**4.1.2 Chemical modification**

The chemical modification of PLA has been achieved mainly through copolymerization and cross-linking.

## **Copolymerization**

The carboxyl and hydroxyl groups of LA make it possible to copolymerize it with other monomers through polycondensation with lactone-type monomers such as ε-caprolactone, which generally leads to low molecular weight copolymers, or alternately through the ringopening copolymerization of lactide with other cyclic monomers including glycolide, δvalerolactone, and trimethylene carbonate, as well as with monomers like ethylene oxide (EO) to produce high molecular weight copolymers. The hydrophobicity and crystallinity of the copolymers can be increased for low to moderate comonomer contents. Besides, poly(ethylene oxide) (PEO) and PEG have been most commonly copolymerized with PLA to prepare copolymers on account that it is highly biocompatible, hydrophilic and non-toxic, non-immunogenic and non-antigenic (Metters et al., 2000). Such properties reduce protein adsorption and enhance resistance to bacterial and animal cell adhesion.

Block copolymers are composed of long sequences (blocks) of the same monomer unit, covalently bound to sequences of a different type. The blocks can be connected in a variety of ways. Fig. 3 shows examples of block copolymer structures. Diblock PLA-PEG copolymers and triblock PLA-PEG-PLA copolymers allow modulation of the biodegradation rate, the hydrophilicity, and the mechanical properties of the copolymers, while phase separation can be tailored with PLA-PEG multi-block copolymers of predetermined block lengths (Wang et al., 2005). Star- and dendrimer-like PLA-PEG copolymers have also been synthesized to lower the *T*g, *T*m, and the crystallinity of the materials (Zhang et al., 2004).

Riley et al. (Riley et al., 2001) prepared a range of PLA-PEG copolymers incorporating a PEG block of constant molecular weight (Mn = 5,000) and varying PLA segment lengths (Mn = 2,000-110,000) by ROP of *D*,*L*-lactide catalyzed by stannous octoate; all the dispersions were stable under physiological conditions. In 2003, Li and Vert (Li & Vert, 2003) prepared series of diblock and triblock copolymers by ring-opening polymerization of *L*(*D*)-lactide from mono- and dihydroxyl PEO, using zinc metal as a catalyst under vacuum. The copolymers were semicrystalline, their composition and molar mass being determining factors affecting their solubility in water. Fu et al. (Fu et al., 2008) prepared series of LA-based polyurethanes modified by castor oil with controllable mechanical properties. In this work, hydroxylterminated prepolymers were synthesized by copolymerization of L-LA and 1, 4-butanediol.

Fig. 3. Schematics of block copolymer structures: (a) diblock; (b) triblock; (c) alternating multiblock; (d); dendrimer-like copolymer; (e) star-like copolymer.

### **Cross-linking**

258 Biomedical Science, Engineering and Technology

Kim et al. (Kim et al., 2010) prepared a series of PLA/exfoliated graphite (EG) nanocomposites and confirmed that the graphite nanoplatelets could be dispersed homogeneously within the PLA matrix. Thermogravimetric analysis also showed that the thermal stability of the nanocomposites was improved with incremental amounts of EG up to 3 wt %. For example, the temperature corresponding to a 3% weight loss for a composite with 3.0 wt % EG increased by 14 degrees to ~364 °C vs. pure PLA. Additionally, the Young's modulus of the composites increased with their graphite content and their electrical resistivity was dramatically lowered. Poly(lactic acid)/hydroxyapatite (PLA/HAP) composite scaffolds processed by foaming with supercritical CO2 were shown to be promising for bone replacement, because their mechanical characteristics closely matched the properties of bone in terms of viscoelasticity and anisotropy (Mathieu et al., 2006).

The chemical modification of PLA has been achieved mainly through copolymerization and

The carboxyl and hydroxyl groups of LA make it possible to copolymerize it with other monomers through polycondensation with lactone-type monomers such as ε-caprolactone, which generally leads to low molecular weight copolymers, or alternately through the ringopening copolymerization of lactide with other cyclic monomers including glycolide, δvalerolactone, and trimethylene carbonate, as well as with monomers like ethylene oxide (EO) to produce high molecular weight copolymers. The hydrophobicity and crystallinity of the copolymers can be increased for low to moderate comonomer contents. Besides, poly(ethylene oxide) (PEO) and PEG have been most commonly copolymerized with PLA to prepare copolymers on account that it is highly biocompatible, hydrophilic and non-toxic, non-immunogenic and non-antigenic (Metters et al., 2000). Such properties reduce protein

Block copolymers are composed of long sequences (blocks) of the same monomer unit, covalently bound to sequences of a different type. The blocks can be connected in a variety of ways. Fig. 3 shows examples of block copolymer structures. Diblock PLA-PEG copolymers and triblock PLA-PEG-PLA copolymers allow modulation of the biodegradation rate, the hydrophilicity, and the mechanical properties of the copolymers, while phase separation can be tailored with PLA-PEG multi-block copolymers of predetermined block lengths (Wang et al., 2005). Star- and dendrimer-like PLA-PEG copolymers have also been synthesized to lower the *T*g, *T*m, and the crystallinity of the

Riley et al. (Riley et al., 2001) prepared a range of PLA-PEG copolymers incorporating a PEG block of constant molecular weight (Mn = 5,000) and varying PLA segment lengths (Mn = 2,000-110,000) by ROP of *D*,*L*-lactide catalyzed by stannous octoate; all the dispersions were stable under physiological conditions. In 2003, Li and Vert (Li & Vert, 2003) prepared series of diblock and triblock copolymers by ring-opening polymerization of *L*(*D*)-lactide from mono- and dihydroxyl PEO, using zinc metal as a catalyst under vacuum. The copolymers were semicrystalline, their composition and molar mass being determining factors affecting their solubility in water. Fu et al. (Fu et al., 2008) prepared series of LA-based polyurethanes modified by castor oil with controllable mechanical properties. In this work, hydroxylterminated prepolymers were synthesized by copolymerization of L-LA and 1, 4-butanediol.

adsorption and enhance resistance to bacterial and animal cell adhesion.

**4.1.2 Chemical modification** 

materials (Zhang et al., 2004).

cross-linking. **Copolymerization** 

> Cross-linked PLA structures can be formed either by irradiation or through chemical reactions. Electron beam and γ-irradiation have been widely applied to cross-linking PLA in the presence of small amounts of cross-linking agents such as triallyl isocyanurate (TAIC) (Quynh et al., 2008; Phong et al., 2010). The thermal stability of PLA-based materials can be significantly improved in this way (Quynh et al., 2007). Quynh et al. (Quynh et al., 2009) obtained stereocomplexes by cross-linking blends of PLLA and low molecular weight PDLA. Alkaline hydrolysis and enzymatic degradation of the stereocomplex could be controlled by radiation cross-linking, because the alkaline solution as well as proteinase hardly attacked the cross-linked polymer network. Unfortunately, irradiation equipment is expensive and the PLA samples must be processed as thin plates to absorb enough energy from the radiation to initiate cross-linking reactions, which significantly limits its practical application.

> Modified PLA with different gel fractions and cross-linking densities can also be obtained through chemical reactions between linking agents and the polymer chains without irradiation (Agrawal et al., 2010). Yang et al. (Yang et al., 2008) thus induced cross-linking via treatment of the PLA melt with small amounts of TAIC and dicumyl peroxide (DCP). The results obtained for samples with different gel fractions and cross-link densities showed that the cross-linking of PLA was initiated at low contents of either TAIC or DCP. The crystallinity of cross-linked PLA samples obtained with 0.5 wt% TAIC and 0.5 wt% DCP decreased from 32% for pure PLA to 24%. Significant increases in tensile modulus from 1.7 GPa to 1.9 GPa, and in tensile strength from 66 GPa to 75 GPa were also observed, and the thermal degradation initiation and completion temperatures were both increased relatively to neat PLA. Additional advantages of this method are that it requires neither extra purification steps nor specialized equipment, since the reaction is carried out in the molten state with only small amounts of cross-linking agent. It is thus economically very advantageous over irradiation, which requires expensive equipment. An increase in brittleness was nevertheless observed following the formation of highly cross-linked structures, which remains a problem to be solved.
