Natural fiber biodegradable composites and nanocomposites

Natural fiber biodegradable composites and nanocomposites: a biomedical application

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Francesca Luzi, Debora Puglia and Luigi Torre Civil and Environmental Engineering Department, Materials Engineering Center, University of Perugia, UdR INSTM, Terni, Italy

10.1

Introduction

Polymer-based composites have attracted considerable interest in biomedical applications, due to their biocompatibility, controllable degradation rate, and degradation into nontoxic components, properties that can be found in natural polymers, such as polysaccharides or proteins and synthetic polymers. Since the level of safety of materials used in biomedical applications is seriously taken into account, due to the direct interaction or contact with the human body, these materials must meet the required specification for which they will be used. Polymers and polymeric-based systems play a key role in most devices used in distinct biomedical applications. Of these, polymers of natural origin are one of the most attractive options, mainly due to their similarities with the extracellular matrix and other polymers found in the human body. Such systems are also chemically versatile, may be modified by well-established chemical methods, and usually exhibit a rather good biological performance [1]. Natural polymers are those that are found in nature and extracted from sources like plants, animals (invertebrates and vertebrates), or microorganisms. They can be polysaccharides, proteins, or glycosaminoglycans (GAGs). Natural polymers exist either as structural or storage polymers, and many of them are extracted and used commercially for several foods, an have medical and industrial uses. Most natural polymers are widely accepted in biomedical research and applications, as they are safe and nonimmunogenic in nature, they are either utilized in native or chemically modified forms and are preferred over synthetic polymers, due to their wide acceptance, abundance, and cost-effectiveness [2] (Fig. 10.1). On the other hand, synthetic biodegradable polyesters are considered the most commercially competitive polymers for these applications as they can be produced reproducibly in a costeffective manner with a wide range of characteristics. In all of the current commercial products, polyesters act as a biologically inert supporting material or they can be modified to tackle issues such as low cell

Biomass, Biopolymer-Based Materials, and Bioenergy. DOI: https://doi.org/10.1016/B978-0-08-102426-3.00010-2 © 2019 Elsevier Ltd. All rights reserved.

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Figure 10.1 Structures of natural polymers (polysaccharides and proteins). Source: Reprinted from Manavitehrani I, Fathi A, Badr H, Daly S, Negahi Shirazi A, Dehghani F. Biomedical applications of biodegradable polyesters. Polymers 2016;8:20.

adhesion, hydrophobicity, and inflammatory side effects [3]. The most commonly used polyesters are polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly-3-hydroxybutyrate (or poly-β-hydroxybutyric acid, PHB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(propylene carbonate) (PPC), poly(butylene succinate) (PBS), and poly(propylene fumarate) (PPF). Coming back to natural polymers, for the purpose of material applications, the most important polysaccharides are cellulose and starch, but more complex carbohydrate polymers are produced by fungi and bacteria. Nevertheless, other natural polymers, such as proteins, can be used to produce biodegradable materials [4] (Fig. 10.2). A quick overview of natural biopolymers and their role in the biomedical field is here reported, with the aim of introducing their importance as matrices in the corresponding natural fiber-reinforced composites or nanocomposites.

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Figure 10.2 Examples of scaffolds based on polysaccharides from vegetable sources as matrices for biomedical devices: chitin (A), starch-based polymeric blend (B), SEM micrograph and digital image of dried scaffolds prepared using 2 wt.% cellulose concentrations in AmimCl (3-methylimidazolium chloride) as a solvent (C), SEM morphology of alginate scaffold crosslinked with EDC (N-ethyl-N0 -(3-dimethylaminopropyl) carbodiimide hydrochloride), light micrograph image in the insert (D). Source: Reprinted from (A) Jayakumar R, Menon D, Manzoor K, Nair SV, Tamura H. Biomedical applications of chitin and chitosan based nanomaterials—a short review. Carbohydr Polym 2010;82(2):227232; (B) Lam CXF, Mo XM, Teoh SH, Hutmacher DW. Scaffold development using 3D printing with a starch-based polymer. Mater Sci Eng C 2002;20(1):4956; (C) Shin EJ, Choi SM, Singh D, Zo SM, Lee YH, Kim JH, et al. Fabrication of cellulose-based scaffold with microarchitecture using a leaching technique for biomedical applications. Cellulose, 2014;21(5):35153525; (D) Barbetta A, Carrino A, Costantini M, Dentini M. Polysaccharide based scaffolds obtained by freezing the external phase of gas-in-liquid foams. Soft Matter 2010;6(20):52135224.

10.1.1 Polysaccharides from marine sources Chitin, the second most abundant natural biopolymer, is a linear copolymer of N-acetyl-glucosamine and N-glucosamine with β-1,4 linkage, where these units are randomly or block distributed throughout the biopolymer chain, depending on the processing method used to obtain the biopolymer. It is usually found in the shells of crabs, shrimp, crawfish, and insects [5]. By partial alkaline N-deacetylation of chitin we can obtain chitosan, insoluble in water and alkaline media, due to its rigid and compact crystalline structure and strong intra- and intermolecular hydrogen bonding [6]. The applications of chitin and chitosan are limited because of their insolubility in most solvents. Since chitosan has amino and hydroxyl reactive groups,

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chemical modifications can be proceeded. These modifications do not change the fundamental skeleton of polymers and keep their physicochemical and biochemical properties [7]. New properties could be introduced depending on the chemical nature of the group introduced. Many different derivatives have been prepared [8,9]. Most of the investigations demonstrated that the interactions of free amino groups of chitosan with plasma proteins or/and blood cells could cause a thrombogenic or/and a hemolytic response [14], however, it was found that water-soluble chitosan and chitosan oligomers did not present thrombogenic activity, but the sulfated derivatives of chitosan demonstrated anticoagulant activity, heme agglutination inhibition activity, antimicrobial, antitumoral, and antioxidant behavior [15]. Because of these excellent characteristics, there are different applications of chitosan and its derivatives not only in biomedicine, such as surgical sutures, bandages, and biodegradable sponges, matrices (in microspheres, microcapsules, membranes, and compressed tablets) for the delivery of drugs, as well as orthopedic materials and dentistry [10].

10.1.2 Polysaccharides from vegetal sources 10.1.2.1 Starch This is a well-known low-cost hydrocolloid biopolymer, abundantly available and one of the cheapest biodegradable polymers. It is produced by agricultural plants in the form of granules, which are hydrophilic, mainly extracted from potatoes, corn, wheat, and rice, and composed of amylose (poly-α-1,4-D-glucopyranoside), a linear and crystalline polymer and amylopectin (poly-α-1,4-D-glucopyranoside and α-1,6-D-glucopyranoside), a branched and amorphous polymer. The relative amounts and molar masses of amylose and amylopectin vary with the starch source, yielding materials with different mechanical properties and biodegradability [16]. As an inexpensive resource, it is widely utilized for the development of biodegradable materials such as soluble films, as well as innovative materials for biomedical applications. To achieve these, numerous methods are used to create starch-based biomaterials, including wet spinning, fiber meshing, injection molding, casting, and extrusion [17]. They lead to various structures ranging from partially crystalline to a completely amorphous state. Starch-based scaffolds have demonstrated great potential applications in the fields of tissue engineering [18] or as biomaterials [19]. Generally they are used in association with other compounds such as chitosan, polycaprolactone, and gelatin.

10.1.2.2 Cellulose This is another widely known polysaccharide produced by plants. It is a linear polymer with very long macromolecular chains of one repeating unit, cellobiose. Intra- and intermolecular hydrogen bonds give cellulose its characteristic crystalline structure, which in combination with a high molecular weight impart properties, such as chemical stability, mechanical strength, biocompatibility, and

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biodegradability [20]. However, the complex chemical nature of cellulose renders it difficult to dissolve in common solvents. This issue complicates the use of natural cellulose in tissue engineering, and thus, considerable effort has been invested in identifying alternatives, such as cellulose derivatives and/or bacterial cellulose (BC) [21], or in the development of solvent systems that can dissolve natural cellulose. Over recent years, it has been shown that ionic liquids (ILs) are good solvents for native cellulose [12].

10.1.2.3 Alginate Alginate is another polysaccharide, present in brown algae, that contains carboxyl groups in each constituent residue and reacts with acid to give alginic acid. Alginate is a nonbranched, binary copolymer. It is composed of β-D-mannuronic acid monomer linked to α-L-guluronic acid monomer, through a 1,4-glycoside linkage. The ratio between the two monomers varies with the source. Alginic acid is able to form gels in the presence of counterions; pH, type of counterion, and the functional charge density of this polymer affect the degree of crosslinking [22]. This gelling property allows the encapsulation of various components.

10.1.3 Proteins Proteins are constituted by both different polar and nonpolar α-amino acids, able to form many intermolecular linkages resulting in different interactions. These offer a wide possibility of chemical functionalities and functional properties, most of them are neither soluble nor fusible [27]. Proteins, as natural biodegradable materials and current progress in their applications in tissue engineering, have generated considered attention, mainly due to the fact that they have excellent biocompatibility and biodegradability, especially because their degradation products, amino acids, are the basic components of life and can be resorbed as nutrients. Consequently, some of them induce minimal tissue inflammatory responses. Some proteins are also available on a large scale and at low cost. As a result, great effort has been expended in developing applications for proteins as tissue engineering materials (Fig. 10.3) [28]. For example, fibrin has gained much attention in the fields of drug delivery and tissue engineering [29], however, there are still some barriers to the further applications of fibrin, such as instability and solubility of fibrin over time in vitro and in vivo due to fibrinolysis. Collagen, a long and fibrous structural protein that contains three peptide chains, is the main protein in the connective tissue in animals, has great tensile strength, and it is the main component of fascia, cartilage, ligaments, tendons, bone, and skin. As a natural material, collagen has excellent biocompatibility, negligible immunogenicity, and high bio-absorbability. Consequently, collagen has been widely used in tissue engineering and other biomedical applications, such as hemostatic agents and construction of artificial skin substitutes used in the management of severe burns [30,31].

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Figure 10.3 Examples of scaffolds based on proteins as matrices for biomedical devices: SEM image demonstrating the nanofiber network structure of fibrin (gel after polymerization in a six-well plate as an insert) (A); SEM image of cross-sections of collagen, scale bar 5 100 μm, image of CellecBiotek commercial collagen scaffold as an insert (B); silk-based scaffolds (C), different products such as keratin films, hydrogels, and composites can be generated from keratin (pure keratin composite as a sponge in the insert) (D). Source: Reprinted from (A) Jockenhoevel S, Flanagan TC. Cardiovascular Tissue Engineering Based on Fibrin-Gel-Scaffolds. In: Daniel Eberli (Ed.) Tissue Engineering for Tissue and Organ Regeneration, © 2010 Jockenhoevel S, Flanagan TC. Published in [short citation] under CC BY-NC-SA 3.0 license. Available from: http://dx.doi.org/10.5772/19761 [23]; (B) Chen S, Zhang Q, Kawazoe N, Chen G. Effect of high molecular weight hyaluronic acid on chondrocytes cultured in collagen/hyaluronic acid porous scaffolds. RSC Adv 2015;5 (114):9440594410 [24]; (C) Bhattacharjee P, Kundu B, Naskar D, Kim HW, Maiti TK, Bhattacharya D, et al. Silk scaffolds in bone tissue engineering: an overview. Acta Biomater 2017;63:117 [25]; (D) Shavandi A, Silva TH, Bekhit AA, Bekhit AEDA. Keratin: dissolution, extraction and biomedical application. Biomater Sci 2017;5(9):16991735 [26].

Zein, the major storage protein of corn, belongs to the family of proteins known as prolamines, it is characterized by an abundance of hydrophobic and uncharged amino acids and has been used widely as a coating agent in the pharmaceutical and food industries. In addition, it has shown potential for application as a drugdelivery carrier and as a scaffold for tissue-engineered bone/cartilage [32]. Silk fibroin is a natural fibrous protein produced by spiders or insects, and is currently being investigated for several biomedical applications due to its unique properties, such as its easy processing, impressive mechanical strength, environmental stability, biocompatibility and controllable proteolytic biodegradability, morphologic flexibility, and because of its ability to undergo amino acid side chain modification to immobilize growth factors. Tissue engineering scaffolds are the

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main product based on silk fibroin [25]. Highly homogeneous and interconnected pores, controllable pore sizes (1001000 μm), suitable porosities ( . 90%), degradability, better biocompatibility, and useful mechanical properties (from several kPa to several MPa) are the characteristics of these scaffolds [33,34]. Casein is a predominant phosphor protein that accounts for nearly 80% of proteins in milk and cheese, consists of a fairly high number of proline peptides, and has no disulfide bonds. Therefore, there is relatively little secondary or tertiary structure. Casein is poorly soluble in water, exhibiting hydrophobic properties, and appears in milk as a suspension of particles. As a tissue engineering material, casein is inexpensive, readily available, nontoxic, and highly stable [35]. Albumin is a class simple, water-soluble, and globular protein. It can be coagulated by heat and is found in egg white, blood serum, milk, and many other animal and plant tissues. Serum albumin is one of the most abundant proteins, comprising about 55% of blood plasma protein. The main applied form of albumin for biomaterials is as pharmaceutical microspheres, which are spherical, with a mean particle size ranging from nanometers to micrometers. Albumin microspheres have so far only been extensively investigated for drug targeting to various organs and tissues [36]. Keratin is a tough, insoluble, and structural protein that is a major component in skin, hair, nail, hooves, and horns. Keratin molecules are fibrous, twisting around each other to form strands called intermediate filaments. Keratin-based biomaterials have been widely produced and used in various biomedical applications. For example, keratin has the ability to function as a synthetic extracellular matrix (ECM) due to its biodegradability, biocompatibility, and ability to create fibronectin-like cellbinding domains that facilitate cell adhesion [26]. It also has biological activities that facilitate and support the proliferation of cells. Moreover, keratin has an amino acid structure that can be fine-tuned and modified depending on the desired function. During the last decade, several mild and gentle techniques of keratin extraction from keratinous materials have been reported that offer the possibility of isolating different keratin fractions suitable for a broad spectrum of functions and applications. Other than natural materials, synthetic polymers are highly useful in the biomedical field as their properties (e.g., porosity, degradation time, and mechanical characteristics) can be tailored for specific applications. The extracellular matrix (ECM) consists of a variety of proteins and polysaccharides that are assembled into an organized network that provides structural support to cells. Naturally derived polymers have the potential advantage of supporting cell adhesion and function, however concerns over the complex structural composition of natural polymers, as well as immunogenicity and pathogen transmission, have driven the development of synthetic polymers as scaffolding materials [37,38]. Synthetic polymers are often cheaper than biologic scaffolds, they can be produced in large uniform quantities, have a long shelf time, and show physicochemical and mechanical properties comparable to those of biological tissues [39]. Synthetic polymers represent the largest group of biodegradable polymers, and they can be produced under controlled conditions. They exhibit, in general, predictable and reproducible mechanical and physical properties, such as tensile

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strength, elastic modulus, and degradation rate. Several synthetic polymers are already FDA licensed for certain applications within the body, such as poly(ethylene glycol) [PEG, or poly(ethylene oxide) (PEO) at high molecular weights] which is an extremely hydrophilic polymer, with excellent solubility in a range of solvents. Poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA), and its derivatives have also been applied, although it is important to note that the use of nondegradable polymers is restricted: the most widely used synthetic degradable polymers are, indeed, poly(α-hydroxy acids), for example, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(caprolactone) (PCL), and their copolymers. These polyesters degrade by hydrolysis, eventually releasing oligomers or monomers that feed into natural metabolic pathways. Poly(α-hydroxy acids) are also known to undergo autocatalytic degradation, whereby the accumulation of acidic breakdown products accelerates the rate of hydrolysis. Some of the limitations of these materials can be overcome by using alternative degradable polymers with a variety of desirable features. To name a few, polycarbonates produce less acidic degradation products, poly(fumarate)s can be crosslinked due to the double carbon bond in their backbone and α-amino acids/peptides can be directly attached to poly(ester amide)s.

10.2

General focus on natural fibers for biomedical applications

Within the past few years, there has been a dramatic increase in the use of natural fibers and recent advances in natural fiber development, genetic engineering, and composites science have offered significant opportunities for improved materials from renewable resources. Advances in fabrication techniques, fiber technology, and composition have even led to numerous new concepts for both products and therapies in the biomedical field, some of which are still in development or in clinical trials. In detail, many studies have been done to look at the possibilities of using natural materials, such as plant-based or animal-based fibers to mix with different types of soft materials to form a new class of biocomposite. In contrast to synthetic fibers that have been adapted for medical use, natural fibers have evolved naturally and so can be particularly suited for medical applications. Biological requirements for these materials are suitable artificial surface for adherence and growth of cells, porosity to enable cell ingrowth and encapsulation, nontoxicity of fiber polymers or fabrication techniques, biocompatibility for interaction with the host in a controlled and predictable way, hemocompatibility without damaging blood cells or causing formation of destructive blood clots, biodegradability or biostability depending on the application [40]. Cellulose, which is obtained from processed cotton or wood pulp, is one of the most common fiber-forming biopolymers. Because of the highly absorbent nature of cellulose fibers, they are commonly used in hygiene products, diapers, and other absorbable applications, but typically are not used in vivo because of the highly

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inflammatory reactions associated with these materials. Also of growing interest are fibers created from modified polysaccharides including alginates, xanthan gum, chitosan, dextran, and reticulated cellulose. In addition to cellulose, there exists one supplementary resource for natural fibers, which is extremely abundant: animal filaments. These have attracted the interest of materials scientists due to their exceptional structural properties, meaning a remarkable alternative as reinforcement materials. Animal-based fibers, commonly extracted from spiders, silkworm, cocoons, chicken feathers, and even human hair, have also demonstrated their effectiveness of reinforcing biocompatible and bioresorbable polymers for implant applications (Fig. 10.4).

Figure 10.4 SEM micrographs of animal filaments: silkworm gut fiber showing the irregularities on the surface of the fiber (A); spider silk fiber (B); untreated wool fiber (C); feather fiber (D). Source: Reprinted from (A) Cenis LJ, Aznar-Cervantes DS, Lozano-Pe´rez AA, Rojo M, Mun˜oz J, Meseguer-Olmo L, et al. Silkworm gut fiber of bombyx mori as an implantable and biocompatible light-diffusing fiber. Int J Mol Sci 2016;17(7):1142; (B) Vierra C, Hsia Y, Gnesa E, Tang S, Jeffery F. (2011). Spider Silk Composites and Applications, Metal, Ceramic and Polymeric Composites for Various Uses, © 2010 Vierra C, Hsia Y, Gnesa E, Tang S, Jeffrey F. Published in [short citation] under CC BY-NC-SA 3.0 license. Available from: http://dx.doi.org/10.5772/22894; (C) Cardamone JM, Nun˜ A, Garcia RA, AldemaRamos M. Characterizing wool keratin. Adv Mater Sci Eng 2009: Article ID 147175, 5 pages, http://dx.doi.org/10.1155/2009/147175; (D) Cheng S, Lau KT, Liu T, Zhao Y, Lam PM, Yin Y. Mechanical and thermal properties of chicken feather fiber/PLA green composites. Compos Part B: Eng 2009;40(7):650654.

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10.2.1 Silkworm silk fiber Within the broad spectrum of naturally derived materials, silks produced by silkworms and spiders stand out as a unique class of structural proteins. Being members of a fibrous protein family, silks possess impressive mechanical strength, which makes them widely suitable as biomaterials. Indeed, the journey of silks (silkworm silk in particular) in biomedical applications began with their use as sutures in wound treatment [45]. With excellent biocompatibility, absent or minimal immunogenicity, limited bacterial adhesion, and controllable biodegradability, this natural biopolymer has been found to be suitable for a variety of applications [46]. Until recently, silks from silkworms have been widely reported in comparison to silks from spiders for biomaterial applications. Spider silks tend to display a wider diversity in composition owing to the multiplicity of their functions, including prey capture, sensing, and serving as draglines. However, owing to the predatory and territorial nature of spiders, spider silks are difficult to obtain in large quantities and thus tend to be produced by recombinant DNA technology, which is still inefficient. Therefore, silkworm silks, with conserved properties and greater abundance, have found wider acceptance and applications. Silk fibers have been used in biomedical applications. particularly as sutures by which the silk fibroin fibers are usually coated with waxes or silicone to enhance material properties and reduce fraying. However, in fact, there are lots of confusing questions about the usage of these fibers as there is absence of a detailed characterization of the fibers used, including the extent of extraction of the sericin coating, the chemical nature of wax-like coatings sometimes used, and many related processing factors. For example, the sericin glue-like proteins are the major cause of adverse problems with biocompatibility and hypersensitivity to silk. This protein layer can be crosslinked, copolymerized, and blended with other macromolecular materials, especially artificial polymers, to produce materials with improved properties. Seves et al. [47] discovered that environmentally friendly biodegradable polymers can be produced by blending silk sericin with other resins. Nomura et al. [48] identified that polyurethane foams incorporating sericin have excellent moistureabsorbing and -desorbing properties. Hatakeyama [49] has also reported producing sericin-containing polyurethane with excellent mechanical and thermal properties. Silk fibroin film has good dissolved oxygen permeability in a wet state but it is too brittle to be used on its own when in a dry state; whereas for chitosan, it is a biocompatible and biodegradable material which can be easily shaped into films and fibers. Park et al. [50] and Kweon et al. [51] have introduced an idea of silk fibroin/ chitosan blends as potential biomedical composites as the crystallinity and mechanical properties of silk fibroin are greatly enhanced with increasing chitosan content. Another type of biocomposite is the silk fibroin/alginate blend sponges. For biotechnological and biomedical fields, silk fibroin’s reproducibility, environmental and biological compatibility, and nontoxicity are of benefit in many different clinical applications. As the collective properties, especially mechanical properties, of silk fibroin sponges in a dry state are too weak to handle as wound dressing, they can be enhanced by blending silk fibroin films with other synthetic or natural polymers, for example, the polysaccharide sodium alginate.

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Furthermore, Katori and Kimura [52] and Lee et al. [53] examined the effect of silk/poly(butylenes succinate) (PBS) biocomposites. They found that the mechanical properties, including tensile strength, fracture toughness, and impact resistance, and thermal stability of biocomposites would be greatly affected by their manufacturing processes. By using silk fiber as reinforcement for biodegradable polymer, the mechanical properties change substantially. Cheung et al. [54] have demonstrated that the use of silk fiber to reinforce poly(lactic acid) (PLA) can increase its elastic modulus and ductility by 40% and 53%, respectively, as compared with a pristine sample. It was also found that the biodegradability of silk/PLA biocomposites was altered with the content of the silk fiber in the composites. It reflects that the resorbability of the biocomposites used inside the human body can be controlled, in which this is the key parameter of using this new type of material

10.2.2 Keratin fibers Keratin-based materials have shown promise for revolutionizing the biomaterial world due to their intrinsic biocompatibility, biodegradability, mechanical durability, and natural abundance [55]. Advances in the extraction, purification, and characterization of keratins led to the exponential growth of keratin materials and their derivatives as fiber component in biomaterials, due to the fact that extracted keratin proteins have an intrinsic ability to self-assemble and polymerize into porous, fibrous scaffolds. In addition, keratin biomaterials derived from wool and human hair have been shown to possess cell-binding motifs, which are capable of supporting cellular attachment [56]. Much has been done to both fabricate and characterize new keratin-based products such as films, sponges, scaffolds, and fibers. In many cases, these novel keratin materials have been shown to possess excellent biocompatibility. In addition, many researchers have discovered methods for modulating the physical and mechanical properties of keratins in order to create biomaterials that have appropriate characteristics for their application of interest. Keratin composites that are prepared without the addition of any additives suffer from a brittle structure which limits their applications. Therefore, a number of reports have tried to overcome this weak structure by reinforcement of the keratin matrix through incorporation of different additives, as natural or synthetic polymers. Improved mechanical properties were generally achieved, but also modified swelling and degradation behaviors of the keratin matrix were reported [57]. In this regard, there has been increasing interest to reinforce the keratin matrix with naturally derived green compounds. As an example, keratin blends with chitosan have been proposed for wound healing and artificial skin substitutes [58]; on the other hand, the interaction between keratin and synthetic polymers has also been widely and deeply studied. Tonin et al. [59] explored the relationship between poly(ethylene oxide) (PEO) and keratin blended films in order to develop a keratin-based material with improved structural properties: the improved structural properties of keratin/PEO blends enable the development of keratin materials for use as scaffolds for cell growth, wound dressings, and drug-delivery membranes. The intermolecular

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interactions between keratin and polyamide 6 (PA6) have also been studied with the goal of creating keratin-based materials that have practical use for a wide variety of applications ranging from biomedical devices to active water filtration and textile fibers [60]. Keratin biomaterials possess many distinct advantages over conventional biomolecules, including a unique chemistry afforded by their high sulfur content, remarkable biocompatibility, propensity for self-assembly, and intrinsic cellular recognition. As these properties become better understood, controlled and exploited, many biomedical applications of keratin biomaterials will make their way into clinical trials and will allow a broader commercialization of keratin materials [55,61]. In order to make keratin a mainstream biomaterial, there are certain issues that need to be addressed in future: (1) the keratin interaction with cells and its role in supporting the cells need to be understood better. Consequently, wound healing, nerve, bone, and skin regeneration processes using keratin biomaterials will experience a significant advancement; (2) the mechanicalphysical properties of keratinbased materials such as films, composites, and sponges need to be improved and the keratin interactions with other natural or synthetic polymers have to be elucidated at the molecular level in order to optimize the structure and function of the biomaterial; and (3) further investigations are required to find simple, costeffective, and yet efficient methodologies such as chemical or enzymatic assisted methods, using new classes of green solvents, or deeply exploring the supercritical fluid technology, for the better extraction of a different fraction of keratin from hair and wool, or from less conventional sources. When these properties of keratin are achieved, it is expected that keratin biomaterials will turn into a mainstream biomaterial for clinical trials.

10.3

Nanotechnology and natural polymers in biomedical applications

Utilization of polymers (natural or synthetic) as biomaterials has greatly impacted the advancement of modern medicine. Specifically, polymeric biomaterials that are biodegradable provide the significant advantage of being able to be broken down and removed after they have served their function. In order to fit functional demand, materials with the desired physical, chemical, biological, biomechanical, and degradation properties must be selected. Fortunately, a wide range of natural and synthetic degradable polymers has been investigated for biomedical applications with novel materials constantly being developed to meet new challenges. In the design of biodegradable biomaterials, many important properties must be considered. These materials must (1) not evoke a sustained inflammatory response; (2) possess a degradation time coinciding with their function; (3) have appropriate mechanical properties for their intended use; (4) produce nontoxic degradation

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products that can be readily resorbed or excreted; and (5) include appropriate permeability and processability for designed application. These properties are greatly affected by a number of features of degradable polymeric biomaterials including, but not limited to: material chemistry, molecular weight, hydrophobicity, surface charge, water adsorption, degradation, and erosion mechanism. Due to the wide-ranging use of polymeric biomaterials, a single, ideal polymer or polymeric family does not exist. Instead, a library of materials is available to researchers that can be synthesized and engineered to best match the specifications of the material’s desired biomedical function. On the basis of this assumption, biomedical application of natural polymers is often dominated by combination of polymers with natural and synthetic bioactive particles towards attaining required mechanical and biological performance. In order to limit the investigation, we limit the study to the use of natural-based polymers (or their blends) in composite systems containing natural or inorganic reinforcements. In the frame of a nanotechnological approach, polysaccharide-based nanocomposites, more than protein-based materials, have certainly attracted a lot of attention in both academic and industrial sectors: even if organic biomedical agents show good inhibition efficiency and a broad spectrum of activity, however their relatively low stability (e.g., low decomposition temperature and short life expectancy) cannot be ignored. As a result, there has been an urgent need to develop biopolymer-based nanocomposite materials for biomedical applications, such as tissue engineering scaffolds, drug delivery, wound dressing, and antibacterial film. According to this request, researchers have dedicated attention to the highly crystalline regions that compose these natural fibers—nanofibrils—to prepare nanoscaled polymeric assemblies based on cellulose [64] and chitosan [65] (Fig. 10.5).

10.3.1 Nanosized cellulose-based material for biomedical applications The potentially more interesting polysaccharide candidate in the biomedical context is certainly cellulose, in the form of nanofibers. Traditionally, cellulose has already been used for a long time in formulations in the pharmaceutical industry in the form of microcrystalline cellulose (MCC) or a salt form or modified cellulose type (e.g., hydroxypropyl methylcellulose). However, in comparison, cellulose in the form of cellulose nanofibers is still a relatively new concept. Thanks to its native molecular arrangement, several unique properties are naturally obtained when it is utilized in the form of cellulose nanofibers, properties that cannot be found when cellulose is present/processed into another solid-state form. Such properties include mechanical properties, barrier properties, and surface chemistry, to mention a few. Also, from a chemical point of view, the presence of many hydroxyl groups on the cellulose surface allows for further surface modification. Thanks to these properties and also their biocompatibility, cellulose materials hold great promise in a wide variety of biotechnological and biomedical applications [66,67].

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Figure 10.5 Biomedical applications of cellulose nanoparticles (A) and schematic representation of the possibilities of processing chitin and chitosan into different forms, including nanofibers and nanoparticles (B). Source: Reprinted from (A) Rojas J, Bedoya M, Ciro Y. Current Trends in the Production of Cellulose Nanoparticles and Nanocomposites for Biomedical Applications, Cellulose— Fundamental Aspects and Current Trends, 2015, Dr. Matheus Poletto (Ed.), InTech, https:// doi.org/10.5772/61334; (B) Anitha A, Sowmya S, Kumar PTS, Deepthi S, Chennazhi KP, Ehrlich H, et al. Chitin and chitosan in selected biomedical applications. Prog Polym Sci 2014;39(9):16441667.

A large number of works have been also developed involving nanocrystalline cellulose, also known as cellulose nanowhiskers or cellulose nanofibrils, which exhibit properties such as lightweight, stiffness, nontoxicity, transparency, low thermal expansion, gas impermeability, and outstanding mechanical properties. These inherent properties of nanocelluloses endow them as good candidates for biomedical applications, such as medical implants, tissue engineering, wound healing/dressing, and drug delivery [6870]. Nanocellulose has been mainly used as a filler in nanocomposites because of its good mechanical properties due to their biodegradability, renewability, availability, sustainability, lower cost, lower weight, higher mechanical strength, biocompatibility, high hydrophilicity, and high surface area. It evades adverse tissue reactions, and, unlike proteins, its polysaccharide nature makes it less immunogenic and nonhemolytic, it also promotes cellular interaction and tissue development. It is a slow/ non degrading material in vivo and in vitro, which makes it suitable for use as a scaffold providing a long-term support, sustains high loads, and has a high wear resistance. The biomedical industry includes skin replacements for burns and wounds; drug-releasing system; blood vessel growth; nerves, gum, and dura mater reconstruction; scaffolds for tissue engineering; stent covering; and bone reconstruction. The cellulose nanoparticle surface dictates the cellular response by interfering with cellular adhesion, proliferation, migration, and functioning. On the other hand, cells support, hold, and synthesize the matrix for the new tissues, and keep the proper growth ambient, whereas the growth factors promote cell regeneration [71].

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In tissue engineering, nanocellulose-based biocomposites are supposed to work as scaffolds or matrices to support crucial cellular activities, such as cell attachment, proliferation, and subsequent tissue formation [72,73]. Other nanocellulosebased biocomposites, such as CNC [74], CNFs [71], CNFs/alginate biocomposites [75], and CNFs/nanochitin biocomposites [76] have also found promising applications in tissue engineering. Other nanocelluloses, especially the CNFs (with or without TEMPO-mediated oxidation), have also been extensively studied for potential wound healing in recent years. CNFs has been shown to be noncytotoxic [77], to impair growth of common wound bacteria [78], to support wound healing-relevant fibroblast cell adhesion, survival, proliferation, and gene expression [79], which are all suitable characteristics for wound-healing applications. Recently, glutaraldehyde crosslinked CNFs were studied to deliver human adipose mesenchymal stem cells into chronic wounds to reduce inflammation and to promote wound healing [80]. Since the 1980s, so-called bacterial cellulose (BC) has shown promising properties for treatment of, for example, skin wounds [81]. Healing of wounds typically involves providing a moist environment, which is desired as it is proven that this gives better and faster wound healing. Therefore, wound dressing is of key importance when treating wounds, especially those arising from burns and those that involve ulcers. The extreme hydration capacity of BC (B99 wt.% is water) makes this material a good candidate for wound dressing. Studies have shown that BC is biocompatible, with good cell attachment and proliferation in vitro and enhanced tissue generation in vivo [82]. In addition, the mechanical properties and highly porous structure of the BC mimic the extracellular matrix of the human skin. BC-based biocomposites have been intensively studied for tissue engineering applications. For example, hydroxyapatite (HA)/BC nanocomposite scaffolds were found to have potency applicable in bone tissue engineering to modulate the proliferation and osteoblastic differentiation of human bone marrow stromal cells [83], and in the bone regeneration of rats with bone defects [84]. BC/collagen biocomposites [85] and BC/heparin biocomposites [86] have been prepared for potential use in various tissue engineering applications. Today there are several companies that commercialize BC for wound healing; Biofill, Bioprocess, and XCell [72,87] (Fig. 10.6A). In a recent review by Jorfi et al. [68], it was reported that nanocellulose dispersions can be used as bioink in three-dimensional (3D) printing with the aim to produce biomaterials with micrometer precision [88]. Bioinks need to be viscous enough to keep their shape during printing and must have crosslinking abilities to retain the wished for 3D form after printing: these characteristics can be achieved using various types of cellulose, including nanofibrils and bacterial cellulose. Here we will focus on some examples in which cellulose has been used to produce tissue like biomaterials. The group of Prof. Gatenholm in Sweden has developed several approaches using various types of cellulose in tissue engineering. For example, Markstedt et al. [75] prepared various bioinks for 3D printing based on formulations based on

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Figure 10.6 (A) A variety of BNC-based bioengineering materials. (a) BNC meniscus implant. (b) BASYC tubes with different sizes. (c) BNC sponge as a tissue engineering scaffold and phase-contrast microscopic graph of fibrous cells growing on the scaffold after in vitro culture for 5 days (S, scaffold; C, cells). (d) SEM image of the porous BNC matrix and immunofluorescence analysis of human urine-derived stem cell seeded BNC scaffold stained by α-smooth muscle actin (scale bar: 200 μm); (B) photograph and SEM micrographs of sponges prepared with chitosan solution at different concentrations on the vertical side (magnification of 3 200) and SEM micrographs of no crosslinked sponges prepared with chitosan solution at different concentration at vertical side (magnification of 3 200); (C) image of a chitosan scaffold and a TGF-β3-loaded chitosan scaffold. Source: Reprinted from (A) Xue Y, Mou Z, Xiao H. Nanocellulose as a sustainable biomass material: structure, properties, present status and future prospects in biomedical applications. Nanoscale 2017;9(39):1475814781; (B) Phaechamud T, Charoenteeraboon J. Antibacterial activity and drug release of chitosan sponge containing doxycycline hyclate. AAPS PharmSciTech 2008;9(3):829835; (C) Jiang K, Wang Z, Du Q, Yu J, Wang A, Xiong Y. A new TGF-β3 controlled-released chitosan scaffold for tissue engineering synovial sheath. J Biomed Mater Res Part A 2014;102(3):801807.

cellulose nanofibrils (CNF) and alginate. The bioinks were prepared by mixing concentrated CNF dispersions and alginate solutions. The viscosity of the CNF/alginate mixtures was first measured to determine the optimal ratio for best printability. The authors then proceeded to demonstrate that the CNF/alginate-based bioink could be used to make 3D constructs that mimic human nasoseptal chondrocytes (hNCs).

10.3.2 Nanosized chitosan-based material for biomedical applications In general, chitosan offers several advantages, and these include its ability to control the release of active agents and to avoid the use of hazardous organic solvents while fabricating particles. Chitosan has some advantages due to its nontoxicity and biodegradability without damaging the environment. In various disciplines of health

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care and hygienic applications, chitosan is used for contact disinfectants in many biomedical applications. Despite the great progress in antimicrobial agent development, many infectious diseases remain difficult to treat, for many reasons, such as the emergence and spread of resistant clones, the lack of antimicrobial structures, and suboptimal pharmacological properties of the existent antimicrobial substances, which sometimes are difficult to reach active concentrations inside bacterial strains or in some body sites. Chitosan, a promising biocompatible and biodegradable biopolymer, shows potential antimicrobial activity [91]. Chitosan-based NPs have recently drawn much attention in nanomedicine due to their stability and ease of surface modification [65,92,93]. Chitosan-based NPs have been prepared using a variety of methods including solvent evaporation, emulsion, diffusion, ionic gelation, coacervation or precipitation, spray drying, self-assembled, and crosslinked [94]. Unlike chitosan, the nanocomposites of chitosan have been found to exhibit a broad spectrum of antimicrobial activity against various pathogens (both Grampositive and Gram-negative bacteria) [95]. Chitosan-based hybrid nanocomposites have also been reported as bone tissue engineering materials, cartilage regeneration, and in liver and nerve tissue engineering [9698]. In addition, chitosan-based nanomaterials, produced in varying formulations like composite scaffolds, chitosanbased sponges, immobilized scaffolds, and drug-loaded scaffolds, have been used in a number of wound-healing applications [99] (Fig. 10.6B). Chitosan was revealed also to improve the nanotechnology field when reinforced with various other nanosized fillers. Depending on the application, the characteristics of each chitosan nanocomposite can be controlled, designed, and modulated regarding the target tissue [100,101]. Independently of the target, the nanocomposite performance is closely related to good dispersion of fillers within its polymeric matrix. The successful dispersion allows a good polymerfiller interface that, independently of the application, always results in high specific interfacial area. Thus, an optimal chitosan/filler interaction is the required key to benefit from nanocomposites with full potential. Moreover, it would be interesting to pursue new studies concerning other material features such as the degradation of nanocomposites. Such improvements could be extremely important, once the durability and toxicity of the device are improved. Other important aspects that require further development concern in vivo or preclinical studies. Along with the aforementioned aspects, insights into unresolved issues, such as the emergence of analytical protocols for quality assessment of chitosan, should be addressed both for scientific and market purposes. The vast opportunities shown by these materials, allied with their incredible nanotechnology potential, are expected to revolutionize the biomedical field in the near future.

10.4 Conclusions The intrinsic properties of natural biopolymers and fibers offer great potential for their use in biomedical applications. More specifically, such properties include

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biocompatibility, nanofiber network formation, high hydration capability, controllable porosity, tailorable rheological properties, lack of toxicity, high specific surface area and unique surface chemistry, excellent mechanical properties, barrier properties, and biodegradability. In this chapter, we have presented an overview of the polysaccharides and protein-based materials and also selected examples of the current state of research on nanocellulose-based materials for biomedical applications. Undoubtedly, the use of natural polymers in biomedicine will grow and there is no doubt that these materials are promising candidates for a wide range of biomedical applications, from simple wound dressings to tissue engineering scaffolds. However, to further revolutionize this specific field, more in vivo studies are needed to understand the interactions between cells and natural polymers.

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