Carbon based nanomaterials for tissue engineering of bone: Building new bone on small black scaffolds: A review

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Carbon based nanomaterials for tissue engineering of bone: Building new bone on small black scaffolds: A review. Tissue engineering is a rapidly-growing approach to replace and repair damaged and defective tissues in the human body. Every year, a large number of people require bone replacements for skeletal defects caused by accident or disease that cannot heal on their own. In the last decades, tissue engineering of bone has attracted much attention from biomedical scientists in academic and commercial laboratories. A vast range of biocompatible advanced materials has been used to form scaffolds upon which new bone can form. Carbon nanomaterial-based scaffolds are a key example, with the advantages of being biologically compatible, mechanically stable, and commercially available. They show remarkable ability to affect bone tissue regeneration, efficient cell proliferation and osteogenic differentiation. Basically, scaffolds are templates for growth, proliferation, regeneration, adhesion, and differentiation processes of bone stem cells that play a truly critical role in bone tissue engineering
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Carbon based nanomaterials for tissue engineering of bone: Building new bone on small black scaffolds: A review. Tissue engineering is a rapidly-growing approach to replace and repair damaged and defective tissues in the human body. Every year, a large number of people require bone replacements for skeletal defects caused by accident or disease that cannot heal on their own. In the last decades, tissue engineering of bone has attracted much attention from biomedical scientists in academic and commercial laboratories. A vast range of biocompatible advanced materials has been used to form scaffolds upon which new bone can form. Carbon nanomaterial-based scaffolds are a key example, with the advantages of being biologically compatible, mechanically stable, and commercially available. They show remarkable ability to affect bone tissue regeneration, efficient cell proliferation and osteogenic differentiation. Basically, scaffolds are templates for growth, proliferation, regeneration, adhesion, and differentiation processes of bone stem cells that play a truly critical role in bone tissue engineering.

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Journal of Advanced Research 18 (2019) 185–201 Contents lists available at ScienceDirect Journal of Advanced Research journal homepage: www.elsevier.com/locate/jare Review Carbon based nanomaterials for tissue engineering of bone: Building new bone on small black scaffolds: A review Reza Eivazzadeh-Keihana, Ali Malekia, Miguel de la Guardiab, Milad Salimi Banic, Karim Khanmohammadi Chenaba, Paria Pashazadeh-Panahid,e, Behzad Baradarane, Ahad Mokhtarzadehe,f,⇑, Michael R. Hambling,h,i,⇑ a Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran b Department of Analytical Chemistry, University of Valencia, Dr. Moliner 50, 46100, Burjassot, Valencia, Spain c Department of Biomedical Engineering, Faculty of Engineering, University of Isfahan, Isfahan, Iran d Department of Biochemistry and Biophysics, Metabolic Disorders Research Center, Gorgan Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Golestan Province, Iran e Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran f Department of Biotechnology, Higher Education Institute of Rab-Rashid, Tabriz, Iran g Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA h Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA i Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA h i g h l i g h t s g r a p h i c a l a b s t r a c t Bone tissue engineering allows stem cells to form mechanically adequate new bone. Nanomaterial scaffolds allow cell adhesion, growth, and differentiation. Carbon nanomaterials have good properties as scaffolds for bone tissue engineering. Includes graphene oxide, carbon nanotubes, fullerenes, carbon dots, and nanodiamond. Biocompatibility, low toxicity, and a nano-patterned surface form ideal scaffold. a r t i c l e i n f o a b s t r a c t Article history: Received 28 January 2019 Revised 23 March 2019 Accepted 23 March 2019 Available online 28 March 2019 Tissue engineering is a rapidly-growing approach to replace and repair damaged and defective tissues in the human body. Every year, a large number of people require bone replacements for skeletal defects caused by accident or disease that cannot heal on their own. In the last decades, tissue engineering of bone has attracted much attention from biomedical scientists in academic and commercial laboratories. A vast range of biocompatible advanced materials has been used to form scaffolds upon which new bone Peer review under responsibility of Cairo University. ⇑ Corresponding authors E-mail addresses: mokhtarzadehah@tbzmed.ac.ir (A. Mokhtarzadeh), hamblin@helix.mgh.harvard.edu (M.R. Hamblin). https://doi.org/10.1016/j.jare.2019.03.011 2090-1232/ 2019 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 186 Keywords: Bone tissue engineering Carbon nanomaterials Scaffold Graphene oxide Carbon nanotubes Carbon dots Nanodiamonds Introduction R. Eivazzadeh-Keihan et al./Journal of Advanced Research 18 (2019) 185–201 can form. Carbon nanomaterial-based scaffolds are a key example, with the advantages of being biolog-ically compatible, mechanically stable, and commercially available. They show remarkable ability to affect bone tissue regeneration, efficient cell proliferation and osteogenic differentiation. Basically, scaf-folds are templates for growth, proliferation, regeneration, adhesion, and differentiation processes of bone stem cells that play a truly critical role in bone tissue engineering. The appropriate scaffold should supply a microenvironment for bone cells that is most similar to natural bone in the human body. A vari-ety of carbon nanomaterials, such as graphene oxide (GO), carbon nanotubes (CNTs), fullerenes, carbon dots (CDs), nanodiamonds and their derivatives that are able to act as scaffolds for bone tissue engineer-ing, are covered in this review. Broadly, the ability of the family of carbon nanomaterial-based scaffolds and their critical role in bone tissue engineering research are discussed. The significant stimulating effects on cell growth, low cytotoxicity, efficient nutrient delivery in the scaffold microenvironment, suit-able functionalized chemical structures to facilitate cell-cell communication, and improvement in cell spreading are the main advantages of carbon nanomaterial-based scaffolds for bone tissue engineering. 2019 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). role in bone cell proliferation and growth [9]. Therefore, the exact influence of the scaffold surface chemical composition requires Scaffolds can be called ‘‘the beating heart” of the tissue engi-neering field. Without the appropriate scaffold, the growth of cells in an artificial environment is not possible. Among all the various cells of the human body, bone cells are one of the most critical types that require a well-designed scaffold to allow engineered liv-ing bone. There is a growing need to repair damaged tissues such as bones or replace them with new healthy ones. Research into new approaches to create such scaffolds has been intensified in recent years, and tissue engineering combined with nanotechnol-ogy is now looked upon as a promising alternative to the existing conventional repair strategies [1,2]. This multidisciplinary science is a novel approach to the restoration and reconstruction of dam-aged tissues. It aims to grow specific and functional tissue that can behave as well (or even better) than natural tissue [3]. Basic science (chemistry, physics and engineering) is combined with life sciences (biology and medicine) in order to enhance the function of damaged tissue [4]. Kidney was the first organ to be transplanted between identical twin brothers. Ronald Herrick conducted this transplant in 1954. In this procedure the donor and recipient were genetically identical which avoided adverse immune response (rejection) [5]. According to recent statistics from the US Depart-ment of Health and Human Services, 22 people die each day while waiting for a transplant [6]. The aim of tissue engineering is to overcome existing transplant bottlenecks by modeling biological structures with the eventual aim to construct artificial organs. Engineers working in the field of tissue engineering utilize natural or synthetic materials to fabricate scaffolds. Scaffolds should be further broad studies. Nanomaterials such as carbon-based, metal-lic and metalloid nanoparticles play a pivotal role in tissue engi-neering [10–16]. Nowadays, nanocarbon materials have been used extensively in energy transfer and energy storage applica-tions. Fullerenes, graphene and CNTs are some of the most widely studied nanocarbon structures [17,18]. These nanomaterials have diameters ranging from tens of nanometers to hundreds of nanometers [19]. They possess unique structures and properties which make them promising candidate materials for use in biomedical applications, such as tissue engineering and regenera-tive medicine. Moreover, carbon nanomaterials have been used as secondary structural reinforcing agents to enhance the mechan-ical properties of two- and three-dimensional cell culture scaffolds such as hydrogels and alginate gels [20]. Graphene (G) materials may be superior to other carbon nano-materials such as CNTs due to their lower levels of metallic impu-rities and the need for less time consuming purification processes to remove the entrapped nanoparticles [21]. However, on the other hand, CNTs possess some unique properties like a cylindrical shape with nanometer scale diameters, longer lengths (4100 nm) and very large aspect ratios. Moreover other physical and mechanical properties of CNTs are important such as high tensile strength 50 GPa, Youngs modulus 1 TPa, conductivity rin 107 S/m, maximum current transmittance Jin 100 MA/cm2, and density q 1600 kg/m3 [17]. All carbon nanomaterials have been shown to be bioactive for one or more purposes. Many show a high capability for bone biocompatible without any stimulation of excessive inflammation, tissue engineering, with good mechanical properties, no or response by the immune system. Furthermore, scaffolds should be compatible with tissue-specific cell types and with the environ-ments found in the body of the individual who will receive the tis-sue [7,8]. Bone is unique amongst tissue engineering targets, since mechanical strength becomes of paramount importance, in addi- cytotoxicity toward osteoblasts, and display an intrinsic antibac-terial activity (without the use of any exogenous antibiotics) [22]. Due to these advantageous properties they have been widely investigated for bone tissue engineering applications, either as a matrix material or as an additional reinforcing mate- tion to good biocompatibility and satisfactory biological function. rial in numerous polymeric nano-composites [20]. In this Some studies have been undertaken to investigate the use of carbon-based nanomaterials for bone tissue engineering in vivo. For instance, Sitharaman et al. utilized CNT/biodegradable polymer nanocomposites for bone tissue engineering in a rabbit model. They utilized single-walled carbon nanotubes (SWCNTs), especially ultra-short SWCNTs (US-SWCNTs) to fabricate polymeric scaffold materials. Their results showed the significant effects of the scaf-fold composition on the cell behavior and the growth rate in the microenvironment of the scaffold surface. In their report, the CNT scaffolds that did not possess the appropriate surface chemical composition did not perform well for cell growth. Their results indicated that a suitable chemical composition played a critical review, the applications of carbon-based scaffolds including GO, CNTs, CDs, fullerenes, nanodiamonds (NDs) and their deriva-tives and compositions in bone tissue engineering have been covered (Fig. 1). For broad and comprehensive coverage of the application of car-bon nanomaterials in bone tissue engineering, the following key-words were employed: scaffold, GO, CNTs, fullerenes, CDs, nanodiamonds, bone tissue engineering, cell proliferation, osteo-genic differentiation, cell spreading, biocompatibility, cytotoxicity and mechanical strength. The focus of this review is on reports that have been published in the last 3–4 years and have been cited in Google scholar and Scopus websites. R. Eivazzadeh-Keihan et al./Journal of Advanced Research 18 (2019) 185–201 187 Fig. 1. Application of carbon-based nanomaterials as scaffolds in bone tissue engineering. Different carbon-based nanoparticles such as CNTs, G, fullerenes and CDs and NDs could act as scaffolds or matrices for various bone forming cells, growth factors and sources of calcium. Graphene oxide in bone tissue engineering G is one allotrope of the crystalline forms of carbon, taking the form of a single monolayer of sp2-hybridized carbon atoms arranged in a hexagonal lattice. It is the basic structural element of many other allotropes of carbon, such as graphite, charcoal, CNTs and fullerenes. Each carbon atom has two r-bonds and one out-of-plane p-bond linked to neighboring carbon atoms. This molecular structure is responsible for the high thermal and electri- cal conductivity, unique optical behaviors, excellent mechanical properties, extreme chemical stability, and a large surface area per unit mass. Additionally, by chemical and physical manipula-tion, G sheets can be restructured into single and multi-layered G or GO. GO is a compound of carbon, oxygen, and hydrogen in vari-able molecular ratios, achieved by treating graphite with strong oxidizing agents. Because of the presence of oxygen, GO is more hydrophilic than pure G, and can more easily disperse in organic solvents, water, and different matrices [23,24]. Recently, basic studies on the physicochemical properties GO, have shown that the hydrophilicity [25], mechanical strength [26], high surface area [27] and adhesive forces [28] are related to how the G sheets inter-act with each other. This interaction can occur by p-p stacking of [29], electrostatic or ionic interactions, and van der Waals forces depending on the exact structure of the functionalized sheets. These various interactions make possible specifically tailored applications of GO-based materials for tissue engineering in differ-ent organs, biosensor technology, and medical therapeutics [30,31]. Different ‘‘Gum-metal” titanium-based alloys like Ti(31.7)- Nb(6.21)-Zr(1.4)-Fe(0.16)-O can be admixed with GO-based mate-rials to enhance their mechanical and electrical properties. Depending on the proposed application, GO can be functionalized in a number of ways. For instance, one way to ensure that the chemically-modified G disperses easily in organic solvents is to attach amine groups through organic covalent functionalization. This makes the material better suited to function in biodevices and for drug delivery [32]. Reports have shown the beneficial effects of kaolin-based materials on the toxicity of G-based materi-als [33,34]. Nowadays, the non-toxicity of G-based nanomaterials that are in the form of 2D-substrates or 3D-foams is the one of the most interesting issues in designing bioactive scaffolds for dif-ferent human and animal stem cells differentiation processes [18,21,35]. G-nanoparticle composites have also shown good potential in tissue engineering because of the appropriate ability for surface modification, acceptable cytotoxicity and biodegrad-ability [36]. In 2015, Xie et al. reported a facile and versatile method that can be used to synthesize these structures based on colloidal chemistry. In their study, they started with aqueous sus-pensions of both GO nano-sheets and citrate-stabilized hydroxya-patite (HAp) nanoparticles. Hydrothermal treatment of the blends of suspensions increased the G to GO ratio, and entrapped colloidal HAp nanoparticles into the 3D-G network owing to for-mation of a self-assembled graphite-like shell around them. Dialy-sis of this shell preparation led to deposition of uniform NPs onto the G walls. The results showed that G/HAp gels were extremely porous, mechanically strong, electrically conductive and biocom- patible, thus promising as scaffolds for bone tissue engineering. 188 R. Eivazzadeh-Keihan et al./Journal of Advanced Research 18 (2019) 185–201 This study has great importance because it studies the effects of G and GO sheet morphology on the artificial bone tissue quality. In 2015, Lee et al. investigated whether nanocomposites of reduced graphene oxide (rGO) and HAp could promote the osteogenic dif-ferentiation of MC3T3-E1 preosteoblasts and stimulate new bone cell growth. rGO/HAp nanocomposites significantly promoted spontaneous osteo-differentiation of MC3T3-E1 cells without any inhibition of their proliferation. This improved osteogenesis was verified by measurement of alkaline phosphatase (ALP) activity as a marker of the early stage of osteo-differentiation and mineral-ization of calcium and phosphate as the late stage. Moreover, rGO/ HAp nanocomposites meaningfully increased the expression pro-cess of osteopontin and osteocalcin. Likewise, rGO/HAp nanocom-posite grafts were found to increase new bone cells formation in animal models without any inflammatory response. rGO/HAp nanocomposites could be suitable for the design of a new class of dental and orthopedic bone grafts to facilitate bone regeneration due to their ability to stimulate osteogenesis. Fig. 2 displays field emission scanning electron microscopy (FESEM) images of the rGO/HAp nanocomposites reported in the study [37]. Acrylic polymers or polymethylmethacrylate (PMMA) based materials have been applied in biomedical applications since the 1930s. They were first utilized for odontology and subsequently in orthopedic applications. Many attempts have been made to improve their mechanical properties due to their initial compara-tive weakness. One of the ways to accomplish this, is the addition of a reinforcing filler or fibers into the polymer matrix. Carbon based nanomaterials, including CNT powders, G and GO have been investigated due to their ability to improve the mechanical proper-ties, thermal and electrical conductivity. For example, in 2017, Paz et al. studied G and GO nano-sized powders, with a loading ranging from 0.1 to 1.0 w/w % as reinforcement agents for PMMA bone cement. They examined the mechanical properties of the resulting and fatigue performance. This was attributed to the G and GO inducing deviations in the crack fronts and hampering crack prop-agation. It was also observed that a high functionalization ratio of GO (as compared with G) resulted in better improvements due to the creation of stronger interfacial adhesion between GO and PMMA. The use of a loading ratio 0.25 wt% led to a decrease in the mechanical properties as a consequence of the formation of agglomerates as well as to an improvement in the porosity [38]. Moreover, the formation of highly porous 3D nanostructure net-works and with a favorable microenvironment makes it possible to use GO in bone tissue engineering [39]. In 2016, Kumar et al. pre-pared PEI (polyethyleneimine)/GO composites for application in bone tissue engineering as scaffolds. They claimed that the PEI/ GO could encourage proliferation and formation of focal adhesion complexes in human mesenchymal stem cells cultured on poly (e-caprolactone) (PCL). The PEI/GO composite induced stem cell osteogenic differentiation causing near doubling of ALP expression and more mineralization compared to unmodified PCL with 5% fil-ler content, and was about 50% better than GO alone. 5% PEI/GO was as effective as addition of soluble osteoinductive factors. They attributed this phenomenon to the enhanced absorption of osteo-genic factors due to the amino and oxygen-containing functional groups on the PEI/GO leading to boosting of the stem cell differen-tiation process. Moreover, they reported that PEI/GO exhibited a better intrinsic bactericidal activity compared to neat PCL with 5% filler ingredients and GO alone. They concluded that PEI/GO-based polymer composites could function as resorbable bioactive biomaterials, as an alternative to using less stable biomolecules in the engineering orthopedic devices for fracture stabilization and tissue engineering. The polymer and GO nanocomposites not only have superior morphological properties for scaffolds, but their high bioactivity makes it possible to allow repair of bone defects [40]. The mechanical strength and stability of the material is an PMMA/G and PMMA/GO nanocomposites such as: bending important factor in the design of scaffolds for tissue engineering. strength, bending modulus, compression strength, fracture tough-ness and fatigue performance. They found that the mechanical strength of PMMA/G and PMMA/GO bone cements was enhanced at low loading ratios (0.25 wt%), especially the fracture toughness Fig. 2. FESEM images of rGO/HAp nanocomposites. The morphology of the HAp was irregular-shaped granules with a mean particle size of 960 ± 300 nm, with the HAp particles partly covered and interconnected by a network of rGO [37]. Open access article with no copyright permission. GO-based composites possess highly porous structures and great mechanical strength that gives them good potential for bone regeneration scaffolds. Liang et al. reported that HAp/collagen (C)/poly(lactic-co-glycolic acid)/GO (nHAp/C/PLGA/GO) composite scaffolds could stimulate proliferation of MC3T3-E1 cells (Fig. 3) [41]. They prepared nHAp/C/PLGA/GO nanomaterials with various GO weight percentage for preparation of scaffolds, measured the mechanical properties of the scaffold. The results showed that 1.5 wt% GO could increase the mechan-ical strength of the scaffold and provided a good substrate for adhesion and proliferation of the cells. In addition to these advan-tages, the presence of GO in (nHAp/C/PLGA/GO) improved the hydrophilic properties of the scaffolds, which can facilitate the adhesion of cells. Changes in contact angle with different percent-ages of GO increased the wettability of the scaffold surface due to the presence of more hydroxyl functional groups in the GO. The nHAp/C/PLGA/GO scaffolds showed different pore diameters (0– 200 nm) and the sample with 1.5% GO had the best mechanical strength. Increasing the weight percentage of GO also increased the MC3T3-E1 osteoblast cell proliferation rate. There were more cells measured at 1, 3, 5 and 7 days with the nHAp/C/PLGA/GO scaffold with 1.5%wt GO compared to lower GO weight percentage. SEM images of the cell proliferation illustrated the GO effect (Fig. 4). According to SEM images, the cell numbers (white areas) after 3, 5 and 7 days for 1.5% GO were higher than those with 0%, 0.5% and 1% GO [41]. Recently, Natarajan et al. described composites of galactitol-polyesters that had different percentages of GO and a high modu-lus and low toxicity. The mechanical strength decreased when the weight percentage of GO increased from 0.5 to 1.0%. A further increase of GO up to 2% wt gave an even worse influence on the mechanical stability. Therefore the GO weight percentage seems R. Eivazzadeh-Keihan et al./Journal of Advanced Research 18 (2019) 185–201 189 Fig. 3. Experimental schematic procedures for nHAp/C/PLGA/GO scaffold preparation [41]. Open access article with no copyright permission. Fig. 4. SEM images of MC3T3-E1 osteoblast cell proliferation with different amounts of GO in the nHAp/C/PLGA/GO scaffolds. (NB the white areas shows the cells) [41]. Open access article with no copyright permission. to be an important factor in scaffolds for bone regeneration [42]. Recently, Zhou and coworkers developed composite fibrous scaf-folds for bone regeneration produced from poly(3-hydroxybuty rate-co-4-hydroxybutyrate) and GO by an electrospinning fabrica-tion technique. The obtained materials showed high porosity, hydrophilic surface, mechanical stability and could stimulate osteogenic differentiation [43]. In another study, Luo et al. described the fabrication of PLGA-GO fibrous biomaterial scaffolds for bone regeneration with good cell adhesion that stimulated pro-liferation and osteogenic differentiation of human mesenchymal stem cells. Composite scaffolds with GO and PLGA can stimulate expression of osteogenesis-related genes, which control the production and release osteocalcin and non-C proteins [44]. GO composite scaffolds could also be candidates as sensitizing agents for photothermal therapy or magnetic hyperthermia of tumors. Zhang et al. described paramagnetic nanocomposite (Fe3O4/GO) scaffolds based on GO and Fe3O4 for hyperthermia of bone tumor cells for the first time. The tumor cells could proliferate on the scaf-fold substrate, and when an adjustable external magnetic field was applied there was a controllable increase in temperature. Three-dimensional b-tricalcium phosphate-based scaffolds with surfaces modified by Fe3O4/GO (named b-TCP–Fe–GO) could also be employed in bone regeneration. The external magnetic field could increase the tumor cell temperature up to 50–80 C, for a 1% Fe3O4/ 190 R. Eivazzadeh-Keihan et al./Journal of Advanced Research 18 (2019) 185–201 GO composite. 75% of the target cells were destroyed, and more-over the results for osteogenic differentiation and proliferation of rabbit bone marrow stromal cells (rBMSCs) were better than with-out b-TCP–Fe–GO [45]. Recent studies have suggested that the presence of certain metal ions at precise concentrations in scaffold materials could accelerate bone cell proliferation. In this regard, Kumar et al. inves-tigated strontium ion release from hybrid rGO(rGO-Sr) nanoparti-cles and its effect on osteoblast proliferation and differentiation. They used a PCL matrix with rGO-Sr composite for the scaffold with a strontium weight percentage in rGO of 22% [46]. The advan-tages of GO in tissue engineering can be summarized as mechani-cal strength and hydrophilicity to enhance the scaffolds, increasing the adhesion, and accelerating the proliferation of cells. One exam-ple is a poly(propylenefumarate)/polyethyleneglycol/GO-nanocom posite-based scaffold (PPF/PEG-GO) reported by Díez-Pascual et al. Their studies showed that the PPF/PEG-GO nanocomposite was the best candidate for bone tissue engineering and medical applica-tions. Along with different amounts of PEG in the PPF polymer, the addition of GO enhanced the physiochemical properties of the PPF/PEG based scaffold. The increase in mechanical strength, biodegradability, a high rate of cell growth and osteogenic differen-tiation of bone cells on this scaffold were better than the PPF/PEG-based polymer alone. The SEM images and schematic representa-tion of the composite are shown in Fig. 5 [47]. Incontinue,Songetal.developedacompositefoamwith3D-rGO and polypyrrole on nickel as a mechanically stable bone regenera-tion scaffold. This demonstrated good ability to stimulate MC3T3-E1 osteoblastic cell proliferation (6.6 times). This new class of scaf-fold were fabricated using a layer-by-layer (LBL) method and an electrochemical deposition technique, proposed to be a low-cost and simple strategy for scaffold fabrication [48]. However, one of unsolved challenges in bone tissue engineering is the weak attach-ment between biopolymers and bioceramics at the molecular scale. However, Peng et al. reported the application of GO as a potential solution for this problem. They reported that electrostatic and p-p interactions have a key role in the formation of strong interactions between polyether-etherketone (PEEK) biopolymer and HAp bioce-ramic [49]. Scaffolds are highly porous biomaterials which can be used as drug loading vehicles to reduce pain and inflammation in surgical sites in the bone. Ji et al. introduced an aspirin-loaded C-GO-HAp-based scaffold, fabricated by LBL biomineralization tech-nique. The loading and controlled release of aspirin from the porous scaffold substrate (300 nm pore size) significantly reduced pain and inflammation in the bone surgical site. Wu et al. prepared a GO-basedb-tricalciumphosphatebioactiveceramicas aboneregenera-tion scaffold with high osteogenic ability both in vivo and in vitro. They found that the addition of GO to b-tricalcium phosphate improvedosteogenicproliferationandactivatedsignalingpathways withinhuman bonecellscomparedto b-tricalciumphosphatealone [50]. The adhesion of bone cells to the underlying substrate is one of the important factors that can influence the mechanical properties of the bone produced in tissue engineering. In recent years, many studies have concentrated on this issue. For instance, Mahmoudi et al. developed a nanofibrous matrix for enhancement of adhesive forces between bone cells, using electrospun material. They used biopolymers and GO hybrids for this purpose with good mechanical strengthandbiocompatibility,andsubsequentlyanefficientwound closure rate. The experimental design process of this material is illustrated in Fig. 6 [51]. In summary, GO based materials have a broad range of applica-tions in bone regeneration and tissue engineering. The high surface area, suitable wettability, remarkable mechanical properties, high adhesion ability, and rapid onset of stimulation effects are impres-sive advantages of GO nanomaterials. Moreover, these materials can solve the weak interaction between bioceramics and biopoly-mers by introducing strong electrostatic and p-p stacking interac-tions. Therefore, GO will likely continue to attract the attention of scientists for bone regeneration and other fields of tissue engineer-ing in the future. Three points concerning the use of GO in bone tis-sue engineering scaffolds are as follows. Firstly, the presence of GO in the natural biopolymer-based scaffolds has better stimulant effects on the mineralization process of bone tissue in comparison to synthetic polymers. Secondly, the presence of GO in the poly-meric scaffold matrix can facilitate the growth of bone cells and their spreading process on the scaffold surface for both the natural and synthetic polymers, but the fraction of dead cells on the GO synthetic polymer scaffold was higher than GO natural biopolymer scaffold. Thirdly, although the fraction of dead cells on the GO syn-thetic polymer scaffold was higher than GO natural biopolymer, GO natural biopolymer scaffolds can produce bone tissues with better mechanical strength. A summary of reports about GO nanomaterials and their appli-cation in bone tissue engineering is shown in Table 1. The contents of this Table cover physiochemical properties of GO nanomaterials, synthesis methods, clinical trials and the type of scaffolds that have been used. Also, the various stem cells, different growth factors and nanomaterials that have been applied. Fig. 5. SEM image of PPF/PEG-GO composite and molecular representation of PPF matrix with PEG-GO that have been applied as a scaffold for bone tissue engineering [47]. Copyright ACS reprinted with permission. R. Eivazzadeh-Keihan et al./Journal of Advanced Research 18 (2019) 185–201 191 Fig. 6. The fabrication process of the biopolymer-GO composite involves chitosan (CS), poly(vinyl pyrrolidone) (PVP) and GO using an electrospinning method [51]. Copyright Elsevier reprinted with permission.

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