Biopolymeric nanocomposite scaffolds for bone tissue engineering applications – A review

Journal of Drug Delivery Science and Technology 55 (2020) 101452

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Biopolymeric nanocomposite scaffolds for bone tissue engineering applications – A review

T

P. Narmatha Christya, S. Khaleel Bashab, V. Sugantha Kumaria,∗∗, A.K.H. Bashirc,d, M. Maazac,d, K. Kaviyarasuc,d,∗, Mariadhas Valan Arasue,f, Naif Abdullah Al-Dhabie, Savarimuthu Ignacimuthuf a

Department of Chemistry, Auxilium College (Autonomous), Vellore, 632006, Tamil Nadu, India Department of Chemistry, C. Abdul Hakeem College, Melvisharam, 632509, Tamil Nadu, India c UNESCO-UNISA Africa Chair in Nanoscience's/Nanotechnology Laboratories, College of Graduate Studies, University of South Africa (UNISA), Muckleneuk Ridge, P O Box 392, Pretoria, South Africa d Nanosciences African Network (NANOAFNET), Materials Research Department (MRD), iThemba LABS-National Research Foundation (NRF), 1 Old Faure Road, 7129, P O Box 722, Somerset West, Western Cape Province, South Africa e Department of Botany and Microbiology, College of Science, King Saud University, P.O. BOX 2455, Riyadh, 11451, Saudi Arabia f Xavier Research Foundation, St.Xavier's College, Palayamkottai, Thirunelveli, Tamilandu, India b

A R T I C LE I N FO

A B S T R A C T

Keywords: Tissue engineering Scaffold Biopolymeric nanocomposites Cell proliferation Chotisan

Tissue engineering is the immense area of research in recent years because of its vast potential in the repair or replacement of impaired tissues and organs. Bone is a nanomaterial composed of organic (collagen) and inorganic (mainly nano-hydroxyapatite) components, with a hierarchical structure ranging from nanoscale to macroscale. The bone disorder has been increasing and the goal is to restore and improve the function of bone tissue by scaffolds, providing a suitable environment for tissue regeneration and repair. In this review biopolymeric nanocomposites provide a closer structural support approximation to native bone architecture for the cells and regulate cell proliferation, differentiation, and migration, which results in bone regeneration. Furthermore, there are some new challenges about the future research on the application of biopolymeric nanocomposites as scaffolds in the bone regeneration.

1. Introduction Tissue engineering is a modern scientific discipline concerning chemical, biological and engineering principles that are attempted to utilize a variety of methods for the intention of tissue regeneration [1,2]. The term “tissue engineering” (TE) was first defined by Langer and Vacanti in the 1990's [3]. In 1988, at a National Science Foundation (NSF) workshop, the term “tissue engineering” was officially coined [4]. Tissue engineering is an interdisciplinary field that focuses on the recovery, maintenance or improvement of tissue functions that are defective or have been lost due to different pathological conditions [144,145]. It applies life sciences and engineering principles and its innovation for such damaged tissues either through the development of biological substitutes or through tissue reconstruction [146,147]. So as to revive, maintain or enhance the function of tissues, tissue engineering helps to understand the structure and function of normal and

pathological mammalian tissues [1,2,5,6]. The goal of tissue engineering is to develop new functional tissues and to regenerate tissue either in vitro or in vivo to cure diseases when surgery is needed [7]. For many more disease states, tissue engineering remains a flourishing research area with potential new treatment [148]. It offers the potential for regeneration of almost every tissue and organ in the human body [6]. Tissue engineering's general strategies can be classified into 3 groups: (i) implantation into the organism of isolated cells or cell replacements, (ii) delivering tissue that induces substances such as growth factor. Traditionally, growth factor refers to proteins or polypeptides that can promote tissue growth, (iii) placing cells in or on various matrices [6]. Tissue engineering is majorly classified into two types: (a) soft tissue engineering that deals with skin, blood vessel, tendon/ligament, cardiac patch, nerve and skeletal muscle, (b) hard tissue engineering that deals with bone [8].

∗

Corresponding author. UNESCO-UNISA Africa Chair in Nanoscience's/Nanotechnology Laboratories, College of Graduate Studies, University of South Africa (UNISA), Muckleneuk Ridge, P O Box 392, Pretoria, South Africa. ∗∗ Corresponding author. E-mail addresses: [email protected] (V.S. Kumari), [email protected] (K. Kaviyarasu). https://doi.org/10.1016/j.jddst.2019.101452 Received 17 September 2019; Received in revised form 24 November 2019; Accepted 4 December 2019 Available online 09 December 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved.

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• Long bones are found in metacarpals, femurs, clavicles, humeri, ulnae, fibulae and Phalanges. • Flat bones are found in skull, mandible, sternum, ribs and scapulae. • Irregular bones are found in vertebrae, sacrum, coccyx and hyoid

1.1. Bone tissue engineering Bone is the world's second most often transplanted tissue with in excess of four million yearly activities utilizing bone grafts or bone substitute materials to treat bone deformities [9]. A standout amongst the most well-known difficulties confronted is bone inadequacy in oral medical procedure and periodontology [10]. The occurrence of bone issues and conditions has expanded all through the world. Bone disorders like infections, bone tumours and bone misfortune need bone recovery yet more these days [11]. Bone possesses an inherent capacity to fix itself however there are numerous circumstances where complete bone recovery can't happen and should be invigorated [149–151]. A huge number of patients experiencing bone imperfections require bone grafts or substitutes. Thus bone regeneration becomes an attractive area in tissue engineering [12]. The goal of bone tissue engineering (BTE) is to optimize material engineering and biological science resources to enhance new bone regeneration [10]. Bone tissue engineering has emerged in the last few decades as one of the most intractable approaches to deal with bone trauma. It normally includes the utilization of biomaterials to treat bone defects because of fractures, osteoporosis, osteoarthritis and neoplasms as whole prostheses, scaffolds, hydrogels and cells [13]. A number of successes in animal models have been found in BTE using biomaterials and cells ranging from primary adult osteoblasts to bone marrow mesenchymal stem cells. Indeed, since the 1980's, the potential of mesenchymal stem cells in bone regeneration has been emphasized [14,152]. BTE is a complicated and complex process that initiates osteoprogenitor cells with migration and recruitment accompanied by their proliferation, differentiation, matrix formation along with bone renovations [11]. The need for substitutes to replace bone results from osteoporosis, cancer, infectious disease, trauma, periodontitis and fracture [1,153,154]. Thus, BTE has become a promising approach to the manufacture of bone replacements by combining specific bone cells [15]. The intention of bone tissue engineering is to: (i) present the standing of translational approaches to engineer bone regeneration, (ii) perfectly understand the physical and chemical factors affecting cellular messages to biomaterials and the tailoring of biomaterial devices that direct cells, (iii) compare various bone tissue engineering methods involving biological scaffold enhancement with osteogenic genes, proteins or cells [16].

bones.

Bone tissue is composed of 80% compact bone and 20% of cancellous bone. Compact bone is otherwise called as cortical bone and cancellous bone is otherwise called as trabecular bone. Compact bone is usually denser and found at the surface of the bone marrow. Cancellous bone has a honeycomb or cavity-like structure composed of trabecular plate and rods and found inside the bone marrow. Both of these bones are formed in a lamellar pattern alternatively that results in the increase of strength in the lamellar bone. Compact bone contains two tissues namely periosteum and endosteum. The periosteum is present at the outer surface of the compact bone connected through a collagenous fiber. It plays an important role in fracture repair. The endosteum is present at the inner surface of both compact and cancellous bone. These are also connected to blood vessels, osteoblasts and osteocytes. Bone remodeling is higher in endosteum than periosteum, in particular the ratio of compact to cancellous bone varies with different sites of bones. The ratio is 25:75 in vertebra, 50:50 in the femoral head and 95:5 in the radial diaphysis. Compact bone and cancellous bone are composed of osteons where compact osteons are called harvesian system and cancellous osteons are called packets. An adult body contains 21 × 106 compact osteons and 141 × 06 cancellous osteons [17]. There are two kinds of protein in the extracellular matrix of the bone: (i) structural protein, (ii) noncollagenous protein. In structural protein, the major component is collagen and the minor component is fibronectin. The hydroxylation and glycosylation of amino acids crosslink the collagen making it ideal for its function. It conjointly provides tissue elasticity, stabilizes the extracellular matrix, supports or templates the initial deposition of minerals and binds different macromolecules. The initial deposition of collagen fibrils is done by fibronectin. Noncollagenous protein helps in cell signalling, matrix organization, metabolism and mineralization [18]. During a lifespan, bone undergoes modeling and remodeling. Modeling would be the process through which bones in response to physiological factors or mechanical pressures alter their overall structure, resulting in a gradual modification of the human skeleton to the forces it experiences [155–158]. Bone formation and resorption are not closely linked during bone modeling. Bone remodeling is the phase of upgrading bone to retain bone strength and homeostasis of minerals [159]. The method of remodeling resorbs aged bone and forms new bone to avoid bone microdamage from accumulating. Remodeling starts before birth and goes on until death. Bone formation and resorption are closely linked during bone remodeling [160]. When there is an imbalance between bone formation and resorption, it causes osteoporosis. It is one of the main reasons for age-related decrease in bone strength [161–164]. Osteoporosis is a Greek word that defines a decrease in bone mass per unit volume of bone [20,23]. Bone renovating in ageing men is believed to increase slightly [17]. The process of bone remodeling or repair involves osteogenic cells with very specific functions and roles. These are osteoblasts, osteocytes, osteoclasts, and cells of the bone lining [20]. Osteoblasts cells are bone forming or building cells. Multipotent mesenchymal stem cells (MSCs) are the osteoblast precursors. Osteoblasts secrete organic and inorganic components in the extracellular matrix of the bone. They are associated in secreting collagen matrix and in protein synthesis, including osteopontin, osteocalcin, etc., After active bone formation, osteoblasts may become lining cells on the bone surface, it may experience apoptosis, and cells may differentiate into osteocytes. They synthesize new bone matrix on bone-forming surfaces [20]. Moreover, 60%–80% of osteoblasts die through apoptosis [23]. Osteoclasts cells are bone resorbing cells. Mononuclear cells of

1.2. Study on bone Bone is typically a highly organized complex tissue, and heterogeneous composite material. This specialized connective tissue is composed of 50–70% of inorganic constituent or mineral phase, 20–40% of organic constituents, 5–10% of water and 3% lipids. The principal component of the mineral phase is hydroxyapatite [Ca10(PO4)6(OH)2], trace amounts of carbonate, magnesium and acid phosphate. The major content of the organic phase is 90% of type I collagen as well as proteoglycans and glycoproteins. Cellular attachment is also enhanced by type I Collagen's abundant tripeptide sequence (Arg-Gly-Asp) [17–20]. The inorganic mineral supports mechanical rigidity and load-bearing capacity whereas the organic matrix produces elasticity and flexibility [17]. Lipids generally surround the body of the cell and help in the functioning of cells and regulate it. Water binds to minerals, fills the pores and interact with collagen fibrils [18]. The main function of bone is to promote mechanical strength, to retain calcium and phosphate ions, to produce good structure, and to assist many organs [21,22]. An adult skeleton has 213 bones except for sesamoid bones. There are four types of bones: (i) short Bones, (ii) long Bones, (iii) flat Bones, (iv) irregular bones.

• Short bones are found in tarsal and carpal bones, patellae and sesamoid bones.

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These are osteoinductive and osteoconductive. They are highly available and cheap. The drawbacks are poor immune response and the risk of animal disease transmission [5]. Some alternate bone graft materials are polymers, ceramics and metals [184–187]. Metal possess good mechanical strength and integrity [188,189]. Its shortcomings are shielding from stress, stiffness, infections, and chronic pain, wear and failure, and revision surgery risk [9,20,190]. There are various scaffolds that victoriously bridged bone regeneration. Porous 3D scaffolds fabricated through a variety of methods have been utilised to help and direct bone regenereation [9,191].

monocyte-macrophage lineage are the osteoclasts precursors. Most osteoclasts cells are secreted by precursors present in the bone marrow. These are connected to the bone matrix through integrin receptors. These are multinucleated cells with ruffled border. They simply absorb and remove old cells [17,20]. All osteoclasts die through apoptosis [23]. Osteocytes are the most abundant bone cells and can live in human bone for decades. These are terminally differentiated osteoblast cells and supports bone structure and metabolism. Osteocytes are capable of transmitting stress-based and strain-felt signal [17]. These are crucial cells in the adult skeleton for normal functioning and homeostasis. Osteocytes play a versatile role in regulating osteoblast and osteoclast functions for bone renovation. Osteocytes are connected to each other and the surface of the bone [20,165,166].

3. Scaffold in bone tissue engineering In 1990, the idea of tissue engineering originated to address the disadvantages of grafts and tissue repair, relying on strategies for synthesizing and regenerating tissue in vivo. The transplantation of biofactors like cells, genes or proteins repairs tissue within a three-dimensional porous material called scaffold [192,193]. This porous nature of the scaffold helps in cell adherence and proliferation and therefore preserving the tissue quantity [27,194]. In the field of bone tissue engineering, scaffolds are biocompatible constructs, capable of imitating native bone extracellular matrix and delivering a three-dimensional (3D) atmosphere wherein cells are affixed and proliferated [195]. A perfect scaffold should be biocompatible to prevent unmanted host replies, biodegradable with sufficient physical and mechanical characteristics [196,197]. The scaffold's interlinked porosity facilitates cell spreading and nutrient, oxygen, waste and growth factors to be transported, promoting the sustained development of bone tissue from the outskirts into the inner part of the scaffold [198]. A scaffold should replace regenerative tissue while retaining the shape and size of the final tissue structure [28,199].

2. Clinical need in bone tissue engineering In youngsters, the majority of fractures will be healed without surgical intervention because of the high bone regeneration capacity [167,168]. Large bone defects need medical assistance since they lack a bone regeneration template [14]. In the case of elderly patients, malunion or non-union problems like severe fractures create a serious problem in natural healing. Non-union or mal-union fractures are a major challenge in bone tissue engineering [20]. Non-healing of bone is due to local immune skills, initial bone loss as a result of surgery, osteitis infection, osteomyelitis, and numerous surgical revisions [24]. In effective treatment, congenital and acquired pathologies such as infection, neoplasm and failed arthroplasty, osteogenesis imperfecta, bone injury and deformities such as trauma, malformation, osteoarthritis, osteomyelitis, osteoporosis, joint arthroplasty, spine arthrodesis, implant fixation, and tumours pose a difficult challenge [20]. The critical size bone defect cannot be cured in the lifetime of a patient and that requires replacement materials [169–172]. This may include bone grafts, bone substitute materials, growth factors, free fibula vascularized grafts, and metal work implantation to aid, stabilize and regenerate the bone [9]. Bone grafts include methods for addressing these bone defects. Bone grafts are osteoconductive and are increasing popularly [25]. Demand for bone grafting is increasing and there is also a rapid expansion of the variety of biomaterials available to replace bone grafts [173–176]. This increased demand reflects the effective treatment of bone regeneration in clinical need [26]. The golden standard in bone repair includes the usage of autologous bone grafts, allografts and xenografts. An autologous bone graft is donated from a non-loading site by the donor himself and transplanted to the defective site [177,178]. The source of autografts is iliac crest for trabecular bone, ribs and fibula for compact bones. Autografts are osteoconductive, osteoinductive and osteogenic in nature. The best clinical outcome for autografts is that they contain cells and growth factors that support the bone regeneration process and have a high success rate. They do not present immune complications, risk of rejection, disease transmission because the donors are the recipients themselves [179–181]. Autografts usage includes limitations such as morbidity of the donor site, pain, low availability of autologous bone, risk of fractures and infection, additional surgery, hematomas including chronic pain. The limited supply in children, in particular, hinders an option for bone repair [13,26]. Allogenic bone grafts are derived from another individual or a cadaver. It possesses different shapes and geometries. Allogenic bone grafts are good since they have greater availability when compared to autografts, and are easy to handle. Since allografts eliminate the need for the host to harvest the bone it avoids the possibility of donor site morbidity [181,183]. Allografts have limitations such as immune rejection, disease transmission like HIV, lymphoma from donor to receptor. Allografts necessitate treatments such as freeze drying, irradiation and acid washing to avoid receptor denial and exclude any available infection. Mechanical and biological properties are affected by this process [5,13]. Xenografts are derived from cows and corals.

3.1. Requirements for scaffolds preparation Other conditions for the usage of scaffolds in bone tissue regeneration include appropriate msicrostructure, closely related mechanical properties with that of bone tissue and strong interaction between cells and scaffolds to enable cell adhesion, proliferation and differentiation [200]. It is possible to determine the transport of nutrient and metabolic waste with the help of the size of the pores. The macroporosity of scaffolds plays a key role in the regeneration of bone tissue [201,202]. Pores below 100 μm promote nutrient adsorption in their surface and are crucial in the phase of cell differentiation [203]. Pores from 100 μm to 300 μm activates cell migration and proliferation [22]. The task for pore scaffolds is to develop one that corresponds to the bone's biomechanical characteristics and is bioactive enough to boost the growth of the bone. Not only do pores play an important part in the permeation and movement of cells, but they also considerably affect the physical characteristics of the scaffold [204,205]. For example, the increase of porosity decreases mechanical characteristics exponentially, while the increased porosity, meanwhile, also increases permeability and bioactivity [206,207]. Porosity is a mechanically adverse element. Its rise is linked to the development of its bioactivity. Greater the porosity, the greater the accessible ground region that promotes cell compliance and propagation [27]. 3.2. Cytotoxicity of scaffolds The Lin & coworkers (2014) study aimed at estimating the relation between the porosity of the scaffold and its cellular activity. Polyethylene glycol (PEG), one strong, the other 500 μm porosity, was generated by stereolithography. It is apparent that more cellular activity occurs in the porous scaffold than in the massive ones after the cell activity tests. This is due to the rise of feasible cell permeation region, since huge scaffolds only enable tissue development on its surface, while porous scaffolds enable cells to reach the framework and 3

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4. Biopolymers

proliferate there, enabling a more detailed tissue operation [208,209]. Roohani-Esfahani et al., suggested that the mechanical properties of the scaffold are significantly altered by both porosity degree and pore structure using a 3D ceramic scaffold of different porosities and pore shape [22]. The porosity of the scaffold not only impacts their biodegradability, but it is known to boost the capacity of fluids to permeate the framework, thereby enhancing the degradation time [210]. The production of biodegradable polymer composites and an inorganic phase in the polymer matrix were developed in order to prevent the issue of mechanical conduct against bioactivity and it succeeded to meet all scaffold needs [211,212]. The wide-ranging uses of these polymeric matrices are due to their biodegradability which is an important factor in the substitution of new tissue for synthetic scaffolds without leaving any waste [27]. Biodegradable scaffolds retain their physical characteristics at least for a period of six months until the regeneration of bone tissue [22]. Surface modifications of the scaffold can exhibit the excellent performance of the scaffold-like antibacterial properties [29,213]. The biofactors are the most common ones used in bone tissue development: angiogenic proteins that guide the development of endothelial cells and bone morphogenetic proteins, that encourage osteogenesis by differentiating cells from osteoblasts. The scaffold should, therefore, be sufficiently porous to enable it not only to carry these biofactors but also to provide a vascularisation, which provides oxygen to the body and allows the removal of remaining material originating from the local cellular environment [27]. Ideally, the scaffold should deteriorate simultaneously with the formation of fresh natural tissue [214]. Scaffolds need a high elastic module to maintain the space for which they are designed for the repair and generation of hard and ductile tissue such as bone and therefore tissue has a sufficient growth space [30].

Biopolymers are polymers which are manufactured from natural sources, either chemically or completely biologically synthesized by living organisms [34]. Biopolymers are chain-like molecules made from repetitive chemical blocks produced from environmentally degradable renewable resources [35]. For pharmaceutical and biomedical applications the use of biopolymers from various sources has been studied for many years. Biopolymers were fed interest due to its varied compositions, tuneable physical conduct, and a broad range of products. The comparatively low price and renewable character also attracts this material class especially in the pharmaceutical and biomedical sectors [34]. A biopolymer can be blended with other biopolymer, a biodegradable synthetic polymer, or a non-degradable synthetic polymer. Biopolymers can also be mixed to form a composite of a bio-polymer matrix with various reinforcing components such as mineral particles or natural fibers. In order to improve the total time of degradation and the mechanical properties, biopolymers are often blended together [36]. Biopolymers are majorly classified into two types based on the source: (i) Natural biopolymers: These are further classified into polysaccharides (starch, alginate, chitin/chitosan, hyaluronic acid derivatives) and proteins (soy, collagen, gelatin, fibrin gels, silk) (ii) Synthetic Polymers: poly(lactic acid), poly(caprolactone), poly(urethane), poly(propylene fumarate), poly(vinyl alcohol), poly(glycolic acid), poly(hydroxybutyrate) etc., [37]. 5. Biopolymeric nanocomposites as scaffolds in bone tissue engineering 5.1. Biopolymeric nanocomposite

3.3. Fabrication method of scaffold

The biopolymeric nanocomposite is a solid polymer composite in which nanomaterials are embedded that at least one of its domain possesses a nanoscopic size range (1–100 nm) [38,39]. The addition of nanosized materials to biopolymer composites can therefore, improve the characteristics of biopolymers [35]. The nanomaterials incorporated can be found in the form of nanocrystals, nanocoatings, nanotubes, nanofibres, nanoparticles etc., [40]. This biopolymeric nanocomposite can exist in the form of nanolayer composite, nanofilament composite or nanoparticulate composites [39].

Fabrication is the most important process of scaffolding. Cells and tissue in the body are arranged in 3D architecture. Scaffolds are to be made using distinct methods to facilitate distribution of cells and guide their development to three-dimensional space to design these functional tissues and organs [215]. Many researches have been carried out in the past to evolve fabrication methods for scaffolding. Some of the noteworthy methods that are formulated towards bone regeneration scaffolding with its advantages and disadvantages [216]. Freeze drying method is used in the fabrication of porous scaffold. As the rate of freezing increases, the size of pore decreases. This process is based on sublimation and biopolymers like silk protein, PGA, PLLA, PLGA and PPF are used. Self assembly process is used in the preparation of nanofibers. Synthetic polymeric nanofibers are mostly fabricated via this method. This process does not use organic solvents thereby reducing the cytotoxicity [217,218]. This method also controls the porosity, pore size and fiber diameter. The parameters are of complicated design and materials are costly [31]. Electrospinning method is majorly used in the fabrication of nanofiber scaffold with better surface area and aspect ratio. Biopolymers like silk fibroin, collagen, chitosan and gelatine are mostly used in this process. This process is fast and there is control over porosity and it's size along with the diameter of fiber. There is reduction in the size of pore with the thickness of fiber and has low mechanical strength [31,32]. Selective laser sintering is one of the additive manufacturing technologies. The source used is laser and it fuses materials like polyamides, metals like stainless steel, cobalt-chromium alloy, titanium etc., and ceramics. In this method a broad variety of biomaterials are used with no further assistance and post-processing but produces poor porous portion with uneven surface [33]. To summarize, the highlights of the various fabrication methods are tabulated in Table 1.

5.1.1. Alginate nanocomposite Alginate is a linear anionic copolymer consisting of (1–4)-linked components of β-D-mannuronate and α-L-guluronate from marine algae (Fig. 1) [41]. Alginate is a natural polysaccharide that is highly biocompatible and biodegradable which makes it efficient in bone tissue engineering [21,42]. Alginate is a polysaccharide that is readily chemically and structurally altered to enable improved implementation in regenerative medication. Its viscosity and porosity enable cellular immobilization, inclusion, and prolonged elimination of cells by scaffold. It lacks inherent mechanical power and is often associated with other compounds like chitosan, gelatin, and hydroxyapatite to enhance osteoconductive and osteointegrative characteristics while offering a powerful biodegradable framework [43]. Alginate with high molecular weight is usually used in bone tissue engineering since it possesses the property of mechanical strength while alginate with low molecular weight shows good biodegradation. Alginate with stem cells is widely used in bone tissue engineering [21]. Alginate microparticle and microfibre scaffold enable vascularisation, oxygenation, and cell migration, adhesion, and growth, which are biological occurrences that are essential for renewal of bone tissue [44]. Alginate-based biomaterials in different tissues and organs such as skin, cartilage, and bone suggest their promising future for repair and regeneration applications [42]. In addition, alginate may be used to 4

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Table 1 Advantages and disadvantages of different fabrication methods. T.No

Methods

Advantages

Disadvantages

Ref.No

1. 2.

Electrospinning Selective laser sintering Self-assembly Phase separation Freeze drying

Low mechanical strength, reduction in pore size with fiber thickness. Thermal degradation, porous portion, uneven surface, material infiltration required. Costly materials, parameters of complicated design. Tough to precisely monitor the scaffold design. Reduced size of pores and time required for the process is prolonged.

[32] [33]

3. 4. 5.

Fast, Control of porosity, fiber diameter and size of pores. A broad variety of biomaterials, No need for assistance and post-processing. Control of porosity, fiber diameter and size of pores. No reduction in molecular activity. No necessity of distinct leaching and elevated temperature.

[31] [31] [31]

bone TE approach [44]. Alginate/hydroxyapatite scaffold by phase separation at 40 °C and of porosity 82% promotes cell adhesion and enhances the mechanical property. At 50/50 composition it exhibited outstanding mechanical property. This scaffold was seeded with rat osteosarcoma UMR106 cell and osteoblastic cell lines. The better cell attachment was found at 50/50 and 75/25 ratio [48]. Calcium phosphate-alginate hydrogel deposits bone minerals with good mechanical property and shows osteodifferentiation [49]. Composite scaffold consisting of sodium alginate and gelatin plays a vital role in the healing and formation of bone [44]. Methacrylated alginate with collagen promotes osteogenic differentiation and facilitates preosteoblast spreading and proliferation. Alginate-nano bioactive glass improves mineralization and protein adsorption. Alginate-octacalcium phosphate enhances osteoblast cell proliferation and bone regeneration. Collagen in alginate-HA fills bone in the rat. Sodium alginate-injectable calcium silicate hydrogel with a pore size of 50–200 μm exhibits rat's mesenchymal stem cells (MSC) cell viability and proliferation along with potential ALP expression and angiogenesis. Alginate/RGD and AlginatePHSRN (proline-histidine-serine-arginine-asparagine) substitutes ECM in bone regeneration [21]. The scaffold of glucosamine grafted hydroxyapatite nanoplate (gHAP) with sodium alginate (SA) nanocomposite promotes osteoblast cell attachment, differentiation and proliferation [50]. The incorporation of 3D mesoporous bioactive glass with alginate scaffold consists of well-ordained nanopores, larger-pore controls, and considerably enhanced physiochemical, biological and medicinal characteristics which are a target for bone TE [21]. An electrospun nanofiber mesh tube with peptide-modified alginate hydrogel regenerates bone in large bone defects and non-union defects [42]. High biodegradation is exhibited by alginate hydrogel with the incorporation of nano-Hydroxyapatite (nano HA)/collagen particle [21]. Alginate scaffolds deliver biologically active cells for bone regeneration. The same is also done by Alginate-HA composite [21]. For relevant applications, three-dimensional scaffolding like hydrogels, microcapsules, sponges, foams and fibres of alginate is easily processed [42]. To summarize, the highlights of alginate biomaterial is tabulated in Table 2.

Fig. 1. Chemical structure of alginate.

promote the neovascularisation in and around the skin to improve bone development with growth factors [43]. In the vicinity of some divalent cations like Ca2+, Mg2+, Fe2+, Ba2+, or Sr2+, alginate has high hydrophilicity and may form stable hydrogels [45]. Ca2+ has been one of the divalent cations most frequently used to cross-link ionically with alginate to form alginate hydrogels [41,45]. To depict the environment of natural cells, biomaterials based on alginates possess unique physical, chemical and biological characteristics [42]. Various composites such as alginate-PLGA(poly lactic-co-glycolic acid), alginate-PEG, alginate-chitosan, alginate-collagen, alginate-gelatin, alginate-ceramic, alginate-bioglass, alginate-biosilica, alginate-bone morphogenetic protein-2, peptides have been evaluated. Increased biochemical importance of alginate composites in terms of porosity, mechanical resistance, cell adhesion, biocompatibility, cell growth, outstanding mineralization and osteogenic differentiation makes it useful for renewal of bone tissue. Inclusion of synthetic polymers in alginate usually enhances the mechanical property. Chemical and physical alginate change can be used to adjust the characteristics and features of alginate such as biodegradability, mechanical resistance, gel characteristics and cell affinity [21]. Hydrogels of (ALG/ECM) Alginate/Extracellular matrix appeared to be extremely osteoinductive and the provision of angiogenic or chondrogenic development contributed to modified bone structure [46]. Alginate was used for bone morphogenic protein (BMP-2) delivery to enhance bone growth and sequentially perform to improve scaffold vascularisation and bone regeneration [43]. Chitosan/alginate hybrid scaffolds showed enhanced mechanical resistance, structural stabilization, fresh bone development and fast vascularisation [44]. For cell encapsulation methods, alginate has been used for a lengthy time to encapsulate cells and regulate matrix stiffness to cell responses for bone repair [47]. Chitosan-alginate and chitosan-alginate with fucoidan using the freeze-drying technique are described as a replacement for bone graft. Arginine-glycin-aspartic acid(RGD)-alginate microspheres with osteogenic and endothelial tissues is a successful fresh injectable

5.1.2. Chitosan nanocomposite Chitosan is an abundant polysaccharide that is found in the exoskeletons of crustaceans, mullusks, cuticles of insects and cell walls of fungi (Fig. 2) [51,52]. Chitosan was found by Rouget in 1859 [52]. The molecular weight ranges from 50 to 1000 KDa [53]. Chitosan is usually insoluble in aqueous solutions and concentrated solutions but when

Table 2 Significance of alginate biomaterial. Alginate biomaterials Alginate/Chitosan Alginate/HA Alginate/Calcium phosphate Methacrylated alginate/Collagen Alginate/nano bioactive glass Alginate/octacalcium Phosphate

Fabrication method & Significance mechanical resistence, structural stabilization • Increased separation. • Phase adhesion, enhanced mechanical property • Cell better mechanical property • Osteodifferentiation, differentiation, osteoblast spreading and proliferation • Osteogenic mineralization and protein adsorption • Improved • Osteoblast cell proliferation

5

Ref.No [44] [48] [49] [21] [21] [21]

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for its orthopedic applications [57]. Chitosan hydrogels are prepared by succinic, glutaric and adipic acids using non-toxic cross-linking agents such as dicarboxylic and tricarboxylic acids that furnishes biocompatibility. The lesser the usage of cross-linking agents, the higher will be the absorption capacity and swelling that makes chitosan an excellent material for biomedical applications [52]. The hydrogel is connected by covalent and noncovalent bond forming a 3D network. The optimal pore size of scaffolds for bone tissue engineering range from 100 to 200 μm [54]. The degree of cross-linking affects its pore size, the percentage of swelling and mechanical strength [52]. Chitosan can be engineered to form a porous scaffold that proliferates osteoblast and mesenchymal cells, inducing mineralization and neovascularisation [57]. The water absorption capacity of chitosan promotes the transport of nutrients and absorption of fluid from the body. Since chitosan is generally stiff and brittle, the usage of cross-linking agents makes it more resistant and elastic. It has a maximum osteoconductive property and minimum osteoinductive property. chitosan derivative such as Ncarboxyl butyl-chitosan, imidazole-chitosan, and 6-oxylchitin also possess good osteoconductivity. In the field of bone tissue engineering, chitosan is modified by quaternization, carboxylation, hydroxylation, phosphorylation, copolymerization, and sulfonation. This modified chitosan has a superior property for bone regeneration [57]. In Bone tissue engineering, chitosan promotes growth and mineral-rich matrix deposition by osteoblasts. In surgical use, chitosan is used as an adjuvant with bone cement for the ease of its injection. By promoting osteogenic cell attachment it helps in bone formation. Because of its similarity with various glycosaminoglycans (GAGs), it can act as a scaffolding material in articular cartilage engineering. Alginate-based chitosan (CS) is used as a loadbearing scaffold for the regeneration of cartilage due to its increased tensile strength. Since CS has a macroporous structure and a predictable degradation rate it would back up osteogenic cells in spinal fusion for spine tissue engineering [58]. Nano TiO2 doped chitosan scaffold by freeze drying method exhibits good biocompatibility, high porosity, minimum density with excellent mechanical property. These properties lead to bone cell attachment, proliferation and mineralization [56]. Healing of wounds is rapid since CS enhance the characteristics of inflammatory cells [51]. Incorporation of chitosan and its derivatives in scaffolds promotes bone and cartilage regeneration [59]. Chitosan is an excellent matrix for nonviral gene therapy since it can complex DNA and also bioabsorbable [58]. Bhowmick et al., developed a chitosan/ Organically modified montmorillonite/hydroxyapatite/Zirconia (CTS/ OMMT/HAP/ZrO2) nanocomposite. Zirconia nanoparticle improves the mechanical property and osteoblastic cell proliferation. Usage of 5% OMMT, 5 wt% HAP-ZrO2 nanocomposite in 90 wt% CTS resulted in strong antibacterial activity, high tensile property, swelling and erythrocyte compatibility [60]. Balagangadharan et al. synthesized a Chitosan/nanohydroxyapatite/nano zirconia scaffold with a bioactive molecule MicroRNA i.e) miR-590–5p. This scaffold improves osteoblast differentiation and enhances the osteoconductive property [61]. When nano ZrO2 is incorporated in a chitin-chitosan scaffold, it promotes osteogenesis, exhibits good swelling property and the degradation rate is controlled. Cubic Zirconia films in nanostructures enhance the adhesion and formation of osteoblast cells [62]. Thus it would be an appropriate material for the use in bone tissue engineering. To summarize, the highlights of chitosan biomaterial is tabulated in Table 3.

Fig. 2. Chemical structure of chitosan.

stirred it is completely soluble in aqueous solutions like acetic acid, formic acid, nitric acid, hydrochloric acid, phosphoric acid etc., [54,55]. Chitosan is obtained via partial or complete deacetylation of chitin. so, chitosan is basically a deacetylated chitin. Chitosan scaffold possesses cationic nature and so negative molecules like proteoglycans can be easily interchanged [55,56].It is a copolymer of 2-amino-2deoxy-β-D-glucopyranose(glucosamine) and 2-acetamide-2-deoxy-β-Dglucopyranose(N-acetylglucosamine) [10,52,55]. It can be modified on amino and hydroxyl groups providing chemical versatility, increase in solubility and new functional property. This modification is easy when compared to chitin since the amino group is present at the C-2 position of the monomer ring [51,52]. Chitosan is semi-crystalline in nature that favours strong intra and intermolecular hydrogen bonding [53]. This degree of crystallinity has an impact on the degree of deacetylation (DD) which determines the percentage of glucosamine units in the chain [52,53]. This DD converts chitin into chitosan by converting acetyl groups into primary amino groups. Commercially available chitosan has a DD between 60 and 90%. The DD is indirectly proportional to the rate of degradation. When the DD is low, between 65 and 82%, faster is the degradation. When the DD is high, between 84 and 90%, slower is the degradation [54]. When the molecular weight is high, the viscosity will also be high that creates resistance in its flow and therefore promoting interaction in tissues. Greater the molecular weight, lesser is the swelling and degradation process [54]. When the pH is less than 6, the free amino group gets protonated and becomes soluble in dilute acids. This protonation creates electrostatic repulsion and promotes swelling of the polymer. When the pH is above 6.5, free amino group deprotonate and is insoluble [52–54]. Chitosan is bioactive, biodegradable, antibacterial, biocompatible, non-antigenic and hydrophilic [10,55]. Different properties of chitosan such as viscosity, solubility and biological activity are highly influenced in the presence of viruses, metal ions and other impurities. It lacks in its weak anti-microbial property and mechanical strength which could be overcome with chemical modification. Chitosan on depolymerization gives oligosaccharides with high anti-microbial properties [57]. This property is also possessed when the amino group is in the cationic form [52]. Addition of antibacterial metal ions such as nanophase copper, zinc, and silver also improves the antibacterial property [57]. As per the acid-base character, both chitosan and its precursor chitin is highly basic [52]. Since chitosan is biodegradable, it degrades as the new tissues form without toxic particles and inflammatory reactions [10]. Chitosan can be processed in many forms such as beads, fibers, films, gels, sponges, microparticles, nanoparticles, nanofibers, scaffolds

Table 3 Significance of chitosan biomaterial. Chitosan biomaterials

Significance

Ref. No

Nano TiO2/Chitosan CS/OMMT/HAP/ZrO2 CS/nHA/nZrO2

Bone cell attachment, proliferation and mineralization Strong antibacterial activity, erythrocyte compatibility, high tensile strength Osteoblast differentiation, enhanced osteoconductive property.

[56] [60] [61]

6

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Fig. 3. Chemical structure of Collagen.

cell proliferation. Collagen membranes are used in guided bone generation due to its excellent biocompatibility and cell affinity. It limits itself to the transmission of disease from animal to human, poor mechanical strength and unmatching degradation rate with the regeneration of tissue. Collagen composites have suitable properties like bioactivity, osteoconductivity and biocompatibility in bone regeneration [63]. Collagen creates a suitable environment for bone formation by mimicking bone forming components. Collagen scaffolds also have a weak mechanical property which could be overcome by crosslinking or even combining with calcium phosphates, silica, Bioactive glass, etc., [63,69,70]. But this process decreases the biocompatibility [63]. Collagen microparticles in scaffolds enhance the growth of osteoblasts. Collagen can be obtained in the form of collagen fibrils which are insoluble and collagen molecules which are soluble. The extraction and purification of collagen are usually done by acid treatment, alkali treatment, precipitation and centrifugation. Collagen's cytotoxicity can be avoided by the purification process. After implantation Collagen scaffold immediately swells since it is hydrophilic in nature. So in order to modify its physicochemical properties, collagen is treated with other polymers or ceramics. Synthetic collagen is synthesized to mimic natural collagen in ECM in order to overcome its limitations like the risk of infection, inadequate bioactivity, inflammatory response etc., [63]. In most tissues, collagen forms a structural network due to the high degree of polymorphism which results in the formation of variable structures. An important characteristic of collagen is its structural integrity, which holds as a template for calcium phosphate and calcium carbonate deposition in bone, making it a very efficient material for bone tissue engineering [69]. It possesses low immunogenicity, low antigenicity and is hemostatic [66,71]. Collagen membrane has potential adherence towards cells and can activate the DNA synthesis of fibroblast cells [71]. They also have the capacity to construct a direct bond to host bone and furnish bone regeneration with calcium [67]. Composite of Collagen/ alginate refine the gene expression in osteocalcin and cell proliferation in vitro. The hydrogel of Collagen/agarose promotes mesenchymal stem cell osteogenic differentiation [72]. Photopolymerised chitosan with collagen gives rise to repair in a bone. Methacrylated glycol chitosan with collagen improves the differentiation and proliferation of bone marrow stromal cells [73]. To summarize, the highlights of collagen biomaterial is tabulated in Table 4.

5.1.3. Collagen nanocomposite Collagen is a natural biopolymer and a plentiful protein that makes up one-third of the entire body's protein (Fig. 3) [63]. Collagen is a natural polymer found in bovine, rat tail, rabbit bone or porcine [64–66]. These are found in the extracellular matrix and majorly found in tendon, skin, ligaments and bone [28,66]. Collagen is the principal element of the periosteum's fibrous layer and therefore Collagen membranes can assist and improve human periosteal cell proliferation. It plays a key role in cell adhesion, migration, proliferation and differentiation [67]. There are 28 types of collagen in vertebrates [63,68]. Among them type I collagen is the most prevailing molecule and found in bone, type II and III collagen is found in cartilage [63,65]. Collagen is highly hydrophilic and possesses primary structure, secondary structure, tertiary structure and quaternary structure. The primary structure is a repetitive tripeptide sequence of amino acids (Gly-a-b)n where a is often proline that contributes 20% and b is Hydroxyproline that contributes 50% to the entire amino acid. Secondary structures are αchains that are formed because of the repeating units of tripeptides. In this structure, collagen molecules crosslinks covalently within themselves or between the other molecules in the ECM. The tertiary structure is a triple helix, where a and b (frequently proline and hydroxyproline) occupy the outer portions of the helix and glycine occupies the central axis. The quaternary structure is collagen fibrils where molecules are self-assembled in a supramolecular form. Collagen molecules are crosslinked to preserve the quaternary structure. Collagen can successfully be transformed into various forms such as blends, gels, films, fibers, powder, particles, solution, membranes, sponges, and composites [63]. Collagen hydrogels have good swelling, gelling ability and excellent susceptibility for enzymatic dehydration that makes it suitable for bone tissue regeneration [63]. In bone tissue engineering, collagen is a widely used scaffold because of its better biocompatibility and biodegradability [68]. Collagen scaffolds enhance cell migration and tissue regeneration. Collagen scaffolds need to be crosslinked to fulfill certain functions for tissue regeneration. The process of crosslinking can be done by physical treatments or by using chemical agents. Dehydrothermal treatment, ultraviolet irradiation, microwave irradiation, gamma irradiation are some of the physical treatments. Glutaraldehyde, carbodiimides are frequently used chemical agents [63]. Collagen and nano bioactive glass composite incorporated with Phosphatidylserine helps in tissue renovations and gets attached to calcium ions because of its high affinity [64]. Collagen with bioactive glass exhibits osteogenesis, angiogenesis and is therefore potential for wound healing. Bioactive glass coated Collagen disks exhibit high porosity after implantation [69]. Collagen with microparticles of hydroxyapatite (HA) stimulates angiogenesis and osteogenesis. When this same scaffold is done by the freeze-drying method, It improves bioactivity and mineralization. Composite of collagen with glycosaminoglycan (GAG) and bioactive glass microparticles with cobalt facilitates osteoblast proliferation, angiogenesis and vascularisation [64]. In simulated body fluid, bioactive glass with collagen scaffold exhibits improved mineralization [66]. Collagen with nanoparticles of hydroxyapatite synthesized by suspension method promotes increased resorbability and mechanical property [70]. Hydroxyapatite in collagen increases the biopolymer's surface area and therefore directing cell adhesion [68]. Collagen in chitosan molecule results in a stiff matrix with enhanced

5.1.4. Fibrin nanocomposite Fibrin is a natural scaffold due to its excellent biocompatibility and biodegradability [74]. It is a naturally occurring polymer created by fibrinogen enzyme polymerisation. Fibrin is acquired autologously or commercially. Fibrin has considerable benefits over other biomaterials as an optimal candidate for TE applications [75]. Fibrin is a critical haemostasis blood element that consists of thrombin, as well as a calcium-contributing fibrinogen activity [76]. The function of Fibrin is directed through an alternation of precursor's concentration such as fibrinogen and thrombin, by manipulating the polymerisation factors such as pH, ion intensity, which is a significant characteristic for the layout of the scaffolds [75]. The composite scaffolds based on fibrin outlined in research are non-toxic, biodegradable, and promote both in vitro and in vivo growth and maturation of cells [77]. Fibrin can also be used as an injectable scaffold. Fibrin may be used 7

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Table 4 Significance of collagen biomaterial. Collagen Biomaterial

Fabrication & Significance susceptibility, swelling and gelling ability. • Excellent renovation, calcium ions attachment • Tissue drying method. • Freeze osteogenesis • Angiogenesis, method. • Suspension resorbability, mechanical property • Increased matrix, enhanced cell proliferation • Stiff proliferation, gene expression in osteocalcin • Cell differentiation • Osteogenic • Osteoblast proliferation, angiogenesis, vascularisation

Collagen hydrogel Collagen/nano bioactive glass/Phosphatidylserine Collagen/micro hydroxyapatite Collagen/nano hydroxyapatite Collagen/chitosan Collagen/alginate Collagen/agarose Collagen-glycosaminoglycan/BAG-colbalt

Significance

Ref. No

Fibrin coated bioactive materials Fibrin/PLLA Fibrin/β-TCP Heterologous fibrin Homologus fibrin

Improves the function of cell

[78]

Fast growth of tissue Regenerated cranial bone in dogs Cures bone Accelerated tissue cells, fast reformation of bone

[79] [80] [78] [78]

[63] [64] [64] [70] [63] [72] [72] [64]

powerful adhesive characteristics on biological surfaces, it is often used to fill bone with coagulation or to create fresh bone cells for subcritical abnormalities. The poly (lactic acid) (PLLA) based scaffold under fibrin coatings improved the adhesive characteristics of the scaffolds thus encouraging rapid growth of the tissue. Fibrin-based hydrogel scaffolds were commonly used for cartilage and bone tissue engineering purposes [79]. Fibrin can be made from autologous plasma and is accessible as a glue. For the fibrin glue implant, greater osseointegration was observed without any graft material. The findings of this research show that platelet-rich fibrin glue can be an appropriate scaffold for improving implant healing and bone inclusion [80]. Autologous bone pieces packed into fibrin glue and blended in with β-tricalcium phosphate (βTCP), effectively regenerated cranial bone in dogs [80]. Fibrin is used as a biological scaffold for stem cells to regenerate bone alone or in conjunction with other materials [80]. The fibrin glue combined with autologous bone in rabbit calvarial failures also showed comparable outcome by Lappalainen et al.,. The prospective function of fibrin in restricting the vessel's entry into the grafted bone and preventing the development of the natural fibrin has described the adverse impact. Bosch et al., say while heterologous fibrin impairment was observed in the bone cures, homologous fibrin accelerated the growth of capillary vessels and connective tissue cells because of the local immune response, resulting in the rapid re-formation of the bone. Adding osteogenic cells to a fibrin matrix encourages bone cure. Fibrin is one of the most successful bone tissue engineering biopolymers. In fact, fibrin is an appealing biomaterial for bone tissue engineering by the mixture of outstanding biocompatibility, biodegradability, inherent bioactivity and many other distinctive features [78]. In summary, the highlights of fibrin biomaterial is tabulated in Table 5.

Table 5 Significance of fibrin biomaterial. Fibrin biomaterials

Ref.No

as a structural scaffold to develop bone, cartilage, liver and tissue cells, in association with the suitable cell source. Some literature surveys indicate that fibrin has an important function to play in the development of the connective and skeletal tissues [76]. Fibrin has various cell and other protein interaction sites. Changes in polymerisation parameters also affect biochemical indications in fibrins, such as extracellular matrix (ECM) ligand's concentration, and growth factors. These can influence the characteristics of cell development, proliferation, differentiation and growth factors expression. Physical influences such as matrix stiffness can also affect cell behaviour. Fibrin is therefore permitted to behave as a bioactive matrix, which is appropriate for cell functionality, supply and assistance [75]. Fibrin is a potential material for use in the manufacture of bone regeneration. Fibrin is a natural scaffold which supports wound healing through angiogenesis and the promotion of cell connection and growth and thus can provide an enhanced bone regeneration atmosphere [77]. Cell-encapsulating fibrin crystals ~3 mm in diameter were produced by Perka et al.,. The building was implanted into rabbit ulna abnormalities. In cell encapsulation, fibrin bead communities assessment disclosed higher bone cure after 28 days. Nair et al., used silica-coated HA cylinders and fibrin-coated bioactive materials for 28 days. Cell viability analysis, morphology, cell cycle analysis have demonstrated that fibrin significantly improve the function of cells [78]. Since fibrin has

5.1.5. Gelatin nanocomposite Gelatin is a natural biopolymer and a water-soluble protein derived from insoluble animal collagen of bones, tendons, skins by acidic or alkaline hydrolytic process (Fig. 4) [66,81–83]. Gelatin can be classified

Fig. 4. Chemical structure of gelatin. 8

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conjunction with hydrochloride tetracycline. This polymer covered scaffolds had enhanced mechanical characteristics and regulated discharge of drugs and were a multi-functioning scaffold for the production of bone tissues [66]. In medical applications, in particular, tissue engineering, the crosslinking of the gelatin strands is essential for enhancing thermal and mechanical strength under physiological circumstances. Physical or chemical procedures can be used to crosslink gelatine hydrogels [82]. A variety of crosslinkers, including formaldehyde, glutaraldehyde, polyepoxide, tannic acid, dimethylsuberimidate and acyl azide were used to interlink gelatin to extend its absorption into living tissues and increase the mechanical properties of the composites. Oligomeric proanthocyanidins (OPCs) are insignificantly less cytotoxic crosslinkers that are available in numerous organic products, vegetables, nuts, seeds, and plant barks. Genipin interconnected gelatin with tricalcium phosphate ceramic particles can be used as a filling bone deficiency scaffold. Gelatin with tricalcium phosphate using OPC as cross-linking agents is used for bone replacement. Tricalcium phosphate-gelatin can be used to create an osteoconductive biocompatible scaffold [84]. The thermally induced phase separation technology in nanofibrous gelatin-apatite composite was used to imitate both the physical and the chemical structures of natural bone ECM. The scaffolds demonstrated outstanding biocompatibility and mechanical strength, and osteogenic differentiation was improved by the inclusion of apatite. When tricalcium phosphate was incorporated into the gelatin nanofibres, increased cell attachment, development, the activism of alkaline phosphatase and osteogenic gene expression in mouse bone marrow mesenchymal stem cells were triggered. The nanofibrous gelatine-tricalcium phosphate composite encourages osteogenesis of bone marrow stem cells [85]. The gelatin methacrylamide hydrogel scaffold plays a significant role in bone tissue engineering because of its increasing cell attachment, proliferation and osteogenic differentiation of adipose-derived stem cells in the rat. This makes it a multifunctional scaffold in the field of bone tissue engineering [86]. Gelatin as a pure polymer, 3D scaffold, nanofibrous scaffold is mostly used in large bone defects [82]. Gelatin is a potential material as a scaffold in tissue engineering since it can blend well with both natural and synthetic polymer promoting high biomechanical and bio-affinity to the scaffold [81]. To summarize, the highlights of the gelatine biomaterial is tabulated in Table 6.

into two types: Gelatin type A and Gelatin type B. Gelatin type A is produced by an acid hydrolytic process of pork skin with HCl and H2SO4 or with bovine Collagen. The isoelectric point of Gelatin type A is 8–9. Gelatin B are produced by Alkaline hydrolytic process of animal skin or porcine collagen. The isoelectric point of Gelatin type B is 4–5. Gelatin is basically a partially denatured derivative of collagen. Gelatin is tasteless, odourless and faint yellow in colour. It consists of 19 amino acids with molecular weight 15,000 to 400,000 Da. There are 330 glycines, 132 prolines, 112 alanines and 93 hydroxyprolines for every 1000 residues. The triple helix structure of gelatin is due to the repeating sequence of (Glycine-Y-Proline)n where Y is usually lysine, arginine, methionine and valine [66,81–84]. Gelatin is amphoteric in nature since its functional groups are present in both acid and alkaline medium. It exhibits good biocompatibility and biodegradability, low antigenicity and non-immunogenicity [83–85]. They are low in cost and the functional groups can be easily modified [81,83]. The incorporation of biphasic calcium phosphate in PVA(poly vinyl alcohol)-Gelatin nanofiber membrane synthesized by electrospinning increases the tensile strength [83]. The inclusion of poly (lactic-coglycolic acid) (PLGA) in gelatin-nano Hydroxyapatite increased the cell adhesion, migration, differentiation and osteogenic differentiation [66]. Gelatin-PCL(polycaprolactone) nanofibers enhance cell adhesion and proliferation and an efficient scaffold in bone marrow stromal cell culture [83,85]. PLLA(polylactic acid) in gelatin-nano Hydroxyapatite regenerated bone in rabbit for 4 weeks and enhances the mechanical property [66]. PLLA-gelatin scaffold supports cell adhesion and growth [85]. In bone tissue engineering, PCL-gelatin scaffold promotes proliferation in human adipose-derived stem cells [81]. Graphene nanoflakes in gelatin- Hydroxyapatite promote differentiation in mesenchymal stem cells [66]. Gelatin-HA microparticle of size 5–10 μm regenerated bone in rat calvaria model. As suitable constructs for use in bone tissue engineering, gelatin composites with HA, tricalcium phosphate, biphasic calcium phosphate and octacalcium phosphate were suggested. In this context, gelatin scaffolds in the rabbit ulnar critical size model, x-ray irradiated designs, rat distal femoral condyle defect model and rat tibial bone defect model have been lately assessed [82]. In the lack of chemical induction, Hydroxyapatite-chitosan-gelatin composite membrane increased the formation of extra-cellular matrix enzymes and osteogenic differentiation of human mesenchymal stem cells (MSCs). A porous nano β-Tricalcium phosphate-gelatin porous matrix scaffold offered a platform for transferring nutrients and removing waste leading in excellent cell bonding and infiltration. A biomimetic composite gelatin/β-TCP, composite fibers enhanced proliferation and osteogenic differentiation of mesenchymal stem cells in rats. Yazdimamaghani et al., produced a fresh structure of the gelatinbioactive glass-silver nanoparticle. Human mesenchymal stem cells viability and antibacterial activity against gram-negative Escherichia coli and gram-positive Staphylococcus aureus were evaluated, suggesting the usage of gelatin-bioactive glass-nanosilver structure as antibacterial scaffolds. Scaffolds from 45S5 Bioglass have been coated with gelatin in

5.2. Synthetic polymeric nanocomposite 5.2.1. Polycaprolactone nanocomposite Polycaprolactone (PCL) is a synthetic polymer which is semi-crystalline in nature. It is biocompatible and has a low degradation rate which is suitable for the application of bone tissue engineering. Some alternations in PCL can enhance the osteoconductive and osteoinductive property [87]. Byun et al., developed porous PCL beads with a porosity range of 53–600 μm or predominantly 425–500 μm by

Table 6 Significance of gelatin biomaterial. Gelatin biomaterial Gelatin/PVA PLGA/gelatin/nano HAP Gelatin/PCL nanofiber PLLA/gelatin/nano HAP Gelatin/PCL Gelatin/HA HAP/chitosan/gelatin Gelatin/nano β-TCP Gelatin/BAG/nano silver Genipin-gelatin/TCP Gelatin/TCP/OPC

Fabrication & Significance

Ref. No

• Electrospinning. tensile strength. • Increased adhesion, migration, differentiation and osteogenic differentiation • Cell adhesion and proliferation • Cell mechanical property. • Enhanced in human adipose stem cells • Proliferation bone in rat calvaria model • Regenerates of ECM, osteogenic differentiation • Formation nutrients, removes waste, cell bonding and infiltration • Transfers viability, antibacterial activity • Cell bone deficiency • Filling • Osteoconductive, biocompatible 9

[83] [66] [83,85] [66] [81] [82] [66] [66] [66] [84] [84]

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Table 7 Significance of PCL biomaterial. PCL biomaterial

Fabrication method

Significance

Ref. No

PCL beads PCL/nHA PCL/Al2O3 PCL beads-on-string membrane PCL/gelatin/chitosan/3% β-TCP PCL/MNP PCL/10% wt.NKB Nanofibrous PCL mat PCL/Collagen nanofiber in sodium alginate

Precipitation technique Solvent casting Solvent casting Electrospinning Electrospinning Salt-leaching RP technology Electrospinning Freeze drying

Bone formation in bone marrow cavity Good in vivo and in vitro compatibility Promotes osteogenesis Promotes osteoblast cell adhesion, differentiation and proliferation in bone Supports cell adherence in scaffold for bone renovation Excellent tissue compatibility, cell adhesion, mineralization. Osteoconductive behaviour, formation of osseous tissue. Growth rate, proliferation increases on PCL. Supports cell adhesion, proliferation and morphogenesis.

[88] [89] [89] [90] [91] [92] [93] [95] [97]

precipitation technique and used it in preliminary animal for filling bones. This porosity characteristic induces the bone formation towards the bone marrow cavity, suggesting that PCL bead with elevated porosity is a prospective polymer in regenerating bone [88]. Chern et al., synthesized porous PCL/nHA, PCL/nAl2O3, PCL/mHA, scaffold by solvent casting method and studied incorporating it in rat's femur. This study reveals PCL/nHA has good in vivo and in vitro biocompatibility whereas PCL/nHA and PCL/Al2O3 is a promising candidate in osteogenesis making it applicable for bone regeneration [89]. Santillán et al., fabricated PCL beads-on-string membrane by electrospinning method promoting osteoblast cell adhesion, differentiation and proliferation in bone tissue engineering [90]. Ezati et al., used PCL/ gelatin/chitosan/β-TCP scaffold by electrospinning method. This scaffold showed enhanced biocompatibility and mechanical property. The scaffold was modified with various percentages of β-TCP such as PCL/ gelatin/chitosan/1% β-TCP, PCL/gelatin/chitosan/3% β-TCP, PCL/gelatin/chitosan/5% β-TCP. Among these scaffolds, PCL/gelatin/chitosan/3% β-TCP is the most potential one for bone regeneration since the cell adherence in the scaffold with 3% β-TCP is higher than 5% βTCP and even scaffold without β-TCP [91]. J.J. Kim et al., developed a PCL/MNP(Magnetic nanoparticles) scaffold by the salt-leaching method which exhibited superparamagnetic property and outstanding physicochemical, magnetic, mechanical and biological properties. The scaffold was investigated in rats for studying tissue compatibility and bone cell responses also. It supports the formation of apatite, cell adhesion, mineralization, hydrophilicity, swelling and excellent tissue compatibility making it suitable for bone renovation [92]. Gómez-Lizárraga et al., fabricated a 3D bioplotted porous pure PCL and composite scaffolds such as PCL/5% wt. ceramic, PCL/10% wt.ceramic, PCL/20% wt.ceramic with by RP technology. The ceramic can be HA or nukbone(NKB) whose inclusion improves cell viability and proliferation. In this study PCL/10% wt.NKB possessed excellent osteoconductive behaviour and also PCL/NKB promotes the formation of osseous tissue and makes itself appropriate for the regeneration of bone tissue [93]. Mitsak et al., fabricated porous PCL scaffold with low permeability (0.688 × 10−7m4/N-s) or high permeability (3.991 × 10−7m4/N-s). This scaffold was evaluated on mice for a duration of 4–8 weeks by seeding bone morphogenic protein (BMP)-7transduced human gingival fibroblasts(HGF). The in vivo study suggests that scaffold with high permeability promotes enhanced bone growth and becomes more useful as a scaffold for bone formation when compared to less permeable scaffold [94]. Sharifi et al., synthesized a nanofibrous PCL mat by electrospinning method. It is modified with O2 Plasma which acts as a substrate and was tested with human fibroblast (HDF) and osteoblast (OST) cells at three different collecting times. The growth rate and proliferation of OSTs are higher than HDFs at a collecting time of 70 min which can be used in bone tissue engineering [95]. Shkarina et al., used PCL/SiHA(Silicate containing hydroxyapatite) scaffold in which human mesenchymal stem cells (hMSCs) were seeded. PCL microfibers were randomly oriented and well aligned. The microparticles of SiHA range from 2.23 μm −12.40 μm in size. The orientation of PCL microfiber and the

incorporation of SiHA microparticle facilitated human mesenchymal stem cell's (hMSCs) viability. The presence of hydrophilic SiHA microparticles increased cell spreading, improves the surface roughness, porosity of the scaffold and therefore mimicking the ECM of the bone [96]. G. Z. Tan and Zhou fabricated 3D PCL/Collagen nanofiber incorporated in sodium alginate hydrogel by free drying method. Human fibroblasts were seeded on the scaffold. This scaffold promoted cell adhesion, proliferation and morphogenesis making itself efficient in tissue engineering [97]. PCL can be suitable for synthesizing 3D scaffolds and is appropriate for implanting bone since it is bioresorbable [96,98,99]. Different types of cells can be attached, proliferated and differentiated by incorporating HA in PCL [96,100]. PCL scaffolds with different pore sizes has its own advantages over bone tissue engineering. PCL scaffolds of pore dimensions between 186 and 200 μm are ideal for fibroblast infiltration, while scaffolds of pore dimensions between 290 and 310 μm indicate the highest bone formation. Pore volumes around 350 and 800 μm does not influence bone growth, scaffolds with pore dimensions below 350 μm show distinct degrees of bone development [87]. To summarize, the highlights of PCL biomaterial is tabulated in Table 7.

5.2.2. Polylactic acid nanocomposite PLA is a polymer of lactic acid and a hydrophobic aliphatic polyester (Fig. 5) [15,101]. It has excellent biocompatibility and degradability and can be easily accessed into a porous membrane [101]. PLA was first discovered by Carothers in 1932 [102]. PLA/HA scaffold exhibits better biocompatibility and bioactivity. HA promotes the osteoconductivity and thus the scaffold aids in bone regeneration [101]. Huang et al., developed a 3D porous scaffold made of poly(L-lactic acid)/nano-hydroxyapatite (PLLA/nHA) with different percentages by low-temperature rapid prototyping method. This scaffold was studied with rat osteoblast cells. The result showed that scaffold with 20% of nHA possessed better cell adhesion, proliferation and was biocompatible. Thus the scaffold can be used in fixing fractures and in repairing bone [103]. Lou, Wang, and Song fabricated Poly(L-lactic acid)/β-TCP (PLLA/β-TCP) nanocomposite scaffold by phase separation method which is thermally induced. This scaffold has better biocompatibility, mechanical strength, adsorption of protein. It also enhances osteoblast differentiation and proliferation [104]. Nga, Hoai, and Viet synthesized a poly(D, L) lactic acid/HA nanorod (PDLLA/HA) scaffold by using both solvent casting and salt leaching method. The scaffold on seeding with human osteoblast cells and on increasing 30 wt% of HA possess excellent adhesion, distribution and proliferation. It also mimics the

Fig. 5. Chemical structure of polylactic acid. 10

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blend that consists of PPF and PCL with mouse MC3T3 cells and rat aortic smooth muscle cells(SMCs). This blend when cross-linked promotes cell attachment, viability, spreading, proliferation than uncrosslinked blend [112]. Lee, Wang, Dadsetan, Yaszemski, & Lu fabricated polypropylene fumarate and hydroxyapatite porous nanocomposite scaffold by solid freeform fabrication technique. This study results in good cell ingrowth and proliferation for bone tissue engineering [114]. Lee et al., synthesized a poly(propylene fumarate)/ diethyl fumarate 3D scaffold, in which BMP-2 is embedded on a poly (DL-lactic-co-glycolic acid) that is incorporated in the 3D scaffold. This scaffold allowed cell differentiation and bone formation [115]. Dadsetan et al., synthesized a PPF scaffold with various types of calcium phosphates coated like magnesium-substituted β-tricalcium phosphate (β-TCMP), carbonated hydroxyapatite (synthetic bone mineral SBM), biphasic calcium phosphate (BCP). This scaffold is studied in rat calvaria with various dosages of recombinant bone morphogenic protein-2 (rhBMP-2). These scaffolds exhibit better osteoconductivity and osteointegration and thus can be used for bone defects [116]. Díez-Pascual and Díez-Vicente fabricated a poly(propylene fumarate)/polyethylene glycol-Graphene oxide (PPF/PEG-GO) nanocomposite by sonication and thermal curling. This scaffold is not toxic to human dermal fibroblasts and possesses enhanced biocide action. The nanocomposites also produce adequate stiffness and thus a suitable material for bone tissue engineering [117]. Mishra et al., approached a poly(propylene fumarate) scaffold on which fibroblast growth factor (FGF), platelet-derived growth factor (PDGF-BB) and epidermal growth factor (EGF) was used for the proliferation of bone marrow-derived human mesenchymal stem cells (BM-hMSCs). Its differentiation was promoted by bone morphogenic protein. It was found that these growth factors induced excellent proliferation and thus used for bone defects [111]. Farshid et al., manufactured a PPF nanocomposite with nanomaterials like boron nitride nanotubes (BNNT) and boron nitride nanoplates (BNNP). This scaffold shows up an increase in Young's modulus and eventually good mechanical property. Thus the scaffold creates suitable environment for bone development [118]. Guo et al., synthesized poly(propylene fumarate-co-caprolactone) (PPF-co-CL) by thermally induced phase separation. This scaffold possesses excellent biocompatibility with bone and hence supporting tissue engineering applications [119]. Trachtenberg et al., produced a porous PPF/HA 3D scaffold based on extrusion-based printing. HA nanoparticles which are osteoconductive in nature increases the compressive mechanical property and therefore favouring tissue engineering applications [120]. Porous Poly(propylene fumarate)/N-vinyl pyrrolidone(N-VP) incorporated with β-TCP increases the mechanical property. Photocrosslinked PPF is not toxic to bone tissue cells. β-TCP or HA in PPF/ PPF- diacrylate (DA) enhances cell interaction. PPF/β-TCP composite in which rat marrow stromal cells embedded exhibits cell attachment and proliferation. Nano-HA incorporated in PPF/N-VP was studied using rat tibia defect. This enhanced osteoconductivity and helped in bone formation [113]. Thus poly(propylene fumarate) acts as bioartificial bone grafts in bone tissue engineering. To summarize, the highlights of PPF is tabulated in Table 9.

extracellular matrix of bone therefore poly (D,L-lactic acid) (PDLLA)/ 30 wt% of HA acts as a suitable candidate in bone tissue regeneration [105]. Guduric et al., fabricated a porous polylactic acid scaffold by 3D printing. This scaffold was produced both in 2D and 3D by the layer-bylayer assembly on which human bone marrow cells are seeded. In 2D, cell viability and proliferation was high. In 3D, osteoblastic differentiation and cell colonization were enhanced that makes the scaffold potential for bone tissue regeneration [106]. Xu et al., synthesized polylactic acid/chitosan (PLA/CS) nanofiber scaffold by electrospinning and phase separation technique. chitosan exist with the island-like topography and MC3T3-E1 cells are cultured over this scaffold. CS accelerates the mineralization of Hydroxyapatite, facilitates the cell spreading, cell adhesion and cell proliferation. Owing to these properties, the scaffold enhances its capacity in the formation of bone [107]. Zhang et al., developed a polylactic acid/hydroxyapatite (PLA/HA) scaffold by 3D printing technology with in vivo bioreactor. The scaffold was cultured with bone marrow stromal cells (BMSCs), incorporated with a vascular bundle and surrounded by periosteum capsule. It shows better osteogenic ability, osteoinductive activity, and creates an environment for bone development [101]. Heureux et al., produced a polylactic acid scaffold by fused deposition modeling technique. This scaffold is seeded with human bone marrow stromal cells (HBMSCs). The scaffold is biocompatible, does not show any cytotoxic effect to HBMSCs and allows colonization of bone cells [15]. Gregor et al., fabricated a PLA scaffold by rapid prototyping technique using a 3D printer. Two types of scaffold were prepared, one scaffold with 30% porosity, with a pore size of 0.35 mm and the other scaffold with 50% porosity, with a pore size of 0.7 mm. To these scaffolds, osteosarcoma cells were seeded. These scaffolds possessed good mechanical strength and allowed an adequate proliferation of cells [108]. Magiera et al., used PLA hybrid scaffolds like Polylactic acid/Gelatin (PLA/GEL) and the same scaffold modified with carbon nanotube(PLA + gCNT/GEL). Both of these scaffolds possess the better osteoconductive property and shows no cytotoxic effect. PLA/GEL scaffold is biocompatible and PLA + CNT/GEL scaffold is biodegradable and has enhanced mechanical property which makes it potential for tissue engineering application [109]. Farzamfar et al., used Poly(e-caprolactone)/Polylactic acid (PCL/PLA) by phase separation technique. Different percentages of tetracycline hydrochloride(TCH) were added such as PCL/PLA/3%TCH, PCL/PLA/5%TCH and PCL/PLA/10%TCH and were injected in rat femora. The MG-63 cells have high proliferation and viability with scaffold consisting of 10% TCH and thus has high capability in bone growth [110]. To summarize, the highlights of PLA biomaterial is tabulated in Table 8.

5.2.3. Poly(Propylene fumarate) nanocomposite Poly(propylene fumarate) (PPF) is a photocrosslinkable and it is an unsaturated polyester [111,112]. It is a linear, degradable and an amorphous oligomer [112,113]. The number-average molecular weight (Mn) of PPF lie between 500 and 5000 g/mol. Sanderson in 1988 patented a bone butty that fall in with PPF [113]. Wang et al., studied a Table 8 Significance of PLA biomaterial. PLA Biomaterials

Fabrication method

Significance

Ref. No

PLLA/nHA PLLA/β-TCP PDLLA/HA PLA scaffold PLA/CS PLA/HA PLA scaffold PLA scaffold PLA/PCL/10% TCH

Rapid prototyping Phase separation Solvent casting and salt leaching 3D Printing Electrospinning and phase separation 3D Printing Fused deposition modelling Rapid prototyping method Phase separation

Better cell adhesion, proliferation, fixes fracture Better protein adsorption, biocompatibility & mechanical strength Mimics ECM & possess excellent cell distribution and proliferation Facilitates cell viability, proliferation, osteoblastic differentiation and colonization Cell spreading, adhesion and proliferation. Osteogenic ability, osteoconductive activity. Biocompatible, no cytotoxic effect Good mechanical strength and adequate cell proliferation. High capacity of bone growth, high cell viability and proliferation.

[103] [104] [105] [106] [107] [101] [15] [108] [110]

11

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Table 9 Significance of PPF biomaterial. PPF Biomaterial

Fabrication technique

Significance

Ref. No

PPF/HA nanocomposite PPF/PCL PPF/diethyl fumarate in PLGA PPF/β-TCMP/SBM/BCP PPF/PEG-GO PPF/FGF/PDGF-BB/EGF PPF/BNNT & BNNP PPF-co-CL PPF/HA

Solid freeform Stereolithography Solid free form Solid free form Sonication and thermal curling Not mentioned Not mentioned

Better cell ingrowth and proliferation Good cell attachment, viability, spreading and proliferation Cell differentiation and bone formation Better osteoconductivity and osteointegration Adequate stiffness, biocide action. Excellent cell proliferation and differentiation Good mechanical property, increase in young's modulus.

[114] [112] [115] [116] [117] [111] [118]

Thermally induced phase separation Extrusion-based printing

Excellent biocompatibility Osteoconductive, increase in compressive mechanical property

[119] [120]

presence of titanium particles increased the biocompatibility and had an impact over these scaffold's mechanical strength and over the viability of both human dental pulp stem cells (HDPSCs) and osteoblast cells. However all these scaffolds facilitated the viability and proliferation of HDPSCs and osteoblast cells of mice, therefore recommended for bone regeneration [127]. Chao, Mani, and Jaganathan fabricated polyurethane scaffolds such as PU/grapeseed oil and PU/ grapeseed oil/honey/propolis by electrospinning method. They possessed an enhanced rate of cell viability of red blood cells (RBCs) and human fibroblast cells (HDF), good blood compatibility, and also did not exhibit any toxic behaviour towards the cells. These features make it suitable for bone tissue regeneration [128]. Wang, Jeng, and Hsu used 3D printing ink for bone scaffolds and synthesized a water-based shape memory polyurethane (PU) as an important scaffold in it, which is biodegradable. The 3D printing ink also contained superparamagnetic iron oxide nanoparticles(SPIO NPs). On adding polyethylene oxide(PEO) and gelatin following scaffolds were developed: PU/PEO, PU/PEO/SPIO, PU/gelatin, PU/gelatin/SPIO. These scaffolds were seeded with human mesenchymal stem cells (hMSCs). Better proliferation was shown by PU/gelatin and PU/gelatin/SPIO. Better cell viability was exhibited by PU/gelatin. When SPIO is released from PU scaffolds, it supports the calcium and collagen secretion in bone and osteogenesis in human mesenchymal stem cells (hMSCs) [129]. HA/PU scaffolds are used as implantable scaffolds and produce a bone adhesive in bone fractures that is degradable due to its bone integrative properties. A porous hexamethylene diisocyanate(HDI)-derived polyurethane elastomers by salt leaching or phase inversion method was injected in an ovine iliac crest. This scaffold facilitates in the formation of new bone with calcium to the phosphorous ratio which helps in presenting a favourable environment for bone regeneration [121]. To summarize, the highlights of PU is tabulated in Table 10.

Fig. 6. Chemical structure of polyurethane.

5.2.4. Polyurethane nanocomposite Polyurethanes (PUs) are synthetic bone grafts which can be in the form of porous scaffolds, injectable composites, and drug delivery systems. These are mainly used in orthopaedic applications as osteoinductive scaffolds, bone void fillers and bone cement (Fig. 6) [121]. β-TCP(Tricalcium phosphate)/PU scaffold shows better osteogenic differentiation and proliferation [107]. Woźniak et al., synthesized a tissue engineering product with polyurethane (PU) scaffold. To this scaffold, human bone-derived cells (HBDCs) or human osteogenic cells were seeded and implanted in an animal body. It exhibited high mechanical strength and produced particular components of the extracellular matrix in bone. Thus it is considered as a potential material in bone tissue engineering [122]. Li et al., developed a porous polyurethane scaffold that carried vanomycin free base (V-FB). This scaffold was injected in the infected rat femoral defect. The controlled release of this antibiotic minimized the infection and thus considered as a reliable scaffold for contaminated bones [123]. Asefnejad et al., fabricated a composite scaffold polyurethane/nano-fluor-hydroxyapatite (PU/nFHA). On increasing the wt% of nano-fluor-hydroxyapatite from 0 to 20, the porosity also increased from 80 to 88% and also the compressive modulus. This excellent porosity and adequate mechanical property make this nanocomposite a predominant scaffold for bone defects [124]. Da Mota, De, and Branco fabricated four different polyurethane scaffold with calcium phosphate(CaP) as an alternate for cancellous bone grafts by gas foaming method. They are polyurethane(PU), polyurethane filled with 30% calcium phosphate(PUL 30%), polyurethane filled with 40% calcium phosphate(PUL 40%), polyurethane coated with calcium phosphate(PUC). Out of these scaffolds, PUL 40% showed high mechanical strength in both dry and wet conditions whereas PUC showed high mechanical strength only in a dry condition which is an important aspect in the growth of tissue for bone. PU scaffold with CaP exhibited high mechanical strength, high roughness and feasible release of Ca and P ions. Both PU and PUL 40% supported cell adhesion, differentiation and proliferation, thus stands as an appropriate candidate for bone tissue regeneration [125]. Reyes et al., developed a poly(3-hydroxybutyrate-g-vinyl alcohol) polyurethane scaffold or P(3HB-g-VA) with interconnected porosity by salt leaching method. It exhibits enhanced mechanical property that allows mammalian cell adhesion, cell growth, vascularisation, proliferation and diffusion of nutrients [126]. Aguilar-Perez et al., synthesized polyurethane (PU) with various percentage of titanium particles by solvent casting method. These three slightly differed scaffolds such as PU/1% Ti, PU/3% Ti, PU/5% Ti were seeded with human dental pulp stem cells (HDPSCs) and osteoblast cells of mice. The

5.2.5. Polyvinyl alcohol nanocomposite Polyvinyl alcohol (PVA) is a linear synthetic polymer and is creamy, tasteless, odourless and semicrystalline in nature [130,131]. Its molecular weight ranges from 20,000 to 40,000 g/mol [130]. Due to its unstable nature, PVA is not synthesized by polymerising vinyl alcohol. It is commercially synthesized by hydrolysing vinyl acetate in presence of a base and therefore ester groups are replaced by hydroxyl groups [130,132]. It can be either fully hydrolysed or partially hydrolysed [133]. Partially hydrolysed PVA has higher aqueous solubility, high flexibility and adhesion on hydrophobic surfaces. It's melting point is 180–190 °C. Fully hydrolysed PVA has low aqueous solubility, high tensile strength and adhesion to hydrophilic surfaces. It's melting point is 230 °C. The Boiling Point of PVA is 228 °C. PVA is soluble in H2O, insoluble in organic solvents, esters, ketones, aliphatic and aromatic hydrocarbons [130,133]. PVA is biodegradable in human tissues and fluids, biocompatible, hydrophilic, non-toxic, possess good mechanical properties, flexible and relatively low cost [133–136]. PVA is available in the form of beads, films, scaffolds, gels, meshes, mats, composites etc., 12

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Table 10 Significance of PU biomaterial. PU biomaterial

Fabrication method

Significance

Ref. No

PU scaffold PU/V-FB PU/nFHA PU/40% Cap P(3HB-g-VA) PU scaffold PU/Ti particles PU/grapeseed oil PU/grapeseed oil/honey/propolis Pu/gelatin, Pu/Gelatin/SPIO

Salt particulate leaching – phase separation One-step bulk polymerisation Salt leaching Solvent casting Elctrospinning Electrospinning Freeze drying

High mechanical strength Minimized infection Excellent porosity, good mechanical property Cell adhesion, differentiation and proliferation Diffusion of proteins, cell growth, vascularisation Increased biocompatility Good blood compatibility, enhanced cell viability, no toxic behaviour Good blood compatibility, enhanced cell viability, no toxic behaviour Better cell viability and proliferation

[122] [123] [124] [125] [126] [127] [128] [128] [129]

properties such as friction, boundary lubrication, porosity, and osteointegration [141]. PVA properties can be better when combined with other natural and synthetic material. PVA-alginate is used in craniofacial tissue regeneration as a substitute for autologous tissues. Its thermal stability and mechanical property did not decay over time which means it is suitable for tissue engineering. Epichlorohydrin crosslinked PVA-chitosan promotes chondrocyte cell growth and formation of neotissue in cartilage tissue regeneration. Graphene oxide used PVA-chitosan composite increases the mechanical strength and proliferates osteoblastic cells for bone tissue regeneration [182]. PVA-fibrin composites promotes cell adhesion and cell growth and thus acts as biosynthetic cartilage scaffold for tissue engineering. PVA-PLGA is a scaffold in tissue regeneration that enhances chondrocyte cell adhesion and proliferation [142]. Stipniece, Narkevica et al., used a coating material hydroxyapatite/poly(vinyl alcohol) nanocomposite over a titania ceramic. This scaffold enhances the mechanical property and in vitro bioactivity [143]. Since PVA is stable in vivo, it possesses suitable physical and chemical properties, it could be a thriving material for future tissue replacement [131]. To summarize, the highlights of PVA is tabulated in Table 11.

PVA hydrogel is a substitute for synthetic articular cartilage to relieve pain and to correct joint deformity due to its high water content [133]. It has similar water content as natural cartilage and does not create inflammation in cartilage but has low bioactivity and protein adsorption capacity. Hydroxyapatite(HAP) coated PVA hydrogel enhances the protein absorption and creates strong adhesion to bone tissues. PVA hydrogel/Hydroxyapatite promotes osteoconductivity, bioactivity and drug incorporation opportunity. Multilayer HAP/PVA hydrogel enhances mechanical and bioactive properties and possesses a porous structure [137]. PVA provides a microenvironment for cartilage and low coefficient of friction for articular joint lubrication [138]. In the case of bone tissue engineering, its semi permeability facilitates the transport of oxygen and nutrients for the purpose of cell survival [134]. PVA scaffolds degrade well due to its porous nature [136]. The 3-D porous microstructure mimics the native ECM [139]. Though PVA has high mechanical properties, it is not strong enough for its suitability in BTE [140]. PVA possess better swelling and antibacterial property compared to parent compound when crosslinked with glutaraldehyde and chitosan. PVA possess better chemical stability when crosslinked with maleic acid. More than 95% of the swelling is possessed when it is crosslinked with xanthan [133]. Being sensitive towards moisture, it is highly undesirable for biomedical application [135]. PVA acts as a promising material for tissue-mimicking and in replacing diseased articular cartilage due to its elastic and compressive mechanical properties [131,136]. In the case of cartilage tissue engineering, the addition of nanofillers to PVA nanocomposites enhances its hydrophilicity, strength and crystallinity [140]. Its resistance to organic solvents makes it suitable for many application. HAP/PVA composites enhances the mechanical properties. Its ability to deform based on the force applied and its degradation rate makes it desirable for bone tissue engineering. It also possess ant-inflammatory and anti-bacterial properties [141]. PVA composites with starch, gelatin and polylactic acid possess enhanced biodegradability and tensile strength in biomedical application [133]. Based on its degradation rate, it can be used in various bone tissue application [134]. PVA is widely used in bone tissue engineering since it has no ill effects when implanted in the human body and can degrade in body fluid [134]. PVA sponges are used in wound healing, ophthalmic surgeries and tissue engineering. It is a promising material for vascular cell culture, vascular implanting, corneal implants, cartilage substitute and tissue mimicking. PVA sponge is utilised for tissue formation, collagen deposition, stem cell survivals and angiogenesis. Fabricated PVA sponge possess better mechanical and swelling properties than commercial PVA sponges [136]. On incorporation of poly (ethylene glycol) diacrylate (PEGDA), poly (chondroitin sulphate) (PCS) in the pores of PVA, it establishes the function of articular cartilage [139]. PVA/nHAP is a potential material for a bone scaffold. Porous electrospun PVA/ cellulose nanofibers (CNF) and PVA/nHAP is a developing candidate in hard tissue engineering [140]. Commercially available PVA sponges are CENEFOM and EYETEC that are mostly used in bone tissue engineering [136]. PVA/Cap (calcium Phosphate) hydrogel is prepared by freeze thawing process. The addition of Cap influence the composite's

6. Conclusion A study on tissue engineering significance for biomaterial based bone implantation scaffolding is carried out to explore the possible avenues of research. The study revealed the application of five natural biopolymeric nanocomposites such as alginate, chitosan, collagen, fibrin and gelatin. In addition, the investigation has been carried out for five synthetic biopolymeric nanocomposites such as PVA, PCL, PLA, PU, PPF and its usefulness in the bone renovation is also explored. The study provided an understanding of all the biopolymeric nanocomposites impacts to provide a perspective of applying biopolymeric nanocomposites in bone implantation. However, the goal of tissue engineering is to develop new functional tissues and to regenerate tissue Table 11 Significance of PVA biomaterial. PVA biomaterials HAP/PVA

PVA/Starch PVA/gelatine PVA/PLA PVA/Chitosan PA/fibrin PVA/PLGA PVA/HA

13

Fabrication method & significance

• Electrospinning. bioactivity, protein • Osteoconductivity, adsorption • Sol-gel. biodegradability, tensile strength. • Enhanced laser sintering. • Selective biodegradability, tensile strength. • Enhanced biodegradability, tensile strength. • Enhanced in mechanical strength, cell • Increase proliferation. adhesion, cell growth • Cell adhesion and proliferation • Cell mechanical property, in vitro • Enhanced bioactivity

Ref. No [137]

[133] [133] [133] [142] [142] [142] [143]

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either in vitro or in vivo to cure diseases, like tissue engineering remains a flourishing research area with potential new treatment. It offers the potential for regeneration of almost every tissue and organ in the human body. Therefore, in this study provided an insight of applying biopolymeric nanocomposites as scaffolds for bone regeneration to ensure the faster noteworthy regeneration process.

[22]

[23] [24]

Declaration of competing interest

[25]

This manuscript or a very similar manuscript has not been published, nor is under consideration by any other journal. All authors have seen and approved the final, submitted version of this manuscript. The authors declare no competing financial interest. There are no conflicts of interest to declare. All authors declare that there is no conflict of interest.

[26] [27]

[28]

Acknowledgement

[29]

The authors are grateful to the management of Auxilium College for providing necessary support to the research work.

[30] [31]

Appendix A. Supplementary data

[32]

Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jddst.2019.101452.

[33]

References

[34] [35]

[1] N. Goonoo, A. Bhaw-Luximon, G.L. Bowlin, D. Jhurry, An assessment of biopolymer and synthetic polymer-based scaffolds for bone and vascular tissue engineering, Polym. Int. 62 (2013) 523–533. [2] P. Zhao, H. Gu, H. Mi, C. Rao, J. Fu, L. sheng Turng, Fabrication of scaffolds in tissue engineering: a review, Front. Mech. Eng. 13 (2018) 107–119. [3] S. Stratton, N.B. Shelke, K. Hoshino, S. Rudraiah, S.G. Kumbar, Bioactive polymeric scaffolds for tissue engineering, Bioact. Mater 1 (2016) 93–108. [4] F.J. O'Brien, Biomaterials & scaffolds for tissue engineering, Mater. Today 14 (2011) 88–95. [5] M.A. Velasco, C.A. Narváez-Tovar, D.A. Garzón-Alvarado, Design, materials, and mechanobiology of biodegradable scaffolds for bone tissue engineering, BioMed Res. Int. (2015) 1–21. [6] B. Dhandayuthapani, Y. Yoshida, T. Maekawa, D.S. Kumar, Polymeric scaffolds in tissue engineering application: a review, Int. J. Polym. Sci. (2011) 1–19. [7] F. Khan, M. Tanaka, Designing smart biomaterials for tissue engineering, Int. J. Mol. Sci. 19 (2018) 1–14. [8] S.G. Kumbar, R. James, S.P. Nukavarapu, C.T. Laurencin, Electrospun nanofiber scaffolds: engineering soft tissues, Biomed. Mater. 3 (2008) 15. [9] G. Turnbull, J. Clarke, F. Picard, P. Riches, L. Jia, F. Han, B. Li, W. Shu, 3D bioactive composite scaffolds for bone tissue engineering, Bioact. Mater. 3 (2018) 278–314. [10] E. Bressan, V. Favero, C. Gardin, L. Ferroni, L. Iacobellis, L. Favero, V. Vindigni, M. Berengo, S. Sivolella, B. Zavan, Biopolymers for hard and soft engineered tissues: application in odontoiatric and plastic surgery field, Polymers 3 (2011) 509–526. [11] T. Gong, J. Xie, J. Liao, T. Zhang, S. Lin, Y. Lin, Nanomaterials and bone regeneration, Bone Res. 3 (2015) 123–129. [12] M. Dang, L. Saunders, X. Niu, Y. Fan, P.X. Ma, Biomimetic delivery of signals for bone tissue engineering, Bone Res. 6 (2018). [13] N. Ramesh, S.C. Moratti, G.J. Dias, Hydroxyapatite–polymer biocomposites for bone regeneration: a review of current trends, J. Biomed. Mater. Res. B Appl. Biomater. 106 (2018) 2046–2057. [14] M.M. Stevens, Biomaterials for bone tissue engineering, Biomech. Biomater. Orthop 11 (2016) 35–57 second ed.. [15] A. Grémare, V. Guduric, R. Bareille, V. Heroguez, S. Latour, N. L'heureux, J. C Fricain, S. Catros, D. Le Nihouannen, Characterization of printed PLA scaffolds for bone tissue engineering, J. Biomed. Mater. Res. A 106 (2018) 887–894. [16] K.E. Healy, R.E. Guldberg, Bone tissue engineering, J. Musculoskelet. Neuronal Interact. 7 (2007) 328. [17] B. Clarke, Normal bone anatomy and physiology, Clin. J. Am. Soc. Nephrol. 3 (2008) S131–S139. [18] A.L. Boskey, Bone composition: relationship to bone fragility and anti-osteoporotic drug effects, BoneKEy Rep. 4 (2015) 1–11. [19] K. Jahan, M. Tabrizian, Composite biopolymers for bone regeneration enhancement in bony defects, Biomater. Sci. 4 (2016) 25–39. [20] D.P. Bhattarai, L.E. Aguilar, C.H. Park, C.S. Kim, A review on properties of natural and synthetic based electrospun fibrous materials for bone tissue engineering, Membranes 8 (2018) 62. [21] J. Venkatesan, I. Bhatnagar, P. Manivasagan, K.H. Kang, S.K. Kim, Alginate

[36] [37] [38]

[39]

[40]

[41]

[42] [43]

[44] [45]

[46]

[47]

[48]

[49] [50]

[51] [52] [53]

14

composites for bone tissue engineering: a review, Int. J. Biol. Macromol. 72 (2015) 269–281. R.C. de Azevedo Gonçalves Mota, E.O. da Silva, L.R. de Menezes, Polymer nanocomposites used as scaffolds for bone tissue regeneration, Mater. Sci. Appl. 9 (2018) 679. S.C. Manolagas, A.M. Parfitt, What old means to bone, Trends Endocrinol. Metab. 21 (2010) 369–374. T. Winkler, F.A. Sass, G.N. Duda, K. Schmidt-Bleek, A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering, Bone Joint Res 7 (2018) 232–243. R. Cancedda, P. Giannoni, M. Mastrogiacomo, A tissue engineering approach to bone repair in large animal models and in clinical practice, Biomaterials 28 (2007) 4240–4250. R. Kroeze, M. Helder, L. Govaert, T. Smit, Biodegradable polymers in bone tissue engineering, Materials 2 (2009) 833–856. R.C. de Azevedo Gonçalves Mota, E.O. da Silva, F.F. de Lima, L.R. de Menezes, A.C.S. Thiele, 3D printed scaffolds as a new perspective for bone tissue regeneration: literature review, Mater. Sci. Appl. 7 (2016) 430–452. G. Brunello, S. Sivolella, R. Meneghello, L. Ferroni, C. Gardin, A. Piattelli, B. Zavan, E. Bressan, Powder-based 3D printing for bone tissue engineering, Biotechnol. Adv. 34 (2016) 740–753. F. Baino, C. Vitale-Brovarone, Three-dimensional glass-derived scaffolds for bone tissue engineering: current trends and forecasts for the future, J. Biomed. Mater. Res. A 97 (2011) 514–535. D.W. Hutmacher, Scaffolds in tissue engineering bone and cartilage, Biomater. Silver Jubil. Compend. 21 (2006) 175–189. B. Subia, J. Kundu, S.C. Kundu, Biomaterial scaffold fabrication techniques for potential tissue engineering applications, Tissue, Eng. Times 141 (2010). M. Orciani, M. Fini, R. Di Primio, M. Mattioli-Belmonte, Biofabrication and bone tissue regeneration: cell source, approaches, and challenges, Front. Bioeng. Biotechnol. 5 (2017) 1–15. X.Y. Zhang, G. Fang, J. Zhou, Additively manufactured scaffolds for bone tissue engineering and the prediction of their mechanical behavior: a review, Materials 10 (2017) 50. A.M. Smith, S. Moxon, G.A. Morris, Biopolymers as Wound Healing Materials vol. 2, Elsevier, United Kingdom, 2016, pp. 261–287. M. Mohiuddin, B. Kumar, S. Haque, Biopolymer Composites in Photovoltaics and Photodetectors, South korea, Elsevier, 2017, pp. 459–486. A. Rudin, P. Choi, The Elements of Polymer Science and Engineering, (2012). B. Imre, B. Pukánszky, Compatibilization in bio-based and biodegradable polymer blends, Eur. Polym. J. 49 (2013) 1215–1233. D. Dehnad, Z. Emam-Djomeh, H. Mirzaei, S.M. Jafari, S. Dadashi, Optimization of physical and mechanical properties for chitosan-nanocellulose biocomposites, Carbohydr. Polym. 105 (2014) 222–228. S. Pandya, S. Jani, A. Chavan, A.K. Singh, S. Bhatt, D. Patel, B. Bhatt, A. Patel, A. Girma, K. Naik, Nanocomposites and it's application-review, Int. J. Pharm. Sci. Res. 4 (2013) 19–28. P.D. Parchi, O. Vittorio, L. Andreani, N. Piolanti, G. Cirillo, F. Iemma, S. Hampel, M. Lisanti, How nanotechnology can really improve the future of orthopedic implants and scaffolds for bone and cartilage defects, J. Nanomed. Biother. Discov. 3 (2013). M. Maisani, D. Pezzoli, O. Chassande, D. Mantovani, Cellularizing hydrogel-based scaffolds to repair bone tissue: how to create a physiologically relevant, J. Tissue Eng. 8 (2017) 1–26. J. Sun, H. Tan, Alginate-based biomaterials for regenerative medicine applications, Materials 6 (2013) 1285–1309. K.S. Griffin, K.M. Davis, T.O. Mckinley, J.O. Anglen, T.G.C. Joel, D.B. Melissa, Evolution of bone grafting: bone grafts and tissue engineering strategies for vascularized bone regeneration, Clin. Rev. Bone Miner. Metabol. 13 (2015) 232–244. J. Venkatesan, R. Nithya, P.N. Sudha, S. Kim, Role of alginate in bone tissue engineering, Adv. Food Nutr. Res. 73 (2014) 45–57. D.J. Indrani, E. Budiyanto, H. Hayun, Preparation and characterization of porous hydroxyapatite and alginate composite scaffolds for bone tissue engineering, Int J Appl Biol Pharm 9 (2017) 98–102. D. Gothard, E.L. Smith, J.M. Kanczler, C.R. Black, J.A. Wells, C.A. Roberts, L.J. White, O. Qutachi, H. Peto, H. Rashidi, L. Rojo, In vivo assessment of bone regeneration in alginate/bone ECM hydrogels with incorporated skeletal stem cells and single growth factors, PLoS One 10 (2015) 1–23. C.J. Kowalczewski, J.M. Saul, Biomaterials for the delivery of growth factors and other therapeutic agents in tissue engineering approaches to bone regeneration, Front. Pharmacol. 9 (2018) 1–15. H. Lin, Y. Yeh, Porous alginate/hydroxyapatite composite scaffolds for bone tissue engineering: preparation , characterization , and in vitro studies, J. Biomed. Mater. Res. B Appl. Biomater. 71 (2004) 52–65. M. Liu, X. Zeng, C. Ma, H. Yi, Z. Ali, X. Mou, S. Li, Y. Deng, N. He, Injectable hydrogels for cartilage and bone tissue engineering, Bon res 5 (2017) 1–20. H. Luo, G. Zuo, G. Xiong, C. Li, C. Wu, Y. Wan, Porous nanoplate-like hydroxyapatite-sodium alginate nanocomposite scaffolds for potential bone tissue engineering, Mater. Technol. 32 (2017) 78–84. H. Patel, M. Bonde, G. Srinivasan, Biodegradable polymer scaffold for tissue engineering, Trends Biomater. Artif. Organs 25 (2011) 20–29. G.A.M. Ruiz, H.F.Z. Corrales, Chitosan, chitosan derivatives and their biomedical applications, Biol. Act. Appl. Mar. Polysaccharides. (2017) 87. D.W. Hutmacher, J.C.H. Goh, S.H. Teoh, An introduction to biodegradable materials for tissue engineering applications, Ann. Acad. Med. Singapore 30 (2001) 183–191.

Journal of Drug Delivery Science and Technology 55 (2020) 101452

P.N. Christy, et al.

[54] M. Rodríguez-Vázquez, B. Vega-Ruiz, R. Ramos-Zúñiga, D.A. Saldaña-Koppel, L.F. Quiñones-Olvera, Chitosan and its potential use as a scaffold for tissue engineering in regenerative medicine, BioMed Res. Int. 2015 (2015) 1–15. [55] S. Saravanan, R.S. Leena, N. Selvamurugan, Chitosan based biocomposite scaffolds for bone tissue engineering, Int. J. Biol. Macromol. 93 (2016) 1354–1365. [56] P. Kumar, Nano-TiO2 doped chitosan scaffold for the bone tissue engineering applications, Int. J. Biom. 2018 (2018). [57] R. Logithkumar, A. Keshavnarayan, S. Dhivya, A. Chawla, S. Saravanan, N. Selvamurugan, A review of chitosan and its derivatives in bone tissue engineering, Carbohydr. Polym. 151 (2016) 172–188. [58] A. Di Martino, M. Sittinger, M.V. Risbud, Chitosan: a versatile biopolymer for orthopaedic tissue-engineering, Biomaterials 26 (2005) 5983–5990. [59] Y. Qiu, Chitosan Derivatives for Tissue Engineering, Dissertation, Clemenson University, 1-226. [60] A. Bhowmick, P. Jana, N. Pramanik, T. Mitra, S.L. Banerjee, A. Gnanamani, M. Das, P.P. Kundu, Multifunctional zirconium oxide doped chitosan based hybrid nanocomposites as bone tissue engineering materials, Carbohydr. Polym. 151 (2016) 879–888. [61] K. Balagangadharan, S. Viji Chandran, B. Arumugam, S. Saravanan, G. Devanand Venkatasubbu, N. Selvamurugan, Chitosan/nano-hydroxyapatite/nano-zirconium dioxide scaffolds with miR-590-5p for bone regeneration, Int. J. Biol. Macromol. 111 (2018) 953–958. [62] S. Dhivya, J. Ajita, N. Selvamurugan, Metallic nanomaterials for bone tissue engineering, J. Biomed. Nanotechnol. 11 (2015) 1675–1700. [63] A.M. Ferreira, P. Gentile, V. Chiono, G. Ciardelli, Collagen for bone tissue regeneration, Acta Biomater. 8 (2012) 3191–3200. [64] R. Yunus Basha, S.K. Sampath, M. Doble, Design of biocomposite materials for bone tissue regeneration, Mater. Sci. Eng. 57 (2015) 452–463. [65] D.A. Wahl, J.T. Czernuszka, Collagen-hydroxyapatite composites for hard tissue repair, eCells & materials 11 (2006) 43–56. [66] S. Kuttappan, D. Mathew, M.B. Nair, Biomimetic composite scaffolds containing bioceramics and collagen/gelatin for bone tissue engineering - a mini review, Int. J. Biol. Macromol. 93 (2016) 1390–1401. [67] C. Chu, J. Deng, X. Sun, Y. Qu, Y. Man, Collagen membrane and immune response in guided bone regeneration: recent progress and perspectives, Tissue Eng. B Rev. 23 (2017) 421–435. [68] D. Zhang, X. Wu, J. Chen, K. Lin, The development of collagen based composite scaffolds for bone regeneration, Bioact. Mater. 3 (2018) 129–138. [69] B. Sarker, J. Hum, S.N. Nazhat, A.R. Boccaccini, Combining collagen and bioactive glasses for bone tissue engineering: a review, Adv. Healthc. Mater. 4 (2015) 176–194. [70] G.M. Cunniffe, G.R. Dickson, S. Partap, K.T. Stanton, F.J. O'Brien, Development and characterisation of a collagen nano-hydroxyapatite composite scaffold for bone tissue engineering, J. Mater. Sci. Mater. Med. 21 (2010) 2293–2298. [71] Z. Sheikh, J. Qureshi, A.M. Alshahrani, H. Nassar, Y. Ikeda, M. Glogauer, B. Ganss, Collagen based barrier membranes for periodontal guided bone regeneration applications, Odontology 105 (2017) 1–12. [72] C.F. Marques, G.S. Diogo, S. Pina, J.M. Oliveira, T.H. Silva, R.L. Reis, Collagenbased bioinks for hard tissue engineering applications: a comprehensive review, J. Mater. Sci. Mater. Med. 30 (2019). [73] C. Arakawa, R. Ng, S. Tan, S. Kim, B. Wu, M. Lee, Photopolymerizable chitosan–collagen hydrogels for bone tissue engineering, J. Tissue Eng. Regenerat. Med. 11 (2017) 164–174. [74] A. Khodakaram-Taft, D. Mehrabani, H. Shaterzadeh-Yazdi, An overview on autologous fibrin glue in bone tissue engineering of maxillofacial surgery, Dent. Res. J. 14 (2017) 1–79. [75] J.R. Ramalho, Heparin Functionalization of Fibrin Hydrogels for Tissue Engineering, Dissertation, Instituto Superior de Engenharia de Lisboa-Escola Superior de Tecnologia da Saúde de Lisboa, 2017. [76] Ö. Lalegül-Ülker, Ş. Şeker, A.E. Elçin, Y.M. Elçin, Encapsulation of bone marrowMSCs in PRP-derived fibrin microbeads and preliminary evaluation in a volumetric muscle loss injury rat model: modular muscle tissue engineering, Artif. Cells, Nanomed. Biotechnol. 47 (2019) 10–12. [77] T. Osathanon, M.L. Linnes, R.M. Rajachar, B.D. Ratner, M.J. Somerman, C.M. Giachelli, Microporous nanofibrous fibrin-based scaffolds for bone tissue engineering, Biomaterials 29 (2008) 4091–4099. [78] A. Noori, S.J. Ashrafi, R. Vaez-Ghaemi, A. Hatamian-Zaremi, T.J. Webster, A review of fibrin and fibrin composites for bone tissue engineering, Int. J. Nanomed. 12 (2017) 4937–4961. [79] E. Barua, A.B. Deoghare, P. Deb, S. Das Lala, Naturally derived biomaterials for development of composite bone scaffold: a review, IOP Conf. Ser. Mater. Sci. Eng. 377 (2018) 012013. [80] T.A.E. Ahmed, E.V. Dare, M. Hincke, Fibrin: a versatile scaffold for tissue engineering applications, Tissue Eng. Part B Rev. 14 (2008) 199–215. [81] M.E. Hoque, T. Nuge, T.K. Yeow, N. Nordin, R.G.S.V. Prasad, Gelatin based scaffolds for tissue engineering-a review, Polym. Res. J. 9 (2015) 1935–2530. [82] M.C. Echave, P. Sánchez, J.L. Pedraz, G. Orive, Progress of gelatin-based 3D approaches for bone regeneration, J. Drug Deliv. Sci. Technol. 42 (2017) 63–74. [83] S. Ranganathan, K. Balagangadharan, N. Selvamurugan, Chitosan and gelatinbased electrospun fibers for bone tissue engineering, Int. J. Biol. Macromol. 133 (2019) 354–364. [84] K.Y. Chen, C.H. Yao, Repair of bone defects with gelatin-based composites: a review, Biomedicine 1 (2011) 29–32. [85] A.A. Aldana, G.A. Abraham, Current advances in electrospun gelatin-based scaffolds for tissue engineering applications, Int. J. Pharm. 523 (2017) 441–453. [86] X. Fang, J. Xie, L. Zhong, J. Li, D. Rong, X. Li, J. Ouyang, Biomimetic gelatin

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102] [103]

[104] [105]

[106]

[107]

[108]

[109]

[110]

[111]

15

methacrylamide hydrogel scaffolds for bone tissue engineering, J. Mater. Chem. B. 4 (2016) 1070–1080. S.M. Mantila Roosa, J.M. Kemppainen, E.N. Moffitt, P.H. Krebsbach, S.J. Hollister, The pore size of polycaprolactone scaffolds has limited influence on bone regeneration in an in vivo model, J. Biomed. Mater. Res. A 92 (2010) 359–368. J.H. Byun, H.A.R. Lee, T.H. Kim, J.H. Lee, S.H. Oh, Effect of porous polycaprolactone beads on boneregeneration: preliminary in vitro and in vivo studies, Biomater. Res. 18 (2014) 1–8. M.J. Chern, L.Y. Yang, Y.K. Shen, J.H. Hung, 3D scaffold with PCL combined biomedical ceramic materials for bone tissue regeneration, Int. J. Precis. Eng. Manuf. 14 (2013) 2201–2207. J. Santillán, E.A. Dwomoh, Y.G. Rodríguez-Avilés, S.A. Bello, E. Nicolau, Fabrication and evaluation of polycaprolactone beads-on-string membranes for applications in bone tissue regeneration, ACS Appl. Bio Mater. 2 (2019) 1031–1040. M. Ezati, H. Safavipour, B. Houshmand, S. Faghihi, Development of a PCL/gelatin/ chitosan/β-TCP electrospun composite for guided bone regeneration, Prog. Biomater. 7 (2018) 225–237. J.J. Kim, R.K. Singh, S.J. Seo, T.H. Kim, J.H. Kim, E.J. Lee, H.W. Kim, Magnetic scaffolds of polycaprolactone with functionalized magnetite nanoparticles: physicochemical, mechanical, and biological properties effective for bone regeneration, RSC Adv. 4 (2014) 17325–17336. K.K. Gómez-Lizárraga, C. Flores-Morales, M.L. Del Prado-Audelo, M.A. ÁlvarezPérez, M.C. Piña-Barba, C. Escobedo, Polycaprolactone- and polycaprolactone/ ceramic-based 3D-bioplotted porous scaffolds for bone regeneration: a comparative study, Mater. Sci. Eng. C 79 (2017) 326–335. A.G. Mitsak, J.M. Kemppainen, M.T. Harris, S.J. Hollister, Effect of polycaprolactone scaffold permeability on bone regeneration in vivo, Tissue Eng. A 17 (2011) 1831–1839. F. Sharifi, S. Irani, M. Zandi, M. Soleimani, S.M. Atyabi, Comparative of fibroblast and osteoblast cells adhesion on surface modified nanofibrous substrates based on polycaprolactone, Prog. Biomater. 5 (2016) 213–222. S. Shkarina, R. Shkarin, V. Weinhardt, E. Melnik, G. Vacun, P. Kluger, K. Loza, M. Epple, S.I. Ivlev, T. Baumbach, M.A. Surmeneva, 3D biodegradable scaffolds of polycaprolactone with silicate-containing hydroxyapatite microparticles for bone tissue engineering: high-resolution tomography and in vitro study, Sci. Rep. 8 (2018) 1–13. G.Z. Tan, Y. Zhou, Tunable 3D nanofiber architecture of polycaprolactone by divergence electrospinning for potential tissue engineering applications, Nano-Micro Lett. 10 (2018) 1–10. A. Sharma, M.S. Molla, K.S. Katti, D.R. Katti, Multiscale models of degradation and healing of bone tissue engineering nanocomposite scaffolds, J. Nanomech Micromech. 7 (2017) 04017015. Y.S. Cho, M.W. Hong, H.J. Jeong, S.J. Lee, Y.Y. Kim, Y.S. Cho, The fabrication of well-interconnected polycaprolactone/hydroxyapatite composite scaffolds, enhancing the exposure of hydroxyapatite using the wire-network molding technique, J. Biomed. Mater. Res. B Appl. Biomater. 105 (2017) 2315–2325. Q. Yao, B. Wei, Y. Guo, C. Jin, X. Du, C. Yan, J. Yan, W. Hu, Y. Xu, Z. Zhou, Y. Wang, Design, construction and mechanical testing of digital 3D anatomical data-based PCL–HA bone tissue engineering scaffold, J. Mater. Sci. Mater. Med. 26 (2015) 51. H. Zhang, X. Mao, D. Zhao, W. Jiang, Z. Du, Q. Li, Three dimensional printed polylactic acid-hydroxyapatite composite scaffolds for prefabricating vascularized tissue engineered bone: an in vivo bioreactor model, Sci. Rep. no. 7 (2017) 15255. R.M.F.M. Savioli lopes, A.L. Jardini, poly(lactic acid) production for tissue engineering applications, Eng. Procedia. 42 (2012) 1402–1413. J. Huang, J. Xiong, J. Liu, W. Zhu, J. Chen, L. Duan, Evaluation of the novel threedimensional porous poly ( L-lactic acid )/nano- hydroxyapatite composite scaffold, Bio Med. Mater. Eng. 26 (2015) 197–205. T. Lou, X. Wang, G. Song, Structure and properties of PLLA/β -TCP nanocomposite scaffolds for bone tissue engineering, J. Mater. Sci. Mater. Med. 26 (2015) 34. N.K. Nga, T.T. Hoai, P.H. Viet, Biomimetic scaffolds based on hydroxyapatite nanorod/poly(d,l) lactic acid with their corresponding apatite-forming capability and biocompatibility for bone-tissue engineering, Colloids Surfaces B Biointerfaces 128 (2015) 506–514. V. Guduric, C. Metz, R. Siadous, R. Bareille, R. Levato, E. Engel, J.C. Fricain, R. Devillard, O. Luzanin, S. Catros, Layer-by-layer bioassembly of cellularized polylactic acid porous membranes for bone tissue engineering, J. Mater. Sci. Mater. Med. 28 (2017) 78. T. Xu, H. Yang, D. Yang, Z. Yu, Polylactic acid nanofiber scaffold decorated with chitosan islandlike topography for bone tissue engineering, ACS Appl. Mater. Interfaces 9 (2017) 21094–21104. A. Gregor, E. Filová, M. Novák, J. Kronek, H. Chlup, M. Buzgo, V. Blahnová, V. Lukášová, M. Bartoš, A. Nečas, J. Hošek, Designing of PLA scaffolds for bone tissue replacement fabricated by ordinary commercial 3D printer, J. Biol. Eng. 11 (2017) 31. A. Magiera, J.B. Markowski, E. Menaszek, J. Pilch, S. Blazewicz, PLA-based hybrid and composite electrospun fibrous scaffolds as potential materials for tissue engineering, J. Nanomater. 2017 (2017) 1–11. S. Farzamfar, M. Naseri-Nosar, H. Sahrapeyma, A. Ehterami, A. Goodarzi, M. Rahmati, G. Ahmadi Lakalayeh, S. Ghorbani, A. Vaez, M. Salehi, Tetracycline hydrochloride-containing poly ( ε - caprolactone )/poly lactic acid scaffold for bone tissue engineering application: in vitro and in vivo study, Int. J. Polym. Mater. Polym. Biomater. 68 (2019) 472–479. R. Mishra, R.S. Sefcik, T.J. Bishop, S.M. Montelone, N. Crouser, J.F. Welter, A.I. CaplanI, D. Dean, Growth factor dose tuning forbone progenitor cell

Journal of Drug Delivery Science and Technology 55 (2020) 101452

P.N. Christy, et al.

[112]

[113] [114]

[115]

[116]

[117]

[118]

[119]

[120]

[121] [122]

[123]

[124]

[125] [126]

[127]

[128]

[129]

[130]

[131]

[132] [133]

[134]

[135] [136]

[137]

[138] [139]

[140]

proliferation and differentiation on resorbable poly(propylene fumarate) scaffolds, Tissue Eng. C Methods 22 (2016) 904–913. K. Wang, L. Cai, F. Hao, X. Xu, M. Cui, S. Wang, Distinct cell responses to substrates consisting of poly(ε- caprolactone) and poly(propylene fumarate) in the presence or absence of cross-links, Biomacromolecules 11 (2010) 2748–2759. E.G. Westbrook, Bone tissue engineering incorporating poly(Propylene Fumarate) Composites: a mini review, Nano Life (2016) 1642011 06. K.W. Lee, S. Wang, M. Dadsetan, M.J. Yaszemski, L. Lu, Enhanced cell ingrowth and proliferation through three-dimensional nanocomposite scaffolds with controlled pore structures, Biomacromolecules 11 (2010) 682–689. J.W. Lee, K.S. Kang, S.H. Lee, J.Y. Kim, B.K. Lee, D.W. Cho, Bone regeneration using a microstereolithography-produced customized poly(propylene fumarate)/ diethyl fumarate photopolymer 3D scaffold incorporating BMP-2 loaded PLGA microspheres, Biomaterials 32 (2011) 744–752. M. Dadsetan, T. Guda, M.B. Runge, D. Mijares, R.Z. LeGeros, J.P. LeGeros, D.T. Silliman, L. Lu, J.C. Wenke, P.R. Baer, M.J. Yaszemski, Effect of calcium phosphate coating and rhBMP-2 on bone regeneration in rabbit calvaria using poly (propylene fumarate) scaffolds, Acta Biomater. 18 (2015) 9–20. A.M. Díez-Pascual, A.L. Díez-Vicente, Poly(propylene fumarate)/polyethylene glycol-modified graphene oxide nanocomposites for tissue engineering, ACS Appl. Mater. Interfaces 8 (2016) 17902–17914. B. Farshid, G. Lalwani, M. Shir Mohammadi, J. Simonsen, B. Sitharaman, Boron nitride nanotubes and nanoplatelets as reinforcing agents of polymeric matrices for bone tissue engineering, J. Biomed. Mater. Res. B Appl. Biomater. 105 (2017) 406–419. J. Guo, X. Liu, A. Lee Miller, B.E. Waletzki, M.J. Yaszemski, L. Lu, Novel porous poly(propylene fumarate-co-caprolactone) scaffolds fabricated by thermally induced phase separation, J. Biomed. Mater. Res. A 105 (2017) 226–235. J.E. Trachtenberg, J.K. Placone, B.T. Smith, J.P. Fisher, A.G. Mikos, Extrusionbased 3D printing of poly(propylene fumarate) scaffolds with hydroxyapatite gradients, J. Biomater. Sci. Polym. Ed. 28 (2017) 532–554. S. Fernando, M. McEnery, S.A. Guelcher, Polyurethanes for bone tissue engineering, Advances in Polyurethane Biomaterials, (2016), pp. 481–501. P. Woźniak, M. Bil, J. Ryszkowska, P. Wychowański, E. Wróbel, A. Ratajska, G. Hoser, J. Przybylski, K.J. Kurzydłowski, M. Lewandowska-Szumieł, Candidate bone-tissue-engineered product based on human-bone-derived cells and polyurethane scaffold, Acta Biomater. 6 (2010) 2484–2493. B. Li, K.V. Brown, J.C. Wenke, S.A. Guelcher, Sustained release of vancomycin from polyurethane scaffolds inhibits infection of bone wounds in a rat femoral segmental defect model, J. Control. Release 145 (2010) 221–230. A. Asefnejad, A. Behnamghader, T.M. Khorasani, B. Farsadzadeh, Polyurethane/ fluor-hydroxyapatite nanocomposite scaffolds for bone tissue engineering. part I: morphological, physical, and mechanical characterization, Int. J. Nanomed. 6 (2011) 93–100. M. Da Mota, V. De, A. Branco, Polyurethane-based Scaffolds for Bone Tissue Regeneration, Dissertation, Instituto Superior Técnico, 2015. A.P. Reyes, A. Martínez Torres, M.D.P. Carreón Castro, J.R. Rodríguez Talavera, S.V. Muñoz, V.M.V. Aguilar, M.G. Torres, Novel poly(3-hydroxybutyrate-g-vinyl alcohol) polyurethane scaffold for tissue engineering, Sci. Rep. 6 (2016) 31140. F.J. Aguilar-Perez, R. Vargas-Coronado, J.M. Cervantes-Uc, J.V. Cauich-Rodriguez, R. Rosales-Ibañez, J.J. Pavon-Palacio, Y. Torres-Hernandez, J.A. Rodriguez-Ortiz, Preparation and characterization of titanium-segmented polyurethane composites for bone tissue engineering, J. Biomater. Appl. 33 (2018) 11–22. C.Y. Chao, M.P. Mani, S.K. Jaganathan, Engineering electrospun multicomponent polyurethane scaffolding platform comprising grapeseed oil and honey/propolis for bone tissue regeneration, PLoS One 13 (2018) 1–17. Y.J. Wang, U.S. Jeng, S.H. Hsu, Biodegradable water-based polyurethane shape memory elastomers for bone tissue engineering, ACS Biomater. Sci. Eng. 4 (2018) 1397–1406. M. Aslam, M.A. Kalyar, Z.A. Raza, Polyvinyl alcohol: a review of research status and use of polyvinyl alcohol based nanocomposites, Polym. Eng. Sci. 58 (2018) 2119–2132. M.I. Baker, S.P. Walsh, Z. Schwartz, B.D. Boyan, A review of polyvinyl alcohol and its uses in cartilage and orthopedic applications, J. Biomed. Mater. Res. B Appl. Biomater. 100 (2012) 1451–1457. S. Saxena, Polyvinyl alcohol (PVA), Chem. Tech. Assess. 1 (2004) 1–3. E. Marin, J. Rojas, Y. Ciro, A review of polyvinylalcohol derivates: promising materials for pharmaceutical and biomedical applications, African J. Pharm. Pharmacol. 8 (2014) 674–684. C. Shuai, Z. Mao, H. Lu, Y. Nie, H. Hu, S. Peng, Fabrication of porous polyvinyl alcohol scaffold for bone tissue engineering via selective laser sintering, Biofabrication 5 (2013) 015014. N. Georgieva, R. Bryaskova, R. Tzoneva, New Polyvinyl alcohol-based hybrid materials for biomedical application, Mater. Lett. 88 (2012) 19–22. A. Karimi, M. Navidbakhsh, S. Faghihi, Fabrication and mechanical characterization of a polyvinyl alcohol sponge for tissue engineering applications, Perfusion 29 (2014) 231–237. B.K. Tan, Y.C. Ching, S.C. Poh, L.C. Abdullah, S.N. Gan, A review of natural fiber reinforced poly(vinyl alcohol) based composites: application and opportunity, Polymers 7 (2015) 2205–2222. A. Kumar, S.S. Han, PVA-based hydrogels for tissue engineering: a review, Int. J. Polym. Mater. Polym. Biomater. 66 (2017) 15–182. H.D. Kim, Y. Lee, Y. Kim, Y. Hwang, N.S. Hwang, Biomimetically reinforced polyvinyl alcohol-based hybrid scaffolds for cartilage tissue engineering, Polymers 9 (2017) 655. M.S. Enayati, T. Behzad, P. Sajkiewicz, M. Rafienia, R. Bagheri, L. Ghasemi-

[141]

[142] [143]

[144]

[145]

[146]

[147]

[148]

[149]

[150]

[151]

[152]

[153]

[154]

[155]

[156]

[157]

[158]

[159]

[160]

16

Mobarakeh, D. Kolbuk, Z. Pahlevanneshan, S.H. Bonakdar, Development of electrospun poly (vinyl alcohol)-based bionanocomposite scaffolds for bone tissue engineering, J. Biomed. Mater. Res. A 106 (2018) 1111–1120. A. Timofejeva, M. D'Este, D. Loca, Calcium phosphate/polyvinyl alcohol composite hydrogels: a review on the freeze-thawing synthesis approach and applications in regenerative medicine, Eur. Polym. J. 95 (2017) 547–565. D.A. Subramanian, The Use of Poly ( Vinyl Alcohol ) -based Hydrogels in Biomedical Applications, The University of Texas, Dissertation, 2018. L. Stipniece, I. Narkevica, M. Sokolova, J. Locs, J. Ozolins, Novel scaffolds based on hydroxyapatite/poly(vinyl alcohol) nanocomposite coated porous TiO2 ceramics for bone tissue engineering, Ceram. Int. 42 (2016) 1530–1537. K. Kaviyarasu, N. Geetha, K. Kanimozhi, C. Maria Magdalane, S. Sivaranjani, A. Ayeshamariam, J. Kennedy, M. Maaza, In vitro cytotoxicity effect and antibacterial performance of human lung epithelial cells A549 activity of Zinc oxide doped TiO2 nanocrystals: investigation of bio-medical application by chemical method, Mater. Sci. Eng. C 74 (2017) 325–333. K. Kasinathan, J. Kennedy, M. Elayaperumal, M. Henini, M. Malik, Photodegradation of organic pollutants RhB dye using UV simulated sunlight on ceria based TiO2 nanomaterials for antibacterial applications, Sci. Rep. 6 (2018) 38064. K. Kaviyarasu, C. Maria Magdalane, K. Kanimozhi, J. Kennedy, B. Siddhardha, E. Subba Reddy, Naresh Kumar Rotte, Chandra Shekhar Sharma, F.T. Thema, Letsholathebe Douglas, Genene Tessema Mola, M. Maaza, Elucidation of photocatalysis, photoluminescence and antibacterial studies of ZnO thin films by spin coating method, J. Photochem. Photobiol. B Biol. 173 (2017) 466–475. C. Maria Magdalane, K. Kaviyarasu, J. Judith Vijaya, Busi Siddhardha, B. Jeyaraj, J. Kennedy, M. Maaza, Evaluation on the heterostructured CeO2/Y2O3 binary metal oxide nanocomposites for UV/Vis light induced photocatalytic degradation of Rhodamine - B dye for textile engineering application, J. Alloy. Comp. 727 (2017) 1324–1337. K. Kaviyarasu, K. Kanimozhi, N. Matinise, C. Maria Magdalane, Genene T. Mola, J. Kennedy, M. Maaza, Antiproliferative effects on human lung cell lines A549 activity of cadmium selenide nanoparticles extracted from cytotoxic effects: investigation of bio-electronic application, Mater. Sci. Eng. C 76 (2017) 1012–1025. C. Maria Magdalane, K. Kaviyarasu, J. Judith Vijaya, Busi Siddhardha, B. Jeyaraj, Photocatalytic activity of binary metal oxide nanocomposites of CeO2/CdO nanospheres: investigation of optical and antimicrobial activity, J. Photochem. Photobiol. B Biol. 163 (2016) 77–86. K. Kaviyarasu, L. Kotsedi, A. Simo, X. Fuku, G.T. Mola, J. Kennedy, M. Maaza, Photocatalytic activity of ZrO2 doped lead dioxide nanocomposites: investigation of structural and optical microscopy of RhB organic dye, Appl. Surf. Sci. 421 (2017) 234–239. A. Angel Ezhilarasi, J. Judith Vijaya, K. Kaviyarasu, M. Maaza, A. Ayeshamariam, L. John Kennedy, Green synthesis of NiO nanoparticles using Moringa oleifera extract and their biomedical applications: cytotoxicity effect of nanoparticles against HT-29 cancer cells, J. Photochem. Photobiol. B Biol. 164 (2016) 352–360. C. Maria Magdalane, K. Kaviyarasu, J. Judith Vijaya, C. Jayakumar, M. Maaza, B. Jeyaraj, Photocatalytic degradation effect of malachite green and catalytic hydrogenation by UV–illuminated CeO2/CdO multilayered nanoplatelet arrays: investigation of antifungal and antimicrobial activities, J. Photochem. Photobiol. B Biol. 169 (2017) 110–123. A. Mobeen Amanulla, S.K. Jasmine Shahina, R. Sundaram, C. Maria Magdalane, K. Kaviyarasu, D. Letsholathebe, S.B. Mohamed, J. Kennedy, M. Maaza, Antibacterial, magnetic, optical and humidity sensor studies of β-CoMoO4-Co3O4 nanocomposites and its synthesis and characterization, J. Photochem. Photobiol. B Biol. 183 (2018) 233–241. K. Kaviyarasu, A. Mariappan, K. Neyvasagam, A. Ayeshamariam, P. Pandi, R. Rajeshwara Palanichamy, C. Gopinathan, Genene T. Mola, M. Maaza, Photocatalytic performance and antimicrobial activities of HAp-TiO2 nanocomposite thin films by sol-gel method, Surfaces and Interfaces 6 (2017) 247–255. A. Raja, S. Ashokkumar, R. Pavithra Marthandam, J. Jayachandiran, Chandra Prasad Khatiwada, K. Kaviyarasu, R. Ganapathi Raman, M. Swaminathan, Eco-friendly preparation of zinc oxide nanoparticles using Tabernaemontana divaricata and its photocatalytic and antimicrobial activity, J. Photochem. Photobiol. B Biol. 181 (2018) 53–58. N. Jayaprakash, J. Judith Vijaya, K. Kaviyarasu, K. Kombaiah, L. John Kennedy, R. Jothi Ramalingam, Murugan A. Munusamy, Hamad A. Al-Lohedan, Green synthesis of Ag nanoparticles using Tamarind fruit extract for the antibacterial studies, J. Photochem. Photobiol. B Biol. 169 (2017) 178–185. S.K. Jesudoss, J. Judith Vijaya, L. John Kennedy, P. Iyyappa Rajan, Hamad A. AlLohedan, R. Jothi Ramalingam, K. Kaviyarasu, M. Bououdina, Studies on the efficient dual performance of Mn1–xNixFe2O4 spinel nanoparticles in photodegradation and antibacterial activity, J. Photochem. Photobiol. B Biol. 165 (2016) 121–132. C. Maria Magdalane, K. Kaviyarasu, A. Raja, M.V. Arularasu, Genene T. Mola, Abdulgalim B. Isaev, Naif Abdullah Al-Dhabi, Mariadhas Valan Arasu, B. Jeyaraj, J. Kennedy, M. Maaza, Photocatalytic decomposition effect of erbium doped cerium oxide nanostructures driven by visible light irradiation: investigation of cytotoxicity, antibacterial growth inhibition using catalyst, J. Photochem. Photobiol. B Biol. 185 (2018) 275–282. D. Saravanakkumar, S. Sivaranjani, K. Kaviyarasu, A. Ayeshamariam, B. Ravikumar, S. Pandiarajan, C. Veeralakshmi, M. Jayachandran, M. Maaza, Synthesis and characterization of ZnO - CuO nanocomposites powder by modified perfume spray pyrolysis method and its antimicrobial investigation, J. Semicond. 39 (3) (2018) 033001. Y.S. Reddy, C.M. Magdalane, K. Kaviyarasu, G.T. Mola, J. Kennedy, M. Maaza,

Journal of Drug Delivery Science and Technology 55 (2020) 101452

P.N. Christy, et al.

[161]

[162]

[163]

[164]

[165]

[166]

[167]

[168]

[169]

[170]

[171]

[172]

[173]

[174]

[175]

[176]

[177]

[178]

[179]

[180]

[181] K. Kombaiah, J. Judith Vijaya, L. John Kennedy, M. Bououdina, R. Jothi Ramalingam, Hamad A. Al-Lohedan, Comparative investigation on the structural, morphological, optical, and magnetic properties of CoFe2O4 nanoparticles, Ceram. Int. 43 (10) (2017) 7682–7689. [182] B. Thomas, B. Vithiya, M. Scholastica, T. Prasad, A. Augustine, S. Mohamed, C. Magdalane, K. Kaviyarasu, M. Maaza, Antioxidant and photocatalytic activity of aqueous leaf extract mediated green synthesis of silver nanoparticles using Passiflora edulis f. flavicarpa, J. Nanosci. Nanotechnol. 19 (5) (2019) 2640–2648. [183] M. Valan Arasu, S. Arokiyaraj, P. Viayaraghavan, T. Sujin Jeba Kumar, V. Duraipandiyan, Naif Abdullah Al-Dhabi, K. Kaviyarasu, One step green synthesis of larvicidal, and azo dye degrading antibacterial nanoparticles by response surface methodology, J. Photochem. Photobiol. B Biol. 190 (2019) 154–162. [184] A. Raja, K. Selvakumar, P. Rajasekaran, M. Arunpandian, S. Ashokkumar, K. Kaviyarasu, S. Asath Bahadur, M. Swaminathan, Visible active reduced graphene oxide loaded titania for photodecomposition of ciprofloxacin and its antibacterial activity, Colloid. Surf. Physicochem. Eng. Asp. 564 (2019) 23–30. [185] D. Saravanakkumar, H. Abou Oualid, Y. Brahmi, A. Ayeshamariam, M. Karunanaithy, A. Mohamed Saleem, K. Kaviyarasu, S. Sivaranjani, M. Jayachandran, Synthesis and characterization of CuO/ZnO/CNTs thin films on copper substrate and its photocatalytic applications, OpenNano 4 (2019) 100025. [186] S.K. Jesudoss, J. Judith Vijaya, K. Kaviyarasu, L. John Kennedy, R. Jothi Ramalingam, Hamad A. Al-Lohedan, Anti-cancer activity of hierarchical ZSM-5 zeolites synthesized from rice-based waste materials, RSC Adv. 8 (1) (2018) 481–490. [187] N. Geetha, S. Sivaranjani, A. Ayeshamariam, M. Siva Bharathy, S. Nivetha, K. Kaviyarasu, M. Jayachandran, High performance photo-catalyst based on nanosized ZnO–TiO2 nanoplatelets for removal of RhB under visible light irradiation, J. Adv. Microsc. Res. 13 (1) (2018) 12–19. [188] K. Kombaiah, J. Judith Vijaya, L. John Kennedy, M. Bououdina, K. Kaviyarasu, R. Jothi Ramalingam, Hamad A. Al-Lohedan, Murugan A. Munusamy, A Green approach: synthesis, characterization and opto-magnetic properties of MgxMn1−xFe2O4 spinel nanoparticles, J. Mater. Sci. Mater. Electron. 28 (14) (2017) 10321–10329. [189] K. Kombaiah, J.J. Vijaya, L.J. Kennedy, K. Kaviyarasu, Catalytic studies of NiFe2O4 nanoparticles prepared by conventional and microwave combustion method, Mater. Chem. Phys. 221 (2019) 11–28. [190] C. Jayakumar, C. Maria Magdalane, K. Kaviyarasu, M. Anbu Kulandainathan, B. Jeyaraj, M. Maaza, Direct electrodeposition of gold nanoparticles on glassy carbon electrode for selective determination catechol in the presence of hydroquinone, J. Nanosci. Nanotechnol. 18 (7) (2018) 4544–4550. [191] P. Iyyappa Rajan, J. Judith Vijaya, S.K. Jesudoss, K. Kaviyarasu, S. Cheol Lee, L. John Kennedy, R. Jothiramalingam, Hamad A. Al-Lohedan, M. Mahamad Abdullah, Investigation on preferably oriented abnormal growth of CdSe nanorods along (0002) plane synthesized by henna leaf extract-mediated green synthesis, Royal Soc. Open Sci. 5 (3) (2018) 171430. [192] P. Parasuraman, V.T. Anju, S.B. Sruthil Lal, A. Sharan, B. Siddhardha, K. Kaviyarasu, M. Arshad, T. Dawoud, A. Syed, Synthesis and antimicrobial photodynamic effect of methylene blue conjugated carbon nanotubes on E. coli and S. aureus, Photochem. Photobiol. Sci. 18 (2) (2019) 563–576. [193] S.K. Jesudoss, J. Judith Vijaya, K. Kaviyarasu, P. Iyyappa Rajan, S. Narayanan, L. John Kennedy, In-vitro anti-cancer activity of organic template-free hierarchical M (Cu, Ni)-modified ZSM-5 zeolites synthesized using silica source waste material, J. Photochem. Photobiol. B Biol. 186 (2018) 178–188. [194] R. Sowmya, K. Noluthando, K. Arockia Jayalatha, J. Bosco Balaguru Rayappan, K. Kaviyarasu, J. Kennedy, M. Maaza, Stalling behaviour of chloride ions: a nonenzymatic electrochemical detection of α-Endosulfan using CuO interface, Sens. Actuators B Chem. 293 (2019) 100–106. [195] K. Kanimozhi, S. KhaleelBasha, V. SuganthaKumari, K. Kaviyarasu, Development and characterization of sodium alginate/poly (vinyl alcohol) blend scaffold with ciprofloxacin loaded in controlled drug delivery system, J. Nanosci. Nanotechnol. 19 (5) (2019) 2493–2500. [196] M. Karunanithy, G. Prabhavathi, A. Hameedha Beevi, B.H. Ibraheem, K. Kaviyarasu, S. Nivetha, N. Punithavelan, A. Ayeshamariam, M. Jayachandran, Nanostructured metal tellurides and their heterostructures for thermoelectric applications - a review, J. Nanosci. Nanotechnol. 18 (10) (2018) 6680–6707. [197] T. Nalini, S.K. Basha, A.M. Sadiq, V.S. Kumari, K. Kaviyarasu, Development and characterization of alginate/chitosan nanoparticulate system for hydrophobic drug encapsulation, J. Drug Deliv. Sci. Technol. 52 (2019) 65–72. [198] P. Parasuraman, Asha P. Antony, A. Sharan, B. Siddhardha, K. Kaviyarasu, Needa A. Bahkali, Turki M.S. Dawoud, A. Syed, Antimicrobial photodynamic activity of toluidine blue encapsulated in mesoporous silica nanoparticles against Pseudomonas aeruginosa and Staphylococcus aureus, Biofouling 35 (1) (2019) 89–103. [199] K. Kanimozhi, S.K. Basha, K. Kaviyarasu, V. SuganthaKumari, Salt leaching synthesis, characterization and in vitro cytocompatibility of chitosan/poly (vinyl alcohol)/methylcellulose–ZnO nanocomposites scaffolds using L929 fibroblast cells, J. Nanosci. Nanotechnol. 19 (8) (2019) 4447–4457. [200] C. Maria Magdalane, K. Kanimozhi, M.V. Arularasu, G. Ramalingam, K. Kaviyarasu, Self-cleaning mechanism of synthesized SnO2/TiO2 nanostructure for photocatalytic activity application for waste water treatment, Surfaces and Interfaces 17 (2019) 100346. [201] S.C. Jeyaseelan, R. Premkumar, K. Kaviyarasu, A.M.F. Benial, Spectroscopic, quantum chemical, molecular docking and in vitro anticancer activity studies on 5-Methoxyindole-3-carboxaldehyde, J. Mol. Struct. 1197 (2019) 134–146. [202] C. Maria Magdalane, K. Kaviyarasu, M.V. Arularasu, K. Kanimozhi, G. Ramalingam, Structural and morphological properties of Co3O4 nanostructures:

Equilibrium and kinetic studies of the adsorption of acid blue 9 and Safranin O from aqueous solutions by MgO decked FLG coated Fuller's earth, J. Phys. Chem. Solids 123 (2018) 43–51. K. Kaviyarasu, C.M. Magdalane, K. Anand, E. Manikandan, M. Maaza, Synthesis and characterization studies of MgO: CuO nanocrystals by wet-chemical method, Spectrochim. Acta A Mol. Biomol. Spectrosc. 142 (2015) 405–409. K. Kaviyarasu, A. Raja, P.A. Devarajan, Structural elucidation and spectral characterizations of Co3O4 nanoflakes, Spectrochim. Acta A Mol. Biomol. Spectrosc. 114 (2013) 586–591. A. Angel Ezhilarasi, J. Judith Vijaya, K. Kaviyarasu, L. John Kennedy, R. Jothi Ramalingam, Hamad A. Al-Lohedan, Green synthesis of NiO nanoparticles using Aegle marmelos leaf extract for the evaluation of in-vitro cytotoxicity, antibacterial and photocatalytic properties, J. Photochem. Photobiol. B Biol. 180 (2018) 39–50. J. Judith Vijaya, N. Jayaprakash, K. Kombaiah, K. Kaviyarasu, L. John Kennedy, R. Jothi Ramalingam, Hamad A. Al-Lohedan, V.M. Mansoor-Ali, M. Maaza, Bioreduction potentials of dried root of Zingiber officinale for a simple green synthesis of silver nanoparticles: antibacterial studies, J. Photochem. Photobiol. B Biol. 177 (2017) 62–68. P. Iyyappa Rajan, J. Judith Vijaya, S.K. Jesudoss, K. Kaviyarasu, L. John Kennedy, R. Jothiramalingam, Hamad A. Al-Lohedan, Mansoor-Ali Vaali-Mohammed, Green-fuel-mediated synthesis of self-assembled NiO nano-sticks for dual applications - photocatalytic activity on Rose Bengal dye and antimicrobial action on bacterial strains, Mater. Res. Express 4 (8) (2017) 085030. S.K. Jesudoss, J.J. Vijaya, P. Iyyappa Rajan, K. Kaviyarasu, M. Sivachidambaram, L. John Kennedy, Hamad A. Al-Lohedan, R. Jothiramalingam, Murugan A. Munusamy, High performance multifunctional green Co3O4 spinel nanoparticles: photodegradation of textile dye effluents, catalytic hydrogenation of nitro-aromatics and antibacterial potential, Photochem. Photobiol. Sci. 16 (5) (2017) 766–778. K. Anand, K. Kaviyarasu, S. Muniyasamy, S. Mohana Roopan, R.M. Gengan, A. Chuturgoon, Bio-synthesis of silver nanoparticles using agroforestry residue and their catalytic degradation for sustainable waste management, J. Clust. Sci. 28 (4) (2017) 2279–2291. C. Maria Magdalane, K. Kaviyarasu, N. Matinise, N. Mayedwa, N. Mongwaketsi, D. Letsholathebe, G.T. Mola, Naif Abdullah Al-Dhabi, M. Valan Arasu, M. Henini, J. Kennedy, M. Maaza, B. Jeyaraj, Evaluation on La2O3 garlanded ceria heterostructured binary metal oxide nanoplates for UV/visible light induced removal of organic dye from urban wastewater, S. Afr. J. Chem. Eng. 26 (2018) 49–60. X.G. Mbuyise, E.A. Arbab, K. Kaviyarasu, G. Pellicane, M. Maaza, G.T. Mola, Zinc oxide doped single wall carbon nanotubes in hole transport buffer layer, J. Alloy. Comp. 706 (2017) 344–350. S. Valsalam, P. Agastian, M. Valan Arasu, Naif Abdullah Al-Dhabi, A.K. Mohammed Ghilan, K. Kaviyarasu, B. Ravindran, S.W. Chang, S. Arokiyaraj, Rapid biosynthesis and characterization of silver nanoparticles from the leaf extract of Tropaeolum majus L. and its enhanced in-vitro antibacterial, antifungal, antioxidant and anticancer properties, J. Photochem. Photobiol. B Biol. 191 (2019) 65–74. K. Kanimozhi, S.K. Basha, V.S. Kumari, K. Kaviyarasu, Development of biomimetic hybrid porous scaffold of chitosan/polyvinyl alcohol/carboxymethyl cellulose by freeze-dried and salt leached technique, J. Nanosci. Nanotechnol. 18 (7) (2018) 4916–4922. M.V. Arularasu, M. Anbarasu, S. Poovaragan, R. Sundaram, K. Kanimozhi, C. Maria Magdalane, K. Kaviyarasu, F.T. Thema, D. Letsholathebe, Genene T. Mola, M. Maaza, Structural, optical, morphological and microbial studies on SnO2 nanoparticles prepared by Co-precipitation method, J. Nanosci. Nanotechnol. 18 (5) (2018) 3511–3517. M. Sivachidambaram, J. Judith Vijaya, K. Kaviyarasu, L. John Kennedy, Hamad A. Al-Lohedan, R. Jothi Ramalingam, A novel synthesis protocol for Co3O4 nanocatalysts and their catalytic applications, RSC Adv. 7 (62) (2017) 38861–38870. S. Poovaragan, R. Sundaram, C.M. Magdalane, K. Kaviyarasu, M. Maaza, Photocatalytic activity and humidity sensor studies of magnetically reusable FeWO4–WO3 composite nanoparticles, J. Nanosci. Nanotechnol. 19 (2) (2019) 859–866. S.I. Shanthi, S. Poovaragan, M.V. Arularasu, S. Nithya, R. Sundaram, C. Maria Magdalane, K. Kaviyarasu, M. Maaza, Optical, magnetic and photocatalytic activity studies of Li, Mg and Sr doped and undoped zinc oxide nanoparticles, J. Nanosci. Nanotechnol. 18 (8) (2018) 5441–5447. S.O. Oseni, K. Kaviyarasu, M. Maaza, G. Sharma, G. Pellicane, G.T. Mola, ZnO: CNT assisted charge transport in PTB7: PCBM blend organic solar cell, J. Alloy. Comp. 748 (2018) 216–222. K. Kanimozhi, S.K. Basha, V.S. Kumari, K. Kaviyarasu, M. Maaza, In vitro cytocompatibility of chitosan/PVA/methylcellulose–Nanocellulose nanocomposites scaffolds using L929 fibroblast cells, Appl. Surf. Sci. 449 (2018) 574–583. K. Kombaiah, J. Judith Vijaya, L. John Kennedy, M. Bououdina, K. Kaviyarasu, R. Jothi Ramalingam, Murugan A. Munusamy, A. AlArfaj, Effect of Cd2+ concentration on ZnFe2O4 nanoparticles on the structural, optical and magnetic properties, Optik 135 (2017) 190–199. K. Kaviyarasu, Genene T. Mola, S.O. Oseni, K. Kanimozhi, C. Maria Magdalane, J. Kennedy, M. Maaza, ZnO doped single wall carbon nanotube as an active medium for gas sensor and solar absorber, J. Mater. Sci. Mater. Electron. 30 (1) (2019) 147–158. C. Jayakumar, C. Maria Magdalane, K. Kanimozhi, K. Kaviyarasu, Fabrication of nano poly cresol red over glassy carbon electrode and its application in selective determination of uric acid in the presence of ascorbic acid, Journal of Nanostructures 7 (2) (2017) 155–164.

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Journal of Drug Delivery Science and Technology 55 (2020) 101452

P.N. Christy, et al.

[203]

[204]

[205]

[206]

[207]

[208]

[209]

[210]

investigation of low temperature oxidation for photocatalytic application for waste water treatment, Surfaces and Interfaces 17 (2019) 100369. V.T. Anju, P. Paramanantham, S.B. Sruthil Lal, A. Sharan, A. Syed, Needa A. Bahkali, Marzouq H. Alsaedi, K. Kaviyarasu, B. Siddhardha, Antimicrobial photodynamic activity of toluidine blue-carbon nanotube conjugate against Pseudomonas aeruginosa and Staphylococcus aureus-understanding the mechanism of action, Photodiagn. Photodyn. Ther. 27 (2019) 305–316. A.M. Amanulla, R. Sundaram, K. Kaviyarasu, An investigation of structural, magnetical, optical, antibacterial and humidity sensing of Zr(MoO4)2-ZrO2 nanocomposites, Surfaces and Interfaces 16 (2019) 132–140. R. Perumalsamy, K. Kaviyarasu, S. Nivetha, A. Ayeshamariam, N. Punithavelan, D. Letsholathebe, G. Ramalingam, M. Jayachandran, Preparation, characterization and structure prediction of In2SnO3 and spectroscopic (FT-IR, FT-Raman, NMR and UV-visible) study using computational approach, J. Nanosci. Nanotechnol. 19 (6) (2019) 3511–3518. K. Kombaiah, J. Judith Vijaya, L. John Kennedy, K. Kaviyarasu, R. Jothi Ramalingam, Hamad A. Al-Lohedan, Green synthesis of Co3O4 nanorods for highly efficient catalytic, photocatalytic, and antibacterial activities, J. Nanosci. Nanotechnol. 19 (5) (2019) 2590–2598. P. Paramanantham, Asha P. Antony, S.B. Sruthil Lal, A. Sharan, A. Syed, M. Ahmed, Abdullah A. Alarfaj, B. Siddhardha, M. Maaza, K. Kaviyarasu, Antimicrobial photodynamic inactivation of fungal biofilm using amino functionalized mesoporus silica-rose bengal nanoconjugate against Candida albicans, Scientific African 1 (2018) e00007. N. Manjula, G. Selvan, A. Hameedha Beevi, K. Kaviyarasu, A. Ayeshamariam, N. Punithavelan, M. Jayachandran, Feasibility studies on avocado as reducing agent in TiO2 doped with Ag2O and Cu2O nanoparticles for biological applications, J. Bionanoscience 12 (5) (2018) 652–659. N. Manjula, K. Kaviyarasu, A. Ayeshamariam, G. Selvan, A. Diallo, G. Ramalingam, S.B. Mohamed, D. Letsholathebe, M. Jayachandran, Structural, morphological and methanol sensing properties of Jet Nebulizer spray pyrolysis effect of TiO2 doped SnO2 thin film for removal of heavy metal ions, J. Nanoelectron. Optoelectron. 13 (10) (2018) 1543–1551. A. Ezhilarasi Angel, J. Vijaya Judith, K. Kaviyarasu, L. Kennedy John, R.J. Ramalingam, H.A. Al-Lohedan, Green synthesis of NiO nanoparticles using Aegle marmelos leaf extract for the evaluation of in-vitro cytotoxicity,

[211]

[212]

[213]

[214]

[215]

[216]

[217]

[218]

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antibacterial and photocatalytic properties, J. Photochem. Photobiol. B Biol. 180 (2018) 39–50. A. Raja, P. Rajasekaran, K. Selvakumar, M. Arunpandian, K. Kaviyarasu, S. Asath Bahadur, M. Swaminathan, Visible active reduced graphene oxide-BiVO4-ZnO ternary photocatalyst for efficient removal of ciprofloxacin, Separ. Purif. Technol. 233 (2020) 115996. G. Theophil Anand, D. Renuka, R. Ramesh, L. Anandaraj, S. John Sundaram, G. Ramalingam, C. Maria Magdalane, A.K.H. Bashir, M. Maaza, K. Kaviyarasu, Green synthesis of ZnO nanoparticle using Prunus dulcis (Almond Gum) for antimicrobial and supercapacitor applications, Surfaces and Interfaces 17 (2019) 100376. N.M.I. Alhaji, D. Nathiya, K. Kaviyarasu, M. Meshram, A. Ayeshamariam, A comparative study of structural and photocatalytic mechanism of AgGaO2 nanocomposites for equilibrium and kinetics evaluation of adsorption parameters, Surfaces and Interfaces 17 (2019) 100375. A. Mobeen, C. Maria Magdalane, S.K. Jasmine Shahina, D. Lakshmi, R. Sundaram, G. Ramalingam, A. Raja, J. Madhavan, D. Letsholathebe, A.K.H. Bashir, M. Maaza, K. Kaviyarasu, Investigation on antibacterial and photocatalytic degradation of rhodamine-B dye under visible light irradiation by titanium molybdate nanoparticles prepared via microwave method, Surfaces and Interfaces 17 (2019) 100381. N. Kana, K. Kaviyarasu, T. Khamliche, C.M. Magdalane, M. Maaza, Stability and thermal conductivity of CuO nanowire for catalytic applications, J. Environ. Chem. Eng. 7 (4) (2019) 103255. A. Angel Ezhilarasi, J. Judith Vijaya, L. John Kennedy, K. Kaviyarasu, Green mediated NiO nano-rods using phoenix dactylifera (Dates) extract for biomedical and environmental applications, Mater. Chem. Phys. 241 (1) (2020) 122419. A.M Christopher Jeyaseelan, R. Premkumar, K. Kaviyarasu, Vibrational spectroscopic, molecular docking and in-vitro cytotoxicity studies against lung cancer cell line on 5-cyano-indole-3-carboxaldehyde, Asian J. Phys. 28 (2) (2019) 71–93. J. Rajkumari, C. Maria Magdalane, B. Siddhardha, J. Madhavan, G. Ramalingam, Naif Abdullah Al-Dhabi, Mariadhas Valan Arasu, A.K.M. Ghilan, V. Duraipandiayan, K. Kaviyarasu, Synthesis of titanium oxide nanoparticles using Aloe barbadensis mill and evaluation of its antibiofilm potential against Pseudomonas aeruginosa PAO1, J. Photochem. Photobiol. B Biol. 201 (2019) 111667.