Bioactive glass–polymer nanocomposites: a comprehensive review on unveiling their biomedical applications

Abstract

Most natural and synthetic polymers are promising materials for biomedical applications because of their biocompatibility, abundant availability, and biodegradability. Their properties can be tailored according to the intended application by fabricating composites with other polymers or ceramics. The incorporation of ceramic nanoparticles such as bioactive glass (BG) and hydroxyapatite aids in the improvement of mechanical and biological characteristics and alters the degradation kinetics of polymers. BG can be used in the form of nanoparticles, nanofibers, scaffolds, pastes, hydrogels, or coatings and is significantly employed in different applications. This biomaterial is highly preferred because of its excellent biocompatibility, bone-stimulating activity, and favourable mechanical and degradation characteristics. Different compositions of nano BG are incorporated into the polymer system and studied for positive results such as enhanced bioactivity, better cell adherence, and proliferation rate. This review summarizes the fabrication and the progress of natural/synthetic polymer-nano BG systems for biomedical applications such as drug delivery, wound healing, and tissue engineering. The challenges and the future perspectives of the composite system are also addressed.

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Radhakrishnan Sreena

Ms Sreena R is a Senior Research Fellow in the Smart Biomaterials lab, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology, Tamil Nadu, starting from July 2022. Her research work focuses on designing and fabricating novel smart composite materials for bone tissue engineering. She was awarded the Savitribai Phule Fellowship for Single Girl Child funded by UGC for a period of 5 years to support her PhD.

Gurusamy Raman

Dr Raman Gurusamy is a renowned plant genomics researcher and International Assistant Professor at Yeungnam University, South Korea. He has made significant contributions to plant molecular evolution and genome organization, authoring 38 international research articles and seven book chapters. Dr Gurusamy has led a National Research Foundation (NRF) project funded by the Korean government, exploring the molecular evolution and historical geography of the Convallaria genus. He has also contributed to major NRF projects focused on plant genome evolution. Proficient in Python, R, and Perl, Dr Gurusamy is skilled in data interpretation and next-generation sequencing technologies, earning several prestigious awards for his research.

Geetha Manivasagam

As a physicist, material scientist, and biomedical engineer, Dr Geetha Manivasagam's academic labels extend beyond the conventional STEM fields. As the Founding Director of the Centre for Biomaterials, Cellular & Molecular Theranostics (CBCMT) at Vellore Institute of Technology, she has been at the forefront of research innovation. Dr Geetha orchestrates research in the development of biomaterials catering to diverse medical applications such as implantology, cancer therapy, drug delivery and theranostics. She has received multiple awards, including the International Women Scientist Award and the Fulbright Award for professional excellence. She has been ranked as the No. 1 scientist in Materials Science by MHRD from 2009 to 2019 and listed in the Top 2% of scientists in the country in Materials Science as per the analysis performed by Stanford University.

A. Joseph Nathanael

Dr. A. Joseph Nathanael is currently working as a permanent faculty and associate Professor at the Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology (VIT), Vellore. His research focuses on nanomaterials, biomaterials, tissue engineering, additive manufacturing, 3D/4D printing, and active food packaging. He has more than 60 research publications to his name and most of them are related to bio-nanomaterials, and bone and alveolar regeneration. He has vast research experience in international labs and received prestigious fellowships like JSPS from Japan and worked in one of the biggest and renowned institutes in Japan (National Institute of Advanced Industrial Science and Technology (AIST)). Recently, he extended his experience in 3D printing, electrospinning and other polymer biomaterial field. Recently he has been awarded the prestigious DBT Ramalingaswami Re-entry Fellowship from the Department of Biotechnology, India, and is working on 4D bioprinting.

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1. Introduction

Bioactive glass (BG) has become a major subject of interest in various biomedical applications since its discovery in 1970 by Hench et al.¹ This inorganic silica-based material has gained a lot of attention in the field of biomaterials because of its innate nature to bond with the bone by the formation of a hydroxycarbonate apatite layer (HCA).^2,3 The main composition includes 46.1 mol% SiO₂, 24.4 mol% Na₂O, 26.9 mol% CaO and 2.6 mol% P₂O₅ and was called 45S5 and Bioglass®.³ The application of BG is not limited to orthopedic and dental implants but is also used in the regeneration of tissues such as skin, cartilage,⁴ biosensors,⁵ and diagnostic systems.⁶ It has also been discovered that the nanoscale dimension of BG plays a key role in cell-to-cell communication in biological tissues.⁷ The change in topography and surface-to-volume ratio from bulk to nano dimension initiates improvement in various properties of biomaterials, especially promoting cell adhesion and proliferation.⁸ BG nanoparticles are typically silicates, phosphates, or borates combined with different proportions of sodium oxide or calcium oxide that are used as glass modifiers. Binary, ternary, and quaternary systems of BG can be synthesized by sol–gel, microemulsion, flame synthesis, and laser spinning techniques. The size and the morphology of the synthesized particles can be tuned by varying the composition and reaction conditions, thereby ultimately changing their properties.^9–13

Synthetic or natural biodegradable polymers are widely employed owing to their low immunogenicity, biocompatibility, and degradability. They can be natural (collagen, alginate, silk-fibroin) or synthetic (polycaprolactone (PCL), poly vinyl alcohol (PVA)).¹² Various polymer matrices can be modified by adding BG nanoparticles to change their physiochemical, mechanical, and biological properties.¹⁰ Fabrication of nanocomposites is a promising area for biomedical applications since combining two or more materials leads to further enhancement of their properties.¹³ The mechanical properties such as elastic moduli, compressive strength, and bone-bonding abilities are improved.^4,14 The addition of BG nanoparticles to the polymers alters the degradation rate. Also, it shows a positive impact on osteoblast proliferation due to the elution of ions from BG.¹⁵ Rapid improvements in nanocomposite engineering have opened the door to a wide range of biomedical uses, such as drug delivery, wound-healing, sensors, tissue engineering, and diagnostic systems. These composites combine the flexibility of the polymer with the bioactive properties of BG.¹⁶

This review summarizes the various techniques adopted for the fabrication of BG–polymer nanocomposites and their major biomedical applications. Primary emphasis is placed on the current research landscape of various BG compositions with ions such as zinc (Zn), strontium (Sr), and magnesium (Mg) and their composites with natural or synthetic polymers. The biomedical applications of BG-based nanocomposites, such as tissue engineering, drug delivery, and wound healing, are also highlighted.

2. Types of BG

BG can be of many types, namely the conventional silicate type commonly known as 45S5 BGs, phosphate glasses, and borate glasses.¹⁷ BG is also doped with elements, such as Zn,¹⁸ copper (Cu),¹⁹ Sr,²⁰ Mg,²¹ selenium (Se), and tellurium (Te),²² and various other ions to form composites for improvement in properties. Borosilicate, boro phosphate glasses,²³ and borate-based BGs are of recent interest because of their positive results in treating chronic wounds such as diabetic ulcers.^17,24 Phosphate-based BGs are also highly preferred owing to their solubility and bioactivity.²⁵ The structure of 45S5 BG and the tetrahedral sites of Si and PO₄³⁻ are shown in Fig. 1.^1,26 These three types of BGs can be used as a modifier in natural polymers such as silk fibroin,^27,28 collagen,²⁹ gelatin, and chitosan and synthetic polymers such as PCL,^30–33 PVA^34,35 and polylactic acid (PLA).³⁶

Fig. 1 (a) Structure of 45S5 BG. NBO and BO stand for non-bridging oxygen and bridging oxygen (reproduced with permission from ref. 1. Copyright 2013, Elsevier); (b) schematic representation of tetrahedral units of silicate glass; and (c) schematic representation of tetrahedral units of phosphate glass. In figure (b) and (c), Q stands for quaternary which represents the number of bridging oxygens that are connected to each tetrahedron (reproduced with permission from ref. 26 under CC-BY license) -Created using Biorender.

2.1. Silicate BG

The fundamental building block of silicate-based BGs is the SiO₄ tetrahedron that can covalently bond to other tetrahedra.³⁷ Silicate-based BGs are extensively used in research for biomedical applications as fillers with polymer matrices.³⁸ Addition of silica particles facilitates higher bioactivity and improved biocompatibility. They also improve the resorption rate and porosity further inducing the formation of calcium phosphate that is found in natural bone.^39,40 In addition, they can also directly bond to the bone tissue by forming HCA.⁴¹ The dissolution of ions such as silicon, calcium, and phosphorus improves the expression of genes in the bone cells and aids in stem cell differentiation. At the same time, they can also promote angiogenesis with specific ions, as mentioned above.³⁸ The most important feature responsible for the bioactivity is the low SiO₂ and high CaO to P₂O₅ ratio. The commercial glass 45S5 is a silicate glass, and its biocompatibility has been very well established over the years. One of the main limitations pertaining to 45S5 BG is that it is very challenging to form three-dimensional scaffolds owing to the difficulties faced in sintering the particles to form a network.¹⁷

2.2. Phosphate BG

Phosphate glasses comprise an inorganic phosphate network covalently connected with three tetrahedral phosphate units.⁴² The P₂O₅ network in the phosphate bio-glass has a wide range of solubility that can be tuned by varying the composition or using a modifier.⁴³ They are widely used as inorganic fillers in bone tissue engineering because of their likeliness to natural bone.⁴⁰ Incorporation of phosphate-based BG nanoparticles not only modulates the physiochemical properties but also has a great influence on the biological properties.³⁸ Low-dissolution phosphate BG has been shown to increase osteoblastic cell proliferation and to participate with a number of bone-associated growth factors.⁴⁴ There is a direct influence on the degradation of the polymer–phosphate BG in a way that the degradation is fast with the decrease in calcium oxide content.⁴⁵

2.3. Borate BG

One of the most important glass-forming oxides is borate-based BG, which is highly preferred because of its high strength and easily tunable properties.⁴⁶ Borate-based BG is widely used due to its bioactivity; however, the biological applications are uncertain because the borate ions released during dissolution can cause cytotoxicity.^41,47 In addition to this, borate glasses find use in a variety of drug-release applications related to orthopaedic infections.⁴⁸ The apatite layer formed post-implantation is induced by the borate ion layer formation in contrast to the silicate-rich layer formation in silicate BG.⁴¹ To overcome their limitation, aluminium oxide or strontium oxide is partially replaced with borate ions to decrease the rate of dissolution. These ions can facilitate better osteoblast cell differentiation.³⁸

3. Fabrication techniques for polymer–BG nanocomposites

Owing to the individual advantages of the polymers and ceramics, combining them and fabricating them into composites has been a milestone for biomedical applications. The composites can be fabricated by using conventional as well as advanced 3D printing techniques. The composites can be fabricated in various forms such as foams, membranes, sheets, single layer or multi-layer scaffolds or fibres. Based on the technique employed, the form of the composites will vary. Some of the most important techniques used in composite fabrication are phase separation, freeze drying, solvent casting technique, foam replica method, electrospinning, salt leaching method and various additive manufacturing techniques such as fused deposition modelling, stereolithography, and selective laser sintering.^49,50 Some of the major techniques adopted for the fabrication of polymer–BG composites will be discussed in this section.

3.1. Freeze drying/lyophilization

This technique of composite fabrication has been conventionally employed and the terms freeze-drying and lyophilization are very much similar in meaning but the former is more accurate. It works on the principle of sublimation and the solvent used is usually water. This method of composite scaffold fabrication aids in producing scaffolds with different pore sizes that can be tuned according to the pre-freezing time. The advantages of the process are that there is no separate step for leaching as in salt leaching and highly porous structures that are random or oriented are formed. The disadvantages are that this method is very time consuming and is very expensive.^49,51 Natural polymers such as alginate, chitosan,^52,53 collagen,⁵¹ and silk fibroin⁵⁴ and synthetic polymers such as PLGA⁵⁵ can be made into composites using this technique.

3.2. Solvent casting

This method is widely employed for fabricating composite films reinforced with nanoparticles such as bioactive glass or any other filler. It involves stirring the polymer solution along with the filler at high speed or under ultrasonication that will induce mixing and further the mixture will be cast into moulds. It is a very simple technique with good reproducibility. The solvent employed for dissolving the polymer will be removed by drying at appropriate temperature. The method can be employed to fabricate very thin sheets or membranes. The disadvantages of this method are non-uniform distribution of the nanoparticles, and brittleness and shrinkage that occurs after the drying process. Various synthetic and natural polymers can be used in this method.^49,56

3.3. Electrospinning

Electrospinning is a fabrication technique in which the polymer will be made into a viscous solution and an electric field will be applied that will aid in the formation of nanofibers and further be collected on a metal plate. The polymer solution can be incorporated with any nanoparticle such as bioactive glass. A high voltage power supply will be required for the generation of nanofibers. The generated fibrous mat will show porosity and the fiber diameter can be easily controlled and varied. The fibers have a very high surface area and the method is comparatively inexpensive. The major disadvantage of this method is that the pore size decreases with increasing fibre thickness and this technique is not applicable for all the polymers. Synthetic polymers such as PLGA,⁵⁷ PVA,⁵⁸ PCL,⁵⁹ and PLA^60,61 and natural polymers such as collagen⁶² and chitosan⁶³ have been employed to make composites along with bioactive glass particles.⁴⁹

3.4. 3D printing

3D printing is an additive manufacturing technique that can aid in the formation of three dimensional composite structures. It is based on computer aided design and is employed to fabricate intricate structures. There are multiple types of 3D printing techniques such as stereolithography, selective laser melting, selective laser sintering, fused deposition modelling and robocasting method. Each method involves different ways of sample preparation and has its own set of advantages and disadvantages. The main aim of the method is that it can be employed to make patient specific composites according to the requirement. The precursor composite solution can be in the form of filaments, powders or printable inks. The cells can also be loaded along with the ink solution facilitating the 3D bioprinting approach. It will be more of a biomimetic kind of approach mimicking the natural tissues of the body.^49,64,65

3.5. Gas foaming

Gas foaming is a composite fabrication technique where porogens will be used to create pores rather than the usage of any solvent. Highly porous structures will be formed and can be controlled. The processing time involved is very long and interconnectivity between the pores can be a challenge.⁴⁹

4. Natural polymer–BG nanocomposites

Natural polymers have been widely employed for various biomedical applications, especially in the regeneration of tissues, since they mimic the extracellular matrix of the human body.⁶⁶ Even though they have advantages such as biocompatibility, bioactivity, and biodegradability, they have disadvantages like poor mechanical strength, low availability, and cost. Owing to their poor mechanical strength, they are used as composites to alter the mechanical properties and the degradation rate.^67,68 They can be classified as either protein-based or polysaccharide-based polymers. Protein-based polymers include silk fibroin, gelatin, fibrin, elastin, and keratin. Polysaccharide-based polymers include chitosan, alginate, starch, dextran, chitin, cellulose, and agarose.⁴⁹ The following section discusses naturally derived polymer–BG nanocomposites.

4.1. Polysaccharide-based polymer–BG nanocomposites

Generally, polysaccharides can be obtained from different sources such as animals (chitin, chitosan), plants (starch, cellulose), and microorganisms (dextran, xanthan gum). Variation in molecular weight and polysaccharide chains can alter their physio-chemical properties. The properties can be tuned according to the need for various biomedical applications.⁶⁹

4.1.1. Alginate–BG composites. Alginate is a polysaccharide with linear copolymer chains obtained from natural sources such as brown seaweeds.⁶⁹ It contains varying amounts of (1–4) β-D-mannuronic acid and α-L-guluronic acid units.⁷⁰ It is an excellent material for biomedical applications because of its biocompatibility, hydrophilicity, low cost,⁷¹ and biodegradability, which is sometimes questionable due to the absence of alginate enzyme in the body.⁷⁰ Divalent and trivalent ions (Ca²⁺, Sr²⁺, Al³⁺, Ga³⁺) are combined with alginate to form stable hydrogels because of the cross-linking of the guluronic acid residues.^10,72 Alginate also has some disadvantages, such as low mechanical strength, poor bioactivity, and osteoconductivity.⁷³ Thus, nanocomposite fabrication along with BG helps to improve the properties of alginate and thus facilitates better cell adhesion, cell proliferation, and an increase in the roughness of the nanocomposite surface.⁷⁴ Further, ions are also doped in the alginate–BG nanocomposite to improve biological properties.⁴ A study has been performed to fabricate alginate–silicate BG scaffolds doped with Zn and Mg ions by the freeze-drying method. The main idea behind the work was to improve the antibacterial activity and mechanical and biological characteristics of the nanocomposite scaffold. The scanning electron micrograph images presented in Fig. 2A(i) show the even distribution of bioactive glass nanoparticles in the composite scaffold. It was also reported that the compression strength of the fabricated scaffold was increased because of the presence of BG nanoparticles. The toughness of the scaffolds increased from 0.24 MJ m⁻³, (toughness of the pure alginate scaffold) to 0.78 MJ m⁻³ (toughness of the alginate–bioactive glass scaffold with 1 g of BG). Increasing the BG concentration above 1 g has shown a reduction in the toughness of the scaffolds. It was also found that the increased addition of BG particles resulted in a decrease in pore size. Apatite formation was seen when the nanocomposite was incubated in simulated body fluid (SBF) for 21 days whereas the pure alginate scaffold had no deposits on it emphasizing the importance of BG. The nanocomposites also exhibited good anti-bacterial activity against Staphylococcus aureus and Escherichia coli when compared to the pure alginate scaffold as depicted in Fig. 2A(ii). In vitro analysis performed using MG-63 cells showed good cell viability, proliferation, and differentiation. The cell viability (Fig. 2A(iii)) was studied using MTT assay and the composite scaffold containing BG was found to be much better than tricalcium phosphate.⁷⁵

Fig. 2 (A) (i) SEM micrographs of the alginate–BG composite at different concentrations. The red arrows indicate the distribution of BG in the scaffold; (ii) antibacterial activity of the composite scaffold against Staphylococcus aureus and Escherichia coli; and (iii) cell viability assessment of the composite scaffolds using MTT assay (reproduced with permission from ref. 75. Copyright 2019, Elsevier); (B) (i) fabricated composite scaffold; (ii) SEM images of the (a) fabricated composite scaffold and (b) open pore microarchitecture of the fabricated composite scaffold; and (iii) SEM images of the ICIE silicate based BG-alginate scaffold immersed in SBF after 2 weeks: (a) 5000×, (b) 10 000×, (c) 15 000×, and (d) 60 000× (reproduced with permission from ref. 76 under CC-BY license).

Another study utilized ICIE16 silicate-based BG modified with Sr and Zn ions and further combined it with alginate to fabricate a nanocomposite scaffold by the freeze-drying method as indicated in Fig. 2B(i). The ICIE16 was developed as an alternative of 45S5 BG with a combination of 48% SiO₂, 6.6% Na₂O, 32.9% CaO, 2.5% P₂O₅, and 10% K₂O which has a comparatively large sintering window.⁷⁷Fig. 2B(ii) shows the SEM micrograph of the scaffold with open pores and the pore size was very much appropriate for osteoinduction. The maximum pore size was found to be 308.9 μm. The amorphous nature of the BG facilitated an enhanced bioactivity evident by the formation of the apatite layer when incubated in SBF (Fig. 2B(iii)). Calcite formation was observed on the surface of the composite between 120 hours and 2 weeks.⁷⁶ Erol et al. fabricated and characterized a new type of boron-based BG coated with alginate with Cu-releasing ability. The SEM images confirmed the presence of alginate. It was found that the mechanical ability and the bioactivity were increased because of the coating and further facilitated copper ion release in a controlled way.⁷⁸

Bio-silica based BG–alginate composite putty was fabricated to act as a bone support material and was evaluated for in vitro capability, bioactivity, and cytotoxicity behaviour. The putties exhibited non-Newtonian behaviour that is suitable for a variety of surgical applications. This composite exhibited higher bioactivity in terms of apatite formation when compared to the commercial silica-based BG–alginate composite.⁷⁹ Zn-substituted mesoporous BG was made into a composite along with alginate and methyl cellulose to fabricate bio-ink for bone regeneration applications. The addition of BG nanoparticles resulted in alteration of the rheological properties as well as an increase in the amount of ion release in the manufactured bio-ink.⁸⁰

4.1.2. Chitosan–BG composites. Chitosan is a natural polymer made of linear polysaccharides and is obtained generally by the deacetylation of chitin.⁸¹ The cationic charge in chitosan enables it to easily bind with the negatively charged cell membrane. The composition is like that of glycosaminoglycans in the extracellular matrix (ECM) of the bone and cartilage. It has a random distribution of deacetylated units (β-D-glucosamine) and acetylated units (N-acetyl-D-glucosamine).⁸² The advantages of chitosan are that it is biocompatible, biodegradable, and also shows good antibacterial activity. However, as it has poor mechanical properties, it is made into a composite along with ceramics such as BG to ameliorate the properties.⁸³ Oudadesse et al. fabricated a scaffold using chitosan and BG nanoparticles by employing the freeze-drying method. The image of the fabricated scaffold is given in Fig. 3A(i). SEM micrographs revealed that the porosity decreased with the increase in the amount of BG nanoparticles. Fig. 3A(ii) depicts the SEM micrograph showing the macroporous structure of the scaffold along with the dispersion of BG nanoparticles. Apatite formation was enhanced during 7 days of immersion in simulated body fluid as observed using SEM micrographs (Fig. 3A(iii)). The addition of BG to the chitosan scaffold reduced the degradation rate and also turned it into a great candidate for drug delivery based applications.⁸⁴ The effect of the cerium-doped BG particles/chitosan/collagen scaffold on cell morphology was studied in mesenchymal stem cells from rabbit bone marrow. The SEM micrographs of the different combinations of scaffolds are shown in Fig. 3B(i). The dispersion is very high in the case of higher addition of BG. The presence of cerium in the BG nanoparticles increased the proliferation rate and enhanced the scaffold's biocompatibility as observed in Fig. 3B(ii). It was also observed that the presence of cerium ions enabled quicker osteogenic proliferation.⁸⁵ The scaffold's properties are highly influenced by the percentage of BG incorporated into it and by the method it is prepared.⁸⁶ Electrospun chitosan, gelatin, and 58S BG scaffolds are widely used in skin tissue engineering to promote rapid wound healing. Compared to the control system, the in vitro characterization study revealed that this combination of the electrospun scaffold did not induce cell toxicity against dermal fibroblasts and also demonstrated improved cell proliferation.⁸⁷

Fig. 3 (A) (i) The image of the fabricated composite scaffold; (ii) SEM micrographs of the composite scaffold: (a) dispersion of the BG nanoparticles in the scaffold and (b) the pore size of the scaffold is 200 μm; (iii) SEM image of the composite scaffold (a) before and (b) after immersion in simulated body fluid for 7 days (reproduced with permission from ref. 84. Copyright 2020, John Wiley and Sons); (B) (i) SEM micrographs of the composite scaffolds: (a) chitosan–collagen, (b) chitosan–collagen with undoped BG, (c) chitosan–collagen with 5 moles% cerium doped BG and (d) chitosan–collagen with 10 moles% cerium doped BG where the red arrows show the dispersion of BG particles in the polymer matrix; and (ii) cell viability assays of the fabricated composite scaffolds (reproduced with permission from ref. 85 under CC.BY license).

4.1.3. Starch–BG composites. Starch is a plant-based highly branched semi-crystalline polymer made of amylose and amylopectin connected through α-(1–4) and α-(1–6) linkages.^88,89 The main advantages of employing starch for various biomedical applications are that it is biocompatible, biodegradable, very readily available, and economical.⁹⁰ Despite the advantages starch displays, the low fracture toughness makes it unsuitable for load-bearing implants. It is thus made into a nanocomposite with ceramics to improve its properties.⁹¹ Fabrication of Aloe vera/starch along with 64S BG and quail eggshell was found to dramatically improve the regeneration of bone. The SEM images in Fig. 4(i) show interconnected micron-sized pores that are very suitable for angiogenesis and bone regeneration. The scaffolds showed excellent adhesion to MG-63 cells. They were also able to penetrate through the pores as shown in Fig. 4(ii). Amongst all, the scaffold with a composition of 10 weight% (wt%) starch, 4 wt% Aloe vera, 4 wt% BG and 1.5 wt% quail egg (S7) was found to exhibit the quickest apatite formation and also the highest expression of bone proteins such as osteocalcin and osteopontin against MG-63 cells. Alizarin red staining results as shown in Fig. 4(iii) indicate that the S7 scaffold shows the highest ARS activity and the calcium nodules are highly seen indicating the mineralization of the ECM. The main reason behind this is the high percentage of Aloe vera and bioactive glass present in it. The synergistic effect of both led to enhanced bone regeneration rate.⁹² In addition, the scaffold also showed increased apatite formation in SBF. An increase in the physical, mechanical, and biological properties was observed in the scaffolds.⁹² One study reported the effect of starch–BG particles on osteoblast cells. The analysis showed higher expression of osteoblastic markers and the adherence of pre-osteoblastic cells to the ceramic as well as the polymer matrix.⁹³ Another study found that the composite of starch and 45S5 BG was non-cytotoxic when tested on L929 fibroblast cells.⁹⁴

Fig. 4 (i) SEM micrographs of the scaffolds fabricated with different compositions (10 wt% starch, 2, 3, and 4 wt% Aloe vera, 2, 3, and 4 wt% BG and 0.5, 1 and 1.5 wt% quail egg shell); (ii) SEM images of MG-63 cells adhered on S5 (10 wt% starch, 2 wt% Aloe vera, 2 wt% BG and 0.5 wt% quail egg shell), S6 (10 wt% starch, 3 wt% Aloe vera, 3 wt% BG and 1 wt% quail egg shell), and S7 (10 wt% starch, 4 wt% Aloe vera, 4 wt% BG and 1.5 wt% quail egg shell) scaffolds after 72 hours; (iii) optical images of Alizarin red staining assay on composite scaffolds (S5, S6, S7) after 7 and 14 days of cell culture (reproduced with permission from ref. 92 Copyright 2022, Elsevier).

4.1.4. Dextran–BG composites. Dextran is a polysaccharide isolated from lactic acid bacteria and is made of D-glucose units linked by α (1–6) linkages. This exopolysaccharide has advantages such as tailorable solubility, and thermal and rheological properties.⁹⁵ Dextran-based hydrogels are employed as scaffolds in engineering tissues, novel drug delivery systems, and anti-fungal materials. They are highly preferred since they are biocompatible, low in cost and are of low toxicity.⁹⁶ Sol–gel derived BG along with dextran was made into a nanocomposite for bone tissue engineering purposes. SEM of this composite revealed a 3D porous network with a pore size of 240 μm. Agglomeration was found when a higher quantity of BG was used. Increased apatite formation with increased BG was observed when the hydrogels were incubated in SBF for 28 days as indicated in Fig. 5(i). Improvement in the mechanical properties and enhanced bioactivity were observed. Further, the dextran hydrogels were also able to support osteoblast growth as seen in the immunofluorescence images in Fig. 5(ii).⁹⁷ Bioactivity assessment of the nanocomposite hydrogels made of different compositions of dextran and BG was made in another study. An increase in apatite formation and apatite crystallite size was found on the nanocomposite surface. Efficient cell adherence and cell spreading were found with the osteosarcoma cell line (Saos-2).⁹⁸

Fig. 5 (i) SEM images of the fabricated composite scaffolds made of dextran and BG at different concentrations, before and after immersing in simulated body fluid for 28 days and (ii) immunofluorescence images of human osteoblast cells cultured on the composite scaffolds (reproduced with permission from ref. 97. Copyright 2018, Elsevier).

4.2. Protein based polymer–BG nanocomposites

Proteins are made of amino acids, and if the side chain changes, it can change both physiochemical and biological properties of the protein. Protein based polymer–BG nanocomposites have disadvantages, like making people sick and having different purification results from one batch to the next. Some examples of biomedical applications of protein-based biopolymers are as scaffolds for tissue engineering and drug delivery systems, among other things. Proteins can be made to break down at different rates, so they can be made to fit the needs of a specific application. Some of the biopolymers made from proteins that are used to make nanocomposites are collagen, gelatin, and silk fibroin.⁶⁹

4.2.1. Silk-fibroin–BG composites. Silk fibroin is a fibrous protein and is derived from spider silk or from the silkworm Bombyx mori (B. mori). The advantages of using silk fibroin are its excellent mechanical properties due to the heavy chain's ability to form sheets, biodegradability, tissue reactivity, and superior biocompatibility.⁹⁹ The use of silk fibroin extends beyond the textile industry to several biomedical applications owing to its excellent properties.¹⁰⁰ One of the most significant drawbacks of silk fibroin is that it is not bioactive and, therefore, cannot form a direct bond with the new bone. To improve this property, it is typically combined with bio-ceramics.¹⁰¹ Mesoporous BG (mBAg) and silk-fibroin were 3D printed into a nanocomposite scaffold with enhanced mechanical and osteogenic properties for bone tissue engineering applications as shown in Fig. 6A(i). The scaffold was compared to mBAg-PCL control scaffolds and showed enhanced bone formation both in vitro and in vivo. The 3D printed silk-fibroin scaffold incorporated with mesoporous bioactive glass showed high compressive strength (20 MPa). When mBAg/silk-fibroin scaffolds were compared to control, apatite formation was found to be greater as indicated in Fig. 6A(ii). SEM micrographs in Fig. 6A(iii) indicate the improved bone marrow stromal cells attached to the mBAg/SF scaffold when compared to the control. The confocal laser scanning microscopy (CLSM) images of the cells seeded onto the composite scaffolds showed that they are compatible with human bone marrow stromal cells (hBMSCs) and they were able to adhere and proliferate in the direction of the scaffolds. In vivo results on nude mice showed that new bone formation was quicker, and the osteogenic markers were better expressed in mBAg and SF scaffolds.²⁷ In another piece of research, a nanocomposite scaffold was fabricated by 3D printing silk fibroin, gelatin, and mesoporous BG doped with strontium. The printing process utilized was direct ink writing. Based on the findings, it was found that the scaffold containing strontium did show enhanced osteogenic differentiation of stem cells. In addition to this, the scaffold was able to stimulate the production of a variety of growth factors that are essential for the formation of in vivo bone, such as osteocalcin, osteopontin, osteonectin, and alkaline phosphatase. The ionic release from the BG facilitated the activation of signalling pathways, which can assist in the formation of new bone.¹⁰² In a separate study, Cu-doped BG nanoparticles were combined with silk fibroin and chitosan to create injectable hydrogels that stimulate in situ bone formation. It was discovered that the hydrogels were highly porous and capable of rapid gelation at physiological pH and temperature. In addition to encouraging the growth of MC3T3-E1 and human umbilical endothelial cells, the gels promoted osteogenesis and angiogenesis.¹⁰³ Together with collagen and silk fibroin, BG nanoparticles were electrospun to make a nanofibrous scaffold as shown in Fig. 6B(i). The entire system was found to be compatible with Saos-2 cells and improved cell viability was found to be higher in the scaffolds containing bioactive glass when compared with the scaffolds without it as shown in Fig. 6B(ii). Rats with osteoporosis were given scaffolds to fix the problem, and it was found that the scaffolds helped in the growth of new blood vessels and in bone regenertion.¹⁰⁴

Fig. 6 (A) (i) Optical image of 3D printed silk fibroin-mesoporous BG nanoparticle scaffolds; (ii) SEM micrograph images of the 3D printed scaffolds after immersion in simulated body fluid for 28 days (A1 and A2: mesoporous BG/silk fibroin scaffold; B1 and B2: mesoporous BG/polycaprolactone scaffold); (iii) SEM images of the human bone marrow stem cells attached on mesoporous BG/silk fibroin scaffolds after 7 days of cell seeding; and (iv) LCSM images of the cells seeded on mesoporous BG/silk fibroin scaffolds for one week. The cell actin and nuclei were labelled with Alexa Fluor 488 phalloidin (reproduced with permission from ref. 27 under CC-BY license); (B) (i) SEM images of the composite nanofiber and (ii) light microscopic images showing the in vitro biocompatibility of Saos-2 of the collagen–silk fibroin system and the composite system with BG at 1, 3, and 7 days (reproduced with permission from ref. 104 under CC-BY license).

4.2.2. Collagen–BG composites. Due to the structural similarities it shares with most of the ECM, collagen is one of the polymers that has been the subject of research. 11% of the matrix is inorganic and 89% is organic. The main benefits of collagen include its biocompatibility, superior haemostatic abilities, hydrophilicity, and ease of processing. Its low mechanical properties and extremely high rate of degradation are the main drawbacks. Mechanical and biological properties can be improved by combining it with inorganic bioactive materials. It can be used for a variety of biomedical applications in the form of films, meshes, gels, and scaffolds.^10,69,105 Collagen has been utilized as a coating material for 45S5 BG scaffolds used in bone tissue engineering. The collagen coating was crosslinked using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxy succinimide (NHS). In comparison to the un-cross-linked scaffolds, the compressive strength of the cross-linked scaffolds was greatly improved, and the in vitro results indicated good cytocompatibility, cell attachment, and proliferation towards the MG-63 cell line (Fig. 7A). After immersion in SBF, the bioactivity of the collagen/BG scaffolds was investigated. Apatite formation was observed as nodules of hydroxyapatite crystals with increased immersion time (Fig. 7B).¹⁰⁶ Dense collagen gels were combined with S53P4 bone stimulating BG to create a composite hybrid seeded with stem cells from the dental pulp for bone regeneration and rested on a murine calvarial defect. Within one day of immersion in SBF, an oxycarbonate apatite layer was observed on the scaffold system. Alkaline phosphatase and collagen type I were discovered to be upregulated in the scaffolds. Based on the results, the composites improved mineralization and vascularization in vivo 8 weeks after implantation.¹⁰⁷ Cu-doped BG along with collagen was fabricated into a scaffold to enhance bone formation and vascularization. There was a 1.9-fold increase in the compressive strength, 66% inhibition was observed against Staphylococcus aureus, and there was a 3.6-fold increase in bone formation and vascularization. In vivo studies were conducted in the chick embryo, and increased bone formation was observed.²⁹ Collagen and nano-BG scaffolds were fabricated and evaluated for osteoinductivity. The compressive modulus was increased by 13-fold and supported the growth of MC3T3-E1 pre-osteoblasts.¹⁰⁸

Fig. 7 (A) SEM images of MG-63 cells seeded on collagen/BG scaffolds (uc – un-crosslinked; cl – crosslinked); (B) SEM images of the collagen/BG scaffolds after immersion for 1, 7 and 10 days (uc – un-crosslinked; cl – crosslinked) (reproduced with permission from ref. 91 under CC-BY license); (C) SEM images of the MG-63 cell line seeded on the surface of gelatin/Mn-mesoporous BG nanoparticles at low and high magnifications; (D) SEM images of the scaffold immersed in simulated body fluid: (a) and (d) 45S5 uncoated BG scaffolds, (b) and (e) Mn-mesoporous BG coated scaffold, (c) and (f) gelatin/Mn-mesoporous BG coated scaffold after 3 (a)–(c) and 21 (d)–(f) days of incubation (reproduced with permission from ref. 109. Copyright 2019, Elsevier).

4.2.3. Gelatin–BG composites. Gelatin is a natural polymer that is identical in composition to collagen because it is derived from collagen by the same processes of thermal denaturation or physical/chemical treatment. It is completely safe to use, and it helps get around collagen's immunogenic and pathogen-transmission problems. Gelatin's biocompatibility and ability to improve cellular adhesion and cell proliferation are two of its primary benefits. It is advantageous for both hard and soft tissues due to its biodegradability and low antigenicity. However, gelatin has low mechanical properties and degrades quickly. BG aids in osteoinduction because it is a type of bioactive ceramic. It is weak in terms of mechanical stability and is easily broken. Thus, by combining gelatin and BG their benefits can be increased while the disadvantages are reduced.^4,10,49 In one study, lyophilization was used to create a gelatin-based scaffold containing varying amounts of BG for bone tissue engineering applications. The scaffold's compressive strength ranged from 1.9 to 5.7 MPa. The scaffold's porosity ranged from 79 to 84 percent. Crosslinking was accomplished with glutaraldehyde, and in vitro studies with the MG-63 cell line revealed adhesion and proliferation of the cells, as well as enhanced apatite formation after incubation in SBF.³⁰ 45S5 BG scaffolds were coated with gelatin synthesized using the foam replica method. The compressive strength of the scaffolds was found to be in the range of compressive strength of cortical bone, and the scaffolds showed enhanced strengthening and toughening effects. The release of the bioactive molecule icariin was further regulated by crosslinking using N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydro-chloride (EDC)/N-hxdroxysuccinimide (NHS). Hydroxyapatite formation was found on the surface of the scaffolds after immersion in SBF for 14 days.¹¹⁰ 45S5 BG scaffolds fabricated via the foam replica method were further coated with a composite of gelatin and Mn-doped BG nanoparticles by a dip coating method. In vitro studies performed on the MG-63 cell line showed improved cell adhesion when compared to the uncoated BG scaffolds (Fig. 7C).¹⁰⁹ Assessment of the bioactivity of the gelatin-coated scaffolds was done by immersing them in SBF for up to 21 days. Increased apatite growth was found in the scaffold coated with gelatin for 21 days (Fig. 7D).¹⁰⁹ In another study, instead of manganese, copper was used for doping BG, which was then coated along with gelatin on 45S5 BG scaffolds for improvement in the osteogenic and mechanical properties. In vitro assays done on MC3T3-E1 cells showed enhanced cell adhesion and proliferation.¹¹¹

Table 1 discusses the different natural polymers made into nanocomposites with bioactive glass along with their key findings and application.

Table 1 Summary of natural polymer–BG-based nanocomposites

Polymer	BG	Ion doping	Technique	Key findings	Applications	Ref.
Alginate	SiO2–P2O5–CaO–ZnO–MgO	Zn and Mg	Scaffold – freeze drying	Compressive strength: 1.7 MPa; improvement in degradation property; induced the formation of apatite on the surface after immersion in SBF	Bone tissue engineering	75
Alginate	ICIE 16M	Sr and Zn	Scaffold– freeze drying	Average pore size of 110 μm; average Young's modulus: 1.83 ± 0.66 MPa; crystal growth observed after immersion of the scaffold in SBF after 120 hours	Bone tissue engineering	76
Alginate	SiO2–CaO–Na2O–P2O5 (biosilica)	Nil	Composite putty – mechanical mixing	Exhibited pseudo plastic fluid behavior; bio silica-based composite putty showed higher bioactivity; not cytotoxic below 5 mg mL^−1 concentration level	Bone tissue engineering	79
Alginate	80SiO2–18B2O3–2SeO2	Se	Composite – freeze drying	The presence of nano BG in the scaffold reduced the swelling and degradation time at 48 hours; positive antimicrobial effect against Staphylococcus aureus	Wound healing	112
Alginate	S53P4 (53% SiO2, 20% CaO, 23% Na2O and 4% P2O5)	Nil	Bioink fabrication – mechanical mixing, 3D printing	Increased compression strength in cross-linked (5.45 ± 0.01 MPa) scaffolds when compared to un-crosslinked (5.08 ± 0.37 MPa) scaffolds; effective anti-bacterial and antifungal activity; increase in cell viability in MC3T3-E1 cells to 100% in 14 days	Bone infections	113
Chitosan	55% SiO2, 40% CaO, 5% P2O5	Nil	Scaffolds – freeze gelation	Pore size: 150–300 μm; scaffold with 20% BG nanoparticles showed better surface area; 9% loss in weight observed after immersion in phosphate buffer saline (PBS); increased bioactivity due to the addition of chitosan to the scaffold	Bone tissue engineering	84
Chitosan	60% SiO2, 36% CaO, 4% P2O5	Nil	Composite scaffold – needle punching technique + dip coating	Porosity: 77.52%; pore size ∼50 μm, compression strength: 7.68 ± 0.38 MPa; water absorption capacity – 59%; elastic modulus: 0.46 ± 0.02 GPa	Bone tissue engineering	114
Chitosan	64% SiO2, 26% CaO, 5% P2O5, 5% MgO	Mg	Films – solvent casting	Increased bioactivity after immersion in SBF	Orthopaedic and maxillofacial application	115
				Increased cell adherence and proliferation in Saos-2 osteoblast-like cells
Chitosan	6% Na2O, 8% K2O, 8% MgO, 22% CaO, 54% B2O3, 2% P2O5	Nil	Injectable bone cement – mechanical mixing	Compressive strength was found to be 31 ± 2 MPa, enhanced cell proliferation and alkaline phosphatase activity in the MC3T3-E1 cell line; bone formation stimulated in rabbit femoral condyle 12 weeks post-implantation	Bone tissue engineering	116
Chitosan	55% SiO2–40% CaO–5% P2O5	Nil	Composite – solvent casting	Increased metabolic activity against human periodontal ligament cells	Periodontal regeneration	117
Starch	64% SiO2–31% CaO–5% P2O5	Nil	Composite scaffold– freeze drying	Cell viability greater than 95%. Increased compressive strength, expression of bone differentiation markers ranged between 30 and 75%	Bone regeneration	92
Starch	45S5 BG	Nil	Scaffold – freeze drying	Calcium phosphate layer formed on the surface proving their bioactivity. Enhanced adhesion and proliferation on rat stromal cells and expression of markers such as osteocalcin and osteopontin	Bone tissue engineering	118
Starch	50% SiO2, 42% CaO, 8% P2O5	Nil	Composite –solvent casting and salt leaching	Increased tensile strength and Young's modulus. Improved formation of the apatite layer when immersed in SBF; the degradation rate decreased as the amount of BG increased	Bone tissue engineering	119
Starch	45S5 BG	Nil	Twin screw extrusion–injection molding	The modulus was found to be 3.8 GPa and the ultimate tensile strength was found to be 38.6 MPa	Temporary bone replacement, fracture fixation	120
Dextran	64% SiO2, 31% CaO, 5% P2O5	Nil	Hydrogel – mechanical mixing, freeze drying	Average particle size: 77 nm, increased apatite layer formation after incubation in SBF; enhanced adherence and spreading of osteosarcoma cells (Saos-2)	Bone regeneration	98
Dextran	64% SiO2, 31% CaO, 5% P2O5	Nil	Scaffold – freeze drying	Average pore size: 240 μm, higher BG content leads to agglomeration and reduced compressive modulus. Increased human osteoblast cell proliferation and alkaline phosphatase activity	Bone tissue engineering	97
Silk fibroin	Mesoporous BG	Nil	Composite scaffolds – 3D printing	Enhanced compressive strength – 20 MPa. No cell toxicity observed against bone marrow stem cells. Increased expression of bone formation markers	Bone tissue engineering	28
Silk fibroin	70S30C – 70% SiO2, 25% CaO, 5% P2O5	Sr	Composite scaffolds – 3D printing	Enhanced bone formation in vivo. High expression levels of biomarkers. Increased proliferation of mesenchymal stem cells	3D bone constructs	102
Silk fibroin/chitosan	45S5 BG	Cu	Hydrogels – mechanical mixing	Promoted osteogenesis and vascularization. Improved cell adhesion in MC3T3-E1 cells	Bone tissue engineering	103
Silk fibroin/alginate	Mesoporous BG	Nil	Hydrogels-mechanical mixing	Large pores for the loading of insulin growth factor; elastic modulus higher than 5 kPa; high mechanical strength	Drug delivery + bone tissue engineering	121
Silk fibroin/collagen	CaO–SiO2 (25 : 75)	Nil	Nanofibers – electrospinning	Enhanced osteogenic ability; highest thermal stability; compatible with Saos-2 cells	Repair osteoporotic bone defects	104
Silk fibroin	58% SiO2–23% CaO–9% P2O5	Nil	Films – solvent casting method	Increased hydrophilicity; improved bioactivity; supports the growth of osteoblast cells	Bone tissue engineering	122
Collagen	S53P4 BG–53% SiO2–23% Na2O–20% CaO–4% P2O5	Nil	Gel scaffolds – plastic compression	Quick mineralization	Delivery of stem cells for bone regeneration	107
				Apatite formation found within 1 day; increased compressive modulus
Collagen	60% SiO2–34% CaO–4% P2O5–2% CuO	Cu	Scaffolds – freeze drying	1.9 fold increase in compression; 3.6 times increase in calcium deposition; 66% inhibition against S. aureus; enhanced vascularisation	Bone tissue engineering	29
Collagen	45S5 BG	Nil	Scaffolds – foam replica method	Compressive modulus: 0.18 ± 0.03 MPa; biocompatible and showed increased adherence and proliferation towards the MG-63 cell line	Bone tissue engineering	106
Collagen	45S5 BG	Nil	Composite gel – plastic compression	Immediate calcium phosphate formation; increase in compression modulus; increased cell viability towards the MC3T3-E1 cell line	Bone tissue engineering	108
Collagen/chitosan	80% SiO2, 15% CaO, 5% P2O5	Ce	Scaffolds – freeze drying	>50% of cell proliferation observed when the cells were seeded on the composite for 24 hours; no toxicity of cells observed (<25% of inhibition observed)	Bone tissue engineering	85
Collagen	58% SiO2, 38% CaO, 4% P2O5	Nil	Membrane/scaffold – electrospinning	Rapid bioactivity; excellent biocompatibility; higher alkaline phosphatase activity	Bone tissue engineering	123
Gelatin	45S5 BG	Nil	Sponge like scaffolds – foam replica method	Increased compressive strength; enhanced bioactivity; increased drug delivery ability	Drug delivery	110
Gelatin	49.2% SiO2, 23.4% Na2O, 25.5% CaO, 1.7% P2O5	Nil	Scaffolds – freeze drying	Porosity ranged between 79 and 84%; compressive strength varied between 1.9 and 5.7 MPa; enhanced bioactivity and osteogenic ability	Bone tissue engineering	30
Gelatin	45S5 BG	Mn	Scaffolds + coating – foam replica method, dip coating	Enhanced biological activity towards the MG-63 cell line; increased bioactivity and biocompatibility	Bone tissue engineering	109
Gelatin	95% SiO2, 2.5% CaO, 2.5% CuO	Cu	Scaffolds + coating – freeze drying, dip coating	Improved bioactivity; enhanced osteogenic ability; improved mechanical properties	Bone regeneration	111
Gelatin	45S5 BG	Nil	Scaffold–solvent casting + lamination technique	Total porosity – 85%; pore size ranged from 200 to 500 μm	Bone regeneration	124
				Positive biological activity towards endothelial cells; increased bone regeneration and angiogenic ability

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5. Synthetic polymer–BG nanocomposites

Synthetic biopolymers are materials that can be easily tuned according to the required properties and can be made into different structures.⁴⁹ Their main advantages, compared to natural polymers, are extended shelf life, economical nature, ability to form any shape, and enhanced biological properties. The problem of employing synthetic polymers is that they lack the sites to bond cells, and various chemical treatments are required for the bonding to occur. The major synthetic polymers used for biomedical applications such as tissue engineering and drug delivery include PLA, poly lactic co glycolic acid (PLGA), poly glycolic acid (PGA), PVA, and poly hydroxy butyrate (PHB). These polymers exhibit varying levels of mechanical properties, biodegradability, and biocompatibility. They can be tuned according to the requirement of the application. These polymers are made into composites to improve their mechanical and biological properties.

5.1. PLA–BG composites

PLA is a biodegradable aliphatic poly ester and is one of the most important synthetic polymers. It is highly in use because of its excellent properties, such as biodegradability and biocompatibility.¹²⁵ It is also environmentally friendly since it can be isolated from feedstock that can be renewed and are not toxic. It is utilized in many applications, but has some limitations, such as the degradation rate being very slow, and hydrophobicity, and, thus, blending with other polymers or ceramics ameliorates the disadvantages.¹²⁶ PLA and BG composite scaffolds were fabricated by the gel pressing technique. The scaffolds were made in two different compositions, and physio-chemical characterization was performed. The SEM micrographs of the scaffolds are shown in Fig. 8A(i) in which BG70–PLA30 scaffolds are homogeneous and dense, whereas BG30–PLA70 scaffolds show cracks due to the higher sintering temperature because of the higher percentage of PLA. The bioactivity test confirmed apatite layer formation on the surface of the scaffold when immersed in SBF for 14 and 28 days. The scaffold with a higher quantity of BG showed increased bioactivity making its presence essential as shown in Fig. 8A(ii). The degradation analysis of the scaffolds were analysed using phosphate buffer saline and was found to degrade with respect to new bone formation.³⁶ In another study, composite scaffolds made of BG and PLA were fabricated using an extrusion-based 3D printing method. The scaffold's bioactivity was assessed by immersion in SBF and characterized by SEM. Apatite formation was observed in 1 day itself. The scaffold was highly porous with an interconnected structure. Weight loss (degradation analysis) was studied using SBF.¹²⁷ PLA was coated onto the surface of the BG scaffolds. The scaffolds were fabricated by robocasting. The presence of this polymer increased the mechanical properties in terms of compression, toughness, and bending.¹²⁸ Mesoporous BG was made into a composite with PLA by 3D bioprinting methodology. The Auto CAD design and the optical images of the scaffolds are shown in Fig. 8B(i) and (ii). The pore size of the composite ranged between 500 and 700 μm. Enhanced mechanical strength was observed, especially the compressive modulus of the composite was found to be 91.5 MPa. The HCA layer was formed on the third day after immersion in SBF. Enhanced cell adherence and proliferation of MG-63 cells when seeded in the bioprinted scaffolds containing BG nanoparticles when compared to the control scaffold was observed as indicated in Fig. 8B(iii).¹²⁹

Fig. 8 (A) (i) SEM images of BG70-PLA30 and BG30-PLA70 scaffolds and (ii) SEM images of the scaffolds (left side: BG70-PLA30 and right side: BG30-PLA70) immersed in simulated body fluid after 28 days (reproduced with permission from ref. 36 under CC-BY license); (B) (i) CAD design of the scaffold; (ii) optical images of the fabricated 3D printed construct; and (iii) live and dead staining of MG-63 cells seeded on 3D printed PLA and PLA with BG construct at 7 and 14 days (reproduced with permission from ref. 129. Copyright 2022, Elsevier).

5.2. PCL–BG composites

PCL is an aliphatic polymer that is semi-crystalline and hydrophobic, preventing the adhesion and proliferation of cells. It shows adequate biocompatibility and mechanical strength.¹¹³ Enhancement of bioactivity is achieved by chemical treatments or surface functionalization. Degradation is very slow, and it takes about 2 to 4 years to get degraded by hydrolysis of the esters.¹³⁰ The main advantages of using PCL are that it is non-toxic, has good mechanical properties and controls cell proliferation and adhesion. The drawbacks of PCL are its low bioactivity and the incapability to attach cells onto its surface.^49,131 To improve the properties, PCL is made into a composite with other polymers or ceramics. In one study, PCL nanofibers were fabricated, and were embedded with BG nanoparticles and a drug called simvastatin. The presence of BG improved the rate of degradation and improved the rate of apatite formation when incubated in SBF. Drug release studies performed on phosphate buffer saline showed that the drug was released in a very controlled manner.¹³² PCL and mesoporous BG were made into a composite using 3D printing technology. Increasing the amount of BG resulted in enhancing the hydrophilicity. The composite showed apatite formation owing to the bioactivity of BG. In vitro analysis showed increased cell adhesion, proliferation, and up-regulation of various biomarkers such as Run-x2 and collagen I.¹³³ Hybrid scaffolds using PCL and BG were fabricated by the porogen leaching method. The scaffold network was found to be highly porous and initiated apatite formation within 24 hours of immersion in SBF. Degradation analysis reported 13.2% weight loss at the end of 8 weeks. The scaffold supported the growth of osteoblast cells and was found to be non-toxic. Similarly, the in vivo analysis showed that the scaffold is biocompatible, bioactive, and biodegradable.¹³⁴

5.3. PVA–BG composites

PVA is a semi-crystalline, well-hydrated polymer with a hydroxyl group. It is formed from the hydrolysis of polyvinyl acetate. The major advantages of using PVA are that it is biocompatible, non-toxic, and has strength like that of cartilage. The drawbacks of using PVA are that there are no cell adhesion sites and very less ingrowth of cells.⁴⁹ PVA is used for applications in the biomedical domain, such as tissue engineering and designing novel drug delivery systems because of its properties. Modification can be easily done according to the requirement of the application.¹³⁵ In one study, the cobalt ion was incorporated into PVA–BG scaffolds fabricated by the foam replica method. The formed scaffolds were highly porous in nature, forming a network-like structure. The fabricated composite supposedly had physical, mechanical, and biological properties same as that of natural bone. In vitro assays performed on umbilical vein endothelial cells showed no cytotoxicity and good mitochondrial activity. Ion release was very fast, and the elastic modulus was 20.19 MPa.³⁴ Injectable hydrogels composed of BG and PVA were fabricated by the physical cross-linking method. The bioactive glass particles were uniformly distributed into the hydrogel network. An increase in the compression strength by 325% and elastic modulus by 150% was observed. The in vivo analysis in adult male rats showed that the composite scaffolds were biocompatible, and no inflammation was seen.¹³⁶ PVA was made into a nanofiber composite along with chitosan and BG by the electrospinning approach and loaded with a drug to treat osteoporosis.¹³⁷ Strontium-doped mesoporous BG was made into a composite with PVA using 3D printing technology. The presence of strontium aids in quick bone regeneration. The amount of BG directly corresponded to the bioactive layer formed in the composite after immersion in SBF. In vitro results indicated that the composite was biocompatible when tested on MC3T3-E1 cells.¹³⁸

5.4. PHB–BG composites

PHB is a highly crystalline homo-polymer that is non-toxic and bio-compatible. It has a slow degradation rate, and it is more advantageous than PLA.⁴⁹ It is a member of polyhydroxyalkanoates, and is highly preferred in biomedical applications owing to its properties like biocompatibility and non-toxicity to cells such as osteoblasts, fibroblasts, and endothelial and epithelial cells. The drawbacks include hydrophilicity and slow degradation. PHB is made into a composite with other polymers or ceramics to improve its properties. Ceramic nanoparticles are used as reinforcements for improving the mechanical strength and the rate of degradation. In one study, nano-fibrous scaffolds were fabricated using BG and PHB by an electrospinning technique. The particles were uniformly distributed in the network structure. The bioactivity results showed that the surface of the scaffolds had increased the apatite formation in 21 days due to the presence of BG.¹³⁹ A composite of PHB, PCL, and BG was fabricated using an electrospinning technique. The composite formed a porous network, and the average fiber diameter increased with respect to the quantity of BG. The Young's modulus decreased from 101 MPa without the addition of BG and varied between 67 and 87 MPa in composites. The strain values increased 40 to 50 times compared to pure electro-spun scaffolds. In vitro analysis showed that the fabricated scaffold was biocompatible and supported the adhesion and proliferation of the MG-63 cell line.¹⁴⁰ PHB/chitosan and multi-walled carbon nanotubes (MWCNTs) were coated on BG and titania scaffolds fabricated by the foam replication method. A high percentage of porosity was observed in the scaffolds, and the surface roughness was increased. The degradation rate was improved, and enhanced bioactivity was found when immersed in SBF.¹⁴¹

Table 2 discusses the different synthetic polymers made into nanocomposites with bioactive glass along with their key findings and application.

Table 2 Summary of synthetic polymer–BG-based nanocomposites

Polymer	BG	Ion doping	Technique	Key findings	Applications	Ref.
PLA	SiO2–CaO–Na2O–P2O5	Nil	Scaffolds – gel pressing technique	Improved bioactivity; steady degradation rate	Bone tissue engineering	36
PLA	45S5 BG	Nil	Composite – 3D printing	Apatite layer observed on the surface of the composite in 1 day	Bone regeneration	127
PLA	45S5 BG	Nil	Scaffold – robocasting	Enhancement of mechanical properties	Bone tissue engineering	128
PLA	Mesoporous BG	Nil	Composite – 3D bioprinting	Increased compression modulus (6.18 GPa); increased apatite formation; yield strength was found to be 80.2 MPa	Bone tissue engineering	129
PLA/chitosan	SiO2, CaO, P2O5, CeO2, CuO, Ag2O	Ce/Cu/Ag	Nanofibers – electrospinning	Antibacterial activity against E. coli; improved bioactivity; enhanced mechanical strength	Bone trauma	142
PCL	BG	Nil	Nanofibers – electrospinning	Improved bioactivity; increased mechanical strength; improved degradation rate	Bone regeneration	132
PCL	58S BG	Nil	Composite – 3D printing	Increase in hydrophilicity; increased mechanical strength; expression of markers such as Run-x2 and collagen I	Bone tissue engineering	133
PCL	58S BG	Nil	Scaffold – porogen leaching method	Enhanced bioactivity; increased mechanical strength; supported cell adhesion and proliferation on primary osteoblasts	Bone tissue engineering	134
PCL	SiO2–CaO–P2O5	Nil	Scaffolds – robocasting	Enhanced biocompatibility with the Saos-2 cell line; increased angiogenesis; evident new bone formation in osteoporotic sheep; enhanced bioactivity	Bone tissue engineering	143
PVA	45S5 BG	Cu	Scaffolds – foam replica method	Increased angiogenic properties; good mitochondrial activity; increased bioactivity; good cell adhesion and proliferation	Bone tissue engineering	34
PVA	45S5BG	Nil	Injectable hydrogels – physical crosslinking	Self-standing hydrogel obtained; compressive strength increased by 325%; elastic modulus increased by 150%	Bone tissue engineering	136
PVA	46% SiO2, 24% CaO, 24% Na2O, 6% P2O5	Nil	Nano-fibrous composite – electrospinning	Drug release efficiency: 93%; sustained drug release was observed; the nanofibers ranged between 20 and 125 nm in diameter	Drug delivery system	137
PVA	SiO2–CaO–P2O5	Sr	Composite – 3D printing	Highly ordered mesoporous structure; increased bioactivity; cell cytocompatibility towards the MC3T3-E1 cell line	Bone tissue engineering	138
PHB	58S BG	Nil	Nanofibrous scaffolds – electrospinning	Increased bioactivity; uniform distribution of BG particles in the porous network	Bone tissue engineering	139
PHB	58S BG (60% SiO2, 36% CaO, 4% P2O5)	Nil	Nanofibrous scaffolds – electrospinning	Strain increased 40 to 50 times; no toxicity observed with the MG-63 cell line	Bone tissue engineering	140
PHB/chitosan/MWCNT	45S5 BG	Nil	Scaffolds – foam replication method	Interconnected porous structure; increased degradation rate; enhanced bioactivity; increased surface roughness	Bone tissue engineering	141
PHB	45S5 BG	Nil	Films – solvent casting	Young's modulus: 0.8 to 1.6 MPa; increased bioactivity; good biocompatibility; increased cell proliferation	Bone tissue engineering	144

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6. Biomedical applications of BG nanocomposite materials

BG is already present in a few of the commercially available products. A toothpaste sold under the brand name “Sensodyne” contains Novamin®, a proprietary BG composition that is highly effective in remineralizing teeth.¹⁴⁵ This is one of the most popular examples of mass-scale products that utilize the numerous biological properties of BGs. In the following sections, a few interesting research works on the applications of BG biopolymer composites are discussed.

6.1. Tissue engineering

Besides their major contribution to bone-based materials, BG-based polymer composites have also been used in tissue engineering due to their osteogenic, angiogenic, and antibacterial properties.¹⁴⁶ Along with these capabilities, the immunomodulatory capabilities of the BG nanoparticles also greatly influence the tissue regeneration process of the body. Inorganic materials, such as silica and calcium phosphate, the major components in BGs, have already been found to have immunomodulatory capabilities.^147–149 The dissolution products of BG have been found to stimulate a favourable response in target cells (e.g., stem cells, fibroblasts, etc.) that contributes to the tissue regeneration process. The BG-composites are also employed for a wide variety of soft tissue engineering applications as indicated in Fig. 9.¹⁵⁰

Fig. 9 Illustration of the use of BG-composites in various aspects of soft tissue engineering (reproduced with permission from ref. 150 under CC-BY 4.0 license).

BG locally establishes a favourable microenvironment for stem cell differentiation by regulating immune cell activities and reducing the inflammatory response.^147,148 Various strategies such as incorporating active inorganic ions, the programmed release of immunomodulatory agents, functionalization, and manipulation of surface features have been used for obtaining an immunomodulatory response from BG-containing biomaterials (Fig. 10).¹⁴⁶ These immunomodulatory capabilities are found to have a great impact in engineering soft tissues such as wound healing and even cancer therapy.^151,152

Fig. 10 Strategies used for developing immunomodulatory BG containing biomaterials (reproduced with permission from ref. 146 (CC-BY 4.0)).

6.2. Drug delivery

Mesoporous BGs have widely been employed for drug delivery applications because of their drug-loading capabilities. BG-based composite systems provide an interesting avenue for multifunctional drug loading and delivery due to the possibility of optimizing release kinetics to suit targeted drug delivery. BG nanoparticles have been loaded with numerous therapeutics ranging from therapeutic ions, macromolecules (e.g., DNA), to small molecules to target various tissue sites for the treatment of pathological conditions ranging from bone diseases, inflammation, to even cancer. One of the major advantages of BGs as drug carriers arises from their non-inert nature inside the body. The dissolution of BG inside the biological environment also leads to the promotion of tissue regeneration along with drug release. Another advantage of BG-based systems is the localized drug delivery mechanism that eliminates the challenges of the peak-plateau effect, frequent administration, a requirement of heavy dosage, patient compliance, and non-specific targeting faced in traditional drug delivery routes.¹⁵² Various routes have been used for drug delivery through BG–biopolymer composites which include scaffolds, microparticles, hydrogels, etc. Electrospinning of polymer-bioactive nano-fibers is an interesting route for achieving drug delivery in a sustained manner over a longer duration. In a study evaluating the drug release kinetics of RIS osteoporotic drug (Risedronate sodium) loaded chitosan–PVA nanofibers, BG nanoparticles were added to achieve sustained release. It was found that the CS/PVA nanofibers loaded with BG showed only 30% RIS release compared to 80% release in non-BG-containing fibers in 30 min duration. The release kinetics of BG-containing drug-loaded CS/PVA nanofibers were further studied over 96 hours. Only 72.21% of the drug was released in that duration, signifying significant improvement over non-BG-loaded fibers.¹³⁷ BGs containing micro and nano-spheres are another avenue used for the controlled release of drugs. PHBV-BG microspheres have been explored to deliver the popular phototherapeutic drug curcumin. The microspheres showed good biological properties in terms of cytotoxicity and bioactivity. The microspheres showed a sustained release of the drug over 24 hours of immersion in phosphate-buffered saline.¹⁵³ Similar to this, there are multiple researchers working on using the polymer–BG composite as a drug delivery vehicle.

6.3. Wound healing

BG has the capability of releasing various ions when in contact with biological fluids that can stimulate various wound healing-related processes. BGs also have other capabilities, such as the antibacterial effect that largely increases the success rate of wound healing.²⁴ BGs can play a role in the multiple stages of the wound healing process. Therapeutic ions can play an important role in the secretion of growth factors.^154–156 Cu-containing mesoporous BG and nano-fibrillated cellulose composites were evaluated for their biological response through gene expression in 3T3 fibroblast cells. It was found that there was up-regulation of VEGF, PDGF, and FGF growth factors due to the release of copper ions from the nanoparticles.¹⁵⁷ Another study examined the angiogenic capabilities of sol–gel based 58S (60SiO₂·36CaO·4P₂O₅, mol%) and 80S (80SiO₂·15CaO·5P₂O₅, mol%) nano BGs by dissolving in cell culture media. The gene expression studies showed 2- to 3-fold more upregulation of VEGF and FGF in glass extract media compared to control media in umbilical vein cells of humans, respectively. These results are attributed to the presence of silicon and calcium ions eluted from the BG nanoparticles.¹⁵⁸ These capabilities of BGs to promote angiogenesis are being widely explored for the development of wound-healing dressings and ointments.¹⁵⁹ BGs doped with ions such as Zn and Ag have also been found to vastly impact wound healing by inhibiting microbial growth.¹⁶⁰ A gelatin/chitosan/BG composite was used to fabricate a nanofibrous membrane for wound healing. In the evaluation of antibacterial activity against Gram-negative Escherichia coli (E. coli) and Gram-positive Actinomyces viscosus (A. viscosus) using the disc diffusion method, the membrane showed significant inhibition of bacterial growth. The membrane also showed no inflammation and degraded within weeks of being implanted in a rat model.¹⁶¹ Different BG containing polymer composites have been used as ointments,^159,162,163 hydrogels^{112,148,164,165} and dressings^161,166 for the treatment of wounds, with all studies showing encouraging results.

7. Challenges and future outlook

One of the major advantages of nano BGs is their market presence. BGs are not restricted to laboratories but are used in various medical and everyday products such as toothpaste. Various formulations have already received approval from authorities such as the US Food and Drug Administration (FDA). The specificity and the optimization of combining biopolymers and nano BG and their influence on the intended application must be well understood. This will make the development and marketing of BG–polymer-based medical products easier and less tedious. However, there are numerous challenges related to their scalability for producing BG nanoparticles on a larger scale. Most studies are limited to in vitro or preliminary in vivo studies, and the long-term impact of the developed composites has not been explored. Due to the higher number of materials involved, there are also concerns regarding the feasibility of the composites for clinical translation. In the future, advanced fabrication technologies such as 4D printing or 5D printing will be used to fabricate stimuli responsive composites or to make complex curved structures. Another major factor that affects the mass acceptance and application of composite materials is the cost. Currently, BG nanoparticles are very steeply priced, making them unaffordable for a significant global population. Thus, for broader acceptance and application of the BG–polymer composites, various concerns related to cost, scalability, and regulations must be addressed.

8. Conclusion

BG polymer composites are an interesting avenue for future research due to their potential for application in multiple areas such as bone and tissue regeneration, wound healing, and drug delivery. The physiochemical and biological properties of BG make them a perfect material for these applications. Apart from the apatite layer forming capability, BG-based systems provide an interesting avenue owing to their unique characteristics like controllable drug release kinetics, biodegradability, and biocompatibility. The important properties of BG, such as bioactivity and solubility, are improved at the nanoscale. The properties of the biopolymers involved are tuned according to the application. Composites fabricated out of biopolymers and nano BG help to develop personalized scaffolds for repair and regeneration. The drug-releasing capability, mechanical strength, and degradation kinetics are also altered when made into a composite. Optimization in pre-clinical studies will also help to develop a proper understanding of this combination. Due to these features, we may expect numerous new advancements in the fabrication techniques as well with respect to the biomedical applications of polymer–BG nanocomposites in the coming years.

Author contributions

Conceptualization: AJN, RS, and GM, writing – original draft preparation: RS and AJN; writing – review and editing: AJN, GM, RG and RS; supervision: AJN, GM, and RG. All authors have read and agreed to the published version of the manuscript.

Data availability

This is a review article. But all the original contents are available on request.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

AJN would like to acknowledge the financial support from the Department of Biotechnology, Government of India, through the Ramalingaswami Re-entry fellowship (D.O. No. BT/HRD/35/02/2006) and Faculty Startup Venture (FSV2024) from Vellore Institute of Technology. RS acknowledges the UGC-Savitribai Jyotirao Phule Fellowship for Single Girl Child (202223UGCES-SJSGC-14584) which supported her PhD. The authors would also like to acknowledge the support of Biorender software for making figures.

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