The applications of injectable systems are many1: scaffolds for cell transplantation; barriers at the cellular or protein level to guide tissue regeneration; tissue adhesives or structural supports to bear mechanical loads during healing or regeneration; local drug delivery systems; provisional matrices (induction of cell migration to regenerate new tissue); and bone cements or bone filling materials.

Although the focus of the current chapter is the topic of injectables used for drug delivery systems, this section will present a brief description of other applications. Detailed information about other applications can be found elsewhere in this book (see, for example, Chapters 3 or 4).

Some injectables have already found commercial applications: PEG-based hydrogel precursors (in situ photocrosslinking) are already used clinically as surgical sealants.52 Polyanhydrides are also already in the market as drug delivery systems in the brain after the removal of tumors.53

2.4.1 Ophthalmic Applications

Injectables are very attractive systems for delivery of pharmaceutical agents into the eye, since the current delivery devices suffer from drawbacks such as the need of a surgery for implantation (bulk preshaped devices) or the migration of injectable microparticles into the visual axis or into adjacent tissue sites.6 Although these disadvantages are also present when the implantation occurs in other sites of the body, they are particularly dangerous in a delicate region such as the eye. Moreover, degradable injectables present advantages over conventional implants because repeated intraocular injections can increase the risk of infection, cataract, vitreous hemorrhage, or retinal detachment. The "peak and valley" effect of conventional administration could result in direct toxicity to ocular tissues followed by a rapid clearance of the drug.

2.4.2 Surgical Barriers

Photopolymerized hydrogels can be used as barriers to prevent adhesion of tissues after surgery. Barriers composed of degradable poly(ethyleneglycol-co-lactic acid) diacrylated macromers were highly resistant to protein adsorption and diffusion as well as to cell adhesion. Intravascular, interfacial photopolymerization of thin hydrogel layers was employed for prevention of thrombosis, while bulk photopolymerization on intraperitoneal surfaces was used for prevention of postoperative adhesion formation.54

2.4.3 Scaffolds for Tissue Engineering

For this application, injectable systems are particularly advantageous because they can fill any shape or defect (provided that they are formulated with the appropriate viscosity), can be easily formulated with cells by simple mixing, and do not require a surgical procedure to be implanted or, in the case of biodegradable ones, to be removed. Moreover, most kinds of injectables do not contain residual solvents (which may be present in preshaped scaffolds); those that do so usually employ physiologically acceptable solvents.

The mechanical properties of hydrogels can be tailored to match those of soft tissues, making them useful in the regeneration of soft tissues. Degradable hydrogels are advantageous because the cells are able to spread and migrate on or in scaffolds produced with them, while in inert ones, the cells are rounded and form clusters (Figure 2.4).51 The cell proliferation and extracellular matrix production also reach higher levels in degradable hydrogels.

Since cartilage is composed mainly of water, devices intended for its substitution or for tissue engineering of cartilage should ideally possess high water content (desirable for transport of nutrients and waste) and be able to withstand the high loads that native cartilage experiences. Therefore, in situ-forming hydrogels are well suited for this application due to their aforementioned advantages, but also due to the high water content and tissue-like elastic properties of hydrogels. However, an obvious balance should be reached between cell viability and compatibility with native tissues (which require high water content) and maintenance of mechanical properties with the time (which require decreased water content and slower degradation rates). It was demonstrated32 that both the PEG and PVA-based networks incorporating PLA were suitable for this application. Both growth factors and chondrocytes were encapsulated in the matrix, and the cells were metabolically active after 8 weeks.

Photopolymerized, crosslinked networks of degradable polymers such as PPF or polyanhydrides are suitable for bone tissue engineering because of their high mechanical properties, which match

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FIGURE 2.4 Human aortic smooth muscle cells growing in degradable (A) and inert (B) PEG photopoly-merized hydrogels. (Reprinted from Mann, B.K. et al., Biomaterials, 22, 3045-3051, 2001. © 2001 Elsevier. With permission.)

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FIGURE 2.4 Human aortic smooth muscle cells growing in degradable (A) and inert (B) PEG photopoly-merized hydrogels. (Reprinted from Mann, B.K. et al., Biomaterials, 22, 3045-3051, 2001. © 2001 Elsevier. With permission.)

(or surpass) those of trabecular bones. For an extended discussion on these materials, please see the next chapter.

2.4.4 Bone Cements

As previously mentioned, bone cements are the most widely used application of inert injectables and are the basis for the development of several degradable systems. Although fully degradable injectables have not yet achieved the requisites to be approved as bone cements, systems being proposed for bone supports, bone filling, or trabecular bone regeneration are being called bone cements.

One example is a multipart bioerodible cement system based on the conventional chemically initiated polymerization (employing vinyl monomer + initiator + activator), but with the incorporation of hydrolytically degradable polymers (PLGA and PPF), which degrade to acidic products and which form a crosslinked network (PPF) reinforcing the system.55 The mechanical properties of the system matched (or surpassed) those of trabecular bone. One week after implantation in rat tibia, there was extensive bone formation, which almost entirely replaced the synthetic material. Neovascularization and osteoblastic activity were also seen. After 7 weeks, the site resembled a normal rat tibia metaphysis.55

A more detailed discussion of these systems can be found in Chapter 3 of this book, and bone cements composed of partially degradable injectables are presented in Chapter 4.

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