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Agarose-Based Biomaterials: Opportunities and Challenges in Cartilage Tissue Engineering

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Agarose-Based Biomaterials: Opportunities and Challenges in Cartilage Tissue Engineering polymers Review Agarose-Based Biomaterials: Opportunities and Challenges in Cartilage Tissue Engineering 1, 1, 1 1 Mohammad Amin Salati y, Javad Khazai y , Amir Mohammad Tahmuri , Ali Samadi , Ali Taghizadeh 2, Mohsen Taghizadeh 2, Payam Zarrintaj 3,* , Josh D. Ramsey 3, Sajjad Habibzadeh 4, Farzad Seidi 5, Mohammad Reza Saeb 6,* and Masoud Mozafari 7,* 1 Polymer Engineering Department, Faculty of Engineering, Urmia University, Urmia 5756151818, Iran; [email protected] (M.A.S.); [email protected] (J.K.); [email protected] (A.M.T.); [email protected] (A.S.) 2 Center of Excellence in Electrochemistry, School of Chemistry, College of Science, University of Tehran, Tehran 11155-4563, Iran; [email protected] (A.T.); [email protected] (M.T.) 3 School of Chemical Engineering, Oklahoma State University, 420 Engineering North, Stillwater, OK 74078, USA; [email protected] 4 Department of Chemical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran 1591639675, Iran; [email protected] 5 Provincial Key Lab of Pulp and Paper Science and Technology and Joint International Research Lab of Lignocellulosic Functional Materials, Nanjing Forestry University, Nanjing 210037, China; [email protected] 6 Department of Resin and Additives, Institute for Color Science and Technology, Tehran P.O. Box 16765-654, Iran 7 Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 144961-4535, Iran * Correspondence: [email protected] (P.Z.); [email protected] (M.R.S.); [email protected] (M.M.) These authors contributed equally to this work. y Received: 29 March 2020; Accepted: 2 May 2020; Published: 18 May 2020 Abstract: The lack of adequate blood/lymphatic vessels as well as low-potential articular cartilage regeneration underlines the necessity to search for alternative biomaterials. Owing to their unique features, such as reversible thermogelling behavior and tissue-like mechanical behavior, agarose-based biomaterials have played a key role in cartilage tissue repair. Accordingly, the need for fabricating novel highly efficient injectable agarose-based biomaterials as hydrogels for restoration of injured cartilage tissue has been recognized. In this review, the resources and conspicuous properties of the agarose-based biomaterials were reviewed. First, different types of signals together with their functionalities in the maintenance of cartilage homeostasis were explained. Then, various cellular signaling pathways and their significant role in cartilage tissue engineering were overviewed. Next, the molecular structure and its gelling behavior have been discussed. Eventually, the latest advancements, the lingering challenges, and future ahead of agarose derivatives from the cartilage regeneration perspective have been discussed. Keywords: agarose; biomaterials; hydrogels; cartilage; tissue engineering; regenerative medicine 1. Introduction Millions of people in the world are suffering from articular cartilage diseases (ACD) and its side effects, such as anterior cruciate ligament (ACL) and osteochondral defects (OCD). It is expected that OCD will be the principal reason for incapacity in the next decades, with 35% of the population affected. Polymers 2020, 12, 1150; doi:10.3390/polym12051150 www.mdpi.com/journal/polymers Polymers 2020, 12, 1150 2 of 15 The occurrence of OCD depends on age, gender, and environmental conditions. Although treating the defects using surgeries is promising, cartilage regeneration remains as a post-surgery complication because of its structural complexity and low metabolic performance [1,2]. Furthermore, the long-term healing period of internal articular cartilage demands new strategies for repairing cartilage without surgery [3]. Tissue engineering is an interdisciplinary branch of science for designing and implementing novel treatment strategies based on natural/synthetic materials along with cell and therapeutic agents to treat the injured tissues [4–6]. Tissue engineering has opened a promising path to regenerate the cartilage using modified natural/synthetic biomacromolecules. The first step in material selection for tissue Polymers 2020, 12, x FOR PEER REVIEW 2 of 16 engineeringthe is thelong-term tissue healing recapitulation period of internal by the selectedarticular cartilage scaffold demands [7–9]. new Therefore, strategies the for mechanicalrepairing behavior of the intendedcartilage material without shouldsurgery [3]. match with its nearby cartilage in order to keep its function [10,11]. Tissue engineering is an interdisciplinary branch of science for designing and implementing Biopolymersnovel such treatment as chitosan strategies [12 based,13], on alginate natural/synthetic [14,15], materials gelatin along [16,17 with], and cell and agarose therapeutic [18] agents have been widely used for tissueto treat engineering the injured tissues [19,20 [4]– because6]. Tissue engineering of their proper has opened biocompatibility, a promising path controllableto regenerate the degradability, and tissue-mimickingcartilage using performance. modified natural/synthetic biomacromolecules. The first step in material selection for Agarosetissue has engineering been used is the vastly tissue reca inpitulation biomedical by theapplications selected scaffold because[7–9]. Therefore, of its the controlled mechanical self-gelling behavior of the intended material should match with its nearby cartilage in order to keep its function properties,[10,11 water-solubility,]. Biopolymers such adjustable as chitosan mechanical[12,13], alginate properties,[14,15], gelatin [16,17 and] non-immunogenic, and agarose [18] have properties. Agarose, basedbeen widely on its used stiff forness tissue and engineering functional [19,20] groups, because of cantheir supportproper biocompatibilit cellular adhesion,y, controllable proliferation, and activity.degradability, Agarose and has tissue adjustable-mimicking water performance adsorption. capacity, which provides the cells with a Agarose has been used vastly in biomedical applications because of its controlled self-gelling suitable microenvironmentproperties, water-solubility, for cellular adjustable activity mechanical [21]. Agarose-basedproperties, and non-immunogenic hydrogels have properties. considerably been utilized in theAgarose, investigation based on its of stiffness mechanical and functional load reaction groups, can for support chondrocytes cellular adhesion, and mesenchymal proliferation, stem cells (MSCs) [22].and Agarose activity. hasAgarose acquired has adjustable a wide water range adsorption of applications capacity, which such provides as drug the delivery cells with [a23 ,24], cancer suitable microenvironment for cellular activity [21]. Agarose-based hydrogels have considerably therapy [25,26been], tissueutilized engineering in the investigation and regenerativeof mechanical load medicine reaction [for27 –chondrocytes30], and disease and mesenchymal diagnosis, controlling, and treatmentstem [ 31cells–33 (MS].Cs) It has[22]. beenAgarose utilized has acquired in various a wide range tissue of engineeringapplications such applications, as drug delivery including the neural system[23,24], [34 cancer], bone therapy formation [25,26], tissue [35], engineering cardiac regeneration,and regenerative woundmedicine [27 healing,–30], and and disease attachment to diagnosis, controlling, and treatment [31–33]. It has been utilized in various tissue engineering tissues suchapplications, as skin [36 including], brain [the37 ],neural and system cornea. [34], The bone properties formation [35], of agarose cardiac regeneration, are tunable wound by concentration, functionalization,healing, andand attachment blending to to tissues mimic such the as skin desired [36], brain tissue [37], performance. and cornea. The properties Figure1 ofexhibits agarose the agarose gel performanceare tunable for various by concentration, tissues and functionalization, cells. and blending to mimic the desired tissue performance. Figure 1 exhibits the agarose gel performance for various tissues and cells. Figure 1. AdjustableFigure 1. Adjustable features features of agarose of agarose can can result result in in flexible flexible characteristics characteristics similar to similar cells and to tissues. cells and tissues. Here, the conductivity and Young’s modulus of agarose-based biomaterials are patterned. Reprinted Here, the conductivitywith permission and from Young’s [18]. modulus of agarose-based biomaterials are patterned. Reprinted with permission from [18]. 2. Cartilage Types, Properties, and Formation Cartilage is a smooth elastic tissue, which covers the end of bones at the joints and protects them against mechanical stresses. There are three types of cartilage: articular (hyaline), fibrous, and elastic [38,39]. Heterotypic collagen II/IX/XI fibrils and proteoglycan–glycosaminoglycan networks Polymers 2020, 12, 1150 3 of 15 Polymers 2020, 12, x FOR PEER REVIEW 3 of 16 of aggrecan2. and Cartilage hyaluronan Types, Properties are the, and dominant Formation structures of the cartilage extracellular matrix (ECM). Hyaline is an elastic,Cartilage flexible, is a smooth and elastic wear-resistant tissue, which covers tissue the end that of isbones accessible at the joints inside and protects the joint them to carry and against mechanical stresses. There are three types of cartilage: articular (hyaline), fibrous, and elastic disrupt the weight.[38,39].
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