Phagocyte responses to degradable polymers Wei-Wu Jiang, 1 Shih-Horng Su, 2 Robert C. Eberhart, 2,3 Liping Tang 2 1 Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030 2 Joint Program in Biomedical Engineering, University of Texas at Arlington, PO Box 19138, Arlington, Texas 76019-0138 and University of Texas Southwestern Medical Center at Dallas, MC 9130, Dallas, Texas 75235-9130 3 Department of Surgery, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hine Blvd, Dallas, Texas 75235-9130 Received 17 July 2006; revised 23 October 2006; accepted 7 November 2006 Published online 12 February 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.31175 Abstract: Although many biodegradable polymers, such as poly-L-lactic acid and poly-L-glycolic acid, are preferen- tially composed of biological residues normally present in the human body, implants made of these materials often trigger inflammatory and fibrotic responses. Unfortunately, the mechanisms involved in degradable material-mediated tissue responses remain largely unknown. Using animal im- plantation and cell culture system models, we found a strong correlation between the rate of material degradation and the degree of inflammatory response to material implants. Furthermore, we have identified that both water- soluble and water-insoluble degradation products are po- tent triggers of phagocyte activation, including at the least, superoxide production. These results support a new con- cept that slow degradation may improve the biocompatibil- ity of degradable drug-releasing particles and tissue engi- neering scaffolds. Ó 2007 Wiley Periodicals, Inc. J Biomed Mater Res 82A: 492–497, 2007 Key words: poly-L-lactic acid; phagocyte; inflammatory responses; degradation; superoxide; degradable polymers; inflammation; neutrophils INTRODUCTION Because of their unique bioadsorption properties, biodegradable polymers have been used in short- term applications that require only the temporary presence of polymeric implants. Typical short-term applications include sutures, drug delivery devices, orthopedic fixation devices, adhesion prevention aids, and temporary vascular grafts and stents. 1 For most applications, polymers made of poly-L-lactic acid (hereafter abbreviated as PLLA) are frequently used. 2 Because the material basic component—lactic acid—is a cellular metabolite, 3–5 it is generally believed that these biodegradable polymers possess good ‘‘biocom- patible’’ properties. 6,7 However, implants made of such materials often trigger inflammatory responses of varying severity. 8–13 Chronic inflammatory res- ponses to the degradable implants have been associ- ated with pathogenesis of fibrosis, 10 amyloidosis, 14,15 and carcinogenesis. 16,17 However, the mechanism(s) governing the degradable polymer-mediated adverse tissue responses are not totally understood and the lack of such knowledge hinders the development of mate- rials with improved bio- and tissue compatibility. Interestingly, many early studies have indicated that the release of degradation products from these materials affects tissue responses. For example, there is a positive relationship between the rapidity of poly- mer degradation and the intensity of inflammatory responses. 8 In addition, the numbers of PLLA par- ticles, foreshortened polymers, oligomers, and mono- mers released during degradation of a polymer in vivo correlate with the intensity of the inflamma- tory responses. 10 It has also been suggested that the acidic environment associated with degradation con- tributes to adverse reactions. On the basis of the avail- able information and our own observations, we have assumed that the release rate of PLLA degradation products affects the degree of the host response to degradable polymers. In this work, using both in vitro and in vivo systems, we discovered that polymer de- gradation rates determine the intensity of biomate- rial-mediated inflammatory responses. Furthermore, both water-soluble fragments and water-insoluble Correspondence to: L. Tang; e-mail: ltang@uta.edu Contract grant sponsor: NIH; contract grant number: R01 GM074021 Contract grant sponsor: American Heart Association (Established Investigator Award); contract grant number: 0245160N ' 2007 Wiley Periodicals, Inc.