For the last few decades, research in drug delivery is mainly focused on delivery of drug in the controlled release manner because of the advantages associated with it compared to drug delivery in immediate release dosage forms. Polymeric materials have gained increasing interest all along the 20th century and served in a vast number of medical and/or pharmaceutical applications such as orthopedic, dental or breast implants, artificial organs, pacemakers, sutures, vascular grafts, heart valves, intraocular and contact lenses, renal dialysers and other medical devices or controlled drug delivery systems1. An intimate and/or prolonged contact between the implanted device and the biological tissues implicates a severe testing schedule before human use and efficacy assessment. To be truly useful for long-term treatment of diseases, the implanted material should be biocompatible. Serious adverse effects have been identified with some implantable biomaterials such as silicone gel filled breast implants2 and 'Norplant' contraceptive implants3.
According to the Williams dictionary of biomaterials, biocompatibility has been defined as "the ability of a material to perform with an appropriate host response in a specific application". The biocompatibility of an implanted material relies on various parameters depending on the host and on the material itself. The factors depending on the host are (i) the species, (ii) the genetic inheritance, (iii) the site of implantation, and (iv) the microenvironment, while the factors depending on the material are (i) shape, (ii) size, (iii) surface chemistry and roughness, (iv) design, (v) morphology and porosity, (vi) composition, (vii) sterility issues, (viii) contact duration and (ix) degradation products1,4.
Biomaterials and Biocompatibility
Polymers used as biomaterials either are naturally occurring, synthetic or a combination of both. Also naturally derived polymers are abundant and usually biodegradable but the principal disadvantage of naturally derived polymers is development of reproducible production methods, because their structural complexity often renders modification and purification difficult. Also there is high possibility that naturally derived polymers show significant batch-to-batch variations because of their 'biopreparation' in living organisms. Synthetic polymers are available in a wide variety of compositions with tailored made properties. Various methods of processing, copolymerization and blending of polymers provide means of optimizing their mechanical characteristics and its diffusive and biological properties. But the synthetic polymers suffer from lack of biocompatibility, although poly(ethylene oxide) (PEO) and poly(lactic-co-glycolic acid) are notable exceptions. Synthetic polymers are therefore often associated with inflammatory reactions, which limit their use to solid, unmoving, impermeable devices5.
Biomaterials are basically non-viable materials, which become a part of the body either temporarily or permanently to restore, augment or replace the natural functions of the living tissues or organs in the body6. Biomaterials as foreign substances are potentially antigenic (immunogenic) and their immunocompatibility, i.e. their ability to elicit the immune response is an important factor in biocompatibility. Due to adverse reactions in patients possibly originating from unforeseen bioincompatibility, a series of well-known and well described biomaterials have been or being withdrawn from the market7. Biocompatibility is dynamic, two way process that involves the time dependent effects of the host on the materials and the material on the host. Solid and soluble polymeric materials can be classified as (a) purely synthetic, e.g. polymethyl-methacrylate, polysulfones, polyacrylonitrile, polycarbonates, polydimethylsiloxanes, polyurethanes, polyamides, polytetrafluoroethylene, polyhydroxyethylmethacrylate, polyvinylpyrrolidone and (b) those derived from naturally occurring materials. e.g. polysaccharide derivatives of cellulose, derivative of dextrans. chitin, chitosan etc7.
Esposito et al.8 evaluated the mucoadhesive properties of several polymers such as sodium alginate, hydroxypropylmethyl cellulose, scleroglucan, xanthan gum, polyacrylic acid (Carbopol) and poly(methyl vinyl ether-co-maleic anhydride) by comparing a thermodynamic and a mechanical approach. They concluded that the calculation of the surface free energy of these materials allowed a prediction of the water-polymer interface free energy. Also surface-energy criterion of biocompatibility of foreign surfaces was also suggested. The criterion was based on an analysis of the surface interactions between blood and the synthetic surfaces. A sufficiently low (but not very low) solid-biological fluid interfacial free energy of the order of 1-3 dyne/cm was found to be necessary in order to fulfill the dual requirements of maintaining both a low thermodynamic driving force for the adsorption of fluid components on the solid surface and a mechanically stable solid-fluid interface. It was also suggested that a drastic reduction in the solid-water interfacial free energy of the polymer surfaces by physical and/or chemical modification of their surface improved their biocompatibility.
Implantable drug delivery devices should degrade, avoiding their retrieval and allowing the release of the drug. Moreover, the thickness of the fibrous capsule resulting from the foreign body reaction (FBR) is of primary importance, since its thickness can disturb the drug diffusion. On the contrary, hormones, neurotransmitters or growth factors producing cells are encapsulated in polymers, which must be resistant to degradation and must protect the cells from the potential immunological reaction of the host. Moreover, the polymeric membrane of the capsules must be semi-permeable in order to allow the diffusion of the molecules released by the cells, and the passage of nutrients from the surrounding tissue to the cells. In this case, the fibrous capsule surrounding the implant is also a critical factor, since it drastically influences cell viability: the more blood vessels it contains, the more nutrients reach cells, and better is the systemic delivery of the molecules secreted by the cells. Finally, certain amount of "non biocompatibility" might be desired to since it has an adjuvant effect in the use of vaccine delivery systems. It is probably the only situation for which a perfectly inert material is not desirable9.
Blood compatibility
Materials that are used in the manufacturing of blood contacting devices (e.g. intravenous catheters, hemodialysis sets, blood transfusion sets, and vascular prostheses) must be characterized for blood compatibility to establish their safety. In practice, all materials are to some degree incompatible with blood because they can either disrupt the blood cells (hemolysis) or activate the coagulation pathways (thrombogenicity) and/or the complement system10,11.
When a biomaterial is exposed to blood, certain blood proteins adsorb rapidly and depending on the type of proteins adsorbed the platelet adhesion follows. The activation of adherent platelets lead to formation of thrombi on the surface and the phenomenon is called thrombosis and all types of polymers are known to induce thrombosis. The thrombus formation on the implanted material can block any major or minor blood vessels. Also thrombus formation on the implanted material may lead to decreased drug release from the device. The blood compatibility of the implanted materials can be improved by modifying the material surface exposed to the blood by coating with poly(ethylene oxide), heparin, albumin or other hydrophilic polymeric chains which minimizes protein adsorption and hence platelet adhesion12,13. These hydrophilic materials prevent protein adsorption and platelet adhesion by steric repulsion mechanism. The hydrophilic flexible molecules on the surface can be regarded as entropic springs14 which are compressed by the adsorbing proteins and platelets and this compression causes development of repulsive energy due to the increased osmotic pressure and elastic forces of the compressed molecules.
The hemolysis assay which measures the damage to red blood cells when they are exposed to materials or their extracts, and compares it to positive and negative controls is recommended for all devices or device materials, except those which come in contact with only the intact skin or mucous membranes. Coagulation assays measure the effect of the test article on human blood coagulation time and are recommended for all devices with blood contact. The coagulation abnormalities in the extrinsic pathway is detected by Prothrombin Time assay (PT) whereas the coagulation abnormalities in the intrinsic pathway is detected by Partial Thromboplastin Time assay (PTT). The preferred test for thrombogenicity is the in vivo method. For devices unsuitable to this test method, ISO 10993-4 requires tests in each of four categories: coagulation, platelets, hematology, and complement system. The implant devices with contact with circulatory blood are subjected to complement activation testing. The exposure of the plasma to the test article or an extract causes complement activation in human plasma which can be measured by in vitro assay. The measure of complement actuation indicates whether a test article is capable of inducing a complement-induced inflammatory immune response in humans. Other blood compatibility tests and specific in vivo studies may be required to complete the assessment of material-blood interactions, especially to meet ISO requirements15.
Tissue compatibility6,16
During the implantation the injury created to the local tissue results in inflammation. Some of the symptoms of the inflammation are reddening, swelling, pain and fever. These signs are accompanied with a series of defensive reactions mediated by neutrophils, eosinophils, macrophages and foreign body giant cells. The primary roles of these cells appear to be phagocytosis of the dead tissue and other particulates resulting from implantation. Macrophages initiate the repair of damaged tissue by forming the scaffold for repair which is called granulation tissue. The granulation tissue start to surround the implant and the foreign body giant cells attach to the implant. If the implant cannot be phagocytosed by the cells the body then isolates the implant by forming a fibrous membrane around the implant.
Approaches for enhancing blood and tissue biocompatibility of the implants
Several approaches for surface modification exist to improve the biocompatibility5,13,17 Both chemical and physical modifications of the polymeric surface may significantly increase their biocompatibility. These include chemical procedures such as oxidation, hydrolysis and quaternization, which change the surface chemistry and functionality. Polymerization or grafting of water soluble polymers to polymer surfaces may reduce protein adsorption and cell adhesion by changing the hydrophilic or hydrophobic characteristics of the polymer surface18,19,23. Nonionic PEO or PEO copolymers with different molecular weights are widely used for this purpose. Poly(vinyl pyrrolidone) is also effective and is common in hydrophilic-polymer surface coatings. Composites coated with these polymers have been accepted by the medical community because of their biocompatibility, processability, protein-repellent properties and commercial availability20. Other approaches for improving the material-blood interactions are based on minimizing or eliminating the thrombogenicity of the biomaterials used in contact with blood21,22. Biological modification via the incorporation of biologically active molecules may also be considered as a means to enhance biocompatibility. The heparinization of surfaces by bonding or adsorption of heparin or heparin fragments is one such example24. Another approach is the synthesis of new heparin-like polymers with improved surface properties. Several recent studies have shown that ionomers containing sulfonic-acid residues have a favourable blood-contact response25. Bioactive compounds, such as enzymes, drugs, proteins, peptide sequences, antigens and cells, have been incorporated into polymeric materials in order to improve their biofunctionality and yield biologically active systems. Such modifications can have a significant influence on the biological response to biomaterials, which may also be used in bioreactors (e.g. immobilized enzymes), artificial organs and drug delivery systems26. A recent goal in the modification of polymers for biocompatibility is the design of specific bioactivity at the polymer surface. A wide variety of functions, including membrane receptors and biosignal peptides, can be grafted onto or incorporated into a polymer surface in order to obtain hybrid materials that display highly specific recognition in living systems27-29. This approach provides possibilities for precisely tailored surfaces that exhibit specific affinity, site-recognition properties and controlled mobility. Such systems show unique selective adsorption properties (for proteins), self-assembly (surface organization) and even the formation of highly ordered structures at the interface30-34.
