Macrophage-mediated biodegradation of poly(DL-lactide-co-glycolide) in vitro Zhidao Xia, 1,2 Yizhong Huang, 3 Iannis E. Adamopoulos, 1 Andrew Walpole, 3 James T. Triffitt, 1 Zhanfeng Cui 2 1 Nuffield Department of Orthopaedic Surgery, The Botnar Research Centre, Institute of Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom 2 Department of Engineering Sciences, The University of Oxford, Oxford, United Kingdom 3 The Department of Materials, The University of Oxford, Oxford, United Kingdom Received 16 November 2005; revised 10 March 2006; accepted 22 March 2006 Published online 30 June 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.30853 Abstract: Biodegradation of poly- DL-lactide- co-glycolide (PLGA) both in vitro and in vivo has been well documented. However, the roles that macrophages and their fused multinucleated giant cells (MNGCs) play in this biodegradation are still unclear. The current study aimed to investigate macrophage- mediated biodegradation of PLGA thin films and of PLGA composites with hydroxyapatite (HA) and tricalcium phos- phate (TCP) ceramic powders in vitro using a murine macro- phage cell line (RAW 264.7). The interactions were analyzed by using cell viability assays, scanning electron microscopy, and focused ion beam microscopy. The results showed that RAW 264.7 cells effectively attached and proliferated on the PLGA films and PLGA-HA, PLGA-TCP composites. The RAW 264.7 cells were observed to aggregate and fuse to form MNGCs. The cell processes on the membrane, or pseudopo- dia, penetrated into the PLGA films and evidently eroded the surface. We conclude that macrophages and fused MNGCs actively respond to PLGA films as substratum and degrade the surface of this polymer. Ó 2006 Wiley Periodicals, Inc. J Biomed Mater Res 79A: 582–590, 2006 Key words: macrophage; multinucleated giant cells (MNGCs); poly-DL-lactide-co-glycolide (PLGA); biodegra- dation; focused ion beam (FIB) microscopy INTRODUCTION Biodegradable polymers have enormous benefits for use in many short-term medical applications, as these materials can completely and safely degrade and be absorbed by the body after they fulfill their functions. 1 The advantages of degradable polymers have paved the way for a number of sophisticated biomedical ap- plications. Poly-DL-lactide-co-glycolide (PLGA) is one of the approved biodegradable polymers, which have been used for surgical sutures, 2 drug delivery sys- tems, 3,4 orthopedic fixing devices, 5 and tissue engineer- ing scaffolds. 6 Degradable polymers were classified into two dis- tinct modes of degradation, surface eroding and bulk eroding ones. 1,7,8 Surface erosion polymers lose ma- terial from the surface only. They get smaller but keep their original geometric shape. 8,9 In bulk ero- sion, degradation is not confined to the surface of the polymer. Therefore, the size of a polymer device will remain constant for a considerable portion of time. 8,9 In the case of PLGA degradation, the interior of the polymer is degraded first and disappears over a period of time, and the outer surface remains as a shell and is degraded later. 10 It is generally accepted that, as an aliphatic polyes- ter, the biodegradation of PLGA occurs by bulk ero- sion. 8,11 The polymer chains are cleaved by hydrolysis to form monomeric acids and are eliminated from the body as carbon dioxide and water. The rate of hydro- lysis of the polymer chain is dependent on significant changes in temperature and pH or the presence of cat- alyst, and little difference is observed in the rate of de- gradation at different sites in vivo. 1,11 Enzymatic in- volvement in the biodegradation of the PLGA has been somewhat controversial. 11 However, it has been shown that 50:50 PLGA degraded significantly faster in vivo in comparison with the degradation in vitro. 12 It has long been recognized that macrophages can effectively respond to biomaterial implantation and engulf various biomaterial particles. 11 Macrophages also participate in extracellular biodegradation of Correspondence to: Prof. Z Cui; e-mail: zhanfeng.cui@eng. ox.ac.uk Contract grant sponsors: The Wellcome Trust and EPSRC ' 2006 Wiley Periodicals, Inc.