth factors loaded highly porous chitosan scaffold: A comparison of bone healing properties Mater. Sci. Eng. C 2013 33 1267 1275 10.1016/j.msec.2012.12.025 23827571 156. Chesnutt B. Yuan Y. Buddington K. Haggard W. Bumgardner J. Composite Chitosan = Nano-Hydroxyapatite Scaffolds Induce Osteocalcin Production by Osteoblasts In vitro and Support Bone Formation In vivo Tissue Eng. A 2009 15 2571 10.1089/ten.tea.2008.0054 19309240 157. DiMartino A. Sittinger M. Risbud M.V. Chitosan: A versatile biopolymer for orthopaedic tissue-engineering Biomaterials 2005 26 5983 5990 10.1016/j.biomaterials.2005.03.016 15894370 158. Chen Y. Chung Y. Wang L.W. Chen K. Chung Y. Wang L.W. Chen K.-T. Li S.-Y. Antibacterial properties of chitosan in waterbone pathogen J. Environ. Sci. Heal. Part A Toxic/Hazard. Subst. Environ. Eng. 2007 4529 37 41 159. Hu S.G. Jou C.H. Yang M.C. Protein adsorption, fibroblast activity and antibacterial properties of poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) grafted with chitosan and chitooligosaccharide after immobilized with hyaluronic acid Biomaterials 2003 24 2685 2693 10.1016/S0142-9612(03)00079-6 12711514 160. Vaz J.M. Taketa T.B. Hernandez-Montelongo J. Chevallier P. Cotta M.A. Mantovani D. Beppu M.M. Antibacterial properties of chitosan-based coatings are affected by spacer-length and molecular weight Appl. Surf. Sci. 2018 445 478 487 10.1016/j.apsusc.2018.03.110 161. Dotto G.L. Campana-Filho S.P. Pinto L.A.A. Chitosan Based Materials and its Applications Bentham Science Publishers Sharjah, UAE 2017 1 322 162. Albanna M.Z. Bou-akl T.H. Blowytsky O. Walters H.L. Matthew H.W.T. Chitosan fibers with improved biological and mechanical properties for tissue engineering applications J. Mech. Behav. Biomed. Mater. 2013 20 217 226 10.1016/j.jmbbm.2012.09.012 23465267 163. Lee K. Jin G. Jang C.H. Jung W. Kim G. Preparation and characterization of multi-layered poly(3-caprolactone)/chitosan scaffolds fabricated with a combination of melt-plotting/in situ plasma treatment and a coating method for hard tissue regeneration J. Mater. Chem. B 2013 1 5831 10.1039/c3tb21123a 32261240 164. Caridade S.G. Merino E.G. Alves N.M. de Bermudez V.Z. Boccaccini A.R. Mano J.F. Chitosan membranes containing micro or nano-size bioactive glass particles: Evolution of biomineralization followed by in situ dynamic mechanical analysis J. Mech. Behav. Biomed. Mater. 2013 20 173 183 10.1016/j.jmbbm.2012.11.012 23466499 165. Oliveira M.B. Luz G.M. Mano J.F. A combinatorial study of nanocomposite hydrogels: On-chip mechanical/viscoelastic and pre-osteoblast interaction characterization J. Mater. Chem. B 2014 2 5627 5638 10.1039/C4TB00437J 32262197 166. Couto D.S. Hong Z. Mano J.F. Development of bioactive and biodegradable chitosan-based injectable systems containing bioactive glass nanoparticles Acta Biomater. 2009 5 115 123 10.1016/j.actbio.2008.08.006 18835230 167. Yang J. Long T. He N.-F. Guo Y.-P. Zhu Z.-A. Ke Q.-F. Fabrication of a chitosan/bioglass three-dimensional porous scaffold for bone tissue engineering applications J. Mater. Chem. B 2014 2 6611 6618 10.1039/C4TB00940A 32261821 168. Cui X. Huang W. Zhou J. Wang H. Zhou N. Wang D. Pan H. Rahaman M.N. Evaluation of an injectable bioactive borate glass cement to heal bone defects in a rabbit femoral condyle model Mater. Sci. Eng. C 2017 73 585 595 10.1016/j.msec.2016.12.101 169. Correia C.O. Leite Á.J. Mano J.F. Chitosan/bioactive glass nanoparticles scaffolds with shape memory properties Carbohydr. Polym. 2015 123 39 45 10.1016/j.carbpol.2014.12.076 25843832 170. Mota J. Yu N. Caridade S.G. Luz G.M. Gomes M.E. Reis R.L. Jansen J.A. Walboomers X.F. Mano J.F. Chitosan/bioactive glass nanoparticle composite membranes for periodontal regeneration Acta Biomater. 2012 8 4173 4180 10.1016/j.actbio.2012.06.040 22771458 171. Xianmiao C. Yubao L. Yi Z. Li Z. Jidong L. Huanan W. Properties and In vitro biological evaluation of nano-hydroxyapatite/chitosan membranes for bone guided regeneration Mater. Sci. Eng. C 2009 29 29 35 10.1016/j.msec.2008.05.008 172. Bottino M.C. Thomas V. Janowski G.M. A novel spatially designed and functionally graded electrospun membrane for periodontal regeneration Acta Biomater. 2011 7 216 224 10.1016/j.actbio.2010.08.019 20801241 173. Dashnyam K. Perez R.A. Singh R.K. Lee E.J. Kim H.W. Hybrid magnetic scaffolds of gelatin-siloxane incorporated with magnetite nanoparticles effective for bone tissue engineering RSC Adv. 2014 4 40841 40851 10.1039/C4RA06621A 174. Nardecchia S. Carriazo D. Ferrer M.L. Gutiérrez M.C. Del Monte F. Three dimensional macroporous architectures and aerogels built of carbon nanotubes and/or graphene: Synthesis and applications Chem. Soc. Rev. 2013 42 794 830 10.1039/C2CS35353A 23160635 175. Turnbull G. Clarke J. Picard F. Riches P. Jia L. Han F. Li B. Shu W. 3D bioactive composite scaffolds for bone tissue engineering Bioact. Mater. 2018 3 278 314 10.1016/j.bioactmat.2017.10.001 29744467 176. Murphy C.M. Haugh M.G. O’Brien F.J. The effect of mean pore size on cell attachment, proliferation and migration in collagen-glycosaminoglycan scaffolds for bone tissue engineering Biomaterials 2010 31 461 466 10.1016/j.biomaterials.2009.09.063 19819008 177. Gupte M.J. Swanson W.B. Hu J. Jin X. Ma H. Zhang Z. Liu Z. Feng K. Feng G. Xiao G. Pore size directs bone marrow stromal cell fate and tissue regeneration in nanofibrous macroporous scaffolds by mediating vascularization Acta Biomater. 2018 82 1 11 10.1016/j.actbio.2018.10.016 30321630 178. Valerio P. Pereira M.M. Goes A.M. Leite M.F. The effect of ionic products from bioactive glass dissolution on osteoblast proliferation and collagen production Biomaterials 2004 25 2941 2948 10.1016/j.biomaterials.2003.09.086 14967526 179. Reffitt D.M. Ogston N. Jugdaohsingh R. Cheung H.F.J. Evans B.A.J. Thompson R.P.H. Powell J.J. Hampson G.N. Orthosilicic acid stimulates collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro Bone 2003 32 127 135 10.1016/S8756-3282(02)00950-X 12633784 180. Orrenius S. Gogvadze V. Zhivotovsky B. Calcium and mitochondria in the regulation of cell death Biochem. Biophys. Res. Commun. 2015 460 72 81 10.1016/j.bbrc.2015.01.137 25998735 181. Kohn A.D. Moon R.T. Wnt and calcium signaling: β-Catenin-independent pathways Cell Calcium 2005 38 439 446 10.1016/j.ceca.2005.06.022 16099039 182. Clapham D. Calcium signaling Cell 2007 131 1047 1058 10.1016/j.cell.2007.11.028 18083096 183. Kühl M. The Wnt/Calcium Pathway Front. Biosci. 2004 9 967 974 10.2741/1307 14766423 184. Khoshakhlagh P. Rabiee S.M. Kiaee G. Heidari P. Miri A.K. Moradi R. Moztarzadeh F. Ravarian R. Development and characterization of a bioglass/chitosan composite as an injectable bone substitute Carbohydr. Polym. 2017 157 1261 1271 10.1016/j.carbpol.2016.11.003 27987831 185. Silver I.A. Deas J. Erecińska M. Interactions of bioactive glasses with osteoblasts in vitro: Effects of 45S5 Bioglass(® ), and 58S and 77S bioactive glasses on metabolism, intracellular ion concentrations and cell viability Biomaterials 2001 22 175 185 10.1016/S0142-9612(00)00173-3 11101161 186. Bonnelye E. Chabadel A. Saltel F. Jurdic P. Dual effect of strontium ranelate: Stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro Bone 2008 42 129 138 10.1016/j.bone.2007.08.043 17945546 187. Chattopadhyay N. Quinn S.J. Kifor O. Ye C. Brown E.M. The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation Biochem. Pharmacol. 2007 74 438 447 10.1016/j.bcp.2007.04.020 17531955 188. Hurtel-lemaire A.S. Mentaverri R. Caudrillier A. Cournarie F. Wattel A. Kamel S. Terwilliger E.F. Brown E.M. Brazier M. The Calcium-sensing Receptor Is Involved in Strontium Ranelate-induced Osteoclast Apoptosis J. Biol. Chem. 2009 284 575 584 10.1074/jbc.M801668200 18927086 189. Isaac J. Nohra J. Lao J. Jallot E. Nedelec J.M. Berdal A. Sautier J.-M. Effects of strontium-doped bioactive glass on the differentiation of cultured osteogenic cells Eur. Cells Mater. 2011 21 130 143 10.22203/eCM.v021a11 190. Zhang W. Shen Y. Pan H. Lin K. Liu X. Darvell B.W. Lu W.W. Chang J. Deng L. Wang D. Effects of strontium in modified biomaterials Acta Biomater. 2011 7 800 808 10.1016/j.actbio.2010.08.031 20826233 191. Naruphontjirakul P. Porter A.E. Jones J.R. In vitro osteogenesis by intracellular uptake of strontium containing bioactive glass nanoparticles Acta Biomater. 2018 66 67 80 10.1016/j.actbio.2017.11.008 29129790 192. Yang F. Yang D. Tu J. Zheng Q. Cai L. Wang L. Strontium enhances osteogenic differentiation of mesenchymal stem cells and in vivo bone formation by activating Wnt/catenin signaling Stem Cells 2011 29 981 991 10.1002/stem.646 21563277 193. Zhang Y. Cui X. Zhao S. Wang H. Rahaman M.N. Liu Z. Huang W. Zhang C. Evaluation of injectable strontium-containing borate bioactive glass cement with enhanced osteogenic capacity in a critical-sized rabbit femoral condyle defect model ACS Appl. Mater. Interfaces 2015 7 2393 2403 10.1021/am507008z 25591177 194. Lin K. Xia L. Li H. Jiang X. Pan H. Xu Y. Lu W.W. Zhang Z. Chang J. Enhanced osteoporotic bone regeneration by strontium-substituted calcium silicate bioactive ceramics Biomaterials 2013 34 10028 10042 10.1016/j.biomaterials.2013.09.056 24095251 195. Luz G.M. Mano J.F. Chitosan/bioactive glass nanoparticles composites for biomedical applications Biomed. Mater. 2012 7 054104 10.1088/1748-6041/7/5/054104 22972166 196. Diba M. Goudouri O.M. Tapia F. Boccaccini A.R. Magnesium-containing bioactive polycrystalline silicate-based ceramics and glass-ceramics for biomedical applications Curr. Opin. Solid State Mater. Sci. 2014 18 147 167 10.1016/j.cossms.2014.02.004 197. Zreiqat H. Howlett C.R. Zannettino A. Evans P. Schulze-Tanzil G. Knabe C. Shakibaei M. Mechanisms of magnesium-stimulated adhesion of osteoblastic cells to commonly used orthopaedic implants J. Biomed. Mater. Res. 2002 62 175 184 10.1002/jbm.10270 12209937 198. Sergi R. Bellucci D. Salvatori R. Cannillo V. Chitosan—Based Bioactive Glass Gauze: Microstructural Properties, In vitro Bioactivity, and Biological Tests Materials 2020 13 2819 10.3390/ma13122819 199. Luz G.M. Boesel L. Campo A. Del Mano J.F. Micropatterning of bioactive glass nanoparticles on chitosan membranes for spatial controlled biomineralization Langmuir 2012 28 6970 6977 10.1021/la300667g 22480212 200. Peter M. Binulal N.S. Soumya S. Nair S.V. Furuike T. Tamura H. Jayakumar R. Nanocomposite scaffolds of bioactive glass ceramic nanoparticles disseminated chitosan matrix for tissue engineering applications Carbohydr. Polym. 2010 79 284 289 10.1016/j.carbpol.2009.08.001 201. Martins T. Oliveira A.A.R. Oliveira A.C. Boaventura T.P. Barrioni B.R. Costa-Júnior E.S. Pereira M.M. Novel 3D composites with highly flexible behavior based on chitosan and bioactive glass for biomedical applications Mater. Chem. Phys. 2017 189 1 11 10.1016/j.matchemphys.2016.12.012 202. Rinaudo M. Biomaterials based on a natural polysaccharide: Alginate. © TIP Rev Espec en Ciencias Químico-Biológicas 2014 17 92 96 203. Venkatesan J. Bhatnagar I. Manivasagan P. Kang K.H. Kim S.K. Alginate composites for bone tissue engineering: A review Int. J. Biol. Macromol. 2015 72 269 281 10.1016/j.ijbiomac.2014.07.008 25020082 204. Rehm B.H.A. Moradali M.F. Alginates and Their Biomedical Applications Springer Berlin/Heidelberg, Germany 2018 Volume 11 1 268 205. Pawar S.N. Edgar K.J. Alginate derivatization: A review of chemistry, properties and applications Biomaterials 2012 33 3279 3305 10.1016/j.biomaterials.2012.01.007 22281421 206. Lee K.Y. Mooney D.J. Alginate: Properties and biomedical applications Prog. Polym. Sci. 2012 37 106 126 10.1016/j.progpolymsci.2011.06.003 22125349 207. Shapiro L. Cohen S. Novel alginate sponges for cell culture and transplantation Biomaterials 1997 18 583 590 10.1016/S0142-9612(96)00181-0 9134157 208. Turco G. Marsich E. Bellomo F. Semeraro S. Donati I. Brun F. Grandolfo M. Accardo A. Paoletti S. Alginate/Hydroxyapatite Biocomposite for Bone Ingrowth: A Trabecular Structure with High and Isotropic Connectivity Gianluca Biomacromolecules 2009 10 1575 1583 10.1021/bm900154b 19348419 209. Gabbai-Armelin P.R. Cardoso D.A. Zanotto E.D. Peitl O. Leeuwenburgh S.C.G. Jansen J.A. Renno A.C.M. van den Beucken J.J.J.P. Injectable composites based on biosilicate® and alginate: Handling and In vitro characterization RSC Adv. 2014 4 45778 45785 10.1039/C4RA07522F 210. Park D. Choi B. Zhu S. Huh J. Kim B. Lee S. Injectable bone using chitosan-alginate gel/mesenchymal stem cells/BMP-2 composites J. Cranio Maxillofac. Surg. 2005 33 50 54 10.1016/j.jcms.2004.05.011 211. Iwasaki N. Development of cartilage tissue engineering techniques based on biomedical research Jpn. Orthop. Assoc. 2014 19 699 706 10.1007/s00776-014-0594-3 212. Igarashi T. Iwasaki N. Kasahara Y. Minami A. A cellular implantation system using an injectable ultra-purified alginate gel for repair of osteochondral defects in a rabbit model J. Biomed. Mater. Res. Part A 2010 94 844 855 10.1002/jbm.a.32762 213. De Long W.G. Einhorn T.A. Koval K. Mckee M. Smith W. Sanders R. Watson T. Bone Grafts and Bone Graft Substitutes in Orthopaedic Trauma Surgery A Critical Analysis J. Bone Jt. Surg. 2007 89 649 658 10.2106/00004623-200703000-00026 214. Zeng Q. Han Y. Li H. Chang J. Bioglass/alginate composite hydrogel beads as cell carriers for bone regeneration J. Biomed. Mater. Res. Part B Appl. Biomater. 2014 102 42 51 10.1002/jbm.b.32978 215. Jell G. Notingher I. Tsigkou O. Notingher P. Polak J.M. Hench L.L. Stevens M.M. Bioactive glass-induced osteoblast differentiation: A noninvasive spectroscopic study J. Biomed. Mater. Res. 2008 86A 31 40 10.1002/jbm.a.31542 17941016 216. Zhao F. Zhang W. Fu X. Xie W. Chen X. Fabrication and characterization of bioactive glass/alginate composite scaffolds by a self-crosslinking processing for bone regeneration RSC Adv. 2016 6 91201 91208 10.1039/C6RA18309C 217. Srinivasan S. Jayasree R. Chennazhi K.P. Nair S.V. Jayakumar R. Biocompatible alginate/nano bioactive glass ceramic composite scaffolds for periodontal tissue regeneration Carbohydr. Polym. 2012 87 274 283 10.1016/j.carbpol.2011.07.058 218. Luo Y. Wu C. Lode A. Gelinsky M. Hierarchical mesoporous bioactive glass/alginate composite scaffolds fabricated by three-dimensional plotting for bone tissue engineering Biofabrication 2013 5 015005 10.1088/1758-5082/5/1/015005 23228963 219. Luo G. Ma Y. Cui X. Jiang L. Wu M. Hu Y. Luo Y. Pan H. Ruan C. 13–93 bioactive glass/alginate composite scaffolds 3D printed under mild conditions for bone regeneration RSC Adv. 2017 7 11880 11889 10.1039/C6RA27669E 220. Wu C. Ramaswamy Y. Zhu Y. Zheng R. Appleyard R. Howard A. Zreiqat H. The effect of mesoporous bioactive glass on the physiochemical, biological and drug-release properties of poly(dl-lactide-co-glycolide) films Biomaterials 2009 30 2199 2208 10.1016/j.biomaterials.2009.01.029 19203787 221. Liu W. Wang T. Yang C. Darvell B.W. Wu J. Lin K. Chang J. Pan H. Lu W.W. Alkaline biodegradable implants for osteoporotic bone defects—Importance of microenvironment pH Osteoporos. Int. 2015 27 93 104 10.1007/s00198-015-3217-8 26134681 222. Dasgupta S. Banerjee S.S. Bandyopadhyay A. Bose S. Zn- and Mg-Doped Hydroxyapatite Nanoparticles for Controlled Release of Protein Langmuir 2010 26 4958 4964 10.1021/la903617e 20131882 223. Badr-Mohammadi M.-R. Hesaraki S. Zamanian A. Mechanical properties and In vitro cellular behavior of zinc- containing nano-bioactive glass doped biphasic calcium phosphate bone substitutes J. Mater. Sci. Mater. Med. 2014 25 185 197 10.1007/s10856-013-5062-7 24101184 224. Zamani D. Moztarzadeh F. Bizari D. Alginate-bioactive glass containing Zn and Mg composite scaffolds for bone tissue engineering Int. J. Biol. Macromol. 2019 137 1256 1267 10.1016/j.ijbiomac.2019.06.182 31279876 225. Loh Q.L. Choong C. Three-dimensional scaffolds for tissue engineering applications: Role of porosity and pore size Tissue Eng. Part B Rev. 2013 19 485 502 10.1089/ten.teb.2012.0437 23672709 226. Jones J.R. Reprint of: Review of bioactive glass: From Hench to hybrids Acta Biomater. 2015 23 S53 S82 10.1016/j.actbio.2015.07.019 26235346 227. Liu J. Rawlinson S.C.F. Hill R.G. Fortune F. Strontium-substituted bioactive glasses in vitro osteogenic and antibacterial effects Dent. Mater. 2016 32 412 422 10.1016/j.dental.2015.12.013 26777094 228. Reginster J. Badurski J. Bellamy N. Bensen W. Chapurlat R. Chevalier X. Christiansen Genant H. Navarro F. Nasonov E. Sambrook P.N. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: Results of a double-blind, randomised placebo-controlled trial Ann. Rheum. Dis. 2013 72 179 186 10.1136/annrheumdis-2012-202231 23117245 229. Tao Z. Zhou W. He X. Liu W. Bai B. Zhou Q. Huang Z.-L. Tu K.-K. Li H. Sun T. comparative study of zinc, magnesium, strontium-incorporated hydroxyapatite-coated titanium implants for osseointegration of osteopenic rats Mater. Sci. Eng. C 2016 62 226 232 10.1016/j.msec.2016.01.034 230. Haider A. Waseem A. Karpukhina N. Mohsin S. Strontium-and zinc-containing bioactive glass and alginates scaffolds Bioengineering 2020 7 10 10.3390/bioengineering7010010 231. Hatton J. Davis G.R. Mourad A.H.I. Cherupurakal N. Hill R.G. Mohsin S. Fabrication of porous bone scaffolds using alginate and bioactive glass J. Funct. Biomater. 2019 10 15 10.3390/jfb10010015 232. Wu C. Chang J. Degradation, Bioactivity, and Cytocompatibility of Diopside, Akermanite, and Bredigite Ceramics J. Biomed. Mater. Res. Part B Appl. Biomater. 2007 81B 66 75 10.1002/jbm.b.30779 233. Li M. Mondrinos M.J. Chen X. Gandhi M.R. Ko F.K. Lelkes P.I. Elastin Blends for Tissue Engineering Scaffolds J. Biomed. Mater. Res. Part A 2006 79 963 973 10.1002/jbm.a.30833 234. Chakkalakal D.A. Mashoof A.A. Novak J. Strates B.S. Mcguire M.H. Mineralization and pH relationships in healing skeletal defects grafted with demineralized bone matrix J. Biomed. Mater. Res. 1994 28 1439 1443 10.1002/jbm.820281209 7876283 235. Kumar S. Biocompatible β-chitin Hydrogel/Nanobioactive Glass Ceramic Nanocomposite Scaffolds for Periodontal Bone Regeneration Trends Biomater. Artif. Organs 2011 25 1 11 236. Thamaria N. Synthesis and characterization of alginate scaffolds containing bioactive glass for bone tissue engineering applications Proceedings of the 2017 24th National and 2nd International Iranian Conference on Biomedical Engineering Tehran, Iran 30 November–1 December 2017 278 237. Liu M. Dai L. Shi H. Xiong S. Zhou C. In vitro evaluation of alginate/halloysite nanotube composite scaffolds for tissue engineering Mater. Sci. Eng. C 2015 49 700 712 10.1016/j.msec.2015.01.037 25686999 238. Yan J. Miao Y. Tan H. Zhou T. Ling Z. Chen Y. Xing X. Hu X. Injectable alginate/hydroxyapatite gel scaffold combined with gelatin microspheres for drug delivery and bone tissue engineering Mater. Sci. Eng. C 2016 63 274 284 10.1016/j.msec.2016.02.071 27040220 239. Zmora S. Glicklis R. Cohen S. Tailoring the pore architecture in 3-D alginate scaffolds by controlling the freezing regime during fabrication Biomaterials 2002 23 4087 4094 10.1016/S0142-9612(02)00146-1 12182310 240. Mouriño V. Newby P. Boccaccini A.R. Preparation and characterization of gallium releasing 3-d alginate coated 45s5 bioglass® based scaffolds for bone tissue engineering Adv. Eng. Mater. 2010 12 283 291 10.1002/adem.200980078 241. Clarkin O.M. Wu B. Cahill P.A. Brougham D.F. Banerjee D. Brady S.A. Fox E.K. Lally C. Novel injectable gallium-based self-setting glass-alginate hydrogel composite for cardiovascular tissue engineering Carbohydr. Polym. 2019 217 152 159 10.1016/j.carbpol.2019.04.016 31079672 242. Brady S.A. Fox E.K. Lally C. Clarkin O.M. Optimisation of a novel glass-alginate hydrogel for the treatment of intracranial aneurysms Carbohydr. Polym. 2017 176 227 235 10.1016/j.carbpol.2017.08.016 28927603 243. Bériault R. Hamel R. Chenier D. Mailloux R.J. Joly H. Appanna V.D. The overexpression of NADPH-producing enzymes counters the oxidative stress evoked by gallium, an iron mimetic BioMetals 2007 20 165 176 10.1007/s10534-006-9024-0 16900398 244. Mourino V. Newby F. Cattalini J. Lucangioli S. Boccaccini A. Physicochemical, biological and drug-release properties of gallium crosslinked alginate/nanoparticulate bioactive glass composite films Soft Matter 2011 7 6705 10.1039/c1sm05331k 245. Cattalini J.P. García J. Boccaccini A.R. Lucangioli S. Mouriño V. A new calcium releasing nano-composite biomaterial for bone tissue engineering scaffolds Procedia Eng. 2013 59 78 84 10.1016/j.proeng.2013.05.096 246. Cattalini J.P. Hoppe A. Pishbin F. Roether J. Boccaccini A.R. Lucangioli S. Mourin˜o V. Novel nanocomposite biomaterials with controlled copper/calcium release capability for bone tissue engineering multifunctional scaffolds J. R. Soc. Interface 2015 12 20150509 10.1098/rsif.2015.0509 26269233 247. Finney L. Vogt S. Fukai T. Glesne D. Copper and angiogenesis: Unravelling a relationship key to cancer progression Clin. Exp. Pharmacol. Physiol. 2009 36 88 94 10.1111/j.1440-1681.2008.04969.x 18505439 248. Barralet J. Gbureck U. Habibovic P. Vorndran E. Gerard C. Doillon C.J. Angiogenesis in calcium phosphate scaffolds by inorganic copper ion release Tissue Eng. Part A 2009 15 1601 1609 10.1089/ten.tea.2007.0370 19182977 249. Gérard C. Bordeleau L.J. Barralet J. Doillon C.J. The stimulation of angiogenesis and collagen deposition by copper Biomaterials 2010 31 824 831 10.1016/j.biomaterials.2009.10.009 19854506 250. Kong N. Lin K. Li H. Chang J. Synergy effects of copper and silicon ions on stimulation of vascularization by copper-doped calcium silicate J. Mater. Chem. B 2014 2 1100 1110 10.1039/C3TB21529F 32261627 251. Li S. Xie H. Li S. Kang Y.J. Copper stimulates growth of human umbilical vein endothelial cells in a vascular endothelial growth factor-independent pathway Exp. Biol. Med. 2012 237 77 82 10.1258/ebm.2011.011267 22185917 252. Mouriño V. Cattalini J.P. Boccaccini A.R. Metallic ions as therapeutic agents in tissue engineering scaffolds: An overview of their biological applications and strategies for new developments J. R. Soc. Interface 2012 9 401 419 10.1098/rsif.2011.0611 22158843 253. Esteban-Tejeda L. Malpartida F. Esteban-Cubillo A. Pecharromn C. Moya J.S. Antibacterial and antifungal activity of a soda-lime glass containing copper nanoparticles Nanotechnology 2009 20 505701 10.1088/0957-4484/20/50/505701 19907067 254. Moon R.J. Martini A. Nairn J. Youngblood J. Martini A. Nairn J. Cellulose nanomaterials review: Structure, properties and nanocomposites Chem. Soc. Rev. 2011 40 3941 3994 10.1039/c0cs00108b 21566801 255. Wang X. Cheng F. Liu J. Smått J.H. Gepperth D. Lastusaari M. Xu C. Hupa L. Biocomposites of copper-containing mesoporous bioactive glass and nanofibrillated cellulose: Biocompatibility and angiogenic promotion in chronic wound healing application Acta Biomater. 2016 46 286 298 10.1016/j.actbio.2016.09.021 27646503 256. Ferreira F. Souza L. Martins T. Lopes J. Mattos B. Mariano M. Pinheiro I.F. Valverde T.M. Livi S. Camilli J.A. Nanocellulose/bioactive glass cryogels as scaffolds for bone regeneration Nanoscale 2019 11 19842 10.1039/C9NR05383B 31441919 257. Cattini A. Latka L. Bellucci D. Bolelli G. Sola A. Lusvarghi L. Pawlowski L. Cannillo V. Suspension plasma sprayed bioactive glass coatings: Effects of processing on microstructure, mechanical properties and in-vitro behavior Surface Coat. Technol. 2013 220 52 59 10.1016/j.surfcoat.2012.10.076 258. Sergi R. Bellucci D. Cannillo V. A comprehensive review of bioactive glass coatings: State of the art, challenges and future perspectives Coatings 2020 10 757 10.3390/coatings10080757 259. Chen Q. Pe R. Munoz J. Pe U. Larraya D. Garmendia N. Yao Q. Boccaccini A.R. Cellulose Nanocrystals-Bioactive Glass Hybrid Coating as Bone Substitutes by Electrophoretic Co-deposition: In situ Control of Mineralization of Bioactive Glass and Enhancement of Osteoblastic Performance ACS Appl. Mater. Interfaces 2015 7 24715 24725 10.1021/acsami.5b07294 26460819 260. Chen Q. Yang Y. Pérez U. Larraya D. Garmendia N. Virtanen S. Boccaccini A.R. Electrophoretic co-deposition of cellulose nanocrystals-45S5 bioactive glass nanocomposite coatings on stainless steel Appl. Surf. Sci. 2016 362 323 328 10.1016/j.apsusc.2015.11.160 261. Parenteau-Bareil R. Gauvin R. Berthod F. Collagen-based biomaterials for tissue engineering applications Materials 2010 3 1863 1887 10.3390/ma3031863 262. Rinaudo M. Chitin and chitosan: Properties and applications Prog. Polym. Sci. 2006 31 603 632 10.1016/j.progpolymsci.2006.06.001 263. Gentleman E. Fredholm Y.C. Jell G. Lotfibakhshaiesh N. O’Donnell M.D. Hill R.G. Stevens M.M. The effects of strontium-substituted bioactive glasses on osteoblasts and osteoclasts in vitro Biomaterials 2010 31 3949 3956 10.1016/j.biomaterials.2010.01.121 20170952