Technological challenges and advances: from lactic acid to polylactate and copolymers

CHAPTER

Technological challenges and advances: from lactic acid to polylactate and copolymers

5

Luciana Fontes Coelho1, Susan Michelz Beitel1 and Jonas Contiero1,2 1

Department of Biochemistry and Microbiology, Institute Bioscience, Sa˜o Paulo State University (UNESP), Sa˜o Paulo, Sa˜o Paulo, Brazil 2Associate Laboratory IPBEN-UNESP, Rio Claro, Sa˜o Paulo, Brazil

5.1 LACTIC ACID Lactic acid (2-hydroxypropanoic acid), CH3CHOHCOOH, is an organic acid that has been extensively used worldwide in a variety of industrial and biotechnological applications. The existence of an asymmetric carbon in the alpha position of the acid function is the source of two enantiomeric forms of this molecule, called L(1) and D( ) (Fig. 5.1) (Ghaffar et al., 2014; Sodegard and Stolt, 2002). Lactic acid may be obtained chemically or by microbial fermentation. Production by fermentation results in the formation of D( ) or L(1) lactic acid, or a racemic mixture, depending on the microorganism used. Homofermentative methods are preferred for use in industrial production, since this pathway results in high product yield and low byproduct formation (Mehta et al., 2007). Lactic acid synthesized by most bacteria occurs in two forms of stereoisomers, however, only a few have the homofermentative character. In the last stage of lactic fermentation, pyruvic acid is converted to lactic acid by the enzyme lactate dehydrogenase (LDH) which is NAD 1 dependent. Each isomer consists of a specific LDH; L-lactate dehydrogenase (L-LDH) is related to the conversion of the L(1) isomer, whereas D( ) lactic acid is produced by D-lactate dehydrogenase (Stock et al., 1997). Some bacteria present the lactate racemase (LR), responsible for the conversion of isomer D( ) to L(1) and vice versa. In addition, the enzymes responsible for determining the lactic acid isomerism produced are expressed at different levels depending on the genetic characteristics of the microorganisms (Garvie, 1980). The purity of the isomers L(1) and D( ) lactic acid is the main factor determining the physical properties of PLA, different types of lactic acid polymers are formed. The properties of PLA depend on the proportion of enantiomers, which allows the production of polymers with different characteristics aimed at specific Materials for Biomedical Engineering: Hydrogels and Polymer-based Scaffolds. DOI: https://doi.org/10.1016/B978-0-12-816901-8.00005-5 © 2019 Elsevier Inc. All rights reserved.

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CHAPTER 5 Technological challenges and advances

FIGURE 5.1 Chemical structures of lactic acid enantiomers (Shi et al., 2013).

industrial applications (Auras et al., 2003). PLA with high crystallinity and a high melting point that is suitable for fiber production can be produced from pure isomers of L(1) lactic acid and D( ) lactic acid, but not from racemic isomers (mixture of L(1) and D( ) isomers). Therefore, many studies aim to obtain the pure form of D( ) (Tanaka et al., 2006; Lu et al., 2009; Beitel et al., 2017) or L(1) isomers (Wee et al., 2006b; Lima et al., 2010; Coelho et al., 2018). The isomeric purity of lactic acid is influenced by the culture medium of the microorganism (Madhavan Nampoothiri et al., 2010). Some studies involving metabolic engineering work on directing the production of only one isomer by silencing a specific LDH in order to obtain high purity lactic acid production (Okano et al., 2010; Assavasirijinda et al., 2016; Awasthi et al., 2018). To solve this problem, bacteria have been engineered to increase the chemical and optical purity of lactic acid. Native Lb. helveticus produces a racemic mixture of L(1) and D( ) lactic acid. By removing the promoter region of the gene for D ( ) lactate dehydrogenase, Lb. helveticus produced only the L(1) isomer (KylaNikkila et al., 2000). In Escherichia coli (Mazumdar et al., 2010), genes encoding enzymes that catalyze the conversion of pyruvate to succinate, acetate, and ethanol were inactivated, resulting in increased lactate production and chemical purity. Lactic acid bacteria are able to ferment sugar through different routes resulting in either a homo- or heterofermentative process. The homofermentative pathway only results in lactic acid as the end product of glucose metabolism via the Embden Meyerhof Parnas pathway (Fig. 5.2A), whereas in the heterofermentative route equimolar amounts of lactic acid, carbon dioxide, and ethanol or acetate are formed from glucose via pentose-phosphate (Fig. 5.2). Although large-scale fermentation technology for the production of L(1) lactic acid has been well established, the processes related to economical and efficient production of D( ) lactic acid on an industrial scale still have to be improved. According to Liu et al. (2014), to obtain relevant information related to largescale production processes of D( ), it is necessary to demonstrate an efficient

5.1 Lactic Acid

(A)

Glucose

(B)

Glucose

1 ATP

Fructose-6P

Glucose-6P

1 ATP

Fructose-1,6DP

4 ATP 2 NADH

2 Pyruvate

2 NADH

2 Lactate

Xylulose-5P

Ethanol

2 NADH Dihydroxyacetone-P Glyceraldehyde-P AcetyI-P

Glyceraldehyde-P

LDH

1 NADH

CO2

2 ATP 1 NADH Pyruvate 1 ATP 1 NADH LDH Acetate Lactate

FIGURE 5.2 Catabolic pathways of lactic acid bacteria: (A) Homofermentative; (B) Heterofermentative. Adapted from Hofvendahl, K., Hahn Ha¨gerdal, B., 2000. Factors affecting the fermentative lactic acid production from renewable resources. Enzyme Microb. Technol., 26, 87 107.

pilot scale fermentation using a promising microbial strain with efficient culture medium conversion and low cost pH neutralizers. In the early 1960s, chemical synthesis of lactic acid was developed, considering the interest in the baking industry. Manufacturing of synthetic lactic acid on a commercial scale began in 1963 in Japan and the United States (Holten and Mu¨ller, 1971; Vickroy, 1985). In chemical synthesis, lactonitrile is produced by the combination of hydrogen cyanide and acetaldehyde, in the presence of a catalyst, in the liquid phase. Then, lactonitrile is hydrolyzed to lactic acid by sulfuric or hydrochloric acid. In this process, ammonium chloride is generated as a byproduct (Pal and Dey, 2012). However, chemical synthesis results in a mixture of D( ) and L(1) lactic acid, moreover, it is not an economically viable process (Wee et al., 2006a). Compared to chemical synthesis, the biotechnological process for the production of lactic acid offers several advantages, such as low substrate cost, and low temperature and energy consumption (Datta and Henry, 2006). Fig. 5.3 shows a diagram with the main steps in the production of lactic acid by chemical and fermentative routes. The number of investigations involving the production of lactic acid by fermentation has increased exponentially since the 1990s (Fig. 5.4). Lactic acid occupies the third position among the 30 most studied molecules of 2016, following C6 sugars and polyhydroxyalkanoates (Biofuelsdigest, 2016).

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CHAPTER 5 Technological challenges and advances

FIGURE 5.3 Lactic acid production methods: (A) Chemical synthesis and (B) Microbial fermentation. Adapted from Wee, Y.J., Kim, J.N., Ryu, H.W., 2006a. Biotechnological production of lactic acid and its recent applications. Food Technol. Biotechnol., 44, 163 172.

800 700

Number of publications

120

600 500 400

July 2016 300 200 100 0

1990

1992

1994

1996

1998

2000

2002

2004

2006

2008

2010

2012

2014

2016

Year

FIGURE 5.4 Number of publications related to the production of lactic acid via fermentation. With permission from Biofuelsdigest. The 30 Hottest Molecules of 2016: sneak preview. Available , http://www.biofuelsdigest.com/bdigest/2016/01/04/the-30-hottest-molecules-of-2016-Sneak . (accessed July 2016).

5.1 Lactic Acid

FIGURE 5.5 Global Market Forecast for Lactic Acid, 2014 22 (US$ Million).

The world production of lactic acid in 2006 was estimated to be between 130,000 and 150,000 metric tons/year, with a 19% annual growth, mainly due to its use in the production of biodegradable polymers such as PLA (Wee et al., 2006a). In 2009, world production was 258,000 metric tons (Global Industry Analysts INC, 2011). The largest producer, NatureWorks, presented a production of 140,000 metric tons of PLA in 2011. By 2013, the world production of lactic acid (D, L, and DL) was 284,000 metric tons (Dammer et al., 2013). A 329,000tonne growth was projected for 2015 (Global Industry Analysts INC, 2011), and the estimated lactic acid production for 2017 is 367,300 metric tons (AbdelRahman et al., 2013). The market forecast for lactic acid by Credence Research (2016) presented an annual estimate of growth from 2014 to 2022, based on public domain information reported by some producer companies (Fig. 5.5).

5.1.1 FACTORS THAT INFLUENCE LACTIC ACID PRODUCTION The use of a microorganism in a biotechnological process generally involves the production of several molecules. However, species found in nature normally do not produce large amounts of metabolites, only the necessary amount for survival. In this way, several works have been developed in order to improve on this level of production, aiming at industrial scale application (Parekh et al., 2000). Operational parameters are controlled in order to optimize the fermentation process. Various factors influence lactic acid production by acid-lactic bacteria, such as pH (Mussatto et al., 2008; Andersen et al., 2009), temperature (Tango and

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Ghaly, 1999), aeration (Okino et al., 2008), carbon source (Bulut et al., 2004), nitrogen source (Nancib et al., 2001; Altaf et al., 2007), mineral salts (Hauly, 2001), and vitamins (Xu et al., 2008), among others. Microorganisms present determined optimum pH and temperature ranges for their growth, which vary according to species or strain. Studies have shown that when pH is controlled during fermentation, lactic acid production is improved (Mussatto et al., 2008). Extracellular pH is one of the main factors related to the production of lactic acid, presenting an influence on the catalytic activity of enzymes. The optimal pH for lactic acid production varies between 5.0 and 7.0; Lactobacillus strains present an optimum pH of around 5.7 and are known as tolerant acid. Fermentation is strongly inhibited by low pH and ceases at a pH below 4.5 (Kashket, 1987; Silva and Mancilha, 1991; Panesar et al., 2007). Many bacteria are sensitive to low pH, and this sensitivity has contributed to food preservation and industrial fermentation manipulation (Miller and Wolin, 1981). pH even has an effect on the fermentation pathway of microorganisms, as reported by Russell and Hino (1985), who, using Streptococcus bovis, showed a production of lactic acid, acetate, and ethanol at neutral pH, but at low extracellular pH showed homolactic fermentation. The same was reported by Stokes (1949) while studying the behavior of E. coli, where it was found that a low pH decreased the production of acetate, formate, and ethanol, however, it increased the production of lactic acid. A pH change may also influence cell growth, as reported by Fiedler et al. (2011); in their research they observed that a change in pH is related to the yield of cell mass produced per mole of ATP in Streptococcus pyogenes and Lactobacillus lactis, while higher yields were verified at pH close to the natural habitat of the microorganisms. Thus, lactic acid produced during fermentation has to be constantly neutralized. To control pH during fermentation, some neutralizing agents are added to the fermentation medium, such as calcium carbonate, which is the most commonly used with agitated bottles and in reactors (Yen et al., 2010). However, there are some problems associated with the addition of agents and neutralization toward pH control, because lactate instead of lactic acid is formed at a high pH value, which will result in an increase in purification costs due to the need for the recovery of lactic acid. In addition, when calcium carbonate or calcium hydroxide are used, calcium sulfate can be produced in the process of converting lactate to lactic acid, which can cause considerable environmental problems due to the formation of gypsum, as well as to extra recovery costs. The recovery and purification of lactic acid accounts for 50% of production costs (Eyal and Bressler, 1993). In order to avoid or minimize the use of neutralizing agents, genetically improved strains that are resistant to acidic environments and are lactic acid producers at low pH may be useful. Engineering strains to increase the growth and production of lactic acid at low pH will reduce the formation of residue and reduce the cost with lactic acid production and purification

5.1 Lactic Acid

Acid stress and end-product inhibition are among the main challenges in lactic acid production. Therefore, more studies on metabolic engineering for the identification of genes and proteins associated with stress responses and tolerance could improve biosynthetic pathways. Mainly using yeast and fungi, once these microorganisms are more acid tolerant than lactic bacterium has been an option (Upadhyaya et al., 2014). Zheng et al. (2010) improved the acid tolerance, as well as the production of D( ) lactic acid of Sporolactobacillus inulinus ATCC 15538, using ultraviolet irradiation, diethyl sulfate mutation, and protoplast fusion. They obtained the recombinant F3-4, which produced 119% more D( ) lactic acid (93.4 g/L) at pH 5.0 compared to the original strain. Temperature is an environmental factor, of which any variation has an effect on the course of fermentation; reactions catalyzed by enzymes are especially sensitive to small changes in temperature (Merritt, 1966). Different species of microorganisms present different optimum temperatures, which are related to cell growth and lactic acid production, so it is convenient to study the appropriate temperature in the fermentation process for each case (Peleg, 1995). When a microorganism is submitted to temperatures different than those considered ideal, inhibition of growth occurs and in some cases destruction of products (Scheper, 2000). The agitation is related to the homogenization of the medium, dissipation of the heat produced by the metabolic reactions, heat transfer to the temperature control, as well as to minimize cell death resulting from the addition of concentrated acid and base for pH control (Charles, 1985; Scheper, 2000).

5.1.2 CULTURE MEDIUM FOR LACTIC FERMENTATION: ALTERNATIVE SOURCES OF CARBON AND NITROGEN Social behaviors and consumption habits culminate in social, environmental, and economic problems, which make sustainability a topic often discussed, drawing the attention of governments, organizations, and the academic community (Malhotra et al., 2013). Concern for the environment has stimulated researchers worldwide to develop methods to produce a wide range of molecules and materials using sustainable technology (Abdel-Rahman et al., 2013). Commercial culture media used for the growth of fastidious microorganisms, such as lactic acid bacteria, are not economically attractive as high nutrient-rich culture media with high-cost carbon source (glucose), nitrogen (yeast extract), amino acids, and mineral salts are needed (Kyla-Nikkila et al., 2000). The use of refined sugars (glucose) as feedstock increases the cost of lactic acid production. The cost of raw materials is between 40% and 70% of the total cost of production and yeast extract, used as a source of nitrogen in the fermentation medium, accounts for 38% of the total cost of production (Tejayadi and Cheryan, 1995). The cost of purification is directly related to the complexity of the culture medium.

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An alternative is the use of alternative substrates, such as molasses (Wee et al., 2004), sugarcane juice (Calabia and Tokiwa, 2007; Farooq et al., 2012), sugar beet (Kotzamanidis et al., 2002), hydrolyzed soybean oil (Kwon et al., 2000), starch (Yumoto and Ikeda, 2004, Ohkouchi and E Inoue, 2006), rice starch (Fukushima et al., 2004), soybean oil waste (Yumoto and Ikeda, 2004), and the water of cassava (Coelho, et al., 2010). As well as several agricultural products and wastes (Narayanan et al., 2004, Zhang et al., 2007, Ezejiofor et al., 2014). The complex alternative sources used to reduce production costs have substances or physical characteristics that may influence the production of lactic acid and even the growth of the microorganism used (Ohkouchi and E Inoue, 2006). Studies have reported the production of lactic acid through biomass conversion (Tokuhiro et al., 2008). However, to make sugars from biomass accessible, the chemical pretreatment and enzymatic hydrolysis of lignocellulosic biomass, or enzymatic saccharification of amylaceous biomass (Li and Cui, 2009) are required. In traditional pretreatments of lignocellulosic biomass, chemicals such as acids and bases are added, which will influence the final stage of separation and purification of the product, besides increasing the cost of the process (Hofvendahl and Hahn Ha¨gerdal, 2000). Due to the high demand for the use of more economical and renewable resources, metabolic engineering appears to be a revolutionary tool for the development of strains that can use the residual lignocellulosic biomass (pentose) and that are resistant to the inhibitory compounds formed during the pretreatment of biomass. However, there are some preferred wastes that do not need biomass pretreatment, and that, therefore, do not form inhibitory compounds (Upadhyaya et al., 2014). The cost of producing lactic acid can be significantly reduced by using the byproducts of other processes, such as whey or sugarcane molasses, which contain readily fermentable sugars (Dumbrepatil et al., 2008). Whey is a byproduct of cheese production, and is rich in proteins, fats, and lactose with excellent functional, nutritional, and technological properties (Pelegrine and Carrasqueira, 2008). Molasses is a viscous material considered as a byproduct of sugar production, composed of sucrose, glucose, and fructose, with a total carbohydrate concentration of 45% 60% (Mariam, et al., 2009). Among the alternative sources of nitrogen reported are: peanut flour (Wang et al., 2011), soybean meal (Kwon et al., 2000), corn steep liquor (Yu et al., 2008), and yeast autolyzed (Lima et al., 2009, Coelho et al., 2011), among others (Tang et al., 2016). Proflo is a fine yellow powder produced from cotton seeds. It is rich in protein (56% w/v), and contains 24% carbohydrate, 5% oil, and 4% ash, the latter being rich in calcium, iron, and phosphorous chloride (Okafor, 2007). Corn steep liquor is an extremely economical alternative to nitrogen sources such as yeast and peptone extract. This residue is a byproduct from corn starch processing (Wee et al., 2006b), with nitrogen being available as amino acids, such as alanine, arginine, aspartic acid, cystine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tyrosine, and valine, with some B vitamins also present (Cardinal and Hedrick, 1948).

5.1 Lactic Acid

To solve the problem of high costs due to the high nutritional requirement of lactic bacteria, Corynebacterium glutamicum, which can produce lactic acid in minimal medium, was engineered to express the D( ) lactate dehydrogenase gene from L. bulgaricus with .99.9% optical purity (Jia et al., 2011). Due to its high availability and reduced cost, glycerol could be an ideal carbon source for the production of lactic acid. With this in mind, some authors have been investigating alternatives for the production of D( ) lactic acid and L(1) lactic acid from glycerol. Mazumdar et al. (2013) performed metabolic engineering on E. coli for the microaerobic production of L(1) lactic acid from glycerol, through knockout of the genes responsible for the synthesis of succinate, acetate, and ethanol, and overexpression of the glycerol dissimilation respiratory pathway (GlpK/GlpD). The modified strain produced 50 g/L of L(1) lactate from 56 g/L of crude glycerol. Similar experimentation was conducted by Mazumdar et al. (2010), but the metabolic pathway was directed toward the production of D( ) lactic acid, in which case E. coli produced 32 g/L of D-lactate from 40 g/L of glycerol. Excess substrate in fermentation, such as carbon and nitrogen source, can inhibit the production of lactic acid by osmotic stress and catabolic repression. In general, the commercial production of lactic acid requires the use of a robust and nonfastidious microorganism that has the ability to ferment both pentose and hexose, does not present inhibition by the substrate and the final product, is resistant to inhibitory compounds formed during the pretreatment of lignocellulosic biomass, and minimizes catabolic repression (Hofvendahl and Hahn Ha¨gerdal, 2000).

5.1.3 PRODUCTION OF LACTIC ACID BY FERMENTATION Lactic acid can be produced by different methods of fermentation, such as submerged or solid-state fermentation, continuous fermentation with simultaneous saccharification, continuous processes with cellular recirculation, batch fermentation, or fed batch fermentation, among others (Marques et al., 2008, Coelho et al., 2011). Fed batch fermentation is a strategy to prevent inhibition by excess substrate and catabolic repression, resulting in higher production, productivity, and cellular growth rate (Bernardo et al., 2016; Marques et al., 2016; Hu et al., 2015). Among the different types of bioreactors used in biotechnological processes, the most used is the stirred tank in submerged processes, corresponding to 90% of the total of bioreactors used industrially. The first application of this process was during the Second World War for the production of penicillin (Baily, 1980). Submerged fermentation allows for a better dissolution of the nutrients of the medium, facilitating their contact with microorganisms, as well as for temperature and pH control during fermentation (Schmidell et al., 2001). The batch process is the most used, but it presents low productivity due to the long fermentation time, as well as low cell concentrations due to inhibition by the

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final product (Abdel-Rahman et al., 2013). An important factor to be considered in batch fermentative processes is catabolic repression by the substrate. Despite the fact that the rate of conversion of the substrate into product by the microorganism is high, the initial substrate is consumed in a short period of time, ceasing the fermentation. However, a high concentration of the starting substrate may lead to inhibition of production. Catabolic repression can be avoided by maintaining a low concentration of substrate within the reactor, providing noninhibitory sugar amounts throughout the process as required, which characterizes the process as fed batch. Several studies have used this technique in order to avoid inhibition of production by the substrate and, thus, to raise production and productivity levels (Abdel-Rahman et al., 2015). Different feeding strategies can be used in fed batch fermentation, such as pulse feed, continuous, pH Stat, and exponential feeding. Several studies have reported improvements in lactic acid production when using the pulse-feeding strategy (Son and Kwon, 2013; Wang et al., 2011; Meng et al., 2012). In this technique, certain concentrations of substrate are inserted once or more into the reactor, at predetermined intervals, as required. Ding and Tan (2006) studied the effects of different feeding strategies for L(1) lactic acid production by Lactobacillus casei, and according to their results, exponential feeding was the most efficient method; increasing lactic acid production by 56.5% compared to the batch process. For exponential feeding, different software are used with specific formulas that are set with predetermined data containing kinetic fermentation values. These programs are able to adjust the feed flow as requested, taking into account the conversion rates as well as the speed at which they need to occur. In the pH stat method, the feed is based on pH control by considering the linear relationship between the consumption of the base used for the control of pH and substrate utilization during lactic fermentation. The base and the substrate are mixed proportionally and then the substrate concentration is controlled through pH adjustment automatically. In continuous batch fermentation, the necessary nutrients are provided continuously, while the cells, products, and process residues are removed. The bioreactor volume and the nutrient concentrations are kept constant. It is not a preferred process in the industrial sector due to the high risk of contamination and mutation of the producing microorganism (Schmidell et al., 2001). Lu et al. (2012) studied a fermentative process in a pilot scale reactor equipped with a microfiltration system for the recycling of cells and for pulse feeding. In this process the cells were recycled 12 times, and according to the authors the method was proven to be efficient and promising for use on an industrial scale. Some studies report lactic acid production using immobilized cells in order to increase the cell density of the process. However, promising results related to increased production and productivity were not reported, and better results were reported using free cells (Hofvendahl and Hahn Ha¨gerdal, 2000).

5.1 Lactic Acid

In order to optimize lactic acid production, metabolic engineering is one alternative to solve the problems faced in fermentation processes, like acidity, end product and substrate tolerance, as well as the high costs of substrates.

5.1.4 MICROORGANISMS INVOLVED IN THE PRODUCTION OF LACTIC ACID The production of lactic acid has been reported by bacteria, fungi, and yeasts (Ilme´nemail et al., 2013, Sun et al., 2012, Ding and Tan, 2006), but the largest number of studies report such production by bacteria. Osawa et al., (2009) reported a production of 85 g/L of L(1) lactic acid by Candida boidinii genetically modified with alterations in the pyruvate carboxylase gene in order to reduce ethanol production. The most reported filamentous fungus for lactic acid production is Rhizopus oryzae, usually presenting production from byproducts such as glycerol (Vodnar et al., 2013), residues such as manure (Sun et al., 2012), or residues rich in starch (Taskin et al., 2012, Yen et al., 2010). Lactic acid bacteria have traditionally been used to produce lactic acid and are the predominant candidates for industrial production (Okano et al., 2010). This group of bacteria is characterized as being: Gram-positive; aerobic or facultative anaerobes; present in the form of cocci or bacilli, which produce lactic acid by fermentation of carbohydrates; incapable of using lactate; and nonpathogenic (recognized as “GRAS”—Generally Recognized As Safe) (Axelsson, 2004; Hofvendahl and Hahn Ha¨gerdal, 2000). They belong to several genera, including Aerococcus, Carnobacterium, Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, Streptococcus, Tetragenococcus, Vagococcus, and Weissella (Rattanachaikunsopon and Phumkhachorn, 2010; Carr et al., 2002). According to Garrity et al. (2004), the bacteria of the genus Lactobacillus belong to the family Lactobacillaceae, order Lactobacillales, class Bacilli, and phylum Firmicutes. Lactobacilli are found in substrates rich in carbohydrates, fermented foods, mammalian mucosa, and plants (Hammes and Vogel, 1995). Some species of this genus, such as Lactobacillus rhamnosus, are able to produce L(1) lactic acid, while others have the potential to produce the D( ) isomer, such as Lactobacillus delbrueckii (Hofvendahl and Hahn Ha¨gerdal, 2000). The bacteria of the species delbrueckii are characterized as being: Grampositive, present in the form of bacilli, facultative anaerobic, without motility, and without the formation of spores. L. delbrueckii, is part of the group of lactic acid bacteria, therefore, it is acid tolerant and has strictly fermentative metabolism and lactic acid is the main end product (Axelsson, 2004; Kandler and Weiss, 1986). Studies have shown lactic acid production by several L. delbrueckii strains from different substrates as well as by other species of the genus Lactobacillus (Table 5.2). Another important genus of D( ) lactic acid producing bacteria is Sporolactobacillus, belonging to the phylum Firmicutes, class Bacilli, order Bacillales, and family Sporolactobacillaceae (NCBI- National Center for

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Table 5.1 Microorganisms of Genus Sporolactobacillus Involved in D( ) Lactic Acid Production Microorganism

D(

) Lactic Acid Production (g/L)

Nitrogen and Carbon Sources

Reference

Sporolactobacillus sp. CASD Sporolactobacillus nakayamae Sporolactobacillus inulinus ATCC 15538 Sporolactobacillus sp. strain CASD

207

Glucose and peanut flour Crystallized sugar and peanut flour Glucose and yeast extract Glucose and yeast extract

Wang et al. (2011) Beitel et al. (2016) Zheng et al. (2010) Zhao et al. (2010)

112.93 93.4 90.00

Biotechnology Information, 2013). It is a Gram-positive bacterium producing spores, microaerophilic and mesophilic, which exclusively produces D( ) lactic acid via homofermentation. Found mainly in wild plant rhizospheres (Holzapfel and Botha, 1988). This genus was named by Oki Nakayama, a Japanese microbiologist who isolated a large number of Sporolactobacillus strains (LPSN, 2013), being known for its ability to tolerate high concentrations of lactic acid as well as its production (Zheng et al., 2010). Few studies involving the production of lactic acid by this genus have been reported (Table 5.1). Some species and strains of Bacillus sp. are commercially promising for the production of lactic acid (Pleissner et al., 2016; Zhou et al., 2013; Ma et al., 2014; Su et al., 2011). The advantages of the use this microorganism include the possibility of producing lactic acid using lignocellulose substrates because of their ability to utilize both C5 and C6 sugars. In addition, they are thermotolerant and nonfastidious. The advantages of using high temperatures in fermentation on an industrial scale are: the increase in enantiomeric purity; lower risk of contamination by mesophiles; faster reactions, therefore, higher productivity; and greater solubility of the fermentation broth. However, there are some bottlenecks for the accomplishment of this, no thermotolerant microorganism producing D( ) lactic acid has been found in nature, it is only possible to find L(1) lactic acid-producing thermotolerant Bacillus. According to Kranenburg et al. (2013) the genus Bacillus is composed of more than 200 different species, however few of them can be modified genetically. For the production of D( ) lactic acid, some strains of Bacillus coagulans have been genetically modified using specific genetic tools. The native ldhL gene from B. coagulans, DSM1 (a producer of L-lactic acid), was deleted and the D-lactate dehydrogenase (ldhD) gene was overexpressed to generate lactic acid (Kranenburg et al., 2013); the engineered strain B. coagulans RDSM1 produced 28 g/L of lactic acid, (99.5% D-lactic acid) from 50 g/L of glucose. The wild strain of B. coagulans, DSM1, produced the same concentration, 28 g/L, of lactic acid, but 99.8% L isomer. Wang et al. (2014) engineered a thermotolerant strain of B. coagulans P4102B (a potent producer of optically pure L-lactic acid .99%), by directing the

5.1 Lactic Acid

Table 5.2 Microorganisms of Genus Lactobacillus involved in D( ) Lactic Acid Production Microorganism

Isomer

Lactic Acid Production ( g/L)

Nitrogen and Carbon Sources

References

Lactobacillus casei

L(

180.0

Glucose and yeast extract Glucose, yeast extract, and peptone Sugar cane juice and yeast extract

Ding and Tan (2006) Yang et al. (2015)

Calabia and Tokiwa (2007) França et al. (2009)

)

Lactobacillus lactis

143

Lactobacillus delbrueckii NCIM 2365 Lactobacillus delbrueckii Lactobacillus delbrueckii ATCC6949 Lactobacillus plantarum LMISM6

D(

)

135

D(

)

120.0

Sugar cane juice

D(

)

101.0

Sugar cane molasses

94.8

Coelho et al. (2011)

Lactobacillus delbrueckii NCIMB 8130 Lactobacillus delbrueckii subsp. lactis QU 41 Lactobacillus manihotivorans LMG 18010

D(

)

88.0

Sugar cane molasses and corn steep liquor Beet molasses and yeast extract

D(

)

20.1

Glucose and yeast extract

Tashiro et al. (2011)

L(1)

12.6

Starch

Guyot et al. (2000)

DL

Kadam et al. (2006)

Kotzamanidis et al. (2002)

gene coding for enzyme D-lactate dehydrogenase to produce high D( ) lactic acid by the deletion of the L-lactate dehydrogenase gene (LdhL) and the acetolactate synthase gene (alsS). The engineered strain produced 90 g/L of D-lactic acid with optical purity greater than 99% from glucose at 50 C. The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology associated with the cas gene forms a bacterial immune system against strange DNA, such as phage or plasmids, and has revolutionized the field of genetic engineering due to its ability to perform the genome quickly and efficiently. It has been used for gene deletion, knockout, and genetic recombination of a variety of microorganism species (Hidalgo-Cantabrana et al., 2017). Technologies based on CRISPR have been successfully used to increase the phage resistance of industrial strains (Stefanovic et al., 2017) The CRISPR-Cas9 system was used by Ozaki et al., 2017 in order to genetically modify Schizosaccharomyces pombe to produce D( ) lactic acid from glucose and cellobiose, by the insertion of a gene encoding D-lactate dehydrogenase

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of Lactobacillus plantarum and the deletion of pyruvate dehydrogenase (ADH) and glycerol-3-phosphate dehydrogenase (GPD). The new strain produced 25.2 g/ L of D( ) lactic acid from 35.5 g/L of glucose. The expression of betaglucosidase was also made to facilitated production through cellobiose and the resulting strain produced 24.4 g/L of D( ) lactic acid from 30 g/L of cellobiose in minimal medium. Mougiakos et al. (2017) have constructed a genomic editing system for thermophilic microorganisms using CRISPR/Cas9 technology, in which it is possible to perform, in only 4 days, the elimination, knockout, and insertion of genes, with an efficiency of 90%, 100%, and 20% respectively, with the great advantage of using only one plasmid and one promoter. In other words, a lot of genetic tools are not required. Thus, homologous recombination was performed using plasmids at between 45 C and 55 C in thermophilic Bacillus smithii as spCas9 is inactive in vivo above 42 C, then the transfer was carried out at 37 C, which allowed for counter-selection because at this temperature spCas9 is active and it is possible to introduce lethal DNA that breaks into unedited cells. In this way, this model can be used as an important tool in genomic editing of thermophilic bacteria to increase the production of D( ) lactic acid and L(1) lactic acid.

5.1.5 EXTRACTION AND PURIFICATION OF LACTIC ACID The technological barriers to the production of low cost lactic acid are mainly in the processes of separation and purification of lactic acid from the fermentative medium. In addition, the efficiency of this process is essential for the subsequent synthesis of PLA, since the presence of sugar, proteins, and other organic acids must be minimal in order to obtain optimum polymerization results. In the conventional method of lactic acid purification, the precipitation of calcium lactate occurs with esterification and hydrolysis through reactive distillation. It is an economical process, simple and reliable, but generates large amounts of calcium sulfate, which is not environmentally friendly. In order to solve this problem, some recovery methods have been developed in the literature to remove the lactic acid from a fermentation broth, such as cross flow filtration with cell recycling (Sikder et al., 2012), electrodialysis (Wang et al., 2013), and ion exchange resins (Boonmee et al., 2016). It is also possible to perform an integrated membrane separation process composed of ultrafiltration, nanofiltration (NF), ion exchange, and vacuum evaporation. Lee et al. (2017) used this method and obtained lactic acid with high purity ( . 99.5%). To recover and purify the L(1) lactic acid produced from microbial fermentation media economically and efficiently, ion exchange chromatography is used among a variety of downstream operations(Tayyba Ghaffar et al., 2014). The purification of lactic acid from ion exchange columns has been shown to be a technological option for the process (Gonza´lez et al., 2008), since the necessary equipment is relatively simple and cheap, however its use is recommended when the solution of lactic acid has low salt concentrations (Quintero et al., 2012).

5.2 Poly(lactic Acid)

Many studies focus on the recovery of lactic acid using polymeric anionic adsorbents. This method presents an advantage: there is no need to acidify the fermentation broth prior to adsorption. The adsorption of ion exchange resin is a practical method in the industry due to its economy, ease of manipulation, reduction in chemical consumption, and low waste production. The NF process has also been shown as an option for the process of separating lactic acid from a fermentation medium. Its selectivity is due both to steric hindrance and to the effect of electrostatic repulsion. Most NF membranes can firmly hold compounds of molecular weight up to 150 250 g/mol, charged species, and polyvalent ions. NF is a purification step that can be performed before and/or after the ion exchange process, since NF membranes have low rates of rejection to lactic acid and high retention of mono- and disaccharides and divalent ions (e.g., Ca12 and Mg12) (Kang et al., 2004), it is also possible to obtain a high recovery rate of lactic acid. With the participation of NF membrane modules and microfiltration in a stable production system, 76 77 L/m2 h was obtained for L(1)lactic acid with a purity greater than 95% (Pal and Dey, 2012). Advances in separation and purification techniques based on membrane technologies, particularly in microfiltration, ultrafiltration, and electrodialysis, has led to the creation of new processes for the production of lactic acid without the generation of residues. The literature shows that the production of lactic acid is viable from lactate salts through the use of bipolar membrane electrodialysis which can convert solutions of salts into acids. First, the monopolar electrodialysis membrane that will be responsible for concentrating and purifying the broth is used, and then the biopolar electrodialysis membrane is used to convert lactate salts into lactic acid (Habova et al., 2004). Through ionic exchanges, the membrane is capable of supplying hydrogen ions to the broth and recovering the cations present, so that the base used during the fermentation can also be recovered. In other words, at the end of the process there is the conversion of the lactate salts into acid form and also the recovery of the base used in the fermentation process. The study of procedures for the purification of lactic acid involves unit operations, and the critical steps are evaluated in relation to lactic acid recovery and the removal of contaminants, such as proteins, sugars, and color.

5.2 POLY(LACTIC ACID) The main challenges for the commercialization and use of PLA include: cost production; physical structure of polymer; PLAs are not produced directly by microorganisms; biodegradation; and biocompatibility. Therefore, the reduction of costs, as well as the development of efficient fermentation processes that result in high productivity are current study objectives (Abdel-Rahman et al., 2013).

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Cost reductions can be achieved using cheap substrates, optimizing lactic acid production processes, substituting energy sources used in PLA production with more sustainable energy sources, such as wind or solar energy, optimizing PLA production processes, and increasing PLA demands (Jamshidian et al., 2010).

5.2.1 PLA CHEMICAL AND PHYSICAL PROPERTIES There are several kinds of degradable polymers, however, PLA is one of the most popular materials as it is considered as a biocompatible, compostable, recyclable, and renewable thermoplastic polyester, with the brightest development prospects, and is denominated as an ecofriendly material (Madhavan Nampoothiri et al., 2010; Maharana et al., 2015). The production of PLA also consumes carbon dioxide (Dorgan et al., 2001) and uses 25% 55% less fossil energy sources than petroleum-based polymers. Cargill Dow developed process improvements, for the near future, where the use of fossil energy sources can be reduced by more than 90% compared to any of the petroleum-based polymers (Vink et al., 2003). Considering the environmental concerns around petroleum-based polymers and the associated “white pollution” that results in severe urban environmental consequences, the low carbon economy has begun receiving the relevant attention. In this way, PLA is an important environmentally friendly plastic derived from renewable sources, with performance comparable to many petroleum-based plastics (Ren, 2010). PLA presents some properties ideal for use in packaging, textiles, and other consumer products, such as its high wicking performance, light weight, good dyeability, antibacterial feature, good ultraviolet resistance, high water vapor transmission rates, good printability, low process temperature, and ease of conversion into different forms (Chen et al., 2016; Lim et al., 2008). On the other hand, its potential market applications could be limited by poor thermal stability, mechanical properties, and processability (Cheng et al., 2015). Unoriented PLA is brittle, however, it displays good strength and stiffness (Auras et al., 2005). It is a semicrystalline polymer with good transparency, mechanical strength, and melt processability; however, the physical properties of PLA can vary widely, depending on its stereochemical composition, processing temperature, annealing time, and molecular weight, which have an effect on its melting point and on the rate and extent of polymer crystallization (Chen and Patel, 2012; Frone et al., 2016). PLA even exhibits mechanical properties comparable to those of poly(ethylene terephthalate) and better than those of polystyrene (Auras et al., 2004). This polymer is considered as a biodegradable polyester due to its potentially hydrolysable ester bonds, and for this reason is considered as a sustainable alternative to petrochemical plastics. PLA exists in three stereochemical forms: poly (L-lactide) (PLLA), poly(D-lactide) (PDLA), and poly(DL-lactide) (PDLLA) (Madhavan Nampoothiri et al., 2010). Savaris et al. (2016) studied the modifications to PLA films after exposure to sterilization methods, and verified that PLA sterilized by saturated steam showed

5.2 Poly(lactic Acid)

morphological, chemical, thermal, and physical changes, thus, this process is not recommended. However, under other sterilization processes, such as ethylene oxide, hydrogen peroxide plasma, electron beam radiation, and gamma radiation, the samples exhibited only thermal and physical changes, therefore, these processes can be used for PLA sterilization.

5.2.2 PLA SYNTHESIS 5.2.2.1 Chemical polymerization Considering that PLA is the best candidate polymer to replace nonbiodegradable synthetic plastics, several studies related to synthesis techniques have been performed in order to increase the optical or mechanical properties of this polymer (Sungyeap Hong, 2014). In the beginning of PLA technology development, its applications were limited to the medical field due the high costs involved (Chen et al., 2016). Attaining a PLA with good physical properties and high molecular weight is desirable (Liu et al., 2013). Over the past decade, new technologies of polymerization were developed, promoting the economical production of polymers with high molecular weight (Lim et al., 2008). There are different polymerization techniques for achieving a high molecular weight PLA, including direct condensation polymerization, azeotropic dehydrative condensation, and polymerization through lactide formation or ring opening polymerization (ROP) (Fig. 5.6). ROP is a common polymerization route used to build hydrolytic polymers, including PLA, and is the most convenient technique for controlling the molecular weight of this polymer (Nair and Laurencin, 2007, Masutani and Kimura, 2014), however, this method is relatively complicated and expensive (Liu et al., 2013). This route, starts with low molecular weight lactic acid oligomers from catalytic depolymerization of internal transesterification using tin catalysis and stereoselective initiators in order to enhance the rate and selectivity of the intramolecular cyclization reaction. Then the ring of lactide opens to form high molecular weight PLA (Auras et al., 2004). Some companies, like NatureWorks LLC (USA) among other manufacturers of PLA, use the ROP route for their production. Currently, much effort is being made to establish the direct polycondensation method, since this technique has been less studied compared to the ROP method (Masutani and Kimura, 2014). However, chemical catalysts have drawbacks, for example, they often require high operating temperatures and metal catalysts may cause problems for certain uses (Xiao et al., 2006). Microwave irradiation has been used in PLA synthesis, and in this technique the polymerization rate is much faster than with conventional heating, also different catalysts can be used. Bakibaev et al. (2015) to get the PLA polymer 100 times faster than the conventional heating method of synthesis, obtained polymer

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FIGURE 5.6 Synthesis of poly(lactic acid) (Lunt, 1998).

with same optical characteristics. Similar results reported by other authors explain that microwave irradiation gives rapid energy transfer and high-energy efficiency, conducive to a faster reaction rate (Singla et al., 2012; Nagahata et al., 2007). Nikolic et al. (2010) compared poly(D, L-lactide) synthesis using ROP to poly (D, L-lactide) synthesis using microwave irradiation, and reported that polymerization by ROP takes over 30 hours in bulk at 120 C, in contrast, microwave irradiation performs the same bulk polymerization process much faster and with less energy consumption, with a reaction time of about 30 minutes at 100 C.

5.2.2.2 Enzymatic polymerization: production of PLA directly by genetically modified microorganism Enzyme catalyzed polycondensation is a green alternative approach that present some advantages compared to chemical synthesis, since mild conditions can be achieved, because the reactions are usually metal free and are carried out at lower temperatures. In this technique, high selectivity, high efficiency, and recyclability of enzymes have also been reported. Therefore, this process has aroused interest for its medical applications, in order to avoid toxic solvents and metal residues (Sen and Puskas, 2015). Researchers have developed a strategy for the efficient production of PLA and its copolymers using microorganisms, in only one step, through metabolic

5.2 Poly(lactic Acid)

engineering. One of the strategies was the use of polyesters containing lactate with different comonomers by using the PHA biosynthetic pathway in recombinant E. coli (Park, Kim, et al., 2012a; Park, Lee, et al., 2012b) Jung et al., (2010) reported the production of a homopolymer PLA and its copolymers, poly(3-hydroxybutyrate-co-lactate), P(3HB-co-LA), by direct fermentation of metabolically engineered E. coli. The introduction of heterologous metabolic routes involving CoA transferase and polyhydroxyalkanoate (PHA) synthase for efficient generation of lactyl-CoA and incorporation of lactyl-CoA into the polymer, respectively, allowed for the synthesis of PLA and P(3HB-co-LA) in E. coli, but the efficiency was low. Jung et al., (2010), in their study, engineered the metabolic pathway of E. coli by knocking out the ackA, ppc, and adhE genes and exchanged the ldhA promoters and acs for trc promoters. Lassalle et al., (2008) reported effective PLA production using lipases. Candida antarctica lipase B (CAL-B) is an effective biocatalyst, presenting 60% lactic acid (LA) conversion and 55% recovered solid polymer. Based on the fact that PHA monomeric constituents are structurally analogous to LA, Taguchi et al., 2008 explored the capacity of PHA synthase to exhibit polymerizing activity toward LA-coenzyme A (CoA), in order to establish a biological process for the synthesis of LA-based polyesters. An LA-CoA producing E. coli strain with a CoA transferase gene was constructed and an engineered PHA synthase gene was introduced into the resultant recombinant strain. As a result, a LA-incorporated copolyester, P(6 mol% LA-co-94 mol% 3HB), was reported.

5.2.3 KINDS OF POLYMERS, COPOLYMERS, AND THEIR FEATURES The bioplastics industry has made dramatic changes over the past decades in order to achieve durable bioplastics with high biobased content. In the automotive and electronics industries, for example, the requirements of this material are that they are tough, strong, and durable. The high strength and low toughness characteristics of PLA are presented as limitations especially in applications where mechanical toughness such as plastic deformation at high impact rates or elongation is required (Nagarajan et al., 2016; Kfoury et al., 2013). The need to improve the chemical and physical properties of PLA to meet consumer and biological applications, brings forth several technologies based on PLA (Rasal et al., 2010). In this way, in order to expand these potential properties, copolymerization or blending with other polymers are been developed to driving to new materials, that presents high performance, low cost and easy processing (Hamad et al., 2014; Schreck and Hillmyer, 2007). Another example of modifications needed relates to the permeability of PLA to oxygen, gas, and moisture, which is much higher than in most other plastics, such as PE, PP, and even PET. The penetration of moisture and consequently the hydrolytic degradation of PLA, as well as its low glass transition temperature,

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poor thermal stability and low toughness and ductility can significantly interfere in the manufacturing, storage, and transport processes of PLA, reducing, in this way, the range of its applications. To extend the applications of PLA, properties such as impact strength or flexibility, stiffness, barrier properties, thermal stability, and production costs should be improved (Jamshidian et al., 2010). Copolymer composition, functionalities, as well molecular weight and terminal groups, need to be controlled in order to drive PLA polymer applications (Masutani and Kimura, 2014). Blends of PLA with other flexible polymers have been previously studied, like poly(lactide-co-glycolide) (PLGA), and applied in various biomedical applications, such as vaccination, cancer treatment, inflammation medication, tissue engineering, and regenerative medicine, among others. PLGA is considered one of the most promising polymers in design, development, and optimization for medical applications (Pan and Ding, 2012; Szle˛k et al., 2016; Danhier et al., 2012). PLGA-based have been used also to prepare microspheres to multiparticulate dosage applications under different sizes, depending on the route of administration (Szle˛k et al., 2016). PLGA nanoparticles have attracted attention due some interesting properties, such as biodegradability and biocompatibility. The Food and Drug Administration and the European Medicine Agency approval in drug delivery systems for parenteral administration, protection of drug from degradation as well as possibility of sustained release (Danhier et al., 2012). In turn, poly(lactic acid)/polycaprolactone (PLA/PCL) blends (80/20) showed the greatest elongation and impact strength compared to that of neat PLA (Chavalitpanya and Phattanarudee, 2013; Rao et al., 2011). The synthesis of poly (D, L-lactic acid)/poly(L-lactic acid) bentonite nanocomposites increases the tensile strength of this polymer as well as its biodegradability and barrier properties (Sitompul et al., 2016). The system of triblock copolymers poly(lactic acid)-poly(ethylene oxide)-poly (lactic acid) has been widely explored for several applications related with controlled and sustained release of drugs and in tissue engineering devices (Saffer et al., 2011). Xu and Guo (2010) reported that blending poly(butylene succinate) (PBS) with PLA improves the tensile strength and elastic modulus of the polymer without much loss of ductility. On the other hand, Hassan et al., (2013) related in their study that the thermal stability of the blends (PLA/PBS) was higher than that of pure PLA and the tensile strength and modulus of the blends decreased with increasing PBS content, however, the impact strength was improved by about twofold compared to pure PLA and PBS also increased the storage modulus. The low heat resistance and slow crystallization rate characteristics of PLA limit its application in food packaging. The combined effect of annealing and cellulose nanofibers on the crystalline structure of PLA was studied by Frone et al. (2016). The transformation of the grained structure specific to amorphous PLA into a crystalline lamellar structure after annealing was detected, showing an improvement of the surface modulus and hardness for the new composites compared to PLA.

5.2 Poly(lactic Acid)

Hashima et al., (2010) developed a ductile polymer with high glass transition temperature by blending PLA with a hydrogenated styrene-butadiene-styrene block copolymer with the aid of reactive compatibilizer, poly(ethylene-co-glycidyl methacrylate). The aging resistance was also improved by incorporating polycarbonate. The architecture of polymers can be controlled by the addition of hydroxylic compounds, which permits precise control over the speed of crystallization, the mechanical properties, and the processing temperatures of the material (Auras et al., 2004). In order to increase the crystalline content under typical polymer processing conditions, Li and Huneault (2007) studied different strategies to promote PLA crystallization. Talc used as a nucleating PLA agent is highly effective in the 80 C 120 C temperature range and the combination of nucleant and plasticizer developed significant crystallinity at high cooling rates. Charles et al., (2010) in their study, prepared poly(L-lactic acid)/hydroxyapatite/poly(ecaprolactone), in order to prepare a bone-repair material that matches with the modulus of bone. They reported the production of composites with flexural moduli near the lower range of bone. There has been much research based on PLA improvements considering the medical field. It was verified through biological assays that PLA scaffolds containing low loads of diamond nanoparticles were not cytotoxic using L929 cells, presenting bioactive properties and favored cell adhesion. The potential range of applicability of electrospun polyesters diamond nanoparticles loaded for tissue engineering purposes was also related (Pereira et al., 2016). In Brazil, BASF offers the Ecovio, which consists of the biodegradable plastic ecoflex (synthetic polyester obtained from the condensation of 1,4-butanediol with terephthalic and adipic acid) and PLA, which is obtained from renewable raw materials based on sugar. This plastic can be adapted according to customer requirements (Araujo et al., 2007). PLA and PLGA have been used commercially as membranes according to their properties (Table 5.3).

5.2.4 PLA APPLICATIONS The actual needs of society drives the progressively increasing plastic production, consequently resulting in high plastic waste generation (Balaguer, et al., 2016). In this context, the concept of ecofriendly materials has attracted attention by several sectors of society all over the world (Sukan et al., 2015). Considering the interest in green alternatives, greater efforts have been made to develop degradable biological materials without any environmental pollution to replace plastics derived from petroleum, increasing the manufacturing of biodegradable PLA materials (Abdel-Rahman et al., 2013; Madhavan Nampoothiri et al., 2010). This biopolymer has bacterial origins, presents a similar level of quality to traditional plastics, and has been considered a candidate to replace unsustainable products, like polystyrene and polyethylene terephthalate, however, the cost of its production is an inconvenience yet (Sukan et al., 2015).

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Table 5.3 The Most Commonly used Commercially Available Reabsorbable Synthetic Polymeric Membranes Commercial Name (Manufacturer)

Materials

Properties

Function Time

Resorption Rate

Guidor (Sunstar Americas, Inc. mnear Chicago, IL, USA) Resolut Adapt (W. L. Gore and ASSOC, Flagstaff, AZ, USA) Resolut Adapt LT (W.L. Gore and ASSOC, Flagstaff, AZ, USA) Epi-Guide (Curasan, Inc., Kleinostheim, Germany) Vivosorb (Polyganics, Groningen, The Netherlands)

Poly-D, L-lactide and Poly-L-lactide, blended with acetyl tri-n-butyl citrate Poly-D, L-lactide/Coglycolide

2-layer

$6 weeks

13 months

Good space maintainer

8 10 weeks

5 6 months

Poly-D, L-lactide/Coglycolide

Good space maintainer

16 24 weeks

5 6 months

Poly-D, L-lactic acid

3-layer Selfsupporting

20 weeks

6 12 months

Poly(D, L-lactideε-caprolactone)

Can also be used as a nerve guide

10 weeks

24 months

Studies have been carried out on the utilization of biodegradable materials for plastic applications, such as packaging, paper coatings, sustained release systems for pesticides/fertilizers, compost bags, and textile applications, among others (Madhavan Nampoothiri et al., 2010; Hamad et al., 2014; Chen et al., 2016). Efforts have been made to develop nanotechnology approaches to packaging material science for improving performances and decreasing prices (Jamshidian et al., 2010). Considering that the major drawback of PLA for packaging applications is its brittleness, Javidi et al., (2016) verified that PLA-essential oil composite films were more flexible than neat PLA films, leading to modification of the tensile behavior. The potential antimicrobial performance of Origanum vulgare L. essential oil (OEO) in PLA-based matrices was evaluated too and the results indicated that antimicrobial PLA film was effective against Staphylococcus aureus and E. coli, suggesting that developed PLA films with active substances could be used in designing antimicrobial packaging materials. Another way to solve the problem of the PLA stiffness limitation, is adding a plasticizer in order to enhance flexibility and improve the electromechanical properties of this polymer. Therefore, several types of plasticizer could be used for this purpose, such as poly (ethylene glycol), glyceryl triacetate, citrate esters, lactide monomer (Lemmouchi et al., 2009; Thummarungsan et al., 2016). Lemmouchi et al., (2009) reported that blending PLA (80 wt.%) with plasticizers (20 wt.% tributyl citrate) improves the

5.2 Poly(lactic Acid)

thermomechanical properties. Besides that, it was evidenced that the plasticizers investigated in their work enhanced the degradation of the PLA matrix in compost conditions. PLA has been used in the medical field, including drug delivery systems, tissue engineering, wound management, orthopedic devices (Hamad et al., 2015), degradable sutures, nanoparticles, porous scaffolds for cellular applications (Lasprilla et al., 2012), implantable composites and bone fixation parts (Madhavan Nampoothiri et al., 2010), and plain membranes for guided tissue regeneration (Vert, 2004), among others. These applications require materials with specific properties to provide efficient therapy (Gupta et al., 2007). PLA had attracted great attention in medical applications due its advantageous features over nonbiodegradable polymers, such as biocompatibility and bioabsorption, eliminating the subsequent need to remove implants (Hamad et al., 2015). The expected trend for future years, is that permanent implants will be replaced by biodegradable devices, which could auxiliate the body to regenerate damaged tissues (Nair and Laurencin, 2007). Bioabsorbable polymers receive significant attention for biomedical applications because their degradation occurs by simple hydrolysis to metabolizable products by the human body (Savioli Lopes et al., 2012). Deepthi et al., (2016) in their study, developed a tendon construct of electrospun aligned PLLA nanofibers in order to mimic aligned collagen fiber bundles, and they layered PLLA fibers with chitosan-collagen hydrogel to mimic the glycosaminoglycans of sheath extracellular matrix for tendon regeneration. Their results indicated that this newly developed scaffold would provide a proper construct for flexor tendon regeneration under immobilized conditions. Proanthocyanidins extracted from grapes have several bioactive properties, giving them potential medical uses. In this way, nanoencapsulation with poly-D,Llactide polymer was accomplished, and in vitro release studies, through stomach and intestinal simulation, showed a sustained release of proanthocyanidins (Ferna´ndez et al., 2016). Considering the packaging industry, PLA is an alternative “green” food packaging polymer, ideal for fresh products, such as fruits, vegetables, salads, and those whose quality is not damaged by PLA oxygen permeability (Jamshidian et al., 2010). Jamshidian et al., (2010) reported in their research an overview of the capabilities of PLA, discussing the antimicrobial and antioxidant trends of this polymer, required in different areas when used in packaging. Some applications of nanomaterials in combination with PLA structures were also reported for creating new PLA nanocomposites with promising abilities. Chang et al., 1996 studied PLA for use as a matrix for controlled release of herbicides as well growth stimulation and yield improvement potential, applied in preplant soil incorporation with soybeans. This research demonstrated that both lactide and PLA were able to increase soybean leaf area, pod number, bean number, and plant dry weight. Also PLA used as an encapsulation matrix for herbicides could provide reduced environmental impacts and improved weed control.

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PLA is already used in cosmetic packaging, and it is well-known that polymeric packaging can interact with components, such as active ingredients, excipients, and solvents, used in a variety of cosmetic formulas. In their study, Capra et al. (2014) evaluated the mechanical, physicochemical, and organoleptic properties of PLA bottles present in the cosmetic market. The results indicated that the polymer was modified under a heating process in combination with chemical treatment.

5.2.5 PLA MARKET DEVELOPMENT On a global scale, about 275,000 tons of lactic acid are produced per year, and the application of lactic acid is directed to several industrial departments, such as food and beverages, personal care, and solvents, however the greater application of lactic acid is directed to the production of polymers (Fig. 5.7) (The essential chemical industry, 2016). Among several applications of PLA, a large part is intended for the packaging industry, followed by applications in agriculture, as shown in Fig. 5.8. Some PLA producer companies have developed PLA that can withstand high temperatures making it suitable for packaging and other applications where this quality is required, such as catering and for serving hot beverages. PLA can be also used for the manufacture of electronic appliances, automotive parts, and many consumer goods like diapers, toys, etc. (Occams Business Research, 2016).

FIGURE 5.7 Biotechnological lactic acid applications. From The Essential Chemical Industry, 2016. essentialchemicalindustry-online, Ed. J.N. Lazonby and D.J. Waddington, Published by the Department of Chemistry, University of York, York, UK. Used with permission from Professor David Waddington, Department of Chemistry.

5.2 Poly(lactic Acid)

FIGURE 5.8 PLA application market, 2013 (Occams Business Research, 2016).

According to a study by Grand View Research (2016), the increasing demand for PLA is expected to reach US$2,169,6 million by 2020 and will increase the lactic acid market, which is expected to reach US$4,312,2 million in the same period.

5.2.6 PLA BIODEGRADATION, BIOCOMPATIBILITY, AND TOXICITY It is desired that biodegradable biomaterials do not cause an inflammatory response; do not produce toxic degradation products, have appropriate mechanical properties, appropriate permeability and processability, as well as, an ideal degradation time depending on the purpose of use. It is also important to be sterilizable (Ikada and Tsuji, 2000). Biodegradable polymers do not require excellent biocompatibility, since they do not stay in the body for a long time but disappear within hours, days, or weeks without leaving any trace of residue. It has not yet been fabricated biocompatible implants for permanent use (Ikada and Tsuji, 2000). Many of factors affect the degradation rate of PLA, such as the local environment (temperature, water, pH, salinity, oxygen, nutrients); and the chemical and physical characteristics of the polymer, such as molecular weight, crystallinity, purity, permeability, porosity, volume, size, and terminal carboxyl or hydroxyl groups (Madhavan Nampoothiri et al., 2010). Low molecular weight polymers can be degraded more easily than high molecular weight as well as amorphous polymers, for example, PDLLA can be degraded more easily than semicrystalline PLLA and PDLA and then scPLA (stereocomplex of PLLA/PDLA with higher crystallinity) (Xu et al., 2006). The decomposition of PLA in the body varies between 6 months to 1 year, depending on the type used (Pietrzak et al., 1997). According to Li et al. (1990), the weight of PLLA did not reduce until 5 weeks in saline solution. Inflammatory responses were observed in the cells of human and animal bodies due to the products generated by the degradation of PLA in the form of implants, drug delivery materials, and sutures (Vainionpa¨a¨ et al., 1989). In general, PLA is a biocompatible polymer with low toxicity. Although some experiments in vitro have shown low cell multiplication (van Sliedregt et al.,

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1992) and high acid concentrations generated due to degradation; hydrolysis of the polymer (Taylor et al., 1994). Because of the pH reduction, some undesired reactions in the tissue were observed, such as osteolysis, bone resorption, as well as irritation at the implant site (Claes and Ignatius, 2002, Suganuma and Alexander, 1993). One way to solve this problem would be the incorporation of hydroxylapatite (HA) or tricalcium phosphate, which controls the rate of acid formation (Hile et al., 2004). Another problem of PLA is its vulnerability, with the risk of breaking during surgery. The structure of the material can be enhanced by the addition of trimethylene carbonate (TMC) (Zhang et al., 2004). Despite the disadvantages reported in the literature, some researchers have found innovative ways for biopolymers indicating that they show great potential for use in tissue engineering. Yoon et al., 2017 verified, in vivo and in vitro, that the weight and microstructure of PLLA were not degraded over time. There was no reduction in PLLA mesh tension in vitro for 180 days. In addition, they did not observe PLLA induction of inflammation in the subcutaneous tissue. A new technology that is nontoxic and biocompatible, NanoMatrix3D (NM3D), was suggested by Pogorielov et al., 2018.

5.3 CONCLUSION PLA have been showed an extraordinary increasing of applications, and, for this reason this demand will increase the lactic acid market for the next years, however the cost of this production is an inconvenience yet. New technologies for polymerization have been developed for promoting the economical production and high molecular weight of PLA. Chemical catalysts are being gradually replaced by different polymerization processes that present easy conditions of operating, and advances have been developed in genetic engineering toward the same purpose. Cost reductions can be achieved using cheap carbon and nitrogen sources in lactic acid fermentation, optimization of fermentation parameters, and the replacement of electric energy with a cheaper sustainable energy source, such as solar or wind energy. To attend to the necessities of consumers, chemical and physical PLA properties are emerging. By boosting copolymerization or blending technologies with other polymers, new materials with interesting characteristics for diverse applications will emerge. Further studies are needed to assess the compatibility of the material in the body and the toxicity of the degradation products that can cause inflammatory responses, as well as the appropriate mechanical properties, permeability and processability, to have an optimal degradation time depending on the purpose of use. Optimizations of lactic acid production processes, polymerization, and the related technologies, as well as biodegradation researches present continuous progress and novelties.

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