**Surface coating**

This is one of the simplest surface modification methods and has been applied to various polymers, but particularly to PLA nanoparticles used for drug delivery. For instance, PEG coating delayed the phagocytosis of PLA nanoparticles and prolonged the circulation time of the nanoparticles in vivo (Gref et al., 1994). Unfortunately the PEG-coated PLA nanoparticles cannot provide specific targeting, which influences their delivery efficiency. One of the most promising alternatives to PEG in this respect is the use of polysaccharides. These materials provide steric protection to the nanoparticles against non-specific interactions with proteins and thereby insure particle stability in the blood circulation system (Ma et al., 2008). Additionally, ligands to achieve active targeting can be conjugated on the surface of these nanoparticles, because many reactive groups are available on the polysaccharides and their derivatives (Gu et al., 2007). Another option is coating of the surface with extracellular matrix (ECM) proteins such as fibronectin, laminin, vitronectin, and collagen, which are conducive to cell adhesion and can greatly improve biocompatibility as well (Lin et al., 2010).

Innovative work was accomplished by Cronin et al. (Cronin et al., 2004), who tested a PLLA fiber scaffold as a substrate for the differentiation of human skeletal muscle cells. Cell attachment (the number of cells attached to the films counted along the center, from one edge to the opposite edge of the film within the field of view) increased significantly on PLLA films coated with ECM gel, fibronectin, or laminin as compared to uncoated or gelatin-coated PLLA films. Myoblasts were able to differentiate into multinucleated myofibers on the ECM gel-coated PLLA fibers and expressed muscle markers such as myosin and α-actinin, as demonstrated by western blot and oligonucleotide microarray analysis.

### **Entrapment**

The entrapment of modifying species (e.g. PEG, alginate, gelatin, etc.) can be achieved through reversible swelling of the PLA surface as illustrated in Fig. 4. This is a simple yet effective method for surface modification requiring no specific functional groups in the polymer chains, as the modifying molecules accumulate merely on the surface of the material without modifying its bulk properties (Lu et al., 2009). Additionally, entrapment can be used to generate different morphologies and thicknesses of 3D scaffolds, which cannot be achieved by other surface modification methods. Finally, entrapment allows the modification of the surface in a controlled fashion because various parameters (e.g. solvent ratio, gelatin concentration, immersion time, and chemical cross-linking) can be varied to tailor the process (Zhu et al., 2003).

The surface properties of materials play a key role in determining their applications. The presence of specific surface chemical functionalities, hydrophilicity, roughness, surface energy, and topography is crucial for biomedical applications of PLA and its interactions with biomacromolecules. Pure PLA causes a mild inflammatory response if it is implanted into human tissues. It is therefore important to design biomaterials with the required surface properties. The different surface modification strategies examined include physical methods, including surface coating, entrapment and plasma treatment, and chemical

This is one of the simplest surface modification methods and has been applied to various polymers, but particularly to PLA nanoparticles used for drug delivery. For instance, PEG coating delayed the phagocytosis of PLA nanoparticles and prolonged the circulation time of the nanoparticles in vivo (Gref et al., 1994). Unfortunately the PEG-coated PLA nanoparticles cannot provide specific targeting, which influences their delivery efficiency. One of the most promising alternatives to PEG in this respect is the use of polysaccharides. These materials provide steric protection to the nanoparticles against non-specific interactions with proteins and thereby insure particle stability in the blood circulation system (Ma et al., 2008). Additionally, ligands to achieve active targeting can be conjugated on the surface of these nanoparticles, because many reactive groups are available on the polysaccharides and their derivatives (Gu et al., 2007). Another option is coating of the surface with extracellular matrix (ECM) proteins such as fibronectin, laminin, vitronectin, and collagen, which are conducive to cell adhesion and can greatly improve

Innovative work was accomplished by Cronin et al. (Cronin et al., 2004), who tested a PLLA fiber scaffold as a substrate for the differentiation of human skeletal muscle cells. Cell attachment (the number of cells attached to the films counted along the center, from one edge to the opposite edge of the film within the field of view) increased significantly on PLLA films coated with ECM gel, fibronectin, or laminin as compared to uncoated or gelatin-coated PLLA films. Myoblasts were able to differentiate into multinucleated myofibers on the ECM gel-coated PLLA fibers and expressed muscle markers such as myosin and α-actinin, as demonstrated by western blot and oligonucleotide microarray

The entrapment of modifying species (e.g. PEG, alginate, gelatin, etc.) can be achieved through reversible swelling of the PLA surface as illustrated in Fig. 4. This is a simple yet effective method for surface modification requiring no specific functional groups in the polymer chains, as the modifying molecules accumulate merely on the surface of the material without modifying its bulk properties (Lu et al., 2009). Additionally, entrapment can be used to generate different morphologies and thicknesses of 3D scaffolds, which cannot be achieved by other surface modification methods. Finally, entrapment allows the modification of the surface in a controlled fashion because various parameters (e.g. solvent ratio, gelatin concentration, immersion time, and chemical cross-linking) can be varied to

**4.2 Surface modification** 

**4.2.1 Physical methods** 

**Surface coating** 

analysis. **Entrapment** 

methods. Both types of approaches are reviewed.

biocompatibility as well (Lin et al., 2010).

tailor the process (Zhu et al., 2003).

Fig. 4. Schematic illustration of entrapment process.

PEG (*M*w = 18,500) and poly(*L*-lysine) (PLL) (*M*w = 29,300) have been trapped on PLA surfaces using 2,2,2-trifluoroethanol (TFE)/water as solvent/nonsolvent mixtures (Quirk et al., 2002). A new entrapment process has also been reported by Liu et al. (Liu et al., 2005), through chemical cross-linking of gelatin with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) HCl and *N*-hydroxysuccinimide (NHS) (97%) in {2-[N-morpholino] ethanesulfonic acid} (MES) hydrate buffer, after the pretreated PLLA films were immersed in the gelatin solution for a set time. Results in comparison to the control scaffolds have shown that the surface hydrophilicity increased with the amount of entrapped gelatin and that cell attachment and proliferation, the deposition of collagen fibers, and other cell excretion (extracellular matrix, etc.) were also significantly improved.

### **Plasma treatment**

Tests with plasma treatment were initiated in the 1960s and have been since then widely utilized to improve the hydrophilicity and cell affinity of PLA surfaces. The obvious advantages of plasma treatment as compared to other surface modification methods include its ability to control the surface structure, energy and charge, and to uniformly modify the surface without impacting bulk properties (Chu et al., 2002). Functional groups such as – NH2, –COOH, and –OH, which are apt to form covalent bonds with other materials for further modification, are most frequently introduced by plasma treatment (Favia et al., 1998).

Liu et al. thus investigated the influence of the main operation parameters, namely the plasma power, the treatment duration (number of treatment cycles) and the electrode gap on a dielectric barrier discharge (DBD) plasma treatment of PLA films in terms of changes in surface wettability and chemistry (Liu et al., 2004). They further developed equations relating the surface properties (water contact angle and oxygen enrichment, as observed by XPS analysis) to these operational parameters. It was determined that the magnitude of the electrode gap played a dominant role in the treatment of PLA, and the observed wettability improvements were attributed to changes in both surface chemistry and microstructure. Chaiwong and coworkers (Chaiwong et al., 2010) investigated the influence of SF6 plasma on the hydrophobicity and barrier properties of PLA. It was found that the SF6 plasma enhanced the hydrophilicity and increased the water absorption time of PLA two-fold. Plasma treatment did not have any significant influence on the water vapor permeability of PLA, however, since the bulk structure controlling the transport properties are unaffected by the treatment. Other types of plasmas such as oxygen, helium, and nitrogen plasmas have also been investigated (Hirotsu et al., 2002).

While plasma treatment has been successfully applied to improving PLA wettability and cell affinity, its main disadvantage is that surface rearrangements caused by thermally activated macromolecular motions, to minimize its interfacial energy, can also influence the surface modification. Moreover, the potential influence of plasma on the degradation of PLA cannot be ignored.
