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Chitosan is a linear polysaccharide consisting of linked D-glucosamine residues with a variable number of randomly located N-acetyl-glucosamine groups. In vivo, chitosan is degraded by enzymatic hydrolysis. The primary agent is lysozyme, which appears to target acetylated residues50. However, there is some evidence that some proteolytic enzymes show low levels of activity with chitosan. The degradation products are chitosan oligosaccharides of variable length. The study on the biocompatibility of chitosan has been carried out by many researchers51-53. In general, these materials have been found to evoke a minimal foreign body reaction. In most cases, no major fibrous encapsulation has been observed. Formation of normal granulation tissue, often with accelerated angiogenesis appears to be the typical course of healing. In the short term studies (<7 days), a significant accumulation of neutrophils in the vicinity of the implants is often seen, but this dissipates rapidly and a chronic inflammatory response does not develop. The stimulatory effects of chitosan and chitosan fragments on immune cells may play a role in inducing local cell proliferation and ultimately integration of the implanted material with the host tissue53.
Poly(lactic acid) (PLA) and poly(lactide-co-glycolide) (PLGA)
Tissue reaction to PLA and its copolymers with glycolic acid (PLGA) has been investigated extensively by many workers and reviews focusing on this subject are available. Anderson and Shive have reviewed biodegradation, biocompatibility and tissue/material interactions and selected examples of PLA and PLGA microsphere controlled release systems54. The review emphasized on polymer and microsphere characteristics which modulated the degradation behaviour and the foreign body reaction to the microspheres. Microspheres injected subcutaneously or intramuscularly constituted a high surface area/low volume biomaterial, compared to a large-sized device with small surface areas. Each microsphere represented a tissue/material interface and inflammatory cells were observed around all the individual microspheres, even though there was a time lag for the cells to reach the center of the inoculum. Foreign body giant cells (FBGC) were observed on various microspheres and the fibrous tissue encapsulating the microspheres covered the entire microsphere implant site. Collagen and new blood capillaries were observed within the interstices between microspheres. The authors divided the tissue response to injected microparticles in three phases. The first two weeks (phase I) correspond to the initiation, resolution and organization of the acute and inflammatory responses. The second phase is initiated by the predominance of monocytes and macrophages, and the length of time of their persistence was determined by the rate of degradation of the polymer. During the third phase, microparticles break and the resulting smaller particles are engulfed by macrophages55.
Polyanhydrides form a new class of biodegradable polymers in the biomaterials family and have hydrophobic backbone with hydrolytically labile anhydride linkages such that hydrolytic degradation can be controlled by manipulation of the polymer composition. They are of great interest because they show no evidence of inflammatory reaction. They degrade in vitro as well as in vivo to their acid counterparts as non-mutagenic and non-cytotoxic products. Polyanhydrides are biocompatible and have excellent controlled release characteristics57. Pharmaceutical research has been focused on polyanhydrides derived from sebacic acid (SA), 1,3-bis( p-carboxyphenoxy) propane (CPP) and fatty acid dimmer (FAD). Recently, the Food and Drug Administration (FDA) has approved the use of the polyanhydride poly(sebacic acid-co-1,3-bis(p-carboxyphenoxy) propane) (P(CPP-SA)) to deliver the chemotherapeutic agent BCNU for the treatment of brain cancer58. Introduction of imide group into polyanhydrides enhances the mechanical properties of the polymers59, while the presence of polyethylene glycol (PEG) groups in polyanhydrides increases hydrophilicity and induces fast drug release60. The major limitation of polyanhydrides is their storage stability requiring storage under refrigeration.
Poly(ortho esters) (POE) are hydrophobic polymers which, when placed in a biological environment, can undergo an erosion process confined to the polymerââ‚¬"water interface. Since the late 1970s, four families of POE have been synthesized to provide bioerodible carriers for drug delivery. Among the four families of POE the third (POE III) and fourth (POE IV) have been studied as promising biomedical materials because of their viscous and injectable properties. POE III is shown to be an excellent biocompatible material and is used for sustained delivery of drug to the posterior segment of the eye. POE IV is comparatively hydrophobic in nature and biocompatible as POE III. It is being investigated for delivery of drugs to eyes, periodontal diseases and as a vehicle for veterinary drugs45-48,56.
Acrylic polymers are not biodegradable. Depending on their structure and surrounding pH, some of them are water soluble. The water-insoluble ones are stable in an aqueous/physiological environment, thus can be used for the encapsulation of cells. Soluble ones can be used for the design of hydrogels61. The biocompatibility of a cross-linked hydrophilic network consisting of 2-hydroxyethyl methacrylate (HEMA) and 2-(20-iodobenzoyl)-ethyl methacrylate in the molar ratio 80:20 respectively, was assessed by Kruft et al.62 after subcutaneous injection in rats. The implant was well tolerated. Tissue necrosis or abscess formation was not observed. The implant was classically surrounded by a vascularized connective tissue capsule including small vessels, fibroblasts and lymphocytes.
Wide approaches are continuously being developed for improved biodegradable drug delivery systems. The innovative engineering and manufacturing methods are under development to fabricate devices and physical platforms having novel three-dimensional structural attributes. One approach is through the preparation of biodegradable cross-linked polymer networks. When cross-linking is carried out using hydrophilic polymers, hydrogels that absorb a significant amount of water can be produced. The cross linking can be achieved either through covalently or by ionic interactions or by formation of highly entangled chain networks. The degradation of these cross-linked polymers can take place by either breaking the cross-linking or by the polymer backbone bonds, or by slow disentanglement and dissolution of polymer network. A number of polymers derived naturally occurring constituents including alginate; dextran, collagen, gelatin and albumin have been employed to prepare hydro gels. Alternatively, proven biocompatible polymers such as PLA and PLG and poly (Î³-benzyl-L-glutamic acid) have also been used to prepare cross-linked synthetic hydrogels. Highly porous polymer platforms with controlled pore density and size have recently been synthesized by the formation of either sponge-like or entangled fibrous matrices. These systems are currently being investigated as extracellular matrices for cell therapy.