Production of PLA and PLGA from a green chemistry perspective

Courtesy: Fernando de Carlos Hernandez, SINTEF

During the last decades, environmental awareness has increased in the scientific sphere and thus, the search for new eco-friendlier technologies. Alternatives to petroleum-based synthetic polymers are a key step since these plastics are typically non-biodegradable and accumulate in the ecosystems, affecting the biodiversity. However, not only the final products can damage the environment but also the waste products generated during their production. These issues are addressed by Green Chemistry (Anastas & Eghbali, 2010). This discipline can be applied in all fields of chemistry, and it involves the design of safer chemical products and processes by reducing or erasing the use of hazardous substances. Green chemistry applies throughout the whole life cycle of the product, from design, production, use and finally, disposal. The focus of green chemistry is the prevention or reduction of the pollution in contrast to just cleaning the residues. The principles of green chemistry are summarized in 12 points showed in figure 1.

Figure 1: The twelve principles of green chemistry.

In particular, a range of new materials suitable for medical use can be extracted from sustainable sources which would imply a greener production. Among these, biopolymers from natural feedstocks such as cellulose, collagen, chitosan or polylactic acid (PLA) are considered promising materials for medical applications (Rebelo, Fernandes, & Fangueiro, 2017). The latter is a biopolymer that has gained interest in the field of biomedicine due to its good biocompatibility and biodegradability. It can be obtained from renewable resources such as corn or potato. The synthesis is divided in two main steps, the fermentation of sugar to obtain the monomer lactic acid (figure 2) and the polymerization to polylactic acid (Li, et al., 2020).

Figure 2: Schematic of fermentation of polysaccharides

The fermentation to produce lactic acid is performed by bacteria, from the genera Lactobacillus, Streptococcus or Pediococcus, for 3-5 days in a low oxygen atmosphere, followed by purification with ultrafiltration, dyeing and electrodialysis. The development in genetic engineering has enhanced the yield of the process by increasing growth rate and controlling the metabolic activity (Vaidya, et al., 2005).

To produce lactic acid, chemical synthesis methods can also be used. However, these methods do not agree with the standards of green chemistry since they use reagents such as hydrogen cyanide or chlorinated compounds (Li, et al., 2020).

For the polymerization of lactic acid into PLA, three methods are reported. The first, the lactide method is based on lactide ring-opening (Figure 3) and is very suitable for medical application as the other two methods, condensation-polymerization and azeotropic dehydration condensation, use coupling agents and catalysts that are toxic and nonbiodegradable (Li, et al., 2020).

Figure 3: Schematic of lactide method to produce polylactic acid.

The lactide method, on the other hand, produces the cyclic dimer lactide by a greener approach, as it is a solvent-free process. However, the polymerization still needs heavy metal catalyst like tin (II)di-ethyl hexanoic acid (tin octoate) (Storey & Sherman, 2002). Organic tin compounds are persistent and nonbiodegradable, as well as cytotoxic, so a better solution has been proposed such as enzymatic polymerization or in vitro bacterial polymerization (Matsumoto & Taguchi, 2010).

From an environmental point of view, it is therefore more sustainable to use bacteria that can undergo simultaneous saccharification and fermentation from starch or cellulosic biomass directly to PLA, reducing costs of production as well as the environmental impact.

Furthermore, PLA can be used to synthesise poly lactic-co-glycolic acid (PLGA) and PLA nanoparticles which are biodegradable, biocompatible and show low cytotoxicity. They have been investigated as drug delivery vehicles due to their versatility in carrying different kind of drugs to specific locations (Loureiro & Pereira, 2020). For example, a recent research study used PLGA nanoparticles as a carrier for smart delivery of a specific growth factor BMP-2 for bone regeneration (Del-Castillo-Santaella, et al., 2019). However, from a green chemistry perspective some of the synthesis methods still use the solvent dichloromethane (DCM) in its production (Danhier, et al., 2012). DCM is known for its bioaccumulation in the environment; thus, it should be replaced by alternative less hazardous solvents such as methanol, ethyl acetate or acetonitrile (Alfonsi, et al., 2008; Hans & Lowman, 2002).

Summarizing, polylactic acid is a great alternative as a polymer for medical applications from an environmental point of view because of the natural origin and the easy biodegradation through composting. Moreover, the production uses biological fermentation instead of chemical methods, decreasing the waste generated, as well as the use of catalyst to enhance the procedure. However, this catalyst based on tin is still not the greenest solution compared to in vitro bacterial production. Also, the preparation of PLGA and PLA nano- and microparticles still involves organic solvents, in some cases hazardous ones.


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Author: Fernando de Carlos Hernandez, SINTEF Industry, Biotechnology and Nanomedicine