Natural Polymeric Biomaterials: Processing and Properties☆

LA Loureiro dos Santos, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
r 2017 Elsevier Inc. All rights reserved.

1 Introduction 1
2 Proteins 1
2.1 Silk 1
2.2 Collagen 2
2.3 Elastin 3
3 Polyhydroxylalkanoates 3
4 Polysaccharides 4
4.1 Cellulose 4
4.2 Alginate 4
4.3 Chitosan 4
4.4 Other Biopolymers 5
5 Concluding Remarks 5
References 5

1 Introduction

Polymeric biomaterials (biopolymers) are materials which can be used within physiological environments over long or short
periods of time, without causing any deleterious local or systemic effects. These polymers can be either synthetic or natural in
origin, and their mechanical properties are similar to tissues. These properties allow their use for the replacement of various types
of tissues. Biopolymers can contain a variety of polymeric chemical compounds which give rise to a wide range of mechanical
properties.
Synthetic biopolymers have several advantages over natural biopolymers, such as the reproducibility of their properties due to
their ability to be synthesized in large batches. Their characteristics, including their mechanical solubility and morphological
properties (porosity, crystallinity, etc.) can be modified during processing. Moreover, the same polymer can be given different
properties by varying the distribution of polymeric chains of different sizes. For example, commercial polyethylene (low-density
polyethylene, LDPE) is typically used to make packaging bags, and has a low mechanical strength and a low melting point (around
1101C); however, the ultra-high molecular weight polyethylene (UHMWPE) is an extremely tough material which is virtually
infusible, and is used in mining scrapers and hip joint prosthesis. The main difference between these two types of polyethylene
(LDPE and UHMWPE) is the size of the polymeric chains, which are about 10-times higher in UHMWPE than LDPE. In addition,
synthetic biopolymers are generally not rejected by the immune system as they have no sites for recognition and cell adhesion.
Furthermore, many synthetic biopolymers are hydrophobic.
In general, the advantageous properties that synthetic polymers provide are the disadvantages of natural biopolymers. Natural
biopolymers can cause rejection due to antigenicity, there is high variability in properties between batches and their properties
cannot be changed easily with processing. Moreover, even with adequate processing, there is a risk of disease transmission.
However, the main advantage of natural biopolymers is that they allow for the recognition, adhesion, migration, proliferation and
differentiation of cells, which allows their use in restoring the structure and function of organs and tissues (Marques et al., 2016).
This article will describe the major natural biopolymers and their characteristics.

2 Proteins

Protein-based biomaterials can be obtained from living organisms or from chemical or physical processing. They can be repro-
cessed after being dissolved by solvents or enzymes or obtained from decellularized structures. The main types of biopolymers
which are derived from protein compounds are discussed below.

2.1 Silk
There are several sources of silk biopolymers, the major one being members of the Arachnida class. The most commonly reported
source of silk biopolymers in the literature are from spiders of the Nephila genus (Nephilia clavipes, Nepenthes madagascarensis and
Neplilia senegalensis) and several worms of the order Lepidoptera, notably Bombyx mori (silkworm). Fibrous silk proteins are
synthesized by the epithelial cells of these living organisms.

☆
Change History: September 2016. L.A. Loureiro dos Santos has rewritten the article title and all the sections including the table; updated the figures; and
included new references to the “References” section.

Reference Module in Materials Science and Materials Engineering doi:10.1016/B978-0-12-803581-8.02253-0 1

2 Natural Polymeric Biomaterials: Processing and Properties

The most commonly known silk is derived from silkworms, and is used in the manufacture of textiles due to its softness, lightness
and brightness. The manufacture of silk textiles was kept secret by the Chinese for about 3000 years until the year AD 300.
The structure of the silk that is expelled from the glands of silkworms consists of layers containing hydrophobic domains
(fibroin) separated by layers containing less hydrophilic domains (sericin). Silk has been investigated as a biomaterial due to its
mechanical and biological properties, and has been used for hundreds of years as a material for non-absorbable sutures (Muffly
et al., 2011).
The silk produced by Nephila spiders consists of two proteins, spidroin I and spidroin II, which are rich in alanine and glycine,
respectively. They also form layered structures, in which the alanine-rich hydrophobic structure is crystalline (20–30%) and the
glycine-rich hydrophilic structure forms the amorphous matrix (70–80%) (Vehoff et al., 2007).
Table 1 shows the mechanical properties of some of the characteristics of silk compared to other biomaterials, and specifically
highlights the mechanical properties which are similar or superior to steel. The elastic modulus is reduced in silk, which makes it
extremely interesting for use in implantable materials as this characteristic prevents stress shielding.
Spider silk has not been extensively commercialized because spiders have not been domesticated to produce silk, and there is
low production yield obtained by these methods. Efforts have been made to obtain genetically engineered spider silk (using
Escherichia coli, transgenic tobacco, Pichia pastoris, baby hamster kidney cells, bovine mammary epithelial alveolar cells and mouse
milk) (Veparia and Kaplan, 2007). In contrast, the silk obtained from Lepidoptera has a high global output for the production of
textiles, which ensures an abundant source of raw material for the production of biomaterials.
When compared with other natural polymers, fibroin has very interesting properties for applications in the medical field. One
of these is its biocompatibility, as natural polymers do not carry the same risks as tissues derived from mammals. Some cases of
silk hypersensitivity have been reported, which have been attributed to sericin. However, the removal of sericin makes it possible
to obtain materials which are suitable for use as a biomaterial (MacIntosh et al., 2008).
Sericin can be removed from silk by treatment with a hot alkaline solution. The purified fibers can then be processed to obtain
silk fibroin cords by twisting, or non-woven silk by partial solubilization. The fibroin fibers can be dissolved in concentrated acids
and salt solutions, of which lithium bromide and calcium chloride are the most commonly used. The silk fibroin solutions can be
used in the formation of materials such as hydrogels, films, sponges and non-woven fibers (Veparia and Kaplan, 2007). Silk fibroin
has been used in medicine for many years in sutures and artificial ligaments.
There has been increasing research into the use of fibroin, including several studies that have investigated its use as a bio-
material in artificial skin, controlled release systems, bone tissue cell culture, cartilage and ligaments, scaffolds and wound
dressings, in addition to many other applications.

2.2 Collagen
Collagen is the main constituent of connective tissue and is the most abundant protein in animals, composing 25% of total
protein mass. It is found in the extracellular matrix and fibrous tissue. The first reported collagen biomaterial was biodegradable
sutures, termed “catgut,” which is a collagen biomaterial derived from the intestines of sheep. The term collagen does not refer to
single protein, but a family of proteins. There are currently 29 types of collagen which have been identified (Chattopadhyay and
Raines, 2014). Collagen biomaterials can be organized into two main groups depending on the type of processing. The first is
collagen derived from the extracellular matrix (ECM) which can be isolated using a combination of chemical solutions that
promote cell disruption, which are then removed using detergents, thus maintaining its structure. Collagen can also be extracted
and processed via chemical or physical methods, and may be in the form of either collagen or gelatin.
Collagen consists of a protein with three polypeptide chains, each of which contain a repeat Gly-X-Y amino acid sequence,
where X and Y are usually proline and hydroxyproline, respectively. The 29 types of collagen are similar in that they all contain
three polypeptide chains in a characteristic triple-helix structure. The variation is related to their structure, where the differences are
restricted to the length of the helix and the number and nature of the carbohydrates attached to the triple-helix. Collagen types I, II,
III, V and XI have fibrillar quaternary structures. Their structure is organized as follows: amino acids form the primary structure; the
secondary structure is the local chain configuration of the Gly-X-Y peptide; the tertiary structure is the triple-helix molecule; and the
quaternary structure is the arrangement of triple-helix molecules to form microfibrils.
The collagen in the skin, tendons and vessels is type I, type II is the predominant collagen in cartilage and type III collagen is
found in the walls of blood vessels. Conversely, type IV collagen is a constituent of the membrane which separates the epithelial
tissue of mesodermal tissues. It is also non-helical and does not form fibrils. Type I collagen is the most abundant type in animals
and is the most commonly used in medicine.

Table 1 Mechanical property of silk and other biomaterials

Source Elastic modulus (GPa) Ultimate tensile strength (MPa) Strain (%) References

Nephilia clavipes silk 13–25 1100–2900 9–11 Cunniff et al. (1994)

Bombyx mori silk 16 650 20 Cunniff et al. (1994)
Steel ISO 5832-1 (cold-worked) 190a 860–1100 12 ISO 5832-1 (2007)
Poly(lactic acid) 0.35–3.5 21–60 2.5–6 Farah et al. (2016)
a
Typical value.
 Natural Polymeric Biomaterials: Processing and Properties 3

The use of collagen derived from animals can elicit an allergic reaction and enable the transmission of pathogens. Collagen
produced by E. coli is a promising alternative to reduce these effects (Pinkas et al., 2011). Another way to reduce the allergic
reaction is by using enzymes which react with the collagen. Eliminating or reducing the risk of disease transmission could be
achieved either by using synthetic collagen-mimetic materials or recombinant collagen (MacNeil, 2008).
A solution containing triple-helix collagen can be converted to gelatin by heating the solution above the transition temperature
of the helix-fold, which is approximately 371C for bovine collagen. Pores can be incorporated by freezing a dilute suspension of
collagen fibers and then sublimating the ice crystals using thermally induced phase separation (TIPS) to obtain sponges and
scaffolds.
Cross-linking of collagen reduces the solubility and absorption of the collagen, in the form of collagen or gelatin. However,
chemical cross-links can encourage the precipitation of calcium compounds on its surface, which is an undesirable property that
sometimes occurs in heart valve implants which are made of bovine or porcine pericardium. A simple cross-linking procedure is
based on the removal of 1% water by weight, which makes collagen or gelatin insoluble.
Cross-linking can also occur by inducing the formation of links between peptide chains. Collagen is able to be cross-linked with
formaldehyde or glutaraldehyde, among others. Although chemical cross-linking can enhance the stability of collagen, residual
reagents and compounds which are formed upon in vivo degradation can be cytotoxic. Physical cross-linking also can be induced
using ultraviolet (UV) light or dehydrothermal treatment (DHT).
There are several companies that make commercial collagen in different forms, such as partially purified skin, sponges, barrier
membranes for dentistry applications, fibers and powder.

2.3 Elastin
Elastin is a biopolymer of amino acids chains with high elasticity, and it is found in the body where this property is important,
particularly in arteries where it aids blood flow. Elastin is also important in the lungs, elastic ligaments, skin and bladder. Elastin is
insoluble due to the cross-linking of amino acid chains. Tropoelastin is a precursor protein of elastin, and is composed of
hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. The hydrophobic domains are
involved in coacervation and the hydrophilic domains are used for cross-linking. Coacervation involves the agglomeration of
protein molecules, which is an important step in the formation of elastin fibers as it enables the tropoelastin monomers to align
and form cross-links. Elastin can be applied in biomaterials in several forms, including insoluble elastin fibers, hydrolyzed soluble
elastin, recombinant tropoelastin (fragments), repeats of synthetic peptide sequences, block copolymers of elastin or used in
combination with other biopolymers (Daamen et al., 2007).
Elastin has been shown to induce the migration and differentiation of keratinocytes, which are necessary to re-establish the
epidermis (Almine et al., 2010). Elastin shows low thrombogenicity in several forms, including elastin fibers, purified elastin,
tropoelastin and elastin peptides (Waterhouse et al., 2011).
Elastin biomaterials can be produced from natural, recombinant or synthetic sources. Elastin can be obtained from the elastin-
rich tissues of animals by hydrolyzing some of the peptide bonds in insoluble elastin. Elastin-like polypeptides that incorporate
repetitive amino acids sequences, like those found in tropoelastin, have previously been produced from peptide synthesis using
biosynthetic approaches, where recombinant elastin sequences encoding the proteins are expressed in hosts such as E. coli, plants
and yeast (Annabi et al., 2013).
Elastin and elastin-based materials are able to be obtained by various processes such as electrospinning, wet spinning, freeze-
drying and cross-linking, and these can be used in solvent casting to obtain particles, fibers, gels, tubes, sheets and films (Yeo et al.,
2015).

3 Polyhydroxylalkanoates

Polymers such as poly(lactic acid) (PLA), polycaprolactone (PCL) and poly(hydroxybutyrate) (PHB) are all resorbable polyesters
used in physiological media. However, derived from bacterial sources, only polyhydroxyalkanoates (PHAs) are used in
biomaterials.
Microbial PHAs are polyesters with various structures and properties, including PHB which contains copolymers of hydro-
xybutyrate and hydroxyvalerate (PHBV). PHBV is a copolymer of hydroxybutyrate with random segments of hydroxyvalerate.
Similar to PHB, PHBV is also produced by bacterial methods. The concentration of the valerate copolymer in polymeric chains
alters the degradation time. The major use of PHA is not in medicine, but in the production of biodegradable food packaging,
where it can be used instead of polypropylene and polyethylene due to its similar properties. However, PHB is a highly crystalline
polymer which gives it lower impact resistance. It also has low thermal stability, which makes it necessary to avoid or reduce
exposure to high temperatures, above its melting temperature, which can hinder processing. Moreover, while PHB is able to be
biodegraded by enzymes when placed in soil, they have a high absorption time when they are implanted due to reduced
hydrolysis.
While PHB can be produced from several different sources (natural isolates, recombinant bacteria and plants), the main route
of production is using bacteria. In bacteria, these polymers are accumulated intracellularly as a carbon and energy reserves. PHAs
are produced from a wide variety of renewable substrates (sucrose, starch, cellulose and triacylglycerol), fossil resources (methane,
mineral oil, lignite and hard coal), byproducts (molasses, whey and glycerol), chemicals (propionic acid, 4-hydroxybutyric acid)
4 Natural Polymeric Biomaterials: Processing and Properties

and carbon dioxide. Transgenic plants containing the microbial PHA biosynthesis genes have recently been developed, with the
aim of reducing the cost of the polymer (Reddy et al., 2003).
The medical applications of PHAs include their uses in sutures, adhesion barriers, valves to guide tissue repair, cardiovascular
patches, articular cartilage repair scaffolds, bone graft substitutes and nerve guides (Chen and Wang, 2013). They can be
used as medical scaffolding materials (to treat bone defects, pulmonary valve leaflets, heart valves, cartilage and as a matrix for
neuronal generation after spinal cord injury), as surgical materials (films for wound healing and sutures) and as drug release
systems (gentamicin, tetracycline, rubomycin, rifampicin, sulbactan-cefoperazone, sulperazone and rhodamine B isothiocyanate)
(Brigham and Sinskey, 2012).

4 Polysaccharides

Polysaccharides are polymeric carbohydrates composed of monosaccharides joined by glycosidic bonds. Hydrolysis of poly-
saccharides results in smaller polysaccharides, oligosaccharides, disaccharides or monosaccharides. In living organisms, poly-
saccharides are classified depending on their role, either as energy reserves or in structural roles. Examples of saccharides used for
energy reserves are the monosaccharides glucose and fructose and polysaccharides glycogen and starch. As a basic rule, poly-
saccharides contain at least 10 monosaccharide units. Polysaccharides that have structural functions are cellulose and chitin, which
are present in the plant cell wall and arthropod exoskeleton, respectively. Polysaccharides have the general formula Cx(H2O)y
where x is typically a number between 200 and 2500.
Polysaccharides contain a variety of compounds, and therefore, have varied properties. They can also have a range of molecular
weights, which affects their properties and the processing of polysaccharide materials. Due to their biological origin, polysaccharides
typically have high biocompatibility, low toxicity and low immunogenicity, and their properties are usually affected by moisture.

4.1 Cellulose
Cellulose (C6H10O5)n is a polymer consisting of straight chains of glucose monosaccharides which are joined by glycosidic bonds. The
polymer chains are held together by hydrogen bonds, which gives stiffness to the structure and tends to form a crystalline config-
uration. Cellulose forms the structural basis of plant cell walls, and can also be produced by other organisms such as algae, fungi and
bacteria. Cellulose derived from plants (wood and cotton) is the raw material used for the production of paper and cardboard.
Cellulose is degraded by enzymes, therefore, when it is implanted into living tissue it has a reduced rate of degradation by non-
enzymatic hydrolysis and can be considered to be non-absorbable. Nevertheless, cellulose and its derivatives are well tolerated by
cells and tissues and induces a moderate foreign body reaction in tissues (Helenius et al., 2006).
Cellulose obtained from bacteria is morphologically different from cellulose obtained from plants, with the advantage of
increased purity and being free of lignin. The structure of bacteria-derived cellulose consists of a network of nanofibers with high
crystallinity (Huang et al., 2011) and high liquid retention capability (hydrophilic), which helps their biocompatibility.
Cellulose that is obtained by bacteria is industrially produced and used in various applications in the biomedical field, such as
in artificial skin and blood vessels (Klemm et al., 2001), scaffolds for tissue engineering, drug delivery systems, healing of nerves, in
the gingival tissue and dura mater, coating stents and as a bone regeneration material (Czaja et al., 2007).

4.2 Alginate
Sodium alginate (NaC6H7O6) is a linear polysaccharide derivative of alginic acid comprised of 1,4-b-D-mannuronic (M) and a-L-
guluronic (G) acids. Sodium alginate is a cell wall component of marine brown algae, and contains approximately 30 to 60% alginic
acid. The conversion of alginic acid to sodium alginate allows its solubility in water, which assists its extraction. Bacterial alginates are
synthesized by only two bacterial genera, Pseudomonas and Azotobacter, and is used for protection from the environment and the
synthesis of biofilms in order to adhere to surfaces. This method of synthesis allows the bacteria to produce alginates with a well-
defined monomer composition, which may allow the production of “tailor-made” bacterial alginates (Hay et al., 2010).
The biggest advantage of alginates is its liquid–gel behavior in aqueous solutions. When monovalent ions (eg, sodium in
sodium alginate) are exchanged for divalent ions (especially calcium), the reaction proceeds almost immediately, changing from a
low viscosity solution to a gel structure. The gelled mass is a copolymer composed of two kinds of monomer units.
Alginic acid is used as a hydrocolloid in various applications such as food manufacturing, pharmaceuticals and in textiles and
cosmetics, particularly as an emulsifier, and is also used in dentistry to make molds. More recently, alginate have been studied
extensively due to its tissue compatibility and use in tissue engineering, including the regeneration of skin tissue, cartilage, bone,
pancreas, liver, muscles and nerves (Lee and Mooney, 2012), in addition to being used in the encapsulation of cells for the
controlled release of drugs.

4.3 Chitosan
Chitin polysaccharide is a b-(1–4)-2-acetamido-2-deoxy-D-glucose (N-acetylglucosamine) with a structure similar to cellulose
fibers. The difference between chitin and cellulose is due to the hydroxyl groups, which are replaced by acetamido groups in chitin.
 Natural Polymeric Biomaterials: Processing and Properties 5

The main natural source of chitin is the shells of crustaceans (crab, shrimp and lobster), and is mainly obtained from the waste of
fishing industry. It is also be found in insects, mollusks and fungi. The major application of chitin is the production of chitosan,
the deacetylation product of chitin, which has several applications.
During the alkaline deacetylation (NaOH) of chitin, the acetyl bonds are broken to form glucosamine, which contains a free
amino group. Chitosan cannot be considered to be a uniform polymer, but a partially acetylated polymer or a copolymer. Only
polymers with a degree of deacetylation above 50% are considered to be chitosan. The properties and applications of chitosan
depend heavily on the degree of deacetylation and the size of the polymer chain. Chitin can also be deacetylated through the use
of enzymes (chitin deacetylase).
Chitosan is soluble in dilute organic and inorganic acids, where it forms a viscous solution. These solutions are used to produce
fibers, films and coatings. Due to these properties, chitosan can be used in several forms including gel particles, nanoparticles,
membranes, fibers, nanofibers, sponges and in solution.
Chitin and chitosan are biocompatible, biodegradable and non-toxic polymers, with biomedical applications in tissue engi-
neering, wound healing, as excipients for drug delivery and also in gene delivery (Jayakumar et al., 2010; Ding et al., 2014).

4.4 Other Biopolymers

There are several other natural polymers with applications as biomaterials, which were not discussed due to their smaller range of
applications. These include biocompatible starches (structure consisting of two types of alphaglucan, amylose and amylopectin)
and other absorbable materials which are mainly used in tissue engineering, usually in combination with other polymers. These
include xanthan, which is mainly used as a thickener and in wound dressings, and hyaluronic acid (glycosaminoglycans), the high
viscosity of which makes it useful for lubricating joints and in dermal applications. A bioactive polymer with a promising
application as a biomaterial is natural rubber obtained from Hevea brasilisensis (poly-cis-isopren), which acts as a granulation
tissue and neovascularization inducer. Natural rubber has been researched for its use as a biomaterial in the production of vascular
prostheses, dermal dressings or as a resorbable biomaterial in blends with PLA for use in cranial springs or as scaffolds for tissue
engineering (Faller et al., 2015). The mechanisms underlying the formation of granulation tissue and induction of neovascular-
ization by natural rubber are not well understood, but have been attributed to proteins bound to the poly(cis-isoprene) chain.

5 Concluding Remarks

Advances in engineering have enabled the development of several synthetic polymers with high purity, reproducibility, an
extended range of properties and a low cost. However, although these polymers may be absorbable in the physiological envir-
onment, usually by hydrolysis, they are limited by their lack of cellular recognition and adhesion properties. Natural biopolymers
are an alternative to these artificial biopolymers as they are synthesized in biological conditions, and therefore, have cellular
recognition and adhesion characteristics, making these materials extremely interesting for use as biomaterials. However, the
variability in properties between batches, the difficulty of obtaining pure materials or materials without harmful contaminants and
their large-scale production are yet to be achieved. Alternatively, these biopolymers can be controlled by synthesis in the
laboratory, usually using genetic engineering approaches including transgenics, bacteria and enzymes, which allow the production
of polymers with tailored properties. The use of natural biopolymers obtained by these approaches have a strong potential for use
in biomedical applications to replace synthetic biopolymers, in addition to other potential applications. This opens technological
opportunities to produce naturally occurring polymers on a large scale from renewable sources with a low ecological impact.

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