9.3.3  Poly(Ortho Esters)

Poly(ortho esters) (POE) are a class of synthetic hydrophobic, bioerodible polymers that have been under development since the 1970s. The orthoester link of POE is less stable under acidic than basic conditions, and thus, the degradation rate of POE can be controlled by incorporating acidic or basic excipients into the polymer matrix (Park and Lakes 2007). Unlike polyesters, which degrade homogeneously throughout the polymer matrix, POEs are highly hydrophobic and water-impermeable, and as a result, degrade via surface erosion (Fig. 9.4g–l). This property has generated interest in the use of POEs for drug delivery, since they can conceivably be used to deliver drugs at a constant rate (i.e., zero-order kinetics) without the burst effect associated with bulk-eroding polymers.

To date, four POE families have been developed, designated as POE I, POE II, POE III, and POE IV (Park et al. 2005; Heller et al. 2002). POE I, POE II, and POE III have limited applicability in biomedicine due to extreme hydrophobicity and/or difficulties in their synthesis. In contrast, POE IV, a modified version of POE II that has a short segment based on lactic acid or glycolic acid incorporated into the polymer backbone, has the necessary attributes for use as a drug delivery vehicle and can be fabricated to form wafers, strands, or microspheres (Heller et al. 2002; Park et al. 2005). POE has demonstrated good tolerability in animals following suprachoroidal and intravitreal injection, suggesting its potential for use in drug delivery to the posterior segment.

9.3.4  Polyanhydrides

PAHs are hydrophobic polymers with hydrolytically labile anhydride linkages. PAH is characterized by a fast rate of degradation, which occurs via surface erosion, but the polymer composition of PAHs can be varied to produce drug delivery systems capable of providing sustained release for days to weeks (Park et al. 2005; Kuno and Fujii 2010). Degradation of PAHs depends on the rate of water uptake, determined by hydrophilicity and crystallinity of the polymer. PAHs are thought to provide more controllable, near-zero order drug release as compared with polymers that degrade by bulk erosion, because drug release depends mainly on the surface degradation of polymers rather than drug diffusion (Fig. 9.4). PAH polymers generally show minimal inflammatory effects in vivo and degrade into nontoxic monomeric acids (Park et al. 2005). The most commonly used PAH for drug delivery is a copolymer of bis(p-carboxyphenoxy) propane and sebacic acid. Its degradation byproducts are carboxyphenoxypropane, which is eliminated via the kidney, and sebacic acid, an endogenous fatty acid, which is metabolized by the liver and expired as CO2 (Kuno and Fujii 2010).

PAHs will react with drugs containing free amino groups, which limit their use as a drug-delivery matrix, and the thermal and mechanical properties of PAHs are

not as useful as those of PCL, since the former contain many more –CH2 groups in the main chain (Park and Lakes 2007). Another drawback is that most PAHs must be stored frozen under anhydrous conditions because of the hydrolytic instability of the anhydride bond (Park et al. 2005).

A PAH copolymer of bis(p-carboxyphenoxy) propane and sebacic acid (80:20 ratio) has been approved by the US FDA as a carmustine delivery system (Gliadel®) for the treatment of brain cancer. PAH has also been investigated as a drug delivery vehicle in glaucoma filtration surgery (see Sect. 9.6); however, the application of PAH for posterior segment drug delivery has yet to be reported.

9.4  Biodegradable Polymers in Nonocular Biomedical

Applications

Biodegradable polymers have a long history of successful use in a variety of medical applications for general surgery, orthopedics, reconstructive surgery, dentistry, and vascular repair (Table 9.4, Fig. 9.6). Sutures and fixation devices composed from biodegradable polymers have been developed to eliminate the need for extra postsurgical removal procedures that would otherwise be required with nonabsorbable materials, thereby providing not only cost and resource savings, but also better healing and greater convenience and safety for patients (Törmälä et al. 1998). Biodegradable polymers, particularly those composed from PLA and PGA, are ideal for such uses because they have a range of physical and chemical properties that can be custom engineered to suit specific biomedical applications. For example, the molecular structure, copolymer ratio, crystallinity, and viscosity of biodegradable polymeric materials can be manipulated to optimize mechanical strength and degradation characteristics.

The first use of biodegradable polymers in medicine was reported in 1966 by Kulkarni and associates, who utilized PLA to develop biodegradable sutures and rods for the repair of mandibular fractures (Kulkarni et al. 1966). In 1971, the first commercial synthetic biodegradable multifilament suture Dexon® (Covidien AG, Switzerland), consisting of 100% PGA, was introduced. This was followed soon after by the commercial introduction of Vicryl® multifilament sutures (Johnson & Johnson Corp., New Brunswick, NJ) composed of PLGA (90:10 PGA:PLA) (Wassermann and Versfelt 1974). Other biodegradable multifilament sutures that were later developed for commercial use include Polysorb® (U.S. Surgical, North Haven, CT) and Panacryl® (Johnson & Johnson), both of which are composed of PLGA. In addition to multifilament sutures, monofilament sutures have been developed using biodegradable polymers; for example, PDS II® sutures, composed from poly-p-dioxane (PDS) (Doddi et al. 1977), and Maxon® sutures composed from PGA and TMC (trimethylene carbonate) (Rosensaft and Webb 1981).

for other clinical applications. Solid, macroscopic, bioabsorbable implants have been used clinically for fixation in orthopedics and reconstructive surgery for more than 25 years. The first clinical studies on applications of this nature were initiated in 1984 by Rokkanen and colleagues, who studied the use of self-rein- forced PGA/PLLA rods for the fixation of displaced malleolar fractures (Rokkanen et al. 1985; Törmälä et al. 1998). Since that time, several biodegradable implant devices have become available commercially for orthopedic use (see reviews by Athanasiou et al. 1996, 1998; Törmälä et al. 1998; Park and Lakes 2007; Chu 2008; Navarro et al. 2008). These comprise pins, screws, rods, and plates for bone fixation; interference screws for anterior cruciate ligament reconstruction; softtissue anchors; and suture anchors for labrum or ligament reattachment in the shoulder. Examples of commercially marketed products include Biologically Quiet (Instrument Makar, Okemos, MI) and SD sorb (Surgical Dynamics, Norwalk, CT) suture anchors; orthopedic fixation devices such as Lactosorb® (Biomet, Warsaw, IN) and BiosorbPDX (Bionx Implants, Bluebell, PA) screws for craniomaxillofacial fixation; Biologically Quiet staples (Instrument Makar) for anterior cruciate ligament reconstruction; SD sorb meniscal staples (Surgical Dynamics) for meniscus repair; SmartPinPDX (Bionx) and OrthoSorb (DePuy) pins for fracture fixation. PLGA copolymers are the most common biomaterials used for the manufacture of such devices, although PLA, PGA, PCL, PDS, and polycarbonate have also been employed (Navarro et al. 2008). Polymers such as PLA degrade relatively slowly and therefore retain their strength for a longer time as compared with PGA, which is more brittle and undergoes more rapid degradation (Athanasiou et al. 1998).

Biodegradable polymers also have been used to manufacture various types of nonocular drug delivery systems. Examples of such drug delivery implants, all of which utilize PLGA, include Zoladex® LA (goserelin acetate, AstraZeneca UK Ltd., UK) for the treatment of prostate cancer, Nutropin® Depot (human growth hormone; Genentech, Inc., South San Francisco, CA) for growth deficiencies, Trelstar® Depot (triptorelin pamoate) for prostate cancer, and Sandostatin LAR® (octreotide; Novartis AG, Switzerland) for acromegaly (Avgoustakis 2008). The diseases that these drug delivery systems are designed to treat are all chronic in nature and require long-term treatment; thus, sustained drug release using biodegradable polymers can reduce the number of treatments needed as compared with conventional shorter ­acting treatments, thereby minimizing inconvenience to patients and potentially improving treatment compliance. For example, Zoladex (goserelin acetate), which is a pituitary down regulator used to lower testosterone levels in patients with ­prostate cancer, is normally administered by subcutaneous abdominal injection every 4 weeks; however, with Zoladex LR, a longer-acting PLGA-based subcutaneous implant, treatment is only required at 12-week intervals. Nutropin Depot is a subcutaneously injected suspension consisting of recombinant human growth hormone (somatotropin) in PLGA-based microsomes. This long-acting, biodegradable ­formulation, used for the treatment of growth hormone deficiency in children, is administered 1–2 times monthly and offers the potential for improved convenience and compliance by decreasing the number of injections

and frequency of administration as compared with conventional once-daily injections of growth hormone (Silverman et al. 2002). However, Nutropin Depot may not be as effective as once-daily treatment in promoting growth rates (Nutropin Depot Prescribing Information 2005).

Stents are devices that are widely used in vascular surgery to maintain blood vessel patency following angioplasty. Bare metal stents, used as a structural scaffold, represent the first generation of devices developed for this purpose; however, restenosis was a frequently associated complication. Second-generation drugeluting metallic stents were subsequently developed for the delivery of therapeutic agents to promote vascular repair as well as to provide structural support; however, these devices were also associated with restenosis, and controversy emerged regarding their value relative to traditional bare-metal stents (Sakhuja and Mauri 2010; Bates 2008). Biodegradable polymer-based stents have been developed as a means of overcoming the limitations of both drug-coated and uncoated nonbiodegradable stents (Rogacka et al. 2008). Such devices can potentially maintain vessel patency as effectively as nonpolymeric stents, while limiting restenosis and other complications and eliminating the possible need for device removal/replacement. Drug-coated biodegradable stents can also be used for drug delivery as an alternative to metallic drug-eluting stents. A variety of biodegradable stents incorporating PLGA and/or PLA have been developed; these include both nondrug eluting types [e.g., bile duct (Xu et al. 2009) and Igaki-Tamai™ (Rogacka et al. 2008) stents] and drug-eluting types to deliver drugs such as sirolimus (Excel, Cura™, and Synchronnium™ stents), Biolimus A9 (Biomatrix™ and Nobori™ stents), genistein (Coronnium™ stent), and tacrolimus (Mahoroba™ stent) (Rogacka et al. 2008).

In addition to the aforementioned commercial applications, biodegradable polymers have been tested as vascular grafts, vascular couplers for vessel anastomosis, nerve growth conduits, ligament/tendon prostheses, intramedullary plugs for total hip replacement, and anastomosis rings for intestinal surgery, and to augment defective bone (Chu 2008). Biodegradable polymers have also shown promise for tissue engineering because they can be fashioned into porous scaffolding systems and carriers of cells, extracellular matrix components, and bioactive agents to facilitate bone grafts and enhance the healing potential of musculoskeletal tissue (Hutmacher et al. 2007). First-generation tissue scaffolds composed of PCL, which have been through extensive clinical testing, have been approved by the US FDA and are available commercially. Tissue scaffolds composed of natural polymers in combination with hydroxyapatite (e.g., collagen-hydroxyapatite composites, chi- tosan–hydroxyapatite) and synthetic polymers (PLA, PLA-polyethylenglycol, PCL) are also being investigated (Hutmacher et al. 2007; Guelcher 2008). To overcome limitations in the use of synthetic polymeric tissue scaffolds in high-load bearing areas, a composite scaffolding matrix system based on PLLA/PDLLA (copolymer ratio 70:30) is under investigation as a carrier for proteins and growth factors (Hutmacher et al. 2007).

Results from human studies on the safety of biodegradable polymeric devices have generally been favorable; reports of severe adverse reactions are rare, and