Journal Article

Polyglycolic Acid-Induced Inflammation: Role of Hydrolysis and Resulting Complement Activation

Gaynor, Anne, Ceonzo, Kathleen, Kojima, Koji, Vacanti, Charles A., Shaffer, Lisa, Stahl, Gregory L.

2006

Overview

Tissue and organ replacement have quickly outpaced available supply. Tissue bioengineering holds the promise for additional tissue availability. Various scaffolds are currently used, whereas polyglycolic acid (PGA), which is currently used in absorbable sutures and orthopedic pins, provides an excellent support for tissue development. Unfortunately, PGA can induce a local inflammatory response following implantation. Therefore, we investigated the molecular mechanism of inflammation in vitro and in vivo . Degraded PGA induced an acute peritonitis, characterized by neutrophil (PMN) infiltration following intraperitoneal injection in mice. Similar observations were observed using the metabolite of PGA, glycolide. Dissolved PGA or glycolide, but not native PGA, activated the classical complement pathway in human sera, as determined by classical complement pathway hemolytic assays, C3a and C5a production, and C3 and immunoglobulin deposition. To investigate whether these in vitro observations translated to in vivo findings, we used genetically engineered mice. Intraperitoneal administration of glycolide or dissolved PGA in mice deficient in C1q, factor D, C1q and factor D, or C2 and factor B demonstrated significantly reduced PMN infiltration compared to congenic controls (WT). Mice deficient in C6 also demonstrated acute peritonitis. However, treatment of WT or C6 deficient mice with a monoclonal antibody against C5 prevented the inflammatory response. These data suggest that the hydrolysis of PGA to glycolide activates the classical complement pathway. Furthermore, complement is amplified via the alternative pathway and inflammation is induced by C5a generation. Inhibition of C5a may provide a potential therapeutic approach to limit the inflammation associated with PGA-derived materials following implantation.

• Publisher: Mary Ann Liebert, Inc,SAGE Publications
• Subject: Acids / Animals / Antibodies, Monoclonal - metabolism / Biochemistry / Biomedical materials / Complement Activation / Complement C3 - genetics / Complement C3 - metabolism / Complement C3a - biosynthesis / Complement C5 - genetics / Complement C5 - metabolism / Complement C5a - biosynthesis / Complement C6 - deficiency / Complement C6 - genetics / Complement C6 - metabolism / Complement Pathway, Classical / Disease Models, Animal / Enzyme-Linked Immunosorbent Assay / Fluorescent Antibody Technique, Indirect / Genetic Engineering / Hemolysis - drug effects / Humans / Hydrolysis / Immunoglobulin G - metabolism / Immunoglobulin M - metabolism / Inflammation - chemically induced / Inflammation - pathology / Injections, Intraperitoneal / Mice / Mice, Congenic / Mice, Inbred C57BL / Mice, Knockout / Neutrophils - pathology / Polyglycolic Acid - administration & dosage / Polyglycolic Acid - metabolism / Polyglycolic Acid - pharmacology / Rodents / Tissue engineering / Transplants & implants