Introduction

In the research and development of implantable drug delivery systems, in vivo biocompatibility studies play an important role in determining the safety (biocompatibility) and efficacy (function) of these devices. The purpose of this review is to present perspectives on the in vivo tissue responses and bio-compatibility of implantable drug delivery systems as they may affect the pharmacokinetics, pharmacodynamics, and metabolism of proteins and pep-tides. The evaluation of the biocompatibility of implantable delivery systems requires an understanding of the inflammatory and healing responses induced by implantable materials. For delivery systems, this includes an appreciation of the inflammatory and healing responses to degradable/resorbable systems as well as nondegradable systems. In this overview, tissue/material interactions and the foreign body reaction are viewed from the classical medical perspective of the pathologist. Tissue/material interactions are commonly referred to as the tissue response continuum, which is the series of responses that are initiated by the implantation procedure, as well as by the presence of the biomaterial, medical device, or drug delivery system. In this chapter, we divide the continuum of tissue/material responses into the early, transient tissue responses and the late, persistent tissue responses. Early, transient tissue/material responses include injury, blood/material interactions, provisional matrix formation, temporal sequence of inflammation and wound healing, acute inflammation, chronic inflammation, and granulation tissue development. These responses are usually of short duration, occurring over the first two to three weeks following implantation of a medical device or drug delivery system. Late, persistent tissue responses include macrophage interactions, foreign body giant cell (FBGC) formation and interactions, and fibrosis and fibrous encapsulation of the drug delivery system. The early, transient tissue responses form the basis for safety or biocompatibility considerations of the medical device or drug delivery system. Late, persistent tissue/material responses, while important to the safety and biocompatibility considerations, may be more important in modulating the performance characteristics of the drug delivery system.

Normal tissue responses to implanted controlled drug delivery systems may have a significant effect on the bioavailability and pharmacokinetics of proteins or peptides, that is, bioactive agent, released from a controlled drug delivery system, due to the release of degradative molecules. In addition to the carrier that functions as a permeability or diffusion barrier, normal tissue responses such as the foreign body reaction and the fibrous capsule may reduce the permeation and diffusion of the bioactive agent and thus lead to a reduction in bioavailability of the bioactive agent.

In vivo biocompatibility studies commonly utilize subcutaneous implantation. Therefore, examples of these types of studies available in the current literature will be used to illustrate important issues pertinent to the biocompatibility of implantable delivery systems. As the desired goal of delivery systems is to deliver or release a drug or therapeutic agent either locally or systemically, in vivo studies that concomitantly monitor the delivery of therapeutic agents in conjunction with the biocompatibility of the system are important. It is not our intent to provide a complete literature review of bio-compatibility studies that have been carried out on degradable/resorbable and nonbiodegradable materials utilized for implantable delivery systems but rather to present fundamental perspectives on the in vivo biocompatibility of drug delivery systems.

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