An overview of advanced biocompatible and biomimetic materials for creation of replacement structures in the musculoskeletal systems: focusing on cartilage tissue engineering
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Tissue engineering, as an interdisciplinary approach, is seeking to create tissues with optimal performance for clinical applications. Various factors, including cells, biomaterials, cell or tissue culture conditions and signaling molecules such as growth factors, play a vital role in the engineering of tissues. In vivo microenvironment of cells imposes complex and specific stimuli on the cells, and has a direct effect on cellular behavior, including proliferation, differentiation and extracellular matrix (ECM) assembly. Therefore, to create appropriate tissues, the conditions of the natural environment around the cells should be well imitated. Therefore, researchers are trying to develop biomimetic scaffolds that can produce appropriate cellular responses. To achieve this, we need to know enough about biomimetic materials. Scaffolds made of biomaterials in musculoskeletal tissue engineering should also be multifunctional in order to be able to function better in mechanical properties, cell signaling and cell adhesion. Multiple combinations of different biomaterials are used to improve above-mentioned properties of various biomaterials and to better imitate the natural features of musculoskeletal tissue in the culture medium. These improvements ultimately lead to the creation of replacement structures in the musculoskeletal system, which are closer to natural tissues in terms of appearance and function. The present review article is focused on biocompatible and biomimetic materials, which are used in musculoskeletal tissue engineering, in particular, cartilage tissue engineering.
KeywordsCartilage tissue engineering Biomaterials Musculoskeletal tissue engineering Biomimetic materials Scaffolds Tissue engineering
amine capped aniline trimer
Alpha actinin skeletal muscle 2
dimethylol propionic acid
Human Wharton’s Jelly Mesenchymal Stem Cells
Mussel adhesive proteins
Mytilus edulis foot proteins
Mesenchymal stem cells
Multiwall Carbon Nanotubes
Poly (glycolic acid)
Poly (lactic acid)
Arginine, Glycine, and Aspartate
Runt-related transcription factor 2
- SOX 9
Volumetric Muscle Loss
The musculoskeletal system contains a variety of supporting tissues, including muscle, bone, ligament, cartilage, tendon, and meniscus, which support the shape and structure of the body. After severe injuries due to various causes such as severe crashes, diseases, or malignancies (prolonged denervation or aggressive tumor ablation), the lost tissue needs repair or replacement with healthy tissue . Tissue transplantation from a local or remote location is the primary treatment of these problems, which itself causes significant complications . The main problem is the morbidity of the donor’s places caused by loss of function and volume deficiency following the donation. The base of tissue engineering is the imitation of organogenesis that has achieved success in recent years . Engineered biomaterials, as 3-dimensional (3D) structures (scaffolds), have an essential role in the regeneration of the musculoskeletal system. Depending on the type of damaged tissue (cartilage, bone, skeletal muscle, tendon and ligament), an extensive range of natural and non-natural biomaterials as a particular scaffold can be used in this regard .
For example, an appropriate scaffold in cartilage tissue engineering should have properties, including appropriate physicochemical properties, simulation of native cartilage ECM, stimulation of cartilage differentiation, biocompatibility, filling of defective areas and adhesion to surrounding tissue. Among the various structures, injectable hydrogels because their properties are essential for cartilage tissue engineering. The hydrated 3D environment of hydrogels can mimic the native ECM of cartilage, can be useful in transporting of nutrients and cellular metabolites and can load and deliver bioactive agents such as drugs and growth factors to target places of cartilage in a minimally invasive way . Also, the porosity of scaffold has a significant role in cartilage tissue engineering. In scaffolds with closed pores, distribution of cells into the scaffold can be limited and lead to the creation of heterogeneous ECM that has poor mechanical properties . Also, in situ forming hydrogels due to their features such as similarity to native ECM and ease implantation by a needle are widely used in bone tissue engineering. Gel-based scaffolds with similar chemical and structural properties to native bone can improve the behavior of stem cells towards bone formation. To have structure with an appropriate osteoconductivity and excellent mechanical properties, incorporation of inorganic materials to hydrogels is promising . The porosity of the scaffold is also significant in bone tissue engineering. Previous studies have shown that the porosity of scaffolds should be more than 80%. Even, pores in the range of between 100 and 500 μm are suitable in this regard. In recent years, hydrogel composite structures have been widely used for bone tissue engineering. The use of glass-ceramics (GC) and bioactive glass (BG) has been considered due to its biomechanical properties, biocompatibility and improved bone tissue formation. GCs and BGs as mineralization factors, which have osteoconductive properties, can support the osteoblast cells. Also, BGs due to their Na, Ca, Si, and P ions can encourage new bone formation in vivo from the osteoblast cells. In some studies, fibrous BG has been used because of its mimicking the ECM .
Another component of the musculoskeletal system, which connects muscle to bone, is the tendon that contains densely packed aligned collagen fibers. Therefore, electrospun aligned Nano and micro-fibers can mimic the native tendon tissue in terms of structural and mechanical properties . On the other hand, the base membrane of muscle is mainly composed of laminin and collagen with a tubular structure that supports muscle integrity. The functional muscle tissue is made of fibers covered by basement membrane and is highly aligned and arranged in muscle bundles. In this regard, there are various methods for fabrication of two-dimensional (2D) micro-patterned surfaces such as electrospinning, groove/ridge micro- and Nano-patterns through photolithography or spin coating . Although 2D micro-patterned surfaces can produce align muscle myoblasts and myotubes, the resulting cell sheets have some drawbacks, for example, limited thickness, which makes it difficult to harvest the cell sheets . Therefore, other scaffolds such as three-dimensional (3D) micro-patterned scaffolds have been considered in skeletal muscle tissue engineering. These types of scaffolds can be fabricated by liquid dispensing and freeze-drying. Prepared muscle tissue in 3D micro-patterned scaffolds can be used as a direct implant for tissue repair .
In skeletal muscle tissue engineering, scaffolds should be made of electroactive biomaterials to emulate ECM of muscle cells . Various conductive materials such as polypyrrole, polyaniline, and multiwall carbon nanotubes (MWNTs) in combination with polymers have been studied for promoting myogenic differentiation . But, there are some limitations for long-term applications of these materials due to the problems like toxicity, biocompatibility, non-biodegradability, and difficulty in fabricating of 3D scaffold [15, 16]. Moreover, the engineering of muscle tissue appears to be difficult due to its structural complexity. The two main challenges in this regard are the organization of the 3D myotubes in highly aligned structures and the stimulation of the myotubes maturation in terms of improvement of sarcomere . In the previous studies, it has indicated that electrical stimulation can enhance the maturation of myoblasts [18, 19]. But, this approach has some limitation such as process scalability. Also, the role of scaffold stiffness on the elongation, spreading, and the cooperative fusion of myoblasts has been studied . In these studies, it has been indicated that the scaffold stiffness affects the making of syncytia, myotube maturation, and assembling of the sarcomeric unit . According to extensive studies conducted in this regard, it has been shown that various organic and inorganic materials are used in musculoskeletal tissue engineering. This review article discusses the types of different biomaterials used in musculoskeletal tissue engineering either alone or in combination with other materials as scaffolds.
Biomimetic biomaterials for musculoskeletal tissue engineering
Biomimetic biomaterials are materials that can be employed in biomedical fields, especially in tissue engineering and drug delivery systems. These are used as an implantable device or part of it that protect the damaged tissues of the body or promote tissue formation . In the past, inert materials were considered as ideal materials for medical applications such as metallic materials in orthopedics and silicone for gel breast implants . But since these materials have no interactions with the environment (tissues or fluids), today the attitude of the ideal biomaterial has changed. In particular, the advent of degradable biomaterials has led to advances in new research fields, including tissue engineering and drug delivery . Typically degradable polymers are known as biodegradable biomaterials, and the first usable biodegradable biomaterials are polyesters, which, as a result of degradation, are converted into smaller portions (lactic acid and glycolic acid) .
One of the significant challenges in the musculoskeletal system therapeutics is the repair of cartilage tissue problems because the ability to regenerate damaged cartilage tissue is limited . One of the main ways to solve this problem is to use biomaterials . Like other tissues in the musculoskeletal system, cartilage tissue also requires the use of biomaterials with specific characteristics. Biocompatibility, biodegradability, support for cellular proliferation and differentiation, the ability to transfer gases and nutrients and waste materials, and having appropriate mechanical properties are among the characteristics required for biomaterials to be used in cartilage tissue engineering . Clinically, researchers in cartilage tissue engineering have used various biomaterials to repair or replace damaged cartilage tissue, which includes a variety of natural materials such as GAGs, polysaccharides, and different proteins and synthetic materials such as polyesters of poly(lactic-co-glycolic acid) (PLGA) family [30, 31, 32].
Molecular markers of musculoskeletal tissues involved during the tissue engineering process on biocompatible and biomimetic materials
SRY-box 9 (SOX 9), Collagen type 1, Collagen type II, Collagen type III, Collagen type IXα3, Aggrecan, and a cartilage-specific proteoglycan
Desmin, myosin heavy chain 2, myocyte enhancer factor 2, Alpha actinin skeletal muscle 2 (ACTN2), MyoD, Myogenin (MYOG) and Troponin T
Runt-related transcription factor 2 (Runx2), Collagen type I, Alkaline phosphatase (ALP), Osteocalcin (Ocn) and Osteopontin (Opn)
Collagen type I, Collagen type III, Scleraxis (SCX), Mohawk homeobox (Mkx), Tenomodulin (TNMD), Tenascin C, Biglycan, and Fibronectin
Collagen type I, Collagen type III, Decorin, Biglycan and Aggrecan
Physical property of biomimetic biomaterials and musculoskeletal tissue engineering
To better imitate a defective tissue in musculoskeletal tissue engineering, materials with chemical and physical characteristics similar to the target tissue should be used. The three common types of biomaterials based on the biophysical properties used for the musculoskeletal system include flexible/ elastic, hard, and soft biomaterials as described below.
Flexible/ elastic biomaterials
In terms of mechanical properties, meniscus (M), tendon (T) and ligament (L) tissues are flexible in the musculoskeletal system and are considered as elastic tissues. M/T/L has a poor vascular system, so the oxygen and nutrients needed to repair and regenerate them are lower than other tissues . Due to the low repair capacity in these tissues, in the event of injury, surgical procedures, including autografts and allografts, are required . But because of the limitations of these methods, such as graft failure and morbidity, the engineering of M/T/L biomaterials is a promising method. Common biomimetic biomaterials for use in engineering of elastic tissues include collagen, elastin, PLLA, PU, and PCL [50, 51]. For example, a composite of Fiber/collagen has been used to create a structure with a high elastic property for use in ligament by Patrick et al. .
Bone tissue is one of the significant components of the musculoskeletal system that requires hard materials to be resuscitated or engineered. In different orthopedic procedures, which increase each day, have been used various materials with their distinct advantages and disadvantages. The first hard biomaterials to use in hard tissues were ceramics and bio-glasses [53, 54]. Then, absorbable and biocompatible biomaterials such as calcium sulfate- and calcium phosphate-based materials appeared. Different combinations of calcium and phosphate for orthopedic applications, for example, as bone cement, have been studied [55, 56]. In addition, as a result of the degradation of these materials, sulfate, phosphate, and calcium are formed, which are part of the ions present in the body and are harmless in this regard. Of the different types of known calcium phosphate, hydroxyapatite (Ca10(PO4)6(OH)2) has been more prominent. Hence scientists have used various hydroxyapatite combinations with natural or synthetic biodegradable polymers for creating composite scaffolds that are usable in hard tissues (osteochondral and bone) [10, 57, 58, 59].
Soft materials that contain some natural and synthetic biomaterials are used to construct structures for use in soft tissues of the musculoskeletal system such as muscle and cartilage. Common natural materials used for soft tissues of the musculoskeletal system include collagen, gelatin, hyaluronic acid, chitosan, and matrix acellular [60, 61]. Specifically, hydrogel structures and sponges made of alginate, agarose, collagen, hyaluronan, fibrin gels, poly (glycolic acid) (PGA) and poly (lactic acid) (PLA), are employed in cartilage tissue engineering .
Natural polymers for musculoskeletal and cartilage tissue engineering
Natural polymers are employed extensively in tissue engineering due to biocompatibility, enzymatic degradation, and the ability to conjugate with various factors, such as growth factors [63, 64]. Of course, it is an advantage if the degree of enzymatic degradation of the polymer is controlled; otherwise, it is a disadvantage of natural polymers . Also, batch-to-batch variability in purity and molecular weight is a disadvantage of biological polymers .
Shangwu Chen et al. prepared 3D micro-grooved scaffolds based on collagen with big concave micro-grooves (about 120–380 μm) for skeletal muscle tissue engineering . These researchers obtained highly aligned and multi-layered scaffold. It was observed that Myoblasts in the engineered muscle tissue were well-aligned with upper expression of myosin heavy chain and high construction of muscle ECM . Because collagen can support cellular activities of mesenchymal stem cells (MSCs) and articular chondrocytes (ACs), and can be prepared as a hydrogel or solid scaffold, it is used extensively in cartilage tissue engineering . Of the sixteen known types of collagen, types I, II, and III form the most considerable amount of collagen in the body, of which type II is the predominant type of collagen in cartilage tissue . It should be noted that the behavior of chondrocytes is affected by the type of collagen present in the extracellular matrix . For example, chondrocytes in the collagen type II retain their spherical phenotype better than when they are in the collagen type I . On the other hand, although collagen type II mimics the natural environment of cartilage tissue better, collagen type I is often used in tissue engineering because it is easily separated by acetic acid solution as an animal by-product . Also, collagen type I is capable of in situ polymerization at physiological temperature and neutral pH [32, 73]. Xingchen Yang et al. used sodium alginate (SA) with collagen type I (COL) as bio-inks for bio-printing and then incorporated chondrocytes to construct in vitro printed cartilage tissue . Finally, the results showed that 3D printed structures have significantly improved mechanical strength compared to sodium alginate alone. It was also observed that SA/COL scaffold helped cell adhesion and proliferation and also increased the expression of cartilage-specific genes, including Sox9, Col2al, and Acan.
Of course, it should be noted that gelatin due to its highly hydrophilic surface and the fast degradation time may not be suitable as a base material for scaffolds. To improve the properties of gelatin-based structures, blending it with other polymers such as PCL can be better. Ke Ren et al. fabricated a composite nanofiber scaffold based on PCL and gelatin using genipin for bone tissue. Results demonstrated the incorporation of gelatin into PCL nanofibers improved the cell adhesion, viability, proliferation, and osteogenic capability. Also, crosslinking by genipin enhanced the tensile properties of nanofibers that are important for bone regeneration .
Also, to improve the treatment of Volumetric muscle loss (VML), Juan Martin Silva Garcia et al. used the hyaluronic acid to make hydrogels that imitate the biomechanical and biochemical properties of the extracellular matrix of myogenic precursor and connective tissue cells . For this purpose, they used poly(ethylene glycol) diacrylate and thiol-modified HA, and also used peptides such as laminin, fibronectin, and tenascin-C to functionalize them. The results showed that functionalized HA hydrogel with laminin peptide showed a better improvement in myogenic cell behaviors compared to other groups.
Elastin is the second part of the ECM that is responsible for helping the elasticity of many living tissues . Elastin is an abundant protein in some tissues of the musculoskeletal system, including ligaments, tendon, and elastic cartilage. Hence, elastin has been studied abundantly in musculoskeletal tissue engineering . Since 50% of elastic ligaments and 4% of tendons are from elastin, this protein is used in the studies related to the ligament and tendon tissues . Helena Almeida et al. used tropoelastin to increase the stem cell tenogenic commitment in the tendon biomimetic scaffolds . For this purpose, they constructed tendon biomimetic scaffolds using poly-ε-caprolactone, chitosan, and cellulose nanocrystals and then coated them with tropoelastin (TROPO) through polydopamine linking (PDA). The results showed that the combination of these scaffolds could modulate the stem cell tenogenic commitment and elastin-rich ECM production. Elastin-based scaffolds have also been used in cartilage engineering . Annabi et al. prepared composite scaffold made of elastin and poly-caprolactone, which eventually porous scaffolds with improved biological and mechanical properties were obtained . In vitro studies indicated that (PCL)/elastin scaffolds can support chondrocyte behaviors, including their adhesion and proliferation. Therefore, these composites have a high ability to repair the cartilage.
In the past few years, Matrigel has also shown excellent performance in animal experiments for cartilage repair [113, 114]. Xiaopeng Xia et al. used Matrigel and chitosan/glycerophosphate (C/GP) gel to repair cartilage defects . To do this, they incorporated transfected-chondrocyte cells with adenovirus holding BMP7 and green fluorescent protein (Ad-hBMP7-GFP) in both types of gel. They then transplanted the gels containing the chondrocytes into the rabbits’ knees, and after four weeks they examined the results. The results showed that the Matrigel containing Ad.hBMP7.GFP transfected chondrocytes successfully increased the repair of cartilage defects in the rabbit’s knee .
In addition to the biological materials discussed above, many materials have been inspired by nature (inspired materials) to be used in tissue engineering and regenerative medicine. A good example is marine mussels, which by secreting mussel adhesive proteins (MAPs) can adhere to different surfaces [132, 133]. Among the six Mytilus edulis foot proteins (Mefps) of MAPs known to be Mefp-1, Mefp-2, Mefp-3, Mefp-4, Mefp-5 and Mefp-6, components of Mefp-3, Mefp-5 and Mefp- 6 have the most critical role in adhesion [134, 135, 136]. Since the last three listed contain 3,4-dihydroxyphenylalanine (DOPA), the researchers concluded that DOPA is a significant factor in the interaction between materials and surfaces . Also, since catechol groups present in the molecule can adhere to wet surfaces in the environment, especially in biological systems, researchers have done extensive research on them [138, 139]. According to the aforementioned, hydrogels prepared from functionalized materials with catechol groups have been used in tissue engineering, in particular, musculoskeletal tissue engineering. For example, Zhang et al. used a hydrogel/ fiber scaffold made of alginate, which was functionalized with DOPA and created alginate-DOPA beads . Finally, they observed increased viability, cell proliferation, and osteogenic differentiation of stem cells in the alginate-DOPA hydrogel. Another inspired substance is mussel-inspired poly norepinephrine (pNE), which acts as a transmitter and catecholamine hormone in the human brain . Ying Liu et al. prepared polycaprolactone (PCL) fibers with the appropriate diameter and then coated the surface with pNE . They did this to integrate the regenerated muscle layer into the surrounding tissues and simulate mechanical strength to native tissue in the affected area. Finally, they achieved promising results with pNE-modified PCL fibers for use in muscle tissue engineering.
Synthetic polymers for musculoskeletal and cartilage tissue engineering
Unlike biological polymers, synthetic polymers can easily be manipulated, depending on the needs . Therefore, in musculoskeletal tissue engineering, depending on the type of tissue, for example, bone, cartilage, muscle, ligament and tendon, scaffolds with different mechanical strengths and different degradation rates can be constructed using synthetic polymers. These polymers have disadvantages, including poor biological properties and poor biocompatibility due to the degradation and release of substances such as acidic products . Due to the wide variation in the properties of various tissues, it is not possible to create the required physical and chemical properties in the scaffold using only natural materials or synthetic polymers. Therefore, in tissue engineering, it is preferred that composites, or hybrid materials, such as polymer-polymer blends, polymer–ceramic blends and co-polymers, be used.
For example, the bone tissue, in addition to organic materials (collagen), contains inorganic components such as calcium phosphate (CaP) minerals. A primary CaP mineral of bone is Hydroxyapatite (HAP) (Ca10(PO4)6(OH)2). So, incorporation of HAP in polymeric matrices can promote the response of bone cells . In recent years, biomimetic mineralized scaffolds have been more considered due to their suitable chemical, physical, and biological properties for the engineering of hard tissues. HAP has been widely studied in biomedical applications due to its bioactivity, biocompatibility, and osteoconductivity. Previous studies demonstrated that nano-HAP could enhance the adhesion and proliferation of osteoblasts. It seems that composite scaffolds based on nano-HAP and natural or synthetic biomaterials can be more suitable for bone regeneration .
Therefore, the blending of minerals as inorganic bioactive materials with polymers can support cell attachment, proliferation, and differentiation in bone tissue. Chetna Dhand et al. have fabricated a composite scaffold using collagen nanofibers combined with catecholamines and CaCl2 . In this study, divalent cation led to oxidative polymerization of catecholamines and crosslinking of collagen nanofibers. The introduction of divalent cation and mineralization of the scaffold by ammonium carbonate caused the prepared structure to have better mechanical properties. In vitro studies have also shown that scaffolds support the expression of osteogenic markers such as osteocalcin, osteopontin, and bone matrix protein . Most of the synthetic polymers used in musculoskeletal tissue engineering, alone or in combination with natural biomaterials, include poly ε-caprolactone (PCL), polyurethane (PU), polylactic acid (PLA), polyglycolic acid (PGA), polyphosphazene and poly (propylene fumarates) [146, 147, 148, 149]. Poly caprolactone, as an FDA approved polymer, because of relatively low melting point (55–60 °C) and excellent blend-compatible with different additives, can be used for fabrication of various scaffolds with specific shape . Despite the mentioned advantages, PCL has some drawbacks, for example, in vivo degradation rate that is slow, and lack of bioactivity that limits its application in bone tissue engineering. The combination of PCL with other biomaterials such as silica, β-tricalcium phosphate, and hydroxyapatite can overcome these limitations. PCL composite nanofibers containing nHA enhance elastic modulus, cellular adhesion and proliferation, and osteogenic differentiation . Also, PCL nanofibers are extensively employed in tendon tissue engineering. PCL has a hydrophobic and semi-crystalline structure that leads to its low degradation rate so that it can be used as a scaffold in the healing process of damaged tendons [9, 151]. But, the hydrophobic nature of PCL leads to insufficient cell attachment, poor tissue integration, and little wettability in tissue engineering . GuangYang et al. fabricated composite scaffolds based on electrospun PCL and methacrylated gelatin (mGLT) . They used a photocrosslinking method for preparation of multilayered scaffold, which mimics the native tendon tissue .
Another suitable synthetic polymer for musculoskeletal tissue engineering is polyurethane (PU). Polyurethanes (PUs), as elastic polymers, due to their features such as mechanical flexibility, biocompatibility, biodegradability, and tunable chemical structures have been considered in regeneration of cartilage, bone and soft tissue . Also, PU due to its soft tissue-like properties and electroactivity can be employed as a scaffold in muscle tissue engineering . Previous studies demonstrated electroactive polymers could support cell proliferation and differentiation .
PU can deposit CaPs on their surface that lead to promoting osteoconductivity. Meskinfam et al. fabricated bio-mineralized PU foams based on calcium and phosphate ions. They showed that bio-mineralization plays a vital role in improving the mechanical properties of scaffolds. It is also said that through this, an appropriate surface for cell attachment and proliferation can be provided .
Polyglycolic and polylactic acid, as polyester polymers, are widely used in tissue engineering because of their biodegradability and biocompatibility. Polyesters as mentioned above, have also been used to repair various tissues of the musculoskeletal system, including cartilage, bone, tendon, ligament, meniscus, muscle, bone–cartilage interfaces and bone–tendon interfaces [156, 157, 158]. Also, polyphosphazene as biodegradable inorganic polymers have vast potential for using in tissue engineering . Polyphosphazenes are subjected to hydrolytic degradation, and the derived products from their degradation are not toxic . So, These have been widely used in drug delivery and tissue engineering, in particular, musculoskeletal tissue engineering, due to their non-toxic degradation products, hydrolytic instability, matrix permeability, and ease of fabrication [159, 160, 161]. A study has shown that this polymer increases adhesion and proliferation of osteoblasts . In addition to bone healing, polyphosphazene has proven to be very good in restoring and repairing other musculoskeletal tissue, such as the tendon and ligament . Along with the mentioned polymers, poly (propylene fumarate) is another case of polymers used in musculoskeletal tissue engineering for cartilage, bone, tendon, and ligament [164, 165, 166, 167, 168].
The occurrence of musculoskeletal injuries or diseases and subsequent functional disorders are one of the most difficult challenges in human health care. Tissue engineering is a new and promising strategy in this regard that introduces biomaterials as extracellular-mimicking matrices for controlling cellular behaviors and subsequent regeneration of damaged tissues. Different types of natural and non-natural biomaterials have been developed for use in musculoskeletal tissue engineering. Depending on the nature of the target tissue and their mechanical, chemical, and biological properties, different biomaterials can be used either singly or in combination, or with other additive materials.
The authors thank the Drug Applied Research Center, Tabriz University of Medical Sciences, Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Student Research Committee, Tabriz University of Medical Sciences, and Council for Stem Cell Sciences and Technologies for all supports provided.
ARDB conceived the study and participated in its design and coordination. All authors helped in drafting the manuscript. All authors read and approved the final manuscript.
The present work was funded by 2019 Drug Applied Research Center, Tabriz University of Medical Sciences Grant (Thesis NO: 61217).
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
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