الفهرس 
Introduction and Literature ReviewOnly 14 pages are availabe for public view
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Abstract
Bone is a vascular and highly specialized form of connective tissue playing a very demanding biomechanical and metabolic role (Salgado et al., 2004). It maintains the shape of the skeleton, protects soft tissues in the cranial, thoracic and pelvic cavities, transmit the forces of muscular contraction during movement, serves as a reservoir for ions and contributes to the regulation of the extracellular matrix (ECM) composition, blood production and blood pH regulation (Dorati et al., 2011). And it affects the quality of life.
Bone is able to heal and remodel without leaving any scar in cases of very limited damage or fracture. However, in pathological fractures, traumatic bone loss or primary tumor resection, where the bone defect exceeds a critical size, bone is no longer able to heal itself (Lee et al., 2014); (Lichte et al., 2011).
Bone is a natural composite in the body which composes of organic and inorganic phases (Fatima et al., 2011). Most of bone properties depend on its composition, which consist of 60-70% mineral, 10-20% collagen and 9-20% water by weight (Wu et al., 2014).
To increase the bone volume in bone defects area, a varity of methods for bone regeneration have been developed, including scaffolds, coating and barrier membrane. An ideal bone tissue implant must provide a suitable matrix for the growth of precursor cells. In addition the implanted scaffold need (i) to be biocompatible to enable cell attachment, differentiation and proliferation, (ii) to be osteoconductive and osteoinductive, i.e. the material should be able to host bone cells and induce strong bonding to bone, (iii) to be biodegradable with a controllable degradation and resorption rate to match tissue growth (Sheikh et al., 2015), which will eventually replace the scaffold. Bone scaffolds should also possess sufficient mechanical strength and fracture toughness to match the intended site of implantation and handling prior to application.
Currently, bone tissue regeneration involves the use of different biomaterials which can mimic various component of natural bone extracellular matrix (ECM) that can provide good mechanical strength, and biocompatibility.
Healthy bone tissue has the ability to generate endogenous electrical signals that stimulate the repair process. Electrically conductive materials in various forms, such as conductive polymers, reduced graphene oxide, carbon nanotube, gold nanoparticles and silver nanoparticles, have been incorporated into scaffolds for bone tissue regeneration.
Currently, the potential of graphene family materials make them more likely to be a candidate of the choice for next bone regeneration materials. Graphene family including GO and rGO posses exceptionally mechanical, electrically conductive, thermal, and optical properties, which has been widely applied in many fields (Khalil et al., 2016).
Different physical, chemical, and biological techniques have been developed to synthesize graphene. They employed various strategies to isolate single graphene sheets with or without changing its properties, and to synthesize a reduced form of GO (Park et al., 2011), (Y. I. Zhang et al., 2013), (Kelly and Billups, 2013) and (Yu et al., 2020). Chemicals such as hydrohalic acid, hydrazine, sodium borohydride, and hydroquinone were used to reduce GO. These chemicals are known for their explosive nature and toxic effect on biological materials so, the resulting rGO cannot be used in biomedical applications (Chua and Pumera, 2014). Hence, there is a demand for eco-friendly and rapid methods (Mallikarjuna et al., 2021). Green synthesis is considered one of the bio-nanotechnological methods that is not harmful to the environment and can be used as an alternative to chemical and physical methods. Some green methods were mediated by gamma irradiation processes (Dumée et al., 2014), where it can be used in the obtaining of colloidal metal nanoparticles and composites with different applications in many fields (Rojas and Castano, 2012), (Rao et al., 2013), (Wang et al., 2013), (Rojas et al., 2015), (Sharin et al., 2015), (Rojas et al., 2016), (Xie et al., 2019) and (Shi et al., 2019).
The mechanisms of these reactions are based on the generation of active radicals through solvent radiolysis (B. Zhang et al., 2012) and (Ansón-Casaos et al., 2014). Exposure of water molecules to gamma radiation results in the production of both oxidative (hydroxyl radical, .OH), and reductive (hydrogen radical and hydrated electron, H. and e-aq) species (Buxton, 2021) and (Toro-González et al., 2021). The aqueous electrons produced from water radiolysis are distributed homogeneously in the medium, and can readily react with solvated metal ions decreasing their oxidation state (Belloni et al., 1998) and (Remita et al., 2007). Ethanol is added, which acts as a radical scavenger to alleviate the oxidative stress of .OH, and converts it to reductive radicals. It is applied to produce a reducing medium for chemical reactions in the absence of oxygen under gamma-ray irradiation (Hareesh et al., 2016) and enhances the reduction of the metal ions without the need for additional reducing agents or any reagents which are typically required to reduce metallic precursors in the chemical method (Belloni, 2006). The reduced metal ions interact with other ionic species forming clusters that grow into particles. The irradiation dose is not the only factor that controls the particles’ growth, but also the use of stabilizers will enhance the formation of nanoparticles (Flores-Rojas et al., 2020).
Graphene and its derivatives have been a hot spot in biomaterial fields as it forms a continuous phase and serves as a substrate for supporting the second component which is usually metal, metal oxides or other inorganic materials (Khan et al., 2017).
Strontium ranelate (SR) is considered as an antifracture drug and a good treatment for osteoporosis, whose active component on bone remodeling is the Sr2+ ion (Aparecida et al., 2016). Numerous studies have demonstrated that Sr+2 in vitro promotes osteoblasts culture differentiation and bone nodule formation, stimulates the type 1 collagen protein formation and also inhibits the osteoclasts growth (Kołodziejska et al., 2021). Strontium also has a similar charge to size ratio to calcium (Blaschko et al., 2013).
The present study is concerned with the synthesis of strontium–reduced graphene oxide (rGO-Sr) nanocomposites as a biomaterial that could be used in the fabrication of functional coatings and tissue engineering scaffolds. Strontium (Sr2+) was chosen for its similarity to calcium. Also, it inhibits bone resorption, stimulates bone formation, and increases bone mineral density (Kumar and Chatterjee, 2015). Some researchers have recently indicated that incorporating Sr2+ into dental and orthopaedic biomaterials inhibits bacterial growth; however, the antibacterial mechanism is still unclear (Hill and Eramo, 2003), (Sixou et al., 2009), (Alkhraisat et al., 2010), (Brauer et al., 2012) and (Liu et al., 2015).
Electrospinning is a technique in which a nano-sized continuous fibers can be obtained from different materials (Liu et al., 2013), which provides very high specific surface areas. Therefore, electrospun nanofibers are very useful for developing nanofibrous scaffolds for tissue regeneration. Nanofibrous scaffolds are a good candidate for treatments based on tissue engineering because of its suitable environment for cell attachment, and proliferation due to similarity to physical properties of natural ECM.
Various polymers have been employed for scaffold fabrication for tissue regeneration. Among these, Polycaprolactone (PCL) has been widely used in tissue regeneration for its good mechanical properties (Pektok et al., 2008), Though PCL has good mechanical strength it, however, shows poor cell adhesion (Recek et al., 2016).
Surface modification of biomaterials to improve the final biocompatibility and/or the cell-interactive behavior of implants has gained increasing interest over the last decades (Chopra et al., 2022). Gelatin as a natural biopolymer drived from hydrolysed Type 1 collagen, which also represents the main portion of the organic bone ECM (Feng, 2009). It is interesting for coatings on porous scaffolds as it is readily available, comparatively cheap (compared to collagen), dispersible in water, nontoxic and can be applied as thin coatings (Gorgieva and Kokol, 2011) . By introducing this polymer into a scaffold, a composite with tailored degradation rate plus a combination of the biological and mechanical/physical properties can be achieved. During the process of cell migration on scaffold surfaces, cells form clots in order to adhere (Salgado et al., 2004). The gelatin molecule is able to support adherence because it exhibits arginine–glycine–aspartic acid sequences in which the cells can connect to it (Echave et al., 2017). Furthermore, gelatin has been proven to stimulate the differentiation of osteogenic precursor cells towards osteoblasts, supporting bone formation within scaffold structures (Takahashi et al., 2005). Many studies have reported that a blend of gelatin with different synthetic polymers can be used for bone tissue engineering applications.