Further development of synthetic materials from glycolic acid and other alpha-hydroxy acids was abandoned in the first half of the last century because the resulting polymers were too unstable for long-term industrial use. However, over the past three decades, this instability, which leads to biodegradation, has proven to be of great importance in medical applications. Polymers made from glycolic and lactic acids have found widespread use in the medical industry, starting with the first approved biodegradable sutures in the 1960s.

Since then, a variety of products based on lactic and glycolic acids, as well as other materials including poly(dioxolanes), poly(trimethylene carbonate) copolymers, and poly(ε-caprolactone) homopolymers and copolymers, have been approved for use as medical devices. In addition to these approved devices, extensive research continues on polyanhydrides, polyorthoesters, polyphosphates, and other biodegradable polymers.

A prototype biodegradable intravascular stent is molded from a blend of polylactide and trimethylene carbonate.

Why would a doctor want a material to degrade? There may be many reasons, but the most basic one is that doctors want to have a device that can be used as an implant and removed without a second surgical intervention. In addition to eliminating the need for a second surgery, biodegradation has other advantages. For example, a fractured bone fixed with a hard, non-biodegradable stainless steel implant has a tendency to fracture when the implant is removed. Since the stress is borne by the hard stainless steel, the bone cannot bear enough load during the healing process. However, implants made with biodegradable polymers can degrade at a rate that slowly transfers the load to the healing bone. Another exciting use for biodegradable polymers that has great potential is as a basis for drug delivery, either as a drug delivery system alone or in combination with medical devices.

Polymer scientists have worked closely with scientists in the device and medical fields to make great advances in the past 50 years. This article will highlight some of these advances. We will also review the chemistry of polymers, including synthesis and degradation, describe how properties can be controlled through appropriate synthetic control (such as copolymer composition), highlight the special requirements for processing and handling, and discuss some commercial devices based on these materials.

1. Polymer Chemistry

Biodegradable polymers can be either natural or synthetic. In general, synthetic polymers offer advantages over natural materials because they can be tailored to provide a wider range of properties and more predictable batch-to-batch consistency than natural materials. Synthetic polymers are also a more reliable source of raw materials and do not pose immunogenicity issues.

Table I. Properties of common biodegradable polymers.

The general criteria for selecting a polymer for use as a biomaterial is to match its mechanical properties and degradation time to the application requirements (see Table I). An ideal polymer for a particular application would have the following characteristics:

•Have mechanical properties that match the application and remain sufficient until surrounding tissue heals strength.

•Does not cause inflammatory or toxic reactions.

•After achieving its purpose, it is metabolized in the body without leaving any trace.

•Easy to process into final product form.

•Acceptable shelf life.

•Easily sterilized.

Factors that influence the mechanical properties of biodegradable polymers are well known to polymer scientists and include monomer selection, initiator selection, processing conditions, and the presence of additives. These factors, in turn, influence the polymer's hydrophilicity, crystallinity, melting and glass transition temperatures, molecular weight, molecular weight distribution, end groups, sequence distribution (random vs. blocky), and the presence of residual monomers or additives. Furthermore, polymer scientists must evaluate the effects of these variables on biodegradation when studying biodegradable materials.

Biodegradation is accomplished by synthesizing polymers that have hydrolytically labile bonds in the backbone. The most common chemical functional groups with this property are esters, anhydrides, orthoesters, and amides. We will discuss important properties that influence biodegradation later in this article.

The next section provides an overview of synthetic biodegradable polymers currently in use or under investigation for use in wound closure (sutures, staples), orthopedic fixation devices (pins, rods, screws, tacks, ligaments), dental applications (guided tissue regeneration), cardiovascular applications (stents, grafts), and enteric applications (anastomotic rings). Most commercially available biodegradable devices are polyesters composed of homopolymers or copolymers of glycolide and lactide. There are also devices made from copolymers of trimethylene carbonate and ε-caprolactone, and suture products made from polydioxanone.

Polyglycolide (PGA). Polyglycolide is the simplest linear aliphatic polyester. The first fully synthetic absorbable suture was developed from PGA by Davis and Geck in the 1960s and marketed as Dexon. Glycolide monomers are synthesized by dimerization of glycolic acid. Ring-opening polymerization produces high molecular weight materials with residual monomer content of approximately 1-3% (see Figure 1). PGA has a high degree of crystallinity (45-55%), a high melting point (220-225°C), and a glass transition temperature of 35-40°C. Due to its high crystallinity, it is insoluble in most organic solvents, with the exception of highly fluorinated organic solvents such as hexafluoroisopropanol. PGA fibers have high strength and modulus, but are too stiff to be used as sutures (unless in the form of braided materials). PGA sutures lose approximately 50% of their strength after 2 weeks, 100% of their strength at 4 weeks, and are completely absorbed within 4-6 months. Copolymerization of glycolide with other monomers can reduce the stiffness of the resulting fibers.

Figure 1. Synthesis of polyglycolide (PGA)

Polylactide (PLA). Lactide is a cyclic dimer of lactic acid and exists in two optical isomers: d and l. L-lactide is the naturally occurring isomer, while dl-lactide is a synthetic mixture of d-lactide and l-lactide. Homopolymers of L-lactide (LPLA) are semicrystalline polymers. These types of materials have high tensile strength and low elongation, and therefore high modulus, making them more suitable for load-bearing applications such as orthopedic fixation and suturing. Poly(dl-lactide) (DLPLA) is an amorphous polymer in which the two isomeric forms of lactic acid are randomly distributed and therefore cannot be arranged into an organized crystalline structure. This material has lower tensile strength, higher elongation, and faster degradation time, making it more attractive as a drug delivery system. Poly(L-lactide) has a crystallinity of about 37%, a melting point of 175-178°C, and a glass transition temperature of 60-65°C. LPLA has a much slower degradation time than DLPLA, requiring more than 2 years to be completely absorbed. Copolymers of L-lactide and dL-lactide have been prepared to disrupt the crystallinity of L-lactide and accelerate the degradation process.

Poly(ε-caprolactone). Ring-opening polymerization of ε-caprolactone yields a semicrystalline polymer with a melting point of 59-64°C and a glass transition temperature of -60°C (see Figure 2). The polymer is considered tissue compatible and is used as a biodegradable suture in Europe. Since the degradation time of the homopolymer is about 2 years, copolymers have been synthesized to accelerate the bioabsorption rate. For example, copolymers of ε-caprolactone with dl-lactide produce materials with faster degradation rates. Block copolymers of ε-caprolactone with glycolide have a lower stiffness than pure PGA and are being sold by Ethicon as a monofilament suture under the trade name Monacryl.

Figure 2. Synthesis of poly(ε-caprolactone).

Polydioxanone (polyetherester). Ring-opening polymerization of p-dioxanone (see Figure 3) produced the first clinically tested monofilament synthetic suture, called PDS (marketed by Ethicon). The material has a crystallinity of approximately 55% and a glass transition temperature of -10 to 0°C. The polymer should be processed at the lowest possible temperature to prevent depolymerization back to monomers. Polydioxanone has been shown to have no acute or toxic effects on implantation. The monofilament loses 50% of its initial breaking strength after 3 weeks and is absorbed within 6 months, which compares favorably with Dexon or other products used for slow-healing wounds.

Figure 3. Synthesis of poly (dioxanone. ε-caprolactone).

Poly(lactide-co-glycolide). Using the properties of poly(glycolide) and poly(L-lactide) as a starting point, the two monomers can be copolymerized to extend the range of homopolymer properties (see Figure 4). Copolymers of glycolide with L-lactide and dl-lactide have been developed for device and drug delivery applications. It is important to note that there is no linear relationship between copolymer composition and the mechanical and degradation properties of the material. For example, a copolymer of 50% glycolide and 50% dl-lactide degrades faster than either homopolymer (see Figure 5). Copolymers of L-lactide with 25-70% glycolide are amorphous because the additional monomers disrupt the regularity of the polymer chains. Ethicon has developed a copolymer of 90% glycolide and 10% L-lactide as an absorbable suture material under the trade name Vicryl. It absorbs within 3-4 months but retains strength slightly longer.

Figure 4. Synthesis of Poly(Lactide-co-glycolide).ε-Caprolactone)

Figure 5. Half-lives of PLA and PGA homopolymers and copolymers implanted in rat tissue.

Copolymers of glycolide and trimethylene carbonate (TMC), called polyglycolates (see Figure 6), have been prepared as sutures (Maxon, by Davis and Geck) and tacks and screws (Acufex Microsurgical). Typically, these are prepared as A-B-A block copolymers in a 2:1 glycolide:TMC ratio, with a glycolide-TMC center block (B) and pure glycolide end blocks (A). These materials have greater flexibility than pure PGA and are absorbed in approximately 7 months. Glycolide has also been polymerized with TMC and p-dioxanone (Biosyn, United States Surgical Corp.) to form terpolymer sutures that are absorbed in 3-4 months and are less stiff than pure PGA fibers.

Figure 6. Synthesis of polyglycolate.

Other polymers in development. Devices made from homopolymers or copolymers of glycolide, lactide, caprolactone, p-dioxanone, and trimethylene carbonate have been approved for marketing by the FDA. However, many other polymers are being investigated for use as materials in biodegradable devices.

In addition to their suitability for medical use, biodegradable polymers are excellent candidates for packaging and other consumer applications. Many companies are evaluating methods for producing low-cost biodegradable polymers. One approach is to bioengineer the polymers, using microorganisms to produce energy-storing polyesters. Two examples of these materials—polyhydroxybutyrate (PHB) and polyhydroxyvalerate (PHV)—are commercially available as copolymers under the trade name Biopol and have been investigated for use in medical devices (see Figure 7). PHB homopolymers are crystalline and brittle, while copolymers of PHB with PHV are less crystalline, more flexible, and easier to process. These polymers generally require the presence of enzymes for biodegradation but can be degraded in a variety of environments and are being considered for a variety of biomedical applications.

Figure 7. Molecular structures of two bioengineered polyesters that require specific enzymes for biodegradation.

Given their widespread occurrence in nature, the use of synthetic poly(amino acids) as polymers for biomedical devices seems a reasonable choice. In practice, however, pure insoluble poly(amino acids) have little practical utility due to their high crystallinity, which makes them difficult to process and results in relatively slow degradation. The antigenicity of polymers with more than three amino acids in the chain also makes them unsuitable for use in vivo. To address these issues, modified “pseudo” poly(amino acids) have been synthesized by using tyrosine derivatives. For example, tyrosine-derived polycarbonates are high-strength materials that can be used as orthopedic implants. Poly (amino acids) can also be copolymerized to modify their properties. The most widely studied class is polyesteramides.

2. Terminology Note

Polymers are often named after the monomer from which they are synthesized. For example, ethylene is used to produce polyethylene. For glycolic and lactic acids, intermediate cyclic dimers are prepared and purified prior to polymerization. These dimers are called glycolide and lactide, respectively. Although polyglycolide or polylactide are mentioned most of the time, you will also find references to polyglycolic acid and polylactic acid. Poly(lactide) exists in two stereo forms, designated d or l for right- or left-handed, or dl for a racemic mixture.

Finding new candidate polymers for drug delivery may also offer potential for medical device applications. In drug delivery, formulation scientists are concerned not only with drug stability during shelf life, but also with stability after implantation, when the drug may remain in the implant for 1-6 months or longer. For hydrolytically unstable drugs, polymers that absorb water may be contraindicated, and researchers have begun evaluating hydrophobic polymers that degrade by surface erosion rather than by bulk hydrolytic degradation. These polymers fall into two categories: polyanhydrides and polyorthoesters.

Polyanhydrides are synthesized by melt polycondensation dehydration of diacid molecules (see Figure 8). Depending on the degree of hydrophobicity of the chosen monomer, the degradation time can be adjusted from days to years. The material degrades primarily by surface erosion and has excellent in vivo compatibility. So far, they have only been approved for sale as drug delivery systems. The Gliadel product, designed for delivery of the chemotherapy drug BCNU in the brain, received regulatory approval from the FDA in 1996 and is manufactured by Guilford Pharmaceuticals.

Figure 8. Molecular structure of poly (SA-HDA anhydride).

Polyorthoesters were first investigated in the 1970s by Alza Corp and SRI International in an effort to find new synthetic biodegradable polymers for drug delivery applications (see Figure 9). These materials have undergone several generations of improvements in synthesis and can now be polymerized at room temperature without forming condensation byproducts. Polyorthoesters are hydrophobic with acid-sensitive but base-stable hydrolytic bonds. They degrade by surface erosion, and the rate of degradation can be controlled by the addition of acidic or basic excipients.

Figure 9. Molecular structure of polyorthoesters.

3.   Packaging and Sterilization

Since biodegradable polymers are hydrolytically unstable, the presence of moisture can cause them to degrade during storage, processing, and after device fabrication. In theory, the solution to hydrolytic instability is simple: eliminate the moisture, and thus the degradation. However, because these materials are naturally hygroscopic, it is difficult to achieve water removal and keep the polymers free of water. The polymers synthesized have relatively low water contents because any residual water in the monomers is consumed in the polymerization reaction. The polymers are quickly packaged after fabrication—usually double-wrapped under an inert atmosphere or vacuum. The bag material can be polymer or foil, but must be highly water-permeable. To minimize the effects of moisture, the polymers are typically stored in a refrigerator. Packaged polymers should always be at room temperature when opened to minimize condensation, and should be handled as little as possible under ambient atmospheric conditions. As expected, there is a relationship between biodegradation rate, storage stability, and polymer properties. For example, the more hydrophilic glycolide polymers are more susceptible to hydrolytic degradation than polymers made from the more hydrophobic lactide.

Final packaging involves placing the suture or device in an airtight, moisture-proof container. A desiccant may also be added to further reduce the effects of humidity. For example, sutures are wrapped in specially prepared drying paper trays that act as a desiccant. In some cases, finished devices can be stored below ambient temperature to prevent degradation.

Devices containing biodegradable polymers cannot be autoclaved and must be sterilized by gamma or electron beam irradiation or exposure to ethylene oxide (ETO) gas. However, both irradiation and ETO sterilization have certain disadvantages. Irradiation, especially at doses above 2 MHz, can cause significant degradation of the polymer chains, resulting in a decrease in molecular weight and affecting final mechanical properties and degradation time. Polyglycolide, polylactide, and polydioxanone are particularly sensitive to ionizing radiation, and these materials are often sterilized with ETO in device applications. Because of the safety concerns posed by highly toxic ETO, great care must be taken to ensure that all gases are purged from the device prior to final packaging. Temperature and humidity conditions should also be considered when submitting a device for sterilization. The temperature must be maintained below the glass transition temperature of the polymer to prevent the geometry of the part from changing during the sterilization process. If necessary, the parts can be kept at 0°C or lower during irradiation.

4.   Processing

All commercially available biodegradable polymers can be melt processed by conventional methods such as injection molding, extrusion, and compression molding. As with packaging, special attention needs to be paid to exclude moisture from the material prior to melt processing to prevent hydrolytic degradation. Special attention must be paid to the drying of the polymer before processing and strict exclusion of moisture during processing.

Since most biodegradable polymers are synthesized by ring-opening polymerization, there is a thermodynamic equilibrium between the forward reaction or polymerization and the reverse reaction leading to monomer formation. Excessive processing temperatures may lead to the formation of monomers during molding or extrusion. The presence of excess monomers can act as a plasticizer, changing the mechanical properties of the material and catalyzing hydrolysis of the equipment, thereby changing the degradation kinetics. Therefore, these materials should be processed at the lowest temperature possible.