Biodegradation and biocompatibility of PLA and PLGA microspheres

doi:10.1016/S0169-409X(97)00048-3

Advanced Drug Delivery Reviews

Volume 28, Issue 1, 13 October 1997, Pages 5-24

https://doi.org/10.1016/S0169-409X(97)00048-3 Get rights and content

Abstract

A fundamental understanding of the in vivo biodegradation phenomenon as well as an appreciation of cellular and tissue responses which determine the biocompatibility of biodegradable PLA and PLGA microspheres are important components in the design and development of biodegradable microspheres containing bioactive agents for therapeutic application. This chapter is a critical review of biodegradation, biocompatibility and tissue/material interactions, and selected examples of PLA and PLGA microsphere controlled release systems. Emphasis is placed on polymer and microsphere characteristics which modulate the degradation behaviour and the foreign body reaction to the microspheres. Selected examples presented in the chapter include microspheres incorporating bone morphogenetic protein (BMP) and leuprorelin acetate as well as applications or interactions with the eye, central nervous system, and lymphoid tissue and their relevance to vaccine development. A subsection on nanoparticles and nanospheres is also included. The chapter emphasizes biodegradation and biocompatibility; bioactive agent release characteristics of various systems have not been included except where significant biodegradation and biocompatibility information have been provided.

Introduction

The design and development of biodegradable microspheres containing bioactive agents for therapeutic application require a fundamental understanding of the in vivo biodegradation phenomena as well as an appreciation of cellular and tissue responses which determine the biocompatibility of the biodegradable microspheres. The objective of this chapter is to provide an overview of the biodegradation phenomena and the biocompatibility of biodegradable microspheres. This chapter is a critical review of the literature which addresses the biodegradation and biocompatibility issues and is focused on and limited to in vivo interactions and responses. Therefore, studies which have focused on in vitro evaluation of the biodegradation and bioactive agent release characteristics of biodegradable microspheres have not been included in this chapter. In part, this review has as its foundation the efforts of the senior author over the past two decades to provide a fundamental understanding of biodegradation and biocompatibility phenomena as they relate to biodegradable polymers in controlled release systems as well as other biomedical polymers utilized in various applications 1, 2, 3, 4.

This review is in three parts: Biodegradation, Biocompatibility and tissue/material interactions, and Selected examples of poly(dl-lactic acid), poly(l-lactic acid) and poly(lactide-co-glycolide) microsphere controlled release systems. Numerous articles in the scientific literature of biodegradable microspheres address the significant issue of drug delivery rates from biodegradable microspheres but do not contain significant information relative to biodegradation or biocompatibility issues. Therefore, the information provided in these articles has not been addressed in this review nor have these articles been included as references as they add little to our fundamental understanding of biodegradation and biocompatibility of biodegradable microspheres. Nonetheless, bioactive agent release rates are important components in the design and development of biodegradable microspheres containing bioactive agents for therapeutic applications [5]. Selected examples of systems containing specific bioactive agents and their respective characteristics and properties are presented in this special issue.

Section snippets

Biodegradation

It is generally considered that the mechanism of degradation of aliphatic polyester microspheres is a hydrolytic mechanism 3, 5, 6. Investigators have considered the possibility that enzyme catalyzed degradation may occur but these studies are not convincing [7]. The hydrolytic mechanism of degradation is strongly supported by the detailed efforts of Vert and coworkers on the chemistry of the hydrolytic degradation mechanism as well as morphological studies of microspheres in in vitro and in

Biocompatibility and tissue/material interactions

The evaluation of the biocompatibility of implantable delivery systems requires an understanding of the inflammatory and healing responses of implantable materials. Inflammation, wound healing and foreign body responses are generally considered as components of the tissue or cellular host responses to injury 1, 2, 3, 4. The response to injury is initiated by the implantation procedure which in the case of microspheres involves injection of the formulation within a solvent vehicle. Humoral and

Selected examples of PLA and PLGA microsphere controlled release systems

Over the past decade and, in particular, the past five years, extensive efforts by numerous groups have been made in the development of poly(dl-lactic acid), poly(l-lactic acid) and poly(lactide-co-glycolide) copolymer microsphere controlled release systems for therapeutic application. As such, these efforts have had as their primary focus the study of release rates of therapeutic agents from the biodegradable microspheres. This section of the review focuses on these publications where

Conclusions

Studies to date indicate that PLA and PLGA microspheres containing bioactive agents are biocompatible and when used in therapeutic applications in vivo do not exhibit untoward reactions either locally or systemically. The biodegradation of PLA and PLGA microspheres occurs through a homogeneous hydrolytic chain cleavage mechanism where the rates of polymer degradation are similar for both the surface and the bulk of the microspheres. However, caution is warranted in the application of this

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Biodegradation and biocompatibility of PLA and PLGA microspheres

Abstract

Introduction

Section snippets

Biodegradation

Biocompatibility and tissue/material interactions

Selected examples of PLA and PLGA microsphere controlled release systems

Conclusions

Biomaterials

Biomaterials

Biomaterials

J. Contr. Rel.

J. Oral Maxillofac. Surg.

Biomaterials

J. Pharm. Sci.

J. Contr. Rel.

J. Contr. Rel.

J. Contr. Rel.

Biomaterials

J. Contr. Rel.

Int. J. Pharm.

J. Contr. Rel.

Biomaterials

Biomaterials

J. Contr. Rel.

Life Sci.

Eur. J. Pharm. Biopharm.

Adv. Drug Del. Rev.

J. Contr. Rel.

Molec. Immunol.

J. Contr. Rel.

In vivo biocompatibility of implantable delivery systems and biomaterials

Eur. J. Pharm. Biopharm.

Mechanisms of inflammation and infection with implanted devices

Cardiovasc. Pathol.

Inflammation and the foreign body response

Prob. Gen. Surgery

Biodegradable microspheres in drug delivery

Crit. Rev. Therap. Drug Carrier Sys.

Enzymatic activity toward poly(l-lactic acid) implants

J. Biomed. Mater. Res.

Attempts to map the structure and degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids

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Recent advances in the field of lactic acid/glycolic acid polymer-based therapeutic systems

Macromol. Symp.

Biodegradation of and tissue reaction to 50:50 poly(dl-lactide-co-glycolide) microcapsules

J. Biomed. Mater. Res.

Note: Biodegradation of and tissue reaction to poly(dl-lactide) microcapsules

J. Biomed. Mater. Res.

Tissue response to biodegradable injectable microcapsules

J. Biomat. Appl.

Effect of particle size on the in vitro and in vivo degradation rates of poly(dl-lactide-co-glycolide) microcapsules

J. Biomed. Mater. Res.

Macrophage phagocytosis of biodegradable microspheres composed of l-lactic acid/glycolic acid homo- and copolymers

J. Biomed. Mater. Res.