Natural and Synthetic Biomedical Polymers

By Sangamesh G. Kum bar and Cato Laurencin

Polymers are important and attractive biomaterials for researchers and clinical applications due to the ease of tailoring their chemical, physical and biological properties for target devices. Due to this versatility they are rapidly replacing other classes of biomaterials such as ceramics or metals. As a result, the demand for biomedical polymers has grown exponentially and supports a diverse and highly monetized research community. Currently worth $1.2bn in 2009 (up from $650m in 2000), biomedical polymers are expected to achieve a CAGR of 9.8% until 2015, supporting a current research community of approximately 28,000+.

Summarizing the main advances in biopolymer development of the last decades, this work systematically covers both the physical science and biomedical engineering of the multidisciplinary field. Coverage extends across synthesis, characterization, design consideration and biomedical applications. The work supports scientists researching the formulation of novel polymers with desirable physical, chemical, biological, biomechanical and degradation properties for specific targeted biomedical applications.

• Combines chemistry, biology and engineering for expert and appropriate integration of design and engineering of polymeric biomaterials
• Physical, chemical, biological, biomechanical and degradation properties alongside currently deployed clinical applications of specific biomaterials aids use as single source reference on field.
• 15+ case studies provides in-depth analysis of currently used polymeric biomaterials, aiding design considerations for the future

• Language: English
• Publisher: Elsevier Science
• Release date: Jan 21, 2014
• ISBN: 9780123972903

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Chapter 1

Polymer Synthesis and Processing

Mahadevappa Y. Kariduraganavar *; Arjumand A. Kittur †; Ravindra R. Kamble *    * Department of Studies in Chemistry, Karnatak University, Dharwad, India

† Department of Chemistry, SDM College of Engineering & Technology, Dharwad, India

Abstract

Polymer scientists have made an extensive research in the development of biodegradable polymers, which could find enormous applications in the area of medical science. Today, various biopolymers have been prepared and utilized in different biomedical applications. Despite the apparent proliferation of biopolymers in medical science, the science and technology of biopolymers is still in its early stages of development. Tremendous opportunities exist and will continue to exist for the penetration of biopolymers in every facet of medical science through intensive research and development. Therefore, this chapter addresses different polymerization methods and techniques employed for the preparation of biopolymers. The emphasis is on the general properties of biopolymers, synthetic protocols, and their biomedical applications. In order to make the useful biomedical devices from the polymers to meet the demands of medical science, various processing techniques employed for the development of devices have been discussed. Further, perspectives in this field have been highlighted and conclusions arrived at. The relevant literature was collected from different sources, including Google sites, books, and reviews.

Keywords

Biopolymers

Polymerization techniques

Polymer extraction

Biomedical applications

Polymer processing

Chapter Outline

1.1 Introduction

1.2 Types of Polymerization

1.2.1 Addition Polymerization

1.2.2 Condensation Polymerization

1.2.3 Metathesis Polymerization

1.3 Techniques of Polymerization

1.3.1 Solution Polymerization

1.3.2 Bulk (Mass) Polymerization

1.3.3 Suspension Polymerization

1.3.4 Precipitation Polymerization

1.3.5 Emulsion Polymerization

1.4 Polymers: Properties, Synthesis, and Their Biomedical Applications

1.4.1 Polycaprolactone

1.4.2 Polyethylene Glycol

1.4.3 Polyurethane

1.4.4 Polydioxanone or Poly-p-Dioxanone

1.4.5 Polymethyl Methacrylate

1.4.6 Polyglycolic Acid or Polyglycolide

1.4.7 Polylactic Acid or Polylactide

1.4.8 Polylactic-co-Glycolic Acid

1.4.9 Polyhydroxybutyrate

1.4.10 Polycyanoacrylates

1.4.11 Polyvinylpyrrolidone

1.4.12 Chitosan

1.4.13 Gelatin

1.4.14 Carrageenan

1.4.15 Hyaluronic Acid

1.4.16 Xanthan Gum

1.4.17 Acacia Gum

1.4.18 Alginate

1.5 Processing of Polymers for Biomedical Devices

1.5.1 Fabrication of Polymer Films

1.5.1.1 Solution Casting

1.5.1.2 Melt Pressing

1.5.1.3 Melt Extrusion

1.5.1.4 Bubble Blown Method

1.5.2 Spinning Industrial Polymers

1.5.2.1 Solution Spinning

1.5.3 Fabrication of Shaped Polymer Objects

1.5.3.1 Compression Molding

1.5.3.2 Injection Molding

1.5.3.3 Reaction Injection Molding

1.5.3.4 Blow Molding

1.5.3.5 Extrusion Molding

1.5.4 Calendaring

1.6 Future Perspectives

1.7 Conclusions

Acknowledgments

The authors wish to thank the UGC, New Delhi, for providing the financial support under UPE-FAR-I program (Contract No. 14-3/2012 [NS/PE]). The authors are grateful to the Department of Tool Design, NTTF, Dharwad, for neatly designing the polymer processing illustrations.

1.1 Introduction

Polymers are the most versatile class of biomaterials, being extensively used in biomedical applications such as contact lenses, pharmaceutical vehicles, implantation, artificial organs, tissue engineering, medical devices, prostheses, and dental materials [1–3]. This is all due to the unique properties of polymers that created an entirely new concept when originally proposed as biomaterials. For the first time, a material performing a structural application was designed to be completely resorbed and become weaker over time. This concept was applied for the first time with catgut sutures successfully and, later, with arguable results, on bone fixation, ligament augmentation, plates, and pins [4,5].

Current research on new and improved biodegradable polymers is focused on more sophisticated biomedical applications to solve the patients' problems with higher efficacy and least possible pains. One example is tissue engineering, wherein biodegradable scaffolds seeded with an appropriate cell type provide a substitute for damaged human tissue while the natural process of regeneration is completed [6,7]. Another important application of biodegradable polymer is in the gene therapy that provides a safer way of gene delivery than use of viruses as vectors [8,9].

Recently, an implant prepared from biodegradable polymer played a tremendous beneficial role in replacing the stainless steel implant during the surgery [10]. This has not necessitated a second surgical event for the removal. In addition to this, the biodegradation may offer other advantages. For example, a fractured bone, fixated with a rigid, nonbiodegradable stainless steel implant, has a tendency for refracture upon removal of the implant. The bone does not carry sufficient load during the healing process, since the load is mainly carried by the rigid stainless steel. However, an implant prepared from biodegradable polymer can be engineered to degrade at a rate that will slowly transfer load to the healing bone [11]. Another exciting application for which biodegradable polymers offer tremendous applications is the basis for the drug delivery, either as drug delivery system alone or in conjunction with functioning as a medical device. In orthopedic applications, the delivery of a polymer-bound morphogenic protein may be used to speed up the healing process after a fracture or delivery of an antibiotic may help to prevent osteomyelitis following surgery [12–14]. Biodegradable polymers also make possible targeting of drugs into sites of inflammation or tumors. Prodrugs with macromolecular carriers have also been used for such purposes. The term prodrug has been coined to describe a harmless molecule, which undergoes a reaction inside the body to release the active drug. Polymeric prodrugs are obtained by conjugating biocompatible polymeric molecules with appropriate drugs. Such macromolecular conjugate accumulates positively in tumors, since the permeability of cell membranes of tumor cells is higher than that of normal cells [1,15,16].

Polymers used as biomaterials can be naturally occurring and synthetic or combination of both. Natural polymers are abundant, usually biodegradable, and offer good biocompatibility [11,17]. The biocompatibility of a polymer depends on the specific adsorption of protein to the polymer surface and the subsequent cellular interactions. These interactions with the surrounding medium are governed mostly by the distribution of functional groups on the surface of biomaterial. Several useful biocompatible polymers of microbial origin are being produced from natural sources by fermentation processes. They are nontoxic and truly biodegradable [18]. Biodegradation is usually catalyzed by enzymes and may involve both hydrolysis and oxidation. Aliphatic chains are more flexible than aromatic ones and can easily fit into the active sites of enzymes, and hence, they are easier to biodegrade. Crystallinity hinders polymer degradation. Irregularities in chain morphology prevent crystallization and favor degradation [19].

Considering the significance and relevance of biodegradable polymers in the area of medical science, we have made an attempt to discuss the different polymerizations and their techniques employed for the preparation of polymers, synthetic methods of both natural and synthetic polymers including their properties and biomedical applications. At the end of the chapter, the methods of polymer processing for the preparation of films, objects, and fibers have also been discussed.

1.2 Types of Polymerization

Polymerizations are generally classified according to the types of reactions involved in the synthesis [20,21]. There are mainly three types of polymerizations.

1.2.1 Addition Polymerization

In this polymerization process, the addition polymers are prepared from monomers without the loss of small molecules. Usually, unsaturated monomers such as olefins, acetylenes, aldehydes, or other compounds undergo addition polymerization. It is also called chain-growth polymerization since reactions are known to proceed in a stepwise fashion by way of reactive intermediates. The process of polymerization is usually exothermic by 8-20 kcal/mol since a π-bond in the monomer is converted to a sigma bond in the polymer. The reaction quickly leads to a polymer with very high molecular weight. The most common and thermodynamically favored chemical transformations of olefins are the addition reactions. Generally, these polymers can be prepared using bulk, solution, suspension, and emulsion polymerization techniques. Sometimes cross-linking can also be achieved using monomers with two double bonds.

Many well-known thermoplastics are the addition-type polymers. Figure 1.1 illustrates some addition polymerization processes.

Figure 1.1Common examples of addition polymerization.

The properties and biomedical applications of some of the important addition polymers are given in Table 1.1 [22,23].

Table 1.1

Properties and Biomedical Uses of Some Common Addition Polymers

1.2.2 Condensation Polymerization

COOH instead of double bonds and each monomer has at least two reactive sites. In this process, high molecular weight can be attained only at high conversions. Most of the reactions have high ΔEa and hence heating is usually required.

NH2 in nylon or proteins). Normally, two or more different monomers are used in the reaction. The bonds between the hydroxyl group, the hydrogen atom, and their respective atoms break forming water from the hydroxyl and hydrogen and the polymer.

Polyester is created through ester linkages between monomers, which involve the functional groups like carboxyl and hydroxyl (an organic acid and an alcohol monomer). Nylon is another common condensation polymer, which can be prepared by reacting diamines with carboxyl derivatives. In this example, the derivative is a dicarboxylic acid, but buta-diacyl chlorides are also used. Another approach used is the reaction of difunctional monomers with one amine and one carboxylic acid group on the same molecule. An example of condensation polymerization is given in Figure 1.2.

Figure 1.2An example of condensation polymerization.

The carboxylic acids and amines link to form peptide bonds, also known as amide groups. Proteins are the condensation polymers made from amino acid monomers. Carbohydrates are also condensation polymers made from sugar monomers such as glucose and galactose. Condensation polymerization is occasionally used to form simple hydrocarbons. This method, however, is expensive and inefficient, so the addition polymer of ethene, i.e., polyethylene, is generally used. Condensation polymers, unlike addition polymers, may be biodegradable. The peptide or ester bonds between monomers can be hydrolyzed by acid catalysts or bacterial enzymes breaking the polymer chain into smaller pieces. The most commonly known condensation polymers are proteins and fabrics such as nylon, silk, or polyester.

As before, a water molecule is removed, and an amide linkage is formed. An acid group remains on one end of the chain, which can react with another amine monomer. Similarly, an amine group remains on the other end of the chain, which can react with another acid monomer. Thus, monomers can continue to join by amide linkages to form a long chain. Because of the type of bond that links the monomers, this polymer is called a polyamide. The polymer made from these two six-carbon monomers is known as nylon 6,6 (Figure 1.3).

Figure 1.3Preparation of nylon 6,6 as an example of condensation polymerization.

Similarly, a carboxylic acid monomer and an alcohol monomer can join together to form an ester linkage followed by a loss of water molecule. The monoester thus formed reacts with another monoester and subsequent reactions yield polyethylene terephthalate (PET). The reaction scheme is shown in Figure 1.4.

Figure 1.4Preparation of polyethylene terephthalate as an example of condensation polymerization.

Since the monomers are joined by ester linkages, the resulting polymer is called polyester. The polycondensation can be achieved in melt, solution, and at interfacial boundary between two liquids in which the respective monomers are dissolved. It is a slow step addition process and molecular weight is > 1,00,000 and highly dependent on monomer stoichiometry. The addition of little amount of tri- or multifunctional monomers develops extensive cross-linking.

1.2.3 Metathesis Polymerization

carbon double bond remains in the polymer backbone chain and such polymers are called polyalkenamers [24]. The mechanism of metathesis polymerization is illustrated in Figure 1.5.

Figure 1.5Mechanism of metathesis polymerization.

The commonly accepted mechanism for the olefin metathesis reaction was proposed by Chauvin. It involves a [2 + 2] cycloaddition reaction between transition metal alkylidene complex and the olefin to form an intermediate metallocyclobutane. This metallocycle then breaks up in the opposite fashion to afford a new alkylidene and new olefin. If this process is repeated, eventually, an equilibrium mixture of olefins will be obtained.

The following are the two different types of metathesis polymerization [25]:

(a) Acyclic diene metathesis (ADMET) polymerization

(b) Ring-opening metathesis polymerization (ROMP)

(a) ADMET polymerization

ADMET starts with an acyclic diene such as 1,5-hexadiene and ends up in a polymer with a double bond in the backbone chain and ethylene as a by-product. The reaction is shown in Figure 1.6.

Figure 1.6The reaction of acyclic diene metathesis polymerization.

(b) ROMP

In this polymerization, a cyclic olefin such as cyclopentene is used to make a polymer that does not have cyclic structures in its backbone and therefore it is called ROMP. Similarly, norbornene is polymerized by ROMP to get polynorbornene (Figure 1.7). Using ROMP, molecules like endo-dicyclopentadiene can also be polymerized to get a polymer with a cyclic olefin in a pendant group and the product is called polydicyclopentadiene. This is used to make big things in one piece. This can also undergo vinyl polymerization to give a cross-linked thermoset material.

Figure 1.7The reaction of ring-opening metathesis polymerization.

1.3 Techniques of Polymerization

Based on the different methods of preparation, the polymerization techniques can be classified broadly into homogeneous and heterogeneous [26–28]. For homogeneous process, the diluted or pure monomers are added directly to one another and the reaction occurs in the media created when mixing the reactants. With heterogeneous process, a phase boundary exists, which acts as an interphase where the reaction occurs.

1.3.1 Solution Polymerization

It is an industrial polymerization technique, wherein a monomer is dissolved in a nonreactive solvent that contains a catalyst. In this method, both the monomer and the resulting polymer are soluble in the solvent. The heat released during the reaction is absorbed by the solvent and thus reduces the reaction rate. Once the maximum or desired conversion is reached, excess solvent is to be removed in order to obtain the pure polymer. The products obtained by this method are relatively low molecular weights because of the possibility of chain transfer. This process is suitable for the production of wet polymers since the removal of excess solvent is difficult and also the solvent is occluded and firmly traps the polymer. Therefore, this polymerization technique is applied when solutions of polymers are required (for ready-made use) for technical applications such as lacquers, adhesives, and surface coatings.

This process is used in the production of sodium polyacrylate, a superabsorbent polymer and neoprene used in disposable diapers and wetsuits, respectively. The polymers produced using this method are generally polyacrylonitrile (PAN), polyacrylic acid, and polytetrafluoroethylene.

1.3.2 Bulk (Mass) Polymerization

Bulk polymerization occurs within the monomer itself. The reaction is catalyzed by additives such as initiator and transfer agents under the influence of heat or light. Since this polymerization process is highly exothermic, it is difficult to control and hence the polymer obtained is generally of nonuniform molecular mass distribution. However, molecular-weight distribution can be easily changed by the use of chain transfer agent. The temperature and pressure can also be varied to control the properties of the final polymer. If the polymer is insoluble in its monomer, it is obtained as a powdery or porous solid. Since the recipe contains primarily the monomers, the polymer formed is usually pure. This is suitable for liquid (or liquefiable) monomers, which can be carried in batch or continuous mode. The product obtained has higher optical clarity, which is suitable for casting especially for clear products (e.g., polymethyl methacrylate (PMMA) films). Low-molecular-weight polymers can also be prepared by this method for adhesives, plasticizers, and lubricants.

1.3.3 Suspension Polymerization

It is a heterogeneous radical polymerization process. Step-growth polymers such as polyesters are manufactured using this technique. In this polymerization, the monomer containing initiator, modifier, etc., is dispersed in a solvent (generally water) by vigorous stirring. The monomer and initiator are insoluble in the liquid phase, so they form beads within the liquid matrix. A suspension agent such as PVA or methyl cellulose is usually added to stabilize the monomer droplets and hinder monomer drops from coming together. The reaction mixture usually has a volume ratio of monomer to liquid phase of 0.10-0.50. A major advantage is that heat transfer is very efficient and the reaction is therefore easily controlled. The reactions are usually carried out in a stirred tank reactor that continuously mixes the solution using turbulent pressure or viscous shear forces. The stirring action helps to keep the monomer droplets separated and creates a more uniform suspension, which leads to a more narrow size distribution of the final polymer beads. The beads look like pearls, hence the name pearl polymerization. This polymerization is not applicable to tacky polymers such as elastomers due to the tendency of agglomerations.

This process is used in the production of many commercial resins, including polyvinyl chloride (PVC), a widely used plastic; styrene resins including polystyrene, expanded polystyrene, and high-impact polystyrene; and PAN and PMMA.

1.3.4 Precipitation Polymerization

It is a heterogeneous polymerization process that begins initially as a homogeneous system in the continuous phase where the monomer and the initiator are completely soluble, but upon initiation, the formed polymer is insoluble and thus precipitates. The precipitated polymer can be separated in the form of a gel or powder by centrifugation or simple filtration. The degree of polymerization is high as there is no problem in heat dissipation. Polyvinyl esters and polyacrylic esters are obtained commercially using hydrocarbons as solvents. PAN is prepared using water as solvent.

1.3.5 Emulsion Polymerization

It is a type of radical polymerization in which the liquid monomer is dispersed in an insoluble liquid leading to an emulsion. The most common type of emulsion polymerization is an oil-in-water emulsion, wherein droplets of monomer (the oil) are emulsified (with surfactants) in a continuous phase of water. Water soluble polymers, such as certain polyvinyl alcohols or hydroxyethyl celluloses, can also be used to act as emulsifiers/stabilizers. The polymerization takes place in the latex particles that form spontaneously in the first few minutes of the process. These latex particles are typically 100 nm in size and are made of many individual polymer chains. The particles are stopped from coagulating with each other because each particle is surrounded by the surfactant (soap); the charge on the surfactant repels other particles electrostatically. When water-soluble polymers are used as stabilizers instead of soap, the repulsion between particles arises as these water-soluble polymers form a hairy layer around a particle that repels other particles, because pushing particles together would involve in compressing these chains. Since polymer molecules are contained within the particles, the viscosity of the reaction medium remains close to that of water and is not dependent on molecular weight. Emulsion polymerizations are designed to operate at high conversion of monomer to polymer. This can result in significant chain transfer to polymer. For dry (isolated) polymers, water removal is an energy-intensive process.

Emulsion polymerization technique is used to manufacture several commercially important polymers. Many of these polymers are used as solid materials and must be isolated from the aqueous dispersion after polymerization. In other cases, the dispersion itself is the end product. A dispersion resulting from the emulsion polymerization technique is often called latex (especially if derived from a synthetic rubber) or an emulsion (even though emulsion strictly speaking refers to a dispersion of an immiscible liquid in water).

1.4 Polymers: Properties, Synthesis, and Their Biomedical Applications

Under this section, general properties, different synthetic methods, and biomedical applications of the most commonly used polymers are discussed.

1.4.1 Polycaprolactone

It is biodegradable polyester with a low melting point around 60 °C and a glass transition temperature of about − 60 °C. Polycaprolactones (PCLs) impart good water, oil, solvent, and chlorine resistance to the polyurethanes (PUs) produced. It is commonly used in the manufacture of specialty PUs. PCL is degraded by hydrolysis of its ester linkages in physiological conditions and has therefore received a great deal of attention for use as an implantable biomaterial. It is especially interesting for the preparation of long-term implantable devices, owing to its degradation, which is even slower than that of polylactide.

This polymer is often used as an additive for resins to improve their processing characteristics and their end-use properties (e.g., impact resistance). Being compatible with a range of other materials, PCL can be mixed with starch to lower its cost and increase biodegradability or it is also added as a polymeric plasticizer to PVC. PCL was approved by the Food and Drug Administration (FDA) in specific applications used in the human body as a drug delivery device and surgical suture (sold under the brand name Monocryl) [29–31]. It is being investigated as a scaffold for tissue repair via tissue engineering and guided bone regeneration membrane. It has been used as the hydrophobic block of amphiphilic synthetic block copolymers used to form the vesicle membrane of polymersomes. In odontology or dentistry (as composite named Resilon), it is used as a component of night guards (dental splints) and in root canal filling. It performs like gutta-percha, has the same handling properties, and for retreatment purposes may be softened with heat or dissolved with solvents like chloroform. The major difference between the PCL-based root canal filling material (Resilon and Real Seal) and gutta-percha is that the PCL-based material is biodegradable but the gutta-percha is not.

PCL is prepared by ring-opening polymerization (ROP) of ε-caprolactone using dibutylzinc-triisobutylaluminum systems as a catalyst [32] such as stannous octoate (Figure 1.8). Recently, a wide range of catalysts for the ROP of caprolactone have been reported [33].

Figure 1.8Synthesis of polycaprolactone.

1.4.2 Polyethylene Glycol

It is known as polyethylene oxide (PEO) or polyoxyethylene, depending on its molecular weight. Polyethylene glycol (PEG) is the basis of a number of laxatives (e.g., macrogol-containing products, such as Movicol and PEG 3350, Softlax, MiraLAX, or GlycoLax). Whole bowel irrigation with PEG and added electrolytes is used for bowel preparation before surgery or colonoscopy. The preparation is sold under the brand names GoLYTELY, GaviLyte-C, NuLytely, GlycoLax, Fortrans, TriLyte, Colyte, Halflytely, Softlax, Lax-a-Day, ClearLax, and MoviPrep. MiraLAX and Dulcolax Balance are sold without prescription for short-term relief of chronic constipation. MiraLAX is currently FDA-approved for adults for a period of 7 days and is not approved for children [34]. The patients suffering from constipation had a better response to these two medications than to tegaserod [35]. These medications soften the fecal mass by osmotically drawing water into the gastrointestinal tract. It is generally well tolerated; however, side effects include bloating, nausea, gas, and diarrhea with excessive use. When attached to various protein medications, PEG allows a slowed clearance of the carried protein from the blood. This makes for a longer-acting medicinal effect and reduces toxicity and allows longer dosing intervals. Examples include PEG-interferon alpha, which is used to treat hepatitis C, and pegfilgrastim (Neulasta), which is used to treat neutropenia. It has been shown that PEG can improve healing of spinal injuries in dogs [36]. It is also noticed that PEG can aid in nerve repair and is also commonly used to fuse β-cells with myeloma cells in monoclonal antibody production.

PEG is used as an excipient in many pharmaceutical products. Lower-molecular-weight variants are used as solvents in oral liquids and soft capsules, whereas solid variants are used as ointment bases, tablet binders, film coatings, and lubricants [37]. When labeled with PEG a near-infrared fluorophore, it has been used in preclinical work as a vascular, lymphatic, and general tumor-imaging agent by exploiting the enhanced permeability and retention effect of tumors [38]. High-molecular-weight PEG (e.g., PEG 8000) has been shown to be a dietary preventive agent against colorectal cancer in animal models [39]. The chemoprevention database shows PEG is the most effective known agent for the suppression of chemical carcinogenesis in rats. The injection of PEG 2000 into the bloodstream of guinea pigs after spinal cord injury leads to rapid recovery through molecular repair of nerve membranes [40]. It is also reported that using PEG can mask antigens without damaging the function and shape of the cell. PEG is being used in the repair of motor neurons damaged in crush or laceration incidents in vivo and in vitro. When coupled with melatonin, 75% of damaged sciatic nerves were rendered viable [41].

PEG is produced by the interaction of ethylene oxide with water, ethylene glycol, or ethylene glycol oligomers [42]. The reaction is catalyzed by acidic or basic catalysts (Figure 1.9). Ethylene glycol and its oligomers are used as a starting material instead of water, as they allow the creation of polymers with a low polydispersity (narrow molecular-weight distribution). Polymer chain length depends on the ratio of reactants.

Figure 1.9Synthesis of polyethylene glycol.

Depending on the type of catalyst, the mechanism of polymerization can be cationic or anionic. The anionic mechanism is preferable since it allows forming PEG with a low polydispersity. Polymerization of ethylene oxide is an exothermic process. Overheating or contaminating ethylene oxide with catalysts such as alkalis or metal oxides can lead to runaway polymerization, which can end in an explosion after a few hours. PEO, or high-molecular-weight PEG, is synthesized by suspension polymerization technique. It is necessary to hold the growing polymer chain in solution in the course of the polycondensation process. The reaction is catalyzed by magnesium-, aluminum-, or calcium-organo element compounds. To prevent coagulation of polymer chains from solution, chelating additives such as dimethylglyoxime are added. Alkali catalysts such as sodium hydroxide (NaOH), potassium hydroxide (KOH), or sodium carbonate (Na2CO3) are used to prepare low-molecular-weight PEG [43].

1.4.3 Polyurethane

This polymer is composed of a chain of organic units joined by urethane links. Most of the PUs are thermosetting polymers, which do not melt upon heating. PUs can outperform many other polymers in flexibility, tear resistance, and abrasion resistance. This is because many devices that are used in these areas can rub against other materials and bend repeatedly. Without PUs, the continued rubbing and bending could result in the device weakening or could cause failure in extreme cases. Today's PUs have been formulated to provide good biocompatibility, flexural endurance, high strength, high abrasion resistance, and processing versatility over a wide range of applications. These attributes are important in supporting new applications continually being found by medical device manufacturers including artificial hearts, catheter tubing, feeding tubes, surgical drapes and drains, intra-aortic balloon pumps, dialysis devices, nonallergenic gloves, medical garments, hospital bedding, wound dressings, and so on [44]. Thermoplastic polyurethanes (TPUs), also called PU elastomers, have molecular structures similar to that of human proteins. Protein absorption, which is the beginning of the blood coagulation cascade, was found to be slower or less than other materials. This makes them ideal candidates for a variety of medical applications requiring adhesive strength and unique biomimetic and antithrombotic properties. For example, TPUs are currently being used as a special sealant to bind bundles of hollow fibers in artificial dialysis cylinders. With the advent of new surgical implants, biomedical PUs can lead the way to eliminate some acute and chronic health challenges. PUs are often used in cardiovascular devices due to their good biocompatibility and their mechanical properties [45]. Patients generally prefer to use PU medical devices compared to other materials due to their comfort. By virtue of their wide range of properties, PUs made significant contributions to the medical industry and will continue to play an important role in the future of science and medicine.

There are two principal methods of forming PUs [46,47], viz., the reaction of bischloroformates prepared from dihydroxy compounds with excess phosgene and with diamines (Method I) and more important from the industrial perspective and the reaction of diisocyanates with dihydroxy compounds (Method II) that has the advantage owing to the nonformation of by-products (Figure 1.10). PU products often are simply called urethanes, but should not be confused with ethyl carbamate, which is also called urethane. PUs neither contain nor are produced from ethyl carbamate.

Figure 1.10Synthesis of polyurethanes.

1.4.4 Polydioxanone or Poly-p-Dioxanone

It is a colorless, crystalline, biodegradable synthetic polymer. Chemically, polydioxanone is a polymer of multiple repeating ether-ester units. It is characterized by a glass transition temperature in the range of − 10 and 0 °C and a crystallinity of about 55%. Polydioxanone is generally extruded into fibers; however, care should be taken to process the polymer to the lowest possible temperature in order to avoid its spontaneous depolymerization back to the monomer. The ether oxygen group in the backbone of the polymer chain is responsible for its flexibility [48,49].

Polydioxanone is used in the preparation of surgical sutures. Other biomedical applications include orthopedics, plastic surgery, drug delivery, cardiovascular devices, and tissue engineering [48,49]. It is degraded by hydrolysis, and the end products are mainly excreted in urine, the remainder being eliminated by digestive or exhaled as CO2. The biomaterial is completely reabsorbed in 6 months and can be seen only a minimal foreign body reaction tissue in the vicinity of the implant [50].

It is obtained by ROP of the monomer p-dioxanone. The process requires heat and an organometallic catalyst like zirconium acetylacetonate or zinc L-lactate. The reaction is shown in Figure 1.11.

Figure 1.11Synthesis of polydioxanone.

1.4.5 Polymethyl Methacrylate

It is a transparent thermoplastic, often used as a lightweight or shatter-resistant alternative to glass [51]. It has a density of 1.17-1.30 g/cm³, which is less than half that of glass. It also has good impact strength higher than both glass and polystyrene. However, the impact strength of PMMA is still significantly lower than polycarbonate and some engineered polymers. Although it is not technically a type of glass, the substance has sometimes historically been called acrylic glass. Chemically, it is the synthetic polymer of methyl methacrylate. It has also been sold under many different names, including ACRYLITE®, Lucite, Plexiglass, and Perspex. The glass transition temperature (Tg) of atactic PMMA is 105 °C. The Tg values of commercial grades of PMMA range from 85 to 165 °C, the range being is so wide because of the vast number of commercial compositions that are copolymers with comonomers other than methyl methacrylate. PMMA is thus an organic glass at room temperature; i.e., it is below its Tg [52]. All common molding processes may be used to prepare biomedical devices including injection molding, compression molding, and extrusion. The highest quality PMMA sheets are produced by cell casting, but in this case, the polymerization and molding steps occur concurrently. The strength of the material is higher than molding grades owing to its extremely high molecular mass. Rubber toughening has been used to increase the strength of PMMA due to its brittle behavior in response to applied loads. PMMA swells and dissolves in many organic solvents. It also has poor resistance to many other chemicals on account of its easily hydrolyzed ester groups. Nevertheless, its environmental stability is superior to most other plastics such as polystyrene and polyethylene. PMMA has a maximum water absorption ratio of 0.3-0.4% by weight. Tensile strength decreases with increased water absorption [53]. Its coefficient of thermal expansion is relatively high at 5-10 × 10− 5 K− 1 [54].

PMMA has a good compatibility with human tissue, and it is used in the manufacture of rigid intraocular lenses in the eye when the original lens has been removed in the treatment of cataracts [55]. Historically, hard contact lenses were frequently made of this material. Soft contact lenses are often made of a related polymer, where acrylate monomers containing one or more hydroxyl groups make them hydrophilic. In orthopedic surgery, PMMA bone cement is used to affix implants and to remodel lost bone. PMMA has also been linked to cardiopulmonary events in the operating room due to hypotension [56]. Bone cement acts like a grout and not so much like a glue in arthroplasty. Although sticky, it does not bond to either the bone or the implant; it primarily fills the spaces between the prosthesis and the bone preventing motion. The disadvantage of this bone cement is that it heats up to 82.5 °C while setting that may cause thermal necrosis of neighboring tissue. A major consideration when using PMMA cement is the effect of stress shielding. Since PMMA has a Young's modulus between 18 and 31 GPa [57], which is greater than that of natural bone (around 14 GPa for human cortical bone) [58], the stresses are loaded into the cement, and hence, the bone no longer receives the mechanical signals to continue bone remodeling and so resorption will occur [59].

Dentures are often made of PMMA and can be color-matched to the patient's teeth and gum tissue. PMMA is also used in the production of ocular prostheses, such as the osteo-odonto-keratoprosthesis. In cosmetic surgery, tiny PMMA microspheres suspended in some biological fluid are injected under the skin to reduce wrinkles or scars permanently. A large majority of white dental filling materials (composites) have PMMA as their main organic component. Emerging biotechnology and biomedical research uses PMMA to create microfluidic lab-on-a-chip devices, which require 100-μm-wide geometries for routing liquids. These small geometries are amenable to use PMMA in a biochip fabrication process and offer moderate biocompatibility. Bioprocess chromatography columns use cast acrylic tubes as an alternative to glass and stainless steel. These are pressure-rated and satisfy stringent requirements of materials for biocompatibility, toxicity, and extractable.

PMMA is produced by emulsion polymerization, solution polymerization, and bulk polymerization. Generally, radical initiation is used (including living polymerization methods), but anionic polymerization of PMMA can also be performed. PMMA produced by radical polymerization (all commercial PMMA) is atactic and completely amorphous. Free-radical polymerization is carried out using benzoyl peroxide as an initiator in the presence of N,N-dimethyl-p-toluidine (Figure 1.12) [60].

Figure 1.12Synthesis of polymethyl methacrylate.

1.4.6 Polyglycolic Acid or Polyglycolide

It is linear aliphatic polyester and undergoes biodegradable. It has been known since 1954 as a tough fiber-forming thermoplastic polymer. Polyglycolide has a glass transition temperature in the range of 35-40 °C and its melting point is reported to be in the range of 225-230 °C. Polyglycolic Acid (PGA) also exhibits an elevated degree of crystallinity of about 45-55%, thus resulting in insolubility in water [61]. The solubility of this polyester also depends on its molecular weight. The low-molecular-weight oligomers are sufficiently soluble in organic solvents, whereas high-molecular-weight polymers are insoluble in almost all common organic solvents such as acetone, dichloromethane, chloroform, ethyl acetate, and tetrahydrofuran. However, polyglycolide is soluble in highly fluorinated solvents like hexafluoroisopropanol and hexafluoroacetone sesquihydrate that can be used to prepare solutions of the high-molecular-weight polymer for melt spinning and film preparation. Fibers of PGA exhibit high strength and modulus (7 GPa) and are particularly stiff [62].

Owing to its hydrolytic instability, initially, its use was limited. Currently, polyglycolide and its copolymers poly(lactic-co-glycolic acid) with lactic acid, poly(glycolide-co-caprolactone) with ε-caprolactone, and poly(glycolide-co-trimethylene carbonate) with trimethylene carbonate) are widely used to develop synthetic absorbable sutures that were marketed under the trade name of Dexon and are now sold as Surgicryl [61].

PGA suture is absorbable and braided multifilament. It is coated with N-laurin and L-lysine, which render the thread extremely smooth, soft, and safe for knotting. It is also coated with magnesium stearate and finally sterilized with ethylene oxide gas. It is naturally degraded in the body within 60-90 days by hydrolysis. Elderly, anemic, and malnourished patients may absorb the suture more quickly. It is commonly used for subcutaneous sutures, intracutaneous closures, and abdominal and thoracic surgeries. The traditional role of PGA as a biodegradable suture material has led to its evaluation in other biomedical fields. Implantable medical devices have been produced with PGA, including anastomosis rings, pins, rods, plates, and screws [61]. It has also been explored for tissue engineering or controlled drug delivery. Tissue engineering scaffolds made with polyglycolide have been generally obtained in the form of nonwoven meshes [63].

Polyglycolide can be obtained through several different processes starting with different materials: polycondensation of glycolic acid, ROP of glycolide, and solid-state polycondensation of halogenoacetates. Polycondensation of glycolic acid is the simplest process available to prepare PGA, but it is not the most efficient since it yields a low-molecular-weight product. The glycolic acid is heated around 175-185 °C at atmospheric pressure until water ceases to distil. Subsequently, pressure is reduced to 150 mmHg at the same temperature for about 2 h to obtain low-molecular-weight polyglycolide [63,64].

The most common method to prepare a high-molecular-weight polymer is ROP of glycolide. Glycolide can be prepared by heating under reduced pressure using low-molecular-weight PGA and collecting the diester by means of distillation. Further ROP of glycolide can be catalyzed by antimony trioxide or antimony trihalides, zinc compounds (zinc lactate) and stannous octoate (Sn(II) 2-ethylhexanoate), or tin alkoxides. Stannous octoate is the most commonly used initiator, as it is approved by the FDA as a food stabilizer. Usage of other catalysts has also been reported. Among these, aluminum isopropoxide, calcium acetylacetonate, and several lanthanide alkoxides (e.g., yttrium isopropoxide) are important. The procedure followed for ROP is briefly outlined: a catalytic amount of initiator is added to glycolide under a nitrogen atmosphere at a temperature of 195 °C. The reaction is allowed to proceed for about 2 h and then temperature is raised to 230 °C for about half an hour. After solidification, the resulting high-molecular-weight polymer is collected [64–66]. The reaction scheme for the preparation of PGA is shown in the Figure 1.13.

Figure 1.13Synthesis of polyglycolic acid.

In the thermally induced solid-state polycondensation of halogenoacetates (X-CH2COO−M+ where M is a monovalent metal-like sodium and X is a halogen-like chlorine), resulting in the formation of polyglycolide and small crystals of a salt, polycondensation is carried out by heating halogenoacetate, like sodium chloroacetate, at temperature around 160-180 °C while continuously purging nitrogen through the reaction vessel. During the reaction, polyglycolide is formed along with sodium chloride, which precipitates within the polymeric matrix; the salt can be conveniently removed by washing the PGA with water [67].

PGA can also be obtained by reacting carbon monoxide, formaldehyde, or one of its related compounds like paraformaldehyde or trioxane, in the presence of an acidic catalyst. The autoclave is loaded with the catalyst (chlorosulfonic acid), dichloromethane, and trioxane, and then it is charged with carbon monoxide until a specific pressure is reached. The reaction mixture is stirred and allowed to proceed at a temperature of about 180 °C for 2 h. Upon completion, the unreacted carbon monoxide is discharged and a mixture of low- and high-molecular-weight polyglycolide is collected [68].

1.4.7 Polylactic Acid or Polylactide

It is an aliphatic polyester derived from renewable resources, such as corn starch, tapioca roots, chips or starch, or sugarcane. Polylactic acid or polylactide (PLA) can withstand temperatures up to 110 °C [69]. PLA is soluble in chlorinated solvents, hot benzene, tetrahydrofuran, and dioxane [70]. It can be processed like other thermoplastics into fiber (for example, using conventional melt spinning processes) and film. Due to the chiral nature of lactic acid, several distinct forms of polylactide exist: poly-L-lactide (PLLA) is the product resulting from polymerization of L,L-lactide (also known as L-lactide). PLLA has a crystallinity of around 37%, a glass transition temperature in the range 60-65 °C, a melting temperature around 173-178 °C, and a tensile modulus about 2.7-16 GPa [71,72]. The melting temperature of PLLA can be increased up to 40-50 °C, and its heat deflection temperature can be increased from approximately 60-190 °C by physically blending the polymer with PDLA (poly-D-lactide). PDLA and PLLA form a highly regular stereocomplex with increased crystallinity. The temperature stability is maximized when a 50:50 blend is used, but even at lower concentrations of 3-10% of PDLA, there is still a substantial improvement. In the latter case, PDLA acts as a nucleating agent, thereby increasing the crystallization rate. Biodegradation of PDLA is slower than that of PLA due to higher crystallinity of PDLA.

PLA is prone to degrade into innocuous lactic acid and it is used as medical implants in the form of screws, pins, rods, and as a mesh. Depending on the type of implants, it breaks down in the body within 6 months to 2 years. This gradual degradation is desirable for a support structure, because it gradually transfers the load to the body (e.g., the bone) as that organ heals. Pure PLLA is primarily used for lipoatrophy of cheeks (facial volume enhancer) [73]. The preparation scheme of PLA is given in Figure 1.14.

Figure 1.14Synthesis of polylactic acid.

There are two important methods for PLA synthesis: direct polycondensation of lactic acid and ROP of lactic acid cyclic dimer, known as lactide. In direct condensation, solvent is used and higher reaction times are required. The resulting polymer is a material of low to intermediate molecular weight. ROP of the lactide needs catalyst but results in PLA with controlled molecular weight. Depending on the monomer and reaction conditions, it is possible to control the ratio and sequence of D- and L-lactic acid units in the final polymer [74,75].

1.4.8 Polylactic-co-Glycolic Acid

It is a copolymer used in therapeutic devices owing to its biocompatibility and biodegradability. Depending on the ratio of lactide to glycolide used for the polymerization, different forms of polylactic-co-glycolic acid (PLGA) can be obtained. Generally, all PLGAs are amorphous rather than crystalline and show a glass transition temperature in the range of 40-60 °C. Unlike the homopolymers of lactic acid (polylactide) and glycolic acid (polyglycolide) that show poor solubility, PLGA can be dissolved in a wide range of common solvents, including chlorinated solvents, tetrahydrofuran, acetone, or ethyl acetate [76].

PLGA degrades by hydrolysis of its ester linkages in the presence of water. It has been shown that the time required for degradation of PLGA is related to the monomers' ratio used in the production. The higher the content of glycolide units, the lower the time required for degradation. An exception to this rule is the copolymer with 50:50 monomers' ratio, which exhibits the faster degradation (about 2 months). In addition, polymers that are end-capped with esters (as opposed to the free carboxylic acid) demonstrate longer degradation half-lives.

PLGA has been successful as a biodegradable polymer as it undergoes hydrolysis in the body to produce the original monomers, lactic acid, and glycolic acid. These two monomers under normal physiological conditions are by-products of various metabolic pathways in the body. Since the body effectively deals with the two monomers, there is minimal systemic toxicity associated with using PLGA for drug delivery or biomaterial applications. Also, the possibility to tailor the polymer degradation time by altering the ratio of the monomers used during synthesis has made PLGA a common choice in the production of a variety of biomedical devices such as grafts, sutures, implants, prosthetic devices, and micro- and nanoparticles and also used in various therapeutic aspects. As an example, a commercially available drug delivery device using PLGA is Lupron Depot® for the treatment of advanced prostate cancer [77,78].

PLGA is synthesized by means of random ring-opening copolymerization of two different monomers, the cyclic dimers (1,4-dioxane-2,5-diones) of glycolic acid and lactic acid. Common catalysts used in the preparation of this polymer include tin(II) 2-ethylhexanoate, tin(II) alkoxides, or aluminum isopropoxide. During polymerization, successive monomeric units of glycolic or lactic acid are linked together in PLGA by ester linkages, thus yielding linear aliphatic polyester [48]. Figure 1.15 illustrates the reaction scheme for PLGA preparation.

Figure 1.15Synthesis of poly(lactic-co-glycolic acid).

1.4.9 Polyhydroxybutyrate

It is a polyhydroxyalkanoate, a polymer belonging to the polyesters class that are of interest as bioderived, nontoxic, and biodegradable plastics [79]. It is water-insoluble and relatively resistant to hydrolytic degradation. This differentiates polyhydroxybutyrate (PHB) from most other currently available biodegradable plastics, which are either water-soluble or moisture-sensitive. It exhibits good oxygen permeability and good ultraviolet resistance but poor resistance to acids and bases. It is soluble in chloroform and other chlorinated hydrocarbons. It melts at 175 °C with a glass transition temperature of about 2 °C. The tensile strength is about 40 MPa and close to that of polypropylene. It sinks in water, while polypropylene floats and therefore facilitates anaerobic biodegradation in sediments. The poly-3-hydroxybutyrate (P3HB) form of PHB is probably the most common type of polyhydroxyalkanoate, but other polymers of this class are produced by a variety of organisms. These include poly-4-hydroxybutyrate, polyhydroxyvalerate (PHV), polyhydroxyhexanoate, polyhydroxyoctanoate, and their copolymers. The structures of P3HB, PHV, and PHBV are shown in Figure 1.16.

Figure 1.16Structures of P3HB, PHV, and PHBV.

PHB is produced by microorganisms (such as Ralstonia eutropha or Bacillus megaterium) apparently in response to conditions of physiological stress. The polymer is primarily a product of carbon assimilation (from glucose or starch) and is employed by microorganisms as a form of energy storage molecule to be metabolized when other common energy sources are not available. Since it is biocompatible, it is suitable for biomedical applications. PHB is sold in the trade name of Biopol. It is currently used in the medical industry for internal suture. It is nontoxic and biodegradable, so it does not have to be removed after recovery [80,81]. Microbial biosynthesis of PHB starts with the condensation of two molecules of acetyl-CoA to give acetoacetyl-CoA, which is subsequently reduced to hydroxybutyryl-CoA. The latter compound is then used as a monomer to polymerize PHB [80,82]. The biosynthesis of PHB is shown in Figure 1.17.

Figure 1.17Biosynthesis of polyhydroxybutyrate.

1.4.10 Polycyanoacrylates

α-Cyanoacrylate is a nontoxic acrylic resin that rapidly polymerizes in the presence of water (hydroxide ion) forming long, straight chains, joining the bonded surfaces together. α-Polycyanoacrylates have the general formula as shown in Figure 1.18, where the group R can be methyl, butyl, hexyl, octyl, and so on [83,84].

Figure 1.18General formula of polycyanoacrylates.

The α-cyanoacrylates polymerize by an anionic mechanism in the presence of water (Figure 1.19). Higher alkyl derivatives polymerize more rapidly. The cyanoacrylates when exposed to normal level of humidity in the air cause polymerization rapidly. Because of this property, α-cyanoacrylate is applied thinly to ensure that reaction proceeds rapidly and forms a strong bond within a reasonable time [85].

Figure 1.19Polymerization of α-cyanoacrylate.

Usually for medical uses, cyanoacrylates with larger alkyl ester groups such as poly(octyl cyanoacrylate) are preferred since short alkyl groups like methyl groups can irritate tissues. Cyanoacrylate adhesives provide unique benefits for their use in medical device manufacturing processes. The usage of cyanoacrylate medical adhesives as a replacement for the classical suture is in view of its good cosmetic effect, reduced pain and recovery period, and preference by the patients. Hence, these are more efficient, offer low surgery time, and therefore reduced cost. Cyanoacrylates find applications in drug delivery and targeting systems. In addition to their use as skin adhesives, they have been used as adhesives in corneal and retinal surgery and as an adjunct to suturing in internal surgery. They have also shown to be effective in skin burns and bone and cartilage grafts. Dentists use cyanoacrylates in dental cements and fillings [86].

1.4.11 Polyvinylpyrrolidone

Polyvinylpyrrolidone (PVP), commonly called polyvidone or povidone, is a water-soluble polymer made from the monomer N-vinylpyrrolidone [87,88]. Dry PVP is a light flaky hygroscopic powder and readily absorbs up to 40% of water by its weight. In solution, it has excellent wetting properties and readily forms films, which makes it good as a coating or an additive to coatings. PVP can be prepared by free-radical polymerization from its monomer N-vinylpyrrolidone in the presence of AIBN as an initiator as shown in Figure 1.20 [87,88].

Figure 1.20Synthesis of polyvinylpyrrolidone.

The PVP was used as a blood plasma expander for trauma victims. It is used as a binder in many pharmaceutical tablets and it simply passes through the body when it is administered orally [89]. However, autopsies have found that crospovidone does contribute to pulmonary vascular injury in substance abusers who have injected pharmaceutical tablets intended for oral consumption [90]. PVP added to iodine forms a complex called povidone-iodine that possesses disinfectant properties. This complex is used in various products like solutions, ointment, pessaries, liquid soaps, and surgical scrubs. It is known under the trade name Betadine and Pyodine. It is used in pleurodesis (fusion of the pleura because of incessant pleural effusions). For this purpose, povidone-iodine is equally effective and safe as talc and may be preferred because of easy availability and low cost [91]. It is used as an aid for increasing the solubility of drugs in liquid and semiliquid dosage forms (syrups and soft gelatin capsules) and as an inhibitor of recrystallization.

1.4.12 Chitosan

It is a linear polysaccharide composed of randomly distributed β-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is made by treating shrimp and other crustacean shells such as crabs and krills with the alkali NaOH. Chitosan is a naturally abundant and renewable polymer and has excellent property such as biodegradability, biocompatibility, nontoxicity, and good adsorption [92]. The structure of chitosan is given in Figure 1.21.

Figure 1.21Structure of chitosan.

Chitosan has a number of biomedical uses. In medicine, it may be useful in bandages to reduce bleeding and as an antibacterial agent. It can also be used to help deliver drugs through the skin. Properties of chitosan allow it to rapidly clot blood, and it has recently gained approval for use in bandages and other hemostatic agents. Chitosan hemostatic products have been used to quickly stop bleeding and to reduce blood loss and hence result in 100% survival [93]. Chitosan hemostatic products reduce blood loss in comparison to gauze dressings and increase patient survival [94]. Chitosan is hypoallergenic and has natural antibacterial properties, which further support its use in field bandages [95].

Chitosan hemostatic agents are often chitosan salts made from mixing chitosan with an organic acid (such as succinic or lactic acid) [96]. The hemostatic agent works by an interaction between the cell membrane of erythrocytes (negative charge) and the protonated chitosan (positive charge) leading to involvement of platelets and rapid thrombus formation [97]. The chitosan salts can be mixed with other materials to make them more absorbent (such as mixing with alginate) [98] or to vary the rate of solubility and bioabsorbability of the chitosan salt [96]. The chitosan salts are biocompatible and biodegradable, making them useful as absorbable hemostats. The protonated chitosan is broken down by lysozyme in the body to glucosamine [97], and the conjugate bases of the acid (such as lactate or succinate) are substances naturally found in the body. The chitosan salt may be placed on an absorbable backing [99].

Chitosan can be used in transdermal drug delivery. It is mucoadhesive in nature and reactive (so it can be produced in many different forms) and, most importantly, has a positive charge under acidic conditions. This positive charge comes from protonation of its free amino groups. Lack of a positive charge means chitosan is insoluble in neutral and basic environments. However, in acidic environments, protonation of the amino groups leads to an increase in solubility. The implications of this are very important to biomedical applications. This molecule will maintain its structure in a neutral environment but will solubilize and degrade in an acidic environment. It means chitosan can be used to transport a drug to an acidic environment, where the chitosan packaging will then degrade, releasing the drug to the desired environment. One example of this drug delivery has been the transport of insulin [100,101].

Chitosan membranes have been proposed as an artificial kidney membrane because of their suitable permeability and high tensile strength. Chitosan and its same derivatives are used to prepare scaffolds for tissue engineering applications. It can also be used for designing artificial skin, treatment of brain-scalp damage, and in plastic skin surgery. Chitosan has replaced the synthetic polymers in ophthalmological applications due to its characteristic properties such as optical clarity, adequate mechanical stability, sufficient optical correction, wettability, and compatibility.

Crustacean shells consist of 30-40% proteins, 30-50% calcium carbonate, and 20-30% chitin and also contain pigments of a lipidic nature such as carotenoids (astaxanthin, canthaxanthin, lutein, and β-carotene). These proportions vary with species and with season. On the other hand, chitin is associated with a higher protein content but lower carbonate concentration. Chitin is extracted by acid treatment to dissolve the calcium carbonate followed by alkaline extraction to dissolve the proteins and by a depigmentation step to obtain a colorless product mainly by removing the astaxanthin [102].

Chitosan is prepared by hydrolysis of acetamide groups of chitin. This is normally conducted by severe alkaline hydrolysis treatment due to the resistance of such groups imposed by the trans arrangement of the C2-C3 substituent in the sugar ring [103]. Thermal treatments of chitin under strong aqueous alkali are usually needed to give partially deacetylated chitin (lower than 30%), regarded as chitosan. Usually, NaOH or KOH are used at a concentration of 30-50% (w/v) at high temperature (100 °C). The steps involved in the extraction of chitosan are illustrated in the Figure 1.22.

Figure 1.22Extraction process of chitosan.

1.4.13 Gelatin

Gelatin is a translucent, natural, nontoxic, colorless, brittle (when dry), flavorless solid polymer. This is obtained by partial hydrolysis of collagen derived from skin, white connective tissue, and animal bones. On a large scale, gelatin is made from by-products of the meat and leather industry [104]. Recently, fish by-products have also been considered because they eliminate some of the religious obstacles surrounding gelatin consumption [105]. The raw materials are prepared by different curing, acid, and alkali processes, which are employed to extract the dried collagen hydrolysate. These processes [106] may take up to several weeks, and differences in such processes have great effects on the properties of the final gelatin products.

Gelatin can also be prepared in the home. Boiling certain cartilaginous cuts of meat or bones will result in gelatin being dissolved into the water. Depending on the concentration, the resulting stock (when cooled) will naturally form a jelly or gel. This process is used for aspic. While there are many processes whereby collagen can be converted to gelatin, they all have several factors in common. The intermolecular and intramolecular bonds that stabilize insoluble collagen rendering it insoluble must be broken, and the hydrogen bonds that stabilize the collagen helix must also be broken [107]. The manufacturing processes of gelatin consist of three main stages:

a. Pretreatments to make the raw materials ready for the main extraction step and to remove impurities that may have negative effects on physicochemical properties of the final gelatin product

b. The main extraction step, which is usually done with hot water or dilute acid solutions as a multistage extraction to hydrolyze collagen into gelatin

c. The refining and recovering treatments including filtration, clarification, evaporation, sterilization, drying, rutting, grinding, and sifting to remove the water from the gelatin solution, to blend the gelatin extracted, and to obtain dried, blended, and ground final product

Although gelatin is 98-99% protein by dry weight, it has less nutritional value than many other complete protein sources. Gelatin is unusually high in the nonessential amino acids glycine and proline (i.e., those produced by the human body) while lacking certain essential amino acids (i.e., those not produced by the human body). It contains no tryptophan and is deficient in isoleucine, threonine, and methionine.

The approximate amino acid composition of gelatin is as follows: glycine 21%, proline 12%, hydroxyproline 12%, glutamic acid 10%, alanine 9%, arginine 8%, aspartic acid 6%, lysine 4%, serine 4%, leucine 3%, valine 2%, phenylalanine 2%, threonine 2%, isoleucine 1%, hydroxylysine 1%, methionine and histidine < 1%, and tyrosine < 0.5%. These values vary, especially the minor constituents, depending on the source of the raw material and processing technique [108]. The structure of gelatin unit is given in Figure 1.23.

Figure 1.23Structure of gelatin unit.

Gelatin is also a topical hemostatic and is applied on bleeding wound and tied in bandage. This hemostatic action is based on platelet damage at the contact of blood with gelatin, which activates the coagulation cascade. Gelatin also causes a tamponading effect—blood flow stoppage into a blood vessel by a constriction of the vessel by an outside force. Gelatin has also been claimed to promote general joint health and found that it relieved knee joint pain and stiffness in athletes [109]. Oral gelatin consumption has beneficial therapeutic effect on hair loss in both men and women [110,111] and has beneficial effect for some fingernail changes and diseases [112–114].

1.4.14 Carrageenan

Carrageenans or carrageenins are a family of linear sulfated polysaccharides that are extracted from red seaweeds. Carrageenans are large, highly flexible molecules that curl forming helical structures, and therefore, they have an ability to form a variety of different gels at room temperature. All carrageenans are high-molecular-weight polysaccharides made up of repeating galactose units and 3,6-anhydrogalactose, both sulfated and nonsulfated. The units are joined by alternating alpha 1-3 and beta 1-4 glycosidic linkages [115]. In view of their gelling, thickening, and stabilizing properties, they are widely used in the food industry. Their main application is in dairy and meat products, due to their strong interactions with protein. The structure of carrageenan is given in Figure 1.24.

Figure 1.24Structure of carrageenan.

There are three main commercial classes of carrageenan (Figure 1.25).

Figure 1.25Structures of kappa, iota, and lambda carrageenans.

a. Kappa forms strong, rigid gels in the presence of potassium ions; it reacts with dairy proteins. It is sourced mainly from Kappaphycus alvarezii [116].

b. Iota forms soft gels in the presence of calcium ions. It is produced mainly from Eucheuma denticulatum [116].

c. Lambda does not form gel and is used to thicken dairy products. The most common source is Gigartina from South America.

The primary differences that influence the properties of kappa, iota, and lambda carrageenans are the number and position of the ester sulfate groups on the repeating galactose units. Many red algal species produce different types of carrageenans during their developmental history. For instance, the genus Gigartina produces mainly kappa carrageenan during its gametophytic stage and lambda carrageenan during its sporophytic stage. All are soluble in hot water, but in cold water, only the lambda forms (and the sodium salts of the other two) are soluble. Carrageenan is mainly composed of dietary fiber, which balances the nutrition better [117]. Technically, carrageenan is considered a dietary fiber