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The chemical structure of polylactic acid (PLA) and polyglycolic acid (PGA) are shown in Figure 6.9. Both PLA and PGA, and their family of materials, are biodegradable polymers that are used extensively as biomaterials for implants in a variety of medical applications. These polymers are polyα-hydroxy acids and are linear polyesters. Their properties have been investigated since the1950s, but the interest in their use as medical implants grew after the pioneering work of Kulkarni and colleagues in the 1960s.2These polymers and their copolymers are now used extensively in thefield of orthopedics as fixation devices for bone and soft tissue in the form of biodegradable plates, screws, and anchors (Figure 6.10). They are also very popular as the scaffolding material for tissue engineering applications and are commercially available as synthetic bone grafts. Additionally, they are used for a variety of dental and controlled drug-delivery applications.

Both the PLA and PGA can be produced using polycondensation techniques to polymerize lactic and glycolic acids, but the yield is usually low molecular weight

C CH 3 CH O n O C CH2 O n O (a) (b) Figure 6.9

Chemical structure of (a) polyglycolic acid (PGA); and (b) polylactic acid (PLA).

Figure 6.10

Example of a typical commercially available medical device made from polylactic acid and polyglycolic acid.

materials. Higher molecular weights can be obtained using ring-opening melt condensation polymerization of lactide and glycolide dimers with catalysts based on antimony, tin, titanium, aluminum, or zinc among others. Stannous octoate is commonly used as a catalyst.

A system or molecule is chiral when it not identical to its mirror image, that is, the mirror images are not superimposable. Chiral molecules are known as enan- tiomers. PLA is a chiral compound and can exist in different enantiomeric states: l and d. Thus, PLA can exist in d or l forms or as their racemic (equal amounts of each enantiomer) mixture dl. The dl-PLA has a lower crystallinity than d-PLA or l-PLA. In contrast, PGA exists in only one form.

Copolymers of PLA and PGA are relatively easy to synthesize and exist in various ratios. For example, Vicryl®, which is widely used for absorbable sutures,

is a 90%PGA–10%PLA copolymer. The 50%PGA–50%PLA copolymer biode-

grades relatively faster than the other copolymers and is often used as a carrier for drug delivery and for fabricating scaffolds for tissue engineering.

The degradation of these polyesters takes place primarily through non-specific hydrolytic scission of their ester bonds. Upon hydrolysis, PGA is converted to glycolic acid, which then reacts to form glycine. The glycine formed ultimately enters the body’s natural tricarboxylic acid cycle and is reduced to water and carbon dioxide. These waste products are excreted in urine or through the respira- tory process. Monomeric units of PGA can be directly excreted through urine. Also, there is evidence that PGA can be degraded by certain enzymes, especially those with esterase activity. In the case of PLA, it isfirst converted to lactic acid upon reaction with water. Lactic acid is a chemical that naturally occurs in the body and is processed by the body to yield water and carbon dioxide.

The physical and degradation properties of the PLA and PGA families of polymers and copolymers are affected by the chemical structure, molecular weight, molecular packing, and copolymer ratios of the polymers. For example, l-PLA is more crystalline and degrades slower than dl-PLA (a mostly amorphous polymer). This is because of the tightly packed l-PLA crystalline structure, which limits the access of water molecules to the ester bonds and thus reduces the rate of hydrolytic scission. The same degradation phenomenon is true when comparing the degradation rates of PLA and PGA. As shown inFigure 6.9, the PLA molecule has a methyl group as a pendant group, which offers stearic hindrance and makes it more hydrophobic. This methyl group provides protection to the backbone, thus yielding a lower degradation rate compared to PGA which has a hydrogen atom in place of the methyl group. On the other hand, PGA molecules without the pendant group can be packed more tightly and thus yield a more crystalline polymer. PLA polymers, because of their higher hydrophobicity and lower crystallinity, are more soluble in organic solvents than PGA.

The molecular weight and the crystallinity both affect the mechanical properties of the poly alpha-hydroxy acids. Both higher molecular weight and higher crys- tallinity result in improved mechanical properties of the polymers up to a limit. Biodegradation results in reduced molecular weight and altered crystallinity and thus can result in significant changes in properties.

The hydrolytic degradation reaction of these polyesters is catalyzed by a low pH environment. As thefirst direct products of degradation for both PLA and PGA are acids, this sets up the potential for autocatalysis. In autocatalysis, the degradation products make the reaction go faster and accelerate the degradation rate. This can be especially true in the interior of large solid implants made of PLA or PGA materials, where there are chances of accumulation of acidic by-products. When these polymers are used as implants, another issue related to the acidic degradation products is the detrimental effect of the acids on the surrounding cells. This can be an issue when PLA or PGA materials are used as implants in areas of the body that have low vascularity and where the body is unable to clear the degradation products in an expedient manner. When used for tissue engineering scaffolds, the relative hydrophobic nature of these polymers can prevent good cell adhesion. This problem can be addressed by surface treatment of the polymers by gas plasma in an oxygen environment or other chemical means to attach more hydrophilic moieties to their surface while still retaining the advantages of their bulk properties and biodegradability. The principle of plasma treatment is dis- cussed inChapter 9.

6.4.4 Polycaprolactone (PCL)

The chemical structure of polycaprolactone (PCL) is shown inFigure 6.11. It is a biodegradable polymer that is often used for tissue engineering applications as well as for drug delivery devices. It is made by the ring-opening polymerization of ϵ-caprolactone in the presence of a catalyst such as stannous octoate.

This polymer has a low melting point (59–64 _{C) and a glass transition} temperature of approximately−60 C. Compared to PLA, PCL is more rubbery in nature at room temperature and biodegrades at a slower pace. The slower

Figure 6.11

biodegradation is because of its relative high crystallinity and hydrophobicity. It is also easily soluble in organic solvents and has the ability to form blends. PCL degrades through the hydrolytic cleavage of its ester bonds and can be used to release drugs over a prolonged period. For example, it has been used to deliver the contraceptive levonorgestrel (a synthetic version of progestogen) for more than a year through an implantable device. PCL has also been studied to deliver anti- cancer drugs through nanoparticles. In some case these particles can be delivered via an injection.